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6006eee37c700632c37e38d8370c5fdac5d195a3 | wikidoc | PSMC6 | PSMC6
26S protease regulatory subunit S10B, also known as 26S proteasome AAA-ATPase subunit Rpt4,is an enzyme that in humans is encoded by the PSMC6 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4 (this protein), Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC6 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. Pseudogenes have been identified on chromosomes 8 and 12. The human gene PSMC6 has 15 exons and locates at chromosome band 14q22.1.
# Protein
The human protein 26S protease regulatory subunit S10B is 44kDa in size and composed of 389 amino acids. The calculated theoretical pI of this protein is 7.09.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring. Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels. | PSMC6
26S protease regulatory subunit S10B, also known as 26S proteasome AAA-ATPase subunit Rpt4,is an enzyme that in humans is encoded by the PSMC6 gene.[1][2][3] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex[4] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4 (this protein), Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[4]
# Gene
The gene PSMC6 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. Pseudogenes have been identified on chromosomes 8 and 12.[3] The human gene PSMC6 has 15 exons and locates at chromosome band 14q22.1.
# Protein
The human protein 26S protease regulatory subunit S10B is 44kDa in size and composed of 389 amino acids. The calculated theoretical pI of this protein is 7.09.[5]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[6][7][8][9][10][11] These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[4]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[12] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[13][14] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[15][16] Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.[17] | https://www.wikidoc.org/index.php/PSMC6 | |
22974a2cbd7279c58ae4330a71e8a9b42fec6733 | wikidoc | PSMD1 | PSMD1
26S proteasome non-ATPase regulatory subunit 1, also as known as 26S Proteasome Regulatory Subunit Rpn2 (systematic nomenclature), is a protein that in humans is encoded by the PSMD1 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.
# Structure
## Gene expression
The gene PSMD1 encodes the largest non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding. The human PSMD1 gene has 25 exons and locates at chromosome band 2q37.1. The human protein 26S proteasome non-ATPase regulatory subunit 1 is 106 kDa in size and composed of 953 amino acids. The calculated theoretical pI of this protein is 5.25. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 797-827 is missing.
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Protein 26S proteasome non-ATPase regulatory subunit 1 (Rpn2) is an essential component of forming the base sub complex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn2 is the largest subunit of 19S regulatory particle and stays at the center of the "base" subcomplex of 19S particle.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO) Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
A clinical study on patients with age related macula degeneration identified four significant proteins, including 26S proteasome non-ATPase regulatory subunit 1 (Rpn2), that were increased, according to semi-quantitative proteomic profiling. The study reported that an LC-MRM assay revealed a significant increase of Rpn2 in 15 macula degeneration patients compared to the control subjects, suggesting that this protein could be a biomarker for this condition. Age-related macular degeneration is the leading cause of blindness in the world. Evidence is accumulating that the suppression of the UPS contributes to the increase of toxic proteins and inflammation in retina pigment epithelium, the functional abnormalities and/or the degeneration of which are believed to be the initiators and major pathologies of macula degeneration. There are only limited options for the treatment of macular degeneration, thus early identification of susceptibility and preventive measures are important therapeutic strategies. New potential biomarkers for neovascular macular degeneratuon and UPS-related proteins that are altered in patients such as Rpn2 may serve as the basis for future clinical studies to determine target proteins involved in the protection of the eye against macula degeneration. | PSMD1
26S proteasome non-ATPase regulatory subunit 1, also as known as 26S Proteasome Regulatory Subunit Rpn2 (systematic nomenclature), is a protein that in humans is encoded by the PSMD1 gene.[1][2] This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.[3]
# Structure
## Gene expression
The gene PSMD1 encodes the largest non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding.[2] The human PSMD1 gene has 25 exons and locates at chromosome band 2q37.1. The human protein 26S proteasome non-ATPase regulatory subunit 1 is 106 kDa in size and composed of 953 amino acids. The calculated theoretical pI of this protein is 5.25. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 797-827 is missing.
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Protein 26S proteasome non-ATPase regulatory subunit 1 (Rpn2) is an essential component of forming the base sub complex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.[4]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[5] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn2 is the largest subunit of 19S regulatory particle and stays at the center of the "base" subcomplex of 19S particle.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [6] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[7] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[8][9] cardiovascular diseases,[10][11][12] inflammatory responses and autoimmune diseases,[13] and systemic DNA damage responses leading to malignancies.[14]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[15] Parkinson's disease[16] and Pick's disease,[17] Amyotrophic lateral sclerosis (ALS),[17] Huntington's disease,[16] Creutzfeldt–Jakob disease,[18] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[19] and several rare forms of neurodegenerative diseases associated with dementia.[20] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[21] ventricular hypertrophy[22] and Heart failure.[23] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[24] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO)[13] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[25] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[26]
A clinical study on patients with age related macula degeneration identified four significant proteins, including 26S proteasome non-ATPase regulatory subunit 1 (Rpn2), that were increased, according to semi-quantitative proteomic profiling. The study reported that an LC-MRM assay revealed a significant increase of Rpn2 in 15 macula degeneration patients compared to the control subjects, suggesting that this protein could be a biomarker for this condition.[27] Age-related macular degeneration is the leading cause of blindness in the world. Evidence is accumulating that the suppression of the UPS contributes to the increase of toxic proteins and inflammation in retina pigment epithelium, the functional abnormalities and/or the degeneration of which are believed to be the initiators and major pathologies of macula degeneration.[28] There are only limited options for the treatment of macular degeneration, thus early identification of susceptibility and preventive measures are important therapeutic strategies. New potential biomarkers for neovascular macular degeneratuon and UPS-related proteins that are altered in patients such as Rpn2 may serve as the basis for future clinical studies to determine target proteins involved in the protection of the eye against macula degeneration.[27][28] | https://www.wikidoc.org/index.php/PSMD1 | |
1eba30ea23865358c9e9d59d492724c523fc0d93 | wikidoc | PSMD2 | PSMD2
26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1 (systematic nomenclature), is an enzyme that in humans is encoded by the PSMD2 gene.
# Structure
## Gene expression
The gene PSMD2 encodes a non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding. The gene PSMD2 encodes one of the non-ATPase subunits of the 19S regulator lid. In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. A pseudogene has been identified on chromosome 1. The human PSMD2 gene has 23 exons and locates at chromosome band 3q27.1. The human protein 26S proteasome non-ATPase regulatory subunit 2 is 100 kDa in size and composed of 909 amino acids. The calculated theoretical pI of this protein is 5.10. Two expression isoforms are generated by alternative splicing, in which either 1-130 or 1-163 of the amino acid sequence is missing.
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, Protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) is an essential component of forming the base subcomplex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn1 is one essential subunit of 19S regulatory particle and it forms the core of the "base" subcomplex. It offers a docking position for another 19S subunit Rpn10 at its central solenoid portion, although such association with Rpn10 is stabilized by a third subunit, Rpn2. Besides its critical roles in 19S complex assembly, Rpn2 also provides docking positions for shuttles of ubiqitinylated substrate trafficking. The majority of shuttles attach to the proteasome via a ubiquitin-like domain (UBL) while they unload the substrate cargo at a C-terminal polyubiquitin-binding domain(s). Recent investigation by Glickman et al. identified that two shuttle proteins, Rad23 and Dsk2, dock at two different receptor sites embedded within subunit Rpn1.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
The protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) which is encoded by PSMD2 has been identified as an important constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers. It was found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with the induction of p21. In addition, patients with higher PSMD2 expression indicated a poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, findings illustrate that lung adenocarcinomas can be divided into two main groups; those with and without general upregulation of proteasome pathway genes including PSMD2.
# Interactions
PSMD2 has been shown to interact with TNFRSF1A and PSMC1. | PSMD2
26S proteasome non-ATPase regulatory subunit 2, also as known as 26S Proteasome Regulatory Subunit Rpn1 (systematic nomenclature), is an enzyme that in humans is encoded by the PSMD2 gene.[1][2]
# Structure
## Gene expression
The gene PSMD2 encodes a non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding.[2] The gene PSMD2 encodes one of the non-ATPase subunits of the 19S regulator lid. In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. A pseudogene has been identified on chromosome 1.[2] The human PSMD2 gene has 23 exons and locates at chromosome band 3q27.1. The human protein 26S proteasome non-ATPase regulatory subunit 2 is 100 kDa in size and composed of 909 amino acids. The calculated theoretical pI of this protein is 5.10. Two expression isoforms are generated by alternative splicing, in which either 1-130 or 1-163 of the amino acid sequence is missing.
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, Protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) is an essential component of forming the base subcomplex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.[3]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[4] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn1 is one essential subunit of 19S regulatory particle and it forms the core of the "base" subcomplex. It offers a docking position for another 19S subunit Rpn10 at its central solenoid portion, although such association with Rpn10 is stabilized by a third subunit, Rpn2.[5] Besides its critical roles in 19S complex assembly, Rpn2 also provides docking positions for shuttles of ubiqitinylated substrate trafficking. The majority of shuttles attach to the proteasome via a ubiquitin-like domain (UBL) while they unload the substrate cargo at a C-terminal polyubiquitin-binding domain(s). Recent investigation by Glickman et al. identified that two shuttle proteins, Rad23 and Dsk2, dock at two different receptor sites embedded within subunit Rpn1.[5]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [6] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[7] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[8][9] cardiovascular diseases,[10][11][12] inflammatory responses and autoimmune diseases,[13] and systemic DNA damage responses leading to malignancies.[14]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[15] Parkinson's disease[16] and Pick's disease,[17] Amyotrophic lateral sclerosis (ALS),[17] Huntington's disease,[16] Creutzfeldt–Jakob disease,[18] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[19] and several rare forms of neurodegenerative diseases associated with dementia.[20] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[21] ventricular hypertrophy[22] and Heart failure.[23] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[24] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[13] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[25] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[26]
The protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) which is encoded by PSMD2 has been identified as an important constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers.[27] It was found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with the induction of p21. In addition, patients with higher PSMD2 expression indicated a poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, findings illustrate that lung adenocarcinomas can be divided into two main groups; those with and without general upregulation of proteasome pathway genes including PSMD2.[27]
# Interactions
PSMD2 has been shown to interact with TNFRSF1A[28][29] and PSMC1.[30][31] | https://www.wikidoc.org/index.php/PSMD2 | |
be5c2432a23e017dc7604ab4430dd987e4a127b9 | wikidoc | PSMD3 | PSMD3
26S proteasome non-ATPase regulatory subunit 3 is an enzyme that in humans is encoded by the PSMD3 gene.
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the non-ATPase subunits of the 19S regulator lid.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Specifically, genetic variants studies at PSMD3 indicated that its involvement in the regulation of insulin signal transduction could be effected by dietary factors. Accordingly, PSMD3 variants appear to be associated with insulin resistance in populations of different ancestries and these relationships can be affected by eating habits. Furthermore, a genome-wide association study (GWAS) has identified that a variant in PSMD3 is associated to neutropenia induced interferon during the therapy of chronic hepatitis C.
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes. The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands. | PSMD3
26S proteasome non-ATPase regulatory subunit 3 is an enzyme that in humans is encoded by the PSMD3 gene.[1][2]
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the non-ATPase subunits of the 19S regulator lid.[2]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[5][6] cardiovascular diseases,[7][8][9] inflammatory responses and autoimmune diseases,[10] and systemic DNA damage responses leading to malignancies.[11]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[12] Parkinson's disease[13] and Pick's disease,[14] Amyotrophic lateral sclerosis (ALS),[14] Huntington's disease,[13] Creutzfeldt–Jakob disease,[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[16] and several rare forms of neurodegenerative diseases associated with dementia.[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[18] ventricular hypertrophy[19] and Heart failure.[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23]
Specifically, genetic variants studies at PSMD3 indicated that its involvement in the regulation of insulin signal transduction could be effected by dietary factors. Accordingly, PSMD3 variants appear to be associated with insulin resistance in populations of different ancestries and these relationships can be affected by eating habits.[24] Furthermore, a genome-wide association study (GWAS) has identified that a variant in PSMD3 is associated to neutropenia induced interferon during the therapy of chronic hepatitis C.[25]
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[26][27] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands. | https://www.wikidoc.org/index.php/PSMD3 | |
0d51aa983562dd2e1e2551860733b27dea0bde32 | wikidoc | PSMD4 | PSMD4
26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10 (systematic nomenclature), is an enzyme that in humans is encoded by the PSMD4 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.
# Gene
The gene PSMD4 encodes one of the non-ATPase subunits of the 19S regulator base, subunit Rpn10. Pseudogenes have been identified on chromosomes 10 and 21. The human PSMD4 gene has 10 exons and locates at chromosome band 1q21.3.
# Protein
The human protein 26S proteasome non-ATPase regulatory subunit 4 is 41 kDa in size and composed of 377 amino acids. The calculated theoretical pI of this protein is 4.68. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 269-377 is missing while the amino sequence between 255-268 is replaced from DSDDALLKMTISQQ to GERGGIRSPGTAGC.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) is an essential component of forming the base subcomplex of 19S regulatory particle. Traditionally, Rpn10 were considered residing between the base subcomplex and the lid subcomplex. However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also has subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn10 is one essential subunit of 19S regulatory particle and it contributes to the assembly of the "base" subcomplex. In the base sub complex, Rpn1 offers a docking position for subunit Rpn10 at its central solenoid portion, although such association with Rpn10 is stabilized by a third subunit, Rpn2. Rpn10 serve as a receptor for poly-ubiquitylated protein substrates.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
# Interactions
PSMD4 has been shown to interact with RAD23A and RAD23B. | PSMD4
26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10 (systematic nomenclature), is an enzyme that in humans is encoded by the PSMD4 gene.[1][2] This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.[3]
# Gene
The gene PSMD4 encodes one of the non-ATPase subunits of the 19S regulator base, subunit Rpn10. Pseudogenes have been identified on chromosomes 10 and 21.[2] The human PSMD4 gene has 10 exons and locates at chromosome band 1q21.3.
# Protein
The human protein 26S proteasome non-ATPase regulatory subunit 4 is 41 kDa in size and composed of 377 amino acids. The calculated theoretical pI of this protein is 4.68. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 269-377 is missing while the amino sequence between 255-268 is replaced from DSDDALLKMTISQQ to GERGGIRSPGTAGC.[4]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, protein 26S proteasome non-ATPase regulatory subunit 2 (Rpn1) is an essential component of forming the base subcomplex of 19S regulatory particle. Traditionally, Rpn10 were considered residing between the base subcomplex and the lid subcomplex. However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.[5]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[6] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also has subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn10 is one essential subunit of 19S regulatory particle and it contributes to the assembly of the "base" subcomplex. In the base sub complex, Rpn1 offers a docking position for subunit Rpn10 at its central solenoid portion, although such association with Rpn10 is stabilized by a third subunit, Rpn2.[7] Rpn10 serve as a receptor for poly-ubiquitylated protein substrates.[7][8]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease,[19] Creutzfeldt–Jakob disease,[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[22] and several rare forms of neurodegenerative diseases associated with dementia.[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[24] ventricular hypertrophy[25] and Heart failure.[26] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[27] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]
# Interactions
PSMD4 has been shown to interact with RAD23A[30][31] and RAD23B.[30] | https://www.wikidoc.org/index.php/PSMD4 | |
7c6f804fc67c82a3e1c7ec856ae7b479a8d48bcd | wikidoc | PSMD5 | PSMD5
26S proteasome non-ATPase regulatory subunit 5 is an enzyme that in humans is encoded by the PSMD5 gene.
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator base.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
# Interactions
PSMD5 has been shown to interact with PSMC2. | PSMD5
26S proteasome non-ATPase regulatory subunit 5 is an enzyme that in humans is encoded by the PSMD5 gene.[1]
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator base.[2]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[5][6] cardiovascular diseases,[7][8][9] inflammatory responses and autoimmune diseases,[10] and systemic DNA damage responses leading to malignancies.[11]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[12] Parkinson's disease[13] and Pick's disease,[14] Amyotrophic lateral sclerosis (ALS),[14] Huntington's disease,[13] Creutzfeldt–Jakob disease,[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[16] and several rare forms of neurodegenerative diseases associated with dementia.[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[18] ventricular hypertrophy[19] and Heart failure.[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23]
# Interactions
PSMD5 has been shown to interact with PSMC2.[24][25] | https://www.wikidoc.org/index.php/PSMD5 | |
588bff070a24c16852030ae1b2f9b8eaa6e07de2 | wikidoc | PSMD6 | PSMD6
26S proteasome non-ATPase regulatory subunit 6 is an enzyme that in humans is encoded by the PSMD6 gene.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes. The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
# Interactions
PSMD6 has been shown to interact with PSMD13. | PSMD6
26S proteasome non-ATPase regulatory subunit 6 is an enzyme that in humans is encoded by the PSMD6 gene.[1][2]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[5][6] cardiovascular diseases,[7][8][9] inflammatory responses and autoimmune diseases,[10] and systemic DNA damage responses leading to malignancies.[11]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[12] Parkinson's disease[13] and Pick's disease,[14] Amyotrophic lateral sclerosis (ALS),[14] Huntington's disease,[13] Creutzfeldt–Jakob disease,[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[16] and several rare forms of neurodegenerative diseases associated with dementia.[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[18] ventricular hypertrophy[19] and Heart failure.[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23]
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[24][25] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
# Interactions
PSMD6 has been shown to interact with PSMD13.[26] | https://www.wikidoc.org/index.php/PSMD6 | |
c03dfad445d545a22edbc01e9806866ad0b553aa | wikidoc | PSMD7 | PSMD7
26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Gene
The gene PSMD7 encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 17. The human gene PSMD7 has 7 Exons and locates at chromosome band 16q22.3.
# Protein
The human protein 26S proteasome non-ATPase regulatory subunit 14 is 37 kDa in size and composed of 324 amino acids. The calculated theoretical pI of this protein is 6.11.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13).s The lid sub complex of 19S regulatory particle consisted of 9 subunits. The assembly of 19S lid is independent to the assembly process of 19S base. Two assembly modules, Rpn5-Rpn6-Rpn8-Rpn9-Rpn11 modules and Rpn3-Rpn7-SEM1 modules were identified during 19S lid assembly using yeast proteasome as a model complex. The subunit Rpn12 incorporated into 19S regulatory particle when 19S lid and base bind together. Recent evidence of crystal structures of proteasomes isolated from Saccharomyces cerevisiae suggests that the catalytically active subunit Rpn8 and subunit Rpn11 form heterodimer. The data also reveals the details of the Rpn11 active site and the mode of interaction with other subunits.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers. | PSMD7
26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.[1][2]
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Gene
The gene PSMD7 encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 17.[2] The human gene PSMD7 has 7 Exons and locates at chromosome band 16q22.3.
# Protein
The human protein 26S proteasome non-ATPase regulatory subunit 14 is 37 kDa in size and composed of 324 amino acids. The calculated theoretical pI of this protein is 6.11.[3]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13).s The lid sub complex of 19S regulatory particle consisted of 9 subunits. The assembly of 19S lid is independent to the assembly process of 19S base. Two assembly modules, Rpn5-Rpn6-Rpn8-Rpn9-Rpn11 modules and Rpn3-Rpn7-SEM1 modules were identified during 19S lid assembly using yeast proteasome as a model complex.[4][5][6][7] The subunit Rpn12 incorporated into 19S regulatory particle when 19S lid and base bind together.[8] Recent evidence of crystal structures of proteasomes isolated from Saccharomyces cerevisiae suggests that the catalytically active subunit Rpn8 and subunit Rpn11 form heterodimer. The data also reveals the details of the Rpn11 active site and the mode of interaction with other subunits.[9]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[10] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [11] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[12] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[13][14] cardiovascular diseases,[15][16][17] inflammatory responses and autoimmune diseases,[18] and systemic DNA damage responses leading to malignancies.[19]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[20] Parkinson's disease[21] and Pick's disease,[22] Amyotrophic lateral sclerosis (ALS),[22] Huntington's disease,[21] Creutzfeldt–Jakob disease,[23] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[24] and several rare forms of neurodegenerative diseases associated with dementia.[25] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[26] ventricular hypertrophy[27] and Heart failure.[28] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[29] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[30] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[31] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32] | https://www.wikidoc.org/index.php/PSMD7 | |
e6edf493dd524f8e674e2ba66a83b231193f571a | wikidoc | PSMD8 | PSMD8
26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 gene.
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 1.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers. | PSMD8
26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 gene.[1][2]
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 1.[2]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[5][6] cardiovascular diseases,[7][8][9] inflammatory responses and autoimmune diseases,[10] and systemic DNA damage responses leading to malignancies.[11]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[12] Parkinson's disease[13] and Pick's disease,[14] Amyotrophic lateral sclerosis (ALS),[14] Huntington's disease,[13] Creutzfeldt–Jakob disease,[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[16] and several rare forms of neurodegenerative diseases associated with dementia.[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[18] ventricular hypertrophy[19] and Heart failure.[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23] | https://www.wikidoc.org/index.php/PSMD8 | |
dde0f64fd21bf6f788991a4eca07a28a30c99354 | wikidoc | PSMD9 | PSMD9
26S proteasome non-ATPase regulatory subunit 9 is an enzyme that in humans is encoded by the PSMD9 gene.
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Gene expression levels of the proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 patients with neuroendocrine pulmonary tumors and compared to controls. The study reviled that PSMB4 mRNA was significantly associated with proliferative activity of neuroendocrine pulmonary tumors. However, a role of PSMA5 was also indicated in neuroendocrine pulmonary tumors. The PSMA5 protein has further been associated with the biosynthesis of conjugated linoleum acid (CLA) in mammary tissue. | PSMD9
26S proteasome non-ATPase regulatory subunit 9 is an enzyme that in humans is encoded by the PSMD9 gene.[1][2]
# Function
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator.[2]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [3] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[4] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[5][6] cardiovascular diseases,[7][8][9] inflammatory responses and autoimmune diseases,[10] and systemic DNA damage responses leading to malignancies.[11]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[12] Parkinson's disease[13] and Pick's disease,[14] Amyotrophic lateral sclerosis (ALS),[14] Huntington's disease,[13] Creutzfeldt–Jakob disease,[15] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[16] and several rare forms of neurodegenerative diseases associated with dementia.[17] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[18] ventricular hypertrophy[19] and Heart failure.[20] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[21] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[10] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[22] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[23]
Gene expression levels of the proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 patients with neuroendocrine pulmonary tumors and compared to controls. The study reviled that PSMB4 mRNA was significantly associated with proliferative activity of neuroendocrine pulmonary tumors.[24] However, a role of PSMA5 was also indicated in neuroendocrine pulmonary tumors. The PSMA5 protein has further been associated with the biosynthesis of conjugated linoleum acid (CLA) in mammary tissue.[25] | https://www.wikidoc.org/index.php/PSMD9 | |
765313fa1d2541c513d532147dbeaf910740d0cb | wikidoc | PTBP1 | PTBP1
Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has four repeats of quasi-RNA recognition motif (RRM) domains that bind RNAs. This protein binds to the intronic polypyrimidine tracts that requires pre-mRNA splicing and acts via the protein degradation ubiquitin-proteasome pathway. It may also promote the binding of U2 snRNP to pre-mRNAs. This protein is localized in the nucleoplasm and it is also detected in the perinucleolar structure. Alternatively spliced transcript variants encoding different isoforms have been described.
# PTBP1 In Mammals
In brains of mammals, transcripts from the PTBP1 gene are missing one exon (exon 9) that is included in the brains of other vertebrates, as a result of alternative splicing. This contributes to the evolutionary difference between the nervous system of mammals and other vertebrates.
# Interactions
PTBP1 has been shown to interact with HNRPK, PCBP2, SFPQ and HNRNPL.
This gene is targeted by the microRNA miR-124. During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. | PTBP1
Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.[1][2][3]
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has four repeats of quasi-RNA recognition motif (RRM) domains that bind RNAs. This protein binds to the intronic polypyrimidine tracts that requires pre-mRNA splicing and acts via the protein degradation ubiquitin-proteasome pathway. It may also promote the binding of U2 snRNP to pre-mRNAs. This protein is localized in the nucleoplasm and it is also detected in the perinucleolar structure. Alternatively spliced transcript variants encoding different isoforms have been described.[3]
# PTBP1 In Mammals
In brains of mammals, transcripts from the PTBP1 gene are missing one exon (exon 9) that is included in the brains of other vertebrates, as a result of alternative splicing. This contributes to the evolutionary difference between the nervous system of mammals and other vertebrates.[4]
# Interactions
PTBP1 has been shown to interact with HNRPK,[5] PCBP2,[5] SFPQ[6][7] and HNRNPL.[5][8]
This gene is targeted by the microRNA miR-124. During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein.[9] | https://www.wikidoc.org/index.php/PTBP1 | |
a9386479f074a61560a8980565b1dda88925f585 | wikidoc | PTCH1 | PTCH1
Protein patched homolog 1 is a protein that is the member of the patched family and in humans is encoded by the PTCH1 gene.
# Function
PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgehog binds PTCH1, smoothened is released and signals cell proliferation.
# Clinical significance
Mutations of this gene have been associated with nevoid basal cell carcinoma syndrome (AKA Gorlin's Syndrome), esophageal squamous cell carcinoma, trichoepitheliomas, transitional cell carcinomas of the bladder, as well as holoprosencephaly. Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences and biological validity cannot be determined currently.
Mutations in PTCH1 cause Gorlin syndrome and mutations have also been found in holoprosencephaly patients. Some of these patients present cleft lip and palate among the holoprosencephaly features, and missense variants in PTCH1 were also found in a sequencing screening of nonsyndromic cleft lip and palate patients. In addition association between SNPs in or near PTCH1 have been found to be associated with nonsyndromic cleft lip and palate. Mutations in PTCH1 are also associated with medulloblastoma. | PTCH1
Protein patched homolog 1 is a protein that is the member of the patched family and in humans is encoded by the PTCH1 gene.[1][2]
# Function
PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgehog binds PTCH1, smoothened is released and signals cell proliferation.
# Clinical significance
Mutations of this gene have been associated with nevoid basal cell carcinoma syndrome (AKA Gorlin's Syndrome), esophageal squamous cell carcinoma, trichoepitheliomas, transitional cell carcinomas of the bladder, as well as holoprosencephaly. Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described, but their full length sequences and biological validity cannot be determined currently.[2]
Mutations in PTCH1 cause Gorlin syndrome and mutations have also been found in holoprosencephaly patients.[3][4][5] Some of these patients present cleft lip and palate among the holoprosencephaly features, and missense variants in PTCH1 were also found in a sequencing screening of nonsyndromic cleft lip and palate patients.[6] In addition association between SNPs in or near PTCH1 have been found to be associated with nonsyndromic cleft lip and palate.[6][7] Mutations in PTCH1 are also associated with medulloblastoma.[8] | https://www.wikidoc.org/index.php/PTCH1 | |
e9225d9d6fefe515c22195fcffc32674430a30e2 | wikidoc | PTCH2 | PTCH2
Patched 2 is a protein that in humans is encoded by the PTCH2 gene.
# Function
This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway.
# Clinical significance
Alterations in this gene have been associated with nevoid basal cell carcinoma syndrome, basal cell carcinoma, medulloblastoma, and susceptibility to congenital macrostomia. | PTCH2
Patched 2 is a protein that in humans is encoded by the PTCH2 gene.[1]
# Function
This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway.[1]
# Clinical significance
Alterations in this gene have been associated with nevoid basal cell carcinoma syndrome, basal cell carcinoma, medulloblastoma, and susceptibility to congenital macrostomia.[1] | https://www.wikidoc.org/index.php/PTCH2 | |
81ec4cd371d7e1e33d178619515f129d0fb7f79f | wikidoc | PTK2B | PTK2B
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.
# Function
This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity.
The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration
, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation. In addition, SOCE-induced Pyk2 activation mediates disassembly of endothelial adherens junctions, via tyrosine (Y1981-residue) phosphorylation of VE-PTP.
This protein has been shown to bind a CRK-associated substrate, a nephrocystin, a GTPase regulator associated with FAK, and the SH2 domain of GRB2.
The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene.
# Interactions
PTK2B has been shown to interact with:
- BCAR1,
- Cbl gene,
- DDEF2,
- DLG3,
- DLG4,
- Ewing sarcoma breakpoint region 1,
- FYN,
- GRIN2A,
- Gelsolin,
- NPHP1,
- PITPNM1,
- PTPN11,
- PTPN6,
- Paxillin,
- RAS p21 protein activator 1,
- RB1CC1,
- SORBS2,
- Src, and
- TGFB1I1,
- VE-PTP | PTK2B
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.[1][2]
# Function
This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. The encoded protein may represent an important signaling intermediate between neuropeptide-activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity.[3]
The encoded protein undergoes rapid tyrosine phosphorylation and activation in response to increases in the intracellular calcium concentration [4]
, nicotinic acetylcholine receptor activation, membrane depolarization, or protein kinase C activation.[3] In addition, SOCE-induced Pyk2 activation mediates disassembly of endothelial adherens junctions, via tyrosine (Y1981-residue) phosphorylation of VE-PTP.[4]
This protein has been shown to bind a CRK-associated substrate, a nephrocystin, a GTPase regulator associated with FAK, and the SH2 domain of GRB2.[3]
The encoded protein is a member of the FAK subfamily of protein tyrosine kinases but lacks significant sequence similarity to kinases from other subfamilies. Four transcript variants encoding two different isoforms have been found for this gene.[3]
# Interactions
PTK2B has been shown to interact with:
- BCAR1,[5][6][7]
- Cbl gene,[8][9]
- DDEF2,[10]
- DLG3,[11]
- DLG4,[11]
- Ewing sarcoma breakpoint region 1,[12]
- FYN,[13][14][15]
- GRIN2A,[11][16]
- Gelsolin,[17]
- NPHP1,[18]
- PITPNM1,[19]
- PTPN11,[20]
- PTPN6,[21][22]
- Paxillin,[6][23][24]
- RAS p21 protein activator 1,[25][26]
- RB1CC1,[27]
- SORBS2,[8]
- Src,[22][28][29] and
- TGFB1I1,[23][30][31]
- VE-PTP [4] | https://www.wikidoc.org/index.php/PTK2B | |
c1197e025ecded098b4be03b4617feadc8d41bc0 | wikidoc | PTPN1 | PTPN1
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.
# Structure and function
PTP1B was first isolated from a human placental protein extract, but it is expressed in many tissues. PTP1B is localized to the cytoplasmic face of the endoplasmic reticulum. PTP1B can dephosphorylate the phosphotyrosine residues of the activated insulin receptor kinase. In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity. Several other tyrosine kinases, including epidermal growth factor receptor, insulin-like growth factor 1 receptor, colony stimulating factor 1 receptor, c-Src, Janus kinase 2, TYK2, and focal adhesion kinase as well as other tyrosine-phosphorylated proteins, including BCAR1, DOK1, beta-catenin and cortactin have also been described as PTP1B substrates.
The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue, a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue. The pTyr loop and Tyr46 residue are located on the surface of the protein, and thus help to determine the depth a substrate can obtain within the cleft. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft. Upon substrate binding, PTP1B undergoes a structural modification in which the WPD loop closes around the substrate, introducing stabilizing pi stacking interactions between the aromatic rings of the phosphotyrosine (pTyr) substrate residue and the Phe182 residue on the WPD loop.
# Mechanism
The phosphatase activity of PTP1B occurs via a two-step mechanism. The dephosphorylation of the pTyr substrate occurs in the first step, while the enzyme intermediates are broken down during the second step. During the first step, there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue, followed by subsequent protonation by Asp181 to yield the neutral tyrosine phenol. The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed, which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack.
# Regulation
The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family. The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide (H2O2), produced in response to EGF and insulin signaling. The thiolate is oxidized to a sulfenic acid, which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue. This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind. This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity. Phosphprylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive.
# Interactions
PTPN1 has been shown to interact with BCAR1, epidermal growth factor receptor, Grb2 and IRS1.
# Clinical Significance
PTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity. PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild-type counterparts. As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity.
Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431, that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B. In addition, PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates. In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases. Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer. | PTPN1
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene.[1] PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes.[2] It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.[3][4][5]
# Structure and function
PTP1B was first isolated from a human placental protein extract,[6][7] but it is expressed in many tissues.[8] PTP1B is localized to the cytoplasmic face of the endoplasmic reticulum.[9] PTP1B can dephosphorylate the phosphotyrosine residues of the activated insulin receptor kinase.[7][10][11] In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity.[12][13] Several other tyrosine kinases, including epidermal growth factor receptor,[14] insulin-like growth factor 1 receptor,[15] colony stimulating factor 1 receptor,[16] c-Src,[17] Janus kinase 2,[18] TYK2,[18] and focal adhesion kinase[19] as well as other tyrosine-phosphorylated proteins, including BCAR1,[20] DOK1,[21] beta-catenin[22] and cortactin[23] have also been described as PTP1B substrates.
The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue, a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue.[24][25] The pTyr loop and Tyr46 residue are located on the surface of the protein, and thus help to determine the depth a substrate can obtain within the cleft. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft.[24] Upon substrate binding, PTP1B undergoes a structural modification in which the WPD loop closes around the substrate, introducing stabilizing pi stacking interactions between the aromatic rings of the phosphotyrosine (pTyr) substrate residue and the Phe182 residue on the WPD loop.[25]
# Mechanism
The phosphatase activity of PTP1B occurs via a two-step mechanism.[24] The dephosphorylation of the pTyr substrate occurs in the first step, while the enzyme intermediates are broken down during the second step. During the first step, there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue, followed by subsequent protonation by Asp181 to yield the neutral tyrosine phenol. The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed, which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack.
# Regulation
The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family.[26] The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide (H2O2), produced in response to EGF and insulin signaling.[27][28][29] The thiolate is oxidized to a sulfenic acid, which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue.[30] This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind.[30][31] This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity.[31] Phosphprylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive.[32]
# Interactions
PTPN1 has been shown to interact with BCAR1,[20] epidermal growth factor receptor,[33][34] Grb2[20][35] and IRS1.[32][35]
# Clinical Significance
PTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity.[12][13] PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild-type counterparts.[12][13] As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity.[36]
Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431, that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B.[37] In addition, PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates.[38] In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases.[4] Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer.[4][5] | https://www.wikidoc.org/index.php/PTPN1 | |
26669cd5705ca41977b05068454ffc90cce389ca | wikidoc | PTPN5 | PTPN5
Protein tyrosine phosphatase non-receptor type 5 is an enzyme that in humans is encoded by the PTPN5 gene.
Protein tyrosine phosphatase (PTP), non-receptor type 5, also known as STEP (STriatal-Enriched protein tyrosine Phosphatase), was the first brain-specific PTP discovered. The human STEP locus maps to chromosome 11p15.2-p15.1 and the murine STEP gene to chromosome 7B3-B5. The single STEP gene is alternatively spliced to produce several isoforms, the best characterized of which are the cytosolic STEP46 protein and the membrane-associated STEP61 protein.
# Substrates
Seven known targets of STEP have been identified as of 2015, including ERK1/2, p38, Fyn, Pyk2, PTPα, and the glutamate receptor subunits GluN2B and GluA2. STEP dephosphorylation of the kinases (ERK1/2, p38, Fyn, and Pyk2) occurs at a regulatory tyrosine within the kinase activation loop and leads to their inactivation. Dephosphorylation of a regulatory tyrosine on PTPα prevents the translocation of PTPα from the cytosol to lipid rafts, where it normally activates Fyn. STEP thereby directly inactivates Fyn and also prevents the translocation of PTPα to compartments where it activates Fyn. STEP dephosphorylation of GluN2B and GluA2 leads to the internalization of NMDARs (GluN1/GluN2B) and AMPARs (GluA1/GluA2). Thus, one function of STEP is to oppose synaptic strengthening by inactivating kinases and internalizing receptors that are critical for the development of synaptic strengthening.
# Clinical significance
STEP levels are disrupted in several diseases. Alzheimer’s disease (AD) was the first illness to be associated with elevated STEP expression both in human cortex and in several mouse models of AD. STEP is also increased in fragile X syndrome, schizophrenia, and Parkinson’s disease. In AD and FXS mouse models, genetic reduction of STEP expression reverses many of the cognitive and behavioral deficits.
Other laboratories have now shown that STEP activity is also reduced in several additional disorders. Thus, STEP levels or activity is decreased in Huntington’s disease, cerebral ischemia, alcohol abuse, and stress disorders. The emergent model suggests that an optimal level of STEP is required at synaptic sites, and that both high and low levels disrupt synaptic function.
# Inhibition
Several STEP inhibitors have now been discovered. GlaxoSmithKline chose STEP as a new project for their Discovery Partnerships with Academia (DPAc) in 2014. This is a relatively new program in drug discovery and brings together the academic world with the drug discovery expertise of GSK to discover new inhibitors of validated targets.
- TC-2153 | PTPN5
Protein tyrosine phosphatase non-receptor type 5 is an enzyme that in humans is encoded by the PTPN5 gene.[1][2]
Protein tyrosine phosphatase (PTP), non-receptor type 5, also known as STEP (STriatal-Enriched protein tyrosine Phosphatase), was the first brain-specific PTP discovered.[1] The human STEP locus maps to chromosome 11p15.2-p15.1 and the murine STEP gene to chromosome 7B3-B5.[3] The single STEP gene is alternatively spliced to produce several isoforms,[4][5] the best characterized of which are the cytosolic STEP46 protein and the membrane-associated STEP61 protein.[6][7]
# Substrates
Seven known targets of STEP have been identified as of 2015, including ERK1/2,[8][9] p38,[8] Fyn,[10] Pyk2,[11] PTPα,[12] and the glutamate receptor subunits GluN2B and GluA2.[13][14][15] STEP dephosphorylation of the kinases (ERK1/2, p38, Fyn, and Pyk2) occurs at a regulatory tyrosine within the kinase activation loop and leads to their inactivation. Dephosphorylation of a regulatory tyrosine on PTPα prevents the translocation of PTPα from the cytosol to lipid rafts, where it normally activates Fyn.[12] STEP thereby directly inactivates Fyn and also prevents the translocation of PTPα to compartments where it activates Fyn. STEP dephosphorylation of GluN2B and GluA2 leads to the internalization of NMDARs (GluN1/GluN2B) and AMPARs (GluA1/GluA2). Thus, one function of STEP is to oppose synaptic strengthening by inactivating kinases and internalizing receptors that are critical for the development of synaptic strengthening.
# Clinical significance
STEP levels are disrupted in several diseases. Alzheimer’s disease (AD) was the first illness to be associated with elevated STEP expression both in human cortex and in several mouse models of AD.[16][17][18][19] STEP is also increased in fragile X syndrome,[20] schizophrenia,[21] and Parkinson’s disease.[22] In AD and FXS mouse models, genetic reduction of STEP expression reverses many of the cognitive and behavioral deficits.[20][23]
Other laboratories have now shown that STEP activity is also reduced in several additional disorders. Thus, STEP levels or activity is decreased in Huntington’s disease,[24][25] cerebral ischemia,[26] alcohol abuse,[27][28][29] and stress disorders.[30][31] The emergent model suggests that an optimal level of STEP is required at synaptic sites, and that both high and low levels disrupt synaptic function.[32][33]
# Inhibition
Several STEP inhibitors have now been discovered.[11][34] GlaxoSmithKline chose STEP as a new project for their Discovery Partnerships with Academia (DPAc) in 2014. This is a relatively new program in drug discovery and brings together the academic world with the drug discovery expertise of GSK to discover new inhibitors of validated targets.
- TC-2153 [35] | https://www.wikidoc.org/index.php/PTPN5 | |
9ebd472cf41ff164d98675bfd975ee388c00168e | wikidoc | PTPN6 | PTPN6
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling, (e.g., the LYN-CD22-SHP-1 pathway). Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported.
# Expression
SHP-1 gene has two promoters: P-1, active in epithelial cells, and P-2, active in hemopoietic cells. In addition the expression of SHP-1 is low in epithelial cells and high in hemopoetic cells. SHP-1 level in epithelial cells increases and in hematopoetic cells decreases in cancer.
# Interactions
PTPN6 has been shown to interact with:
- BCR gene,
- CD117,
- CD22,
- CD31,
- CTNND1,
- EGFR,
- EPOR,
- FCRL3,
- Grb2,
- HOXA10,
- JAK2,
- LAIR1,
- LILRB2,
- LILRB4,
- Lck,
- LCP2,
- PRKCD,
- PTK2B,
- ROS1,
- SIRPA,
- SYK, and
- TYK2. | PTPN6
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.[1]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling, (e.g., the LYN-CD22-SHP-1 pathway). Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported.[2]
# Expression
SHP-1 gene has two promoters: P-1, active in epithelial cells, and P-2, active in hemopoietic cells. In addition the expression of SHP-1 is low in epithelial cells and high in hemopoetic cells. SHP-1 level in epithelial cells increases and in hematopoetic cells decreases in cancer.[3]
# Interactions
PTPN6 has been shown to interact with:
- BCR gene,[4]
- CD117,[5][6]
- CD22,[7][8][9][10][11]
- CD31,[12][13]
- CTNND1,[14]
- EGFR,[15][16]
- EPOR,[17]
- FCRL3,[18]
- Grb2,[19][20][21]
- HOXA10,[22]
- JAK2,[23][24]
- LAIR1,[25][26][27][28][29]
- LILRB2,[30][31]
- LILRB4,[32]
- Lck,[33][34][35]
- LCP2,[36][37]
- PRKCD,[38]
- PTK2B,[19][39]
- ROS1,[40]
- SIRPA,[25][41]
- SYK,[19][42] and
- TYK2.[43] | https://www.wikidoc.org/index.php/PTPN6 | |
dad73411bdf8da3d6b83f096699990378762ee47 | wikidoc | PTPRB | PTPRB
Receptor-type tyrosine-protein phosphatase beta or VE-PTP is an enzyme specifically expressed in endothelial cells that in humans is encoded by the PTPRB gene.
# Function
VE-PTP is a member of the classical protein tyrosine phosphatase (PTP) family. The deletion of the gene in mouse models was shown to be embryonically lethal, thus indicating that it is important for vasculogenesis and blood vessel development. In addition, it was shown to participate in adherens junctions complex and regulate vascular permeability. Recently, Soni et al. have shown that tyrosine phosphorylation of VE-PTP via Pyk2 kinase downstream of STIM1-induced calcium entry mediates disassembly of the endothelial adherens junctions.
# Interactions
VE-PTP contains an extracellular domain composed of multiple fibronectin type_III repeats, a single transmembrane segment and one intracytoplasmic catalytic domain, thus belongs to R3 receptor subtype PTPs.
The extracellular region was shown to interact with the angiopoietin receptor Tie-2 and with the adhesion protein VE-cadherin.
VE-PTP was also found to interact with Grb2 and plakoglobin through its cytoplasmatic domain. | PTPRB
Receptor-type tyrosine-protein phosphatase beta or VE-PTP is an enzyme specifically expressed in endothelial cells that in humans is encoded by the PTPRB gene.[1][2]
# Function
VE-PTP is a member of the classical protein tyrosine phosphatase (PTP) family. The deletion of the gene in mouse models was shown to be embryonically lethal,[3] thus indicating that it is important for vasculogenesis and blood vessel development. In addition, it was shown to participate in adherens junctions complex and regulate vascular permeability.[4][5] Recently, Soni et al. have shown that tyrosine phosphorylation of VE-PTP via Pyk2 kinase downstream of STIM1-induced calcium entry mediates disassembly of the endothelial adherens junctions.[5]
# Interactions
VE-PTP contains an extracellular domain composed of multiple fibronectin type_III repeats, a single transmembrane segment and one intracytoplasmic catalytic domain, thus belongs to R3 receptor subtype PTPs.
The extracellular region was shown to interact with the angiopoietin receptor Tie-2[2] and with the adhesion protein VE-cadherin.[5][6]
VE-PTP was also found to interact with Grb2 and plakoglobin through its cytoplasmatic domain. | https://www.wikidoc.org/index.php/PTPRB | |
c825f2c052539bf345a33667ca8ea9cf72fadaed | wikidoc | PTPRC | PTPRC
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocyte common antigen (LCA).
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus belongs to receptor type PTP. This gene is specifically expressed in hematopoietic cells. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and, thus, functions as a negative regulator of cytokine receptor signaling. Four alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.
It is a type I transmembrane protein that is in various forms present on all differentiated hematopoietic cells, except erythrocytes and plasma cells, that assists in the activation of those cells (a form of co-stimulation). It is expressed in lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia. A monoclonal antibody to CD45 is used in routine immunohistochemistry to differentiate between histological sections from lymphomas and carcinomas.
# Isoforms
The CD45 family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons and three exons of the primary transcripts are alternatively spliced to generate up to eight different mature mRNAs and after translation eight different protein products. These three exons generate the RA, RB and RC isoforms.
Various isoforms of CD45 exist:
CD45RA, CD45RB, CD45RC, CD45RAB, CD45RAC, CD45RBC, CD45R0, CD45R (ABC).
CD45RA is located on naive T cells and CD45R0 is located on memory T cells.
CD45 is also highly glycosylated. CD45R is the longest protein and migrates at 200 kDa when isolated from T cells. B cells also express CD45R with heavier glycosylation, bringing the molecular weight to 220 kDa, hence the name B220; B cell isoform of 220 kDa. B220 expression is not restricted to B cells and can also be expressed on activated T cells, on a subset of dendritic cells and other antigen-presenting cells.
Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45R0, which lacks RA, RB, and RC exons. This shortest isoform facilitates T cell activation.
The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cells) and activates it.
# Interactions
PTPRC has been shown to interact with:
- GANAB,
- LYN,
- Lck, and
- SKAP1.
CD45 has been recently shown to interact with the HCMV UL11 protein. This interaction results in functional paralysis of T cells. In addition, CD45 was shown to be the target of the species D adenovirus 19a E3/49K protein to inhibit the activation of NK and T cells.
# Clinical importance
CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells, but CD45 positioning within lipid rafts is modified during their oncogenic transformation to acute myeloid leukemia. CD45 colocalizes with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells.
# Use as a congenic marker
There are two identifiable alleles of CD45 in mice: CD45.1 (Ly5.1 historically) and CD45.2 (Ly5.2 historically). These two types of CD45 are believed to be functionally identical. As such, they are routinely used in scientific research to allow identification of cells. For instance, leukocytes can be transferred from a CD45.1 donor mouse, into a CD45.2 host mouse, and can be subsequently identified due to their expression of CD45.1. This technique is also routinely used when generating chimeras. An alternative system is the use of CD90 (Thy1) alleles, which CD90.1/CD90.2 system is used in the same manner as the CD45.1/CD45.2 system. | PTPRC
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene.[1] PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leukocyte common antigen (LCA).[2]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus belongs to receptor type PTP. This gene is specifically expressed in hematopoietic cells. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and, thus, functions as a negative regulator of cytokine receptor signaling. Four alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported.[2]
It is a type I transmembrane protein that is in various forms present on all differentiated hematopoietic cells, except erythrocytes and plasma cells, that assists in the activation of those cells (a form of co-stimulation). It is expressed in lymphomas, B-cell chronic lymphocytic leukemia, hairy cell leukemia, and acute nonlymphocytic leukemia. A monoclonal antibody to CD45 is used in routine immunohistochemistry to differentiate between histological sections from lymphomas and carcinomas.[3]
# Isoforms
The CD45 family consists of multiple members that are all products of a single complex gene. This gene contains 34 exons and three exons of the primary transcripts are alternatively spliced to generate up to eight different mature mRNAs and after translation eight different protein products. These three exons generate the RA, RB and RC isoforms.
Various isoforms of CD45 exist:
CD45RA, CD45RB, CD45RC, CD45RAB, CD45RAC, CD45RBC, CD45R0, CD45R (ABC).
CD45RA is located on naive T cells and CD45R0 is located on memory T cells.
CD45 is also highly glycosylated. CD45R is the longest protein and migrates at 200 kDa when isolated from T cells. B cells also express CD45R with heavier glycosylation, bringing the molecular weight to 220 kDa, hence the name B220; B cell isoform of 220 kDa. B220 expression is not restricted to B cells and can also be expressed on activated T cells, on a subset of dendritic cells and other antigen-presenting cells.
Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45R0, which lacks RA, RB, and RC exons. This shortest isoform facilitates T cell activation.
The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cells) and activates it.
# Interactions
PTPRC has been shown to interact with:
- GANAB,[4][5][6]
- LYN,[7]
- Lck,[8][9] and
- SKAP1.[10]
CD45 has been recently shown to interact with the HCMV UL11 protein. This interaction results in functional paralysis of T cells.[11] In addition, CD45 was shown to be the target of the species D adenovirus 19a E3/49K protein to inhibit the activation of NK and T cells.[12]
# Clinical importance
CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells, but CD45 positioning within lipid rafts is modified during their oncogenic transformation to acute myeloid leukemia. CD45 colocalizes with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells.[13]
# Use as a congenic marker
There are two identifiable alleles of CD45 in mice: CD45.1 (Ly5.1 historically) and CD45.2 (Ly5.2 historically).[14] These two types of CD45 are believed to be functionally identical. As such, they are routinely used in scientific research to allow identification of cells. For instance, leukocytes can be transferred from a CD45.1 donor mouse, into a CD45.2 host mouse, and can be subsequently identified due to their expression of CD45.1. This technique is also routinely used when generating chimeras. An alternative system is the use of CD90 (Thy1) alleles, which CD90.1/CD90.2 system is used in the same manner as the CD45.1/CD45.2 system. | https://www.wikidoc.org/index.php/PTPRC | |
07d40835a5bee45b6150175ddd42f7047d47d857 | wikidoc | PTPRD | PTPRD
Receptor-type tyrosine-protein phosphatase delta is an enzyme that in humans is encoded by the PTPRD gene.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains. Studies of the similar genes in chick and fly suggest the role of this PTP is in promoting neurite growth, and regulating neurons axon guidance. Multiple tissue specific alternatively spliced transcript variants of this gene have been reported.
# Clinical significance
Mutations in the PTPRD gene are associated with autism, obsessive–compulsive disorder, and breast cancer.
# Interactions
PTPRD has been shown to interact with PTPRS and liprin-alpha-1. | PTPRD
Receptor-type tyrosine-protein phosphatase delta is an enzyme that in humans is encoded by the PTPRD gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains. Studies of the similar genes in chick and fly suggest the role of this PTP is in promoting neurite growth, and regulating neurons axon guidance. Multiple tissue specific alternatively spliced transcript variants of this gene have been reported.[3]
# Clinical significance
Mutations in the PTPRD gene are associated with autism,[4] obsessive–compulsive disorder,[5] and breast cancer.[6]
# Interactions
PTPRD has been shown to interact with PTPRS[7] and liprin-alpha-1.[8] | https://www.wikidoc.org/index.php/PTPRD | |
2e6d44d46b99ef62d4f101069fba0946e1761500 | wikidoc | PTPRK | PTPRK
Receptor-type tyrosine-protein phosphatase kappa is an enzyme that in humans is encoded by the PTPRK gene. PTPRK is also known as PTPkappa and PTPκ.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
The human PTPRK gene is located on the long arm of chromosome 6, a putative tumor suppressor region of the genome.
## During development
The same reporter construct used by Shen and colleagues, and described above was created by Skarnes et al. during a screen to identify genes important in mouse development. The transgenic mouse was created by combining a β-galactosidase (β-gal) reporter gene with a signal sequence and the transmembrane domain of the type I transmembrane protein CD4. If the transgene was incorporated into a gene with a signal sequence, β-gal activity would remain in the cytosol of the cell and therefore be active. If the reporter gene was incorporated into a gene that lacked a signal sequence, β-gal activity would be in the ER where it would lose β-gal activity. This construct inserted into the phosphatase domain of PTPkappa. Mice generated from these ES cells were viable, suggesting that PTPkappa phosphatase activity is not necessary for embryonic development.
Additional studies have suggested a function for PTPkappa during nervous system development. PTPkappa promotes neurite outgrowth from embryonic cerebellar neurons, and thus may be involved in axonal extension or guidance in vivo. Neurites are extensions from neurons that can be considered the in vitro equivalent of axons and dendrites. The extension of cerebellar neurites on purified PTPkappa fusion proteins was demonstrated to require Grb2 and MEK1 activity.
## In T cells
PTPkappa has also been shown to regulate CD4+ positive T cell development. PTPkappa and the THEMIS gene are both deleted in the rat Long-Evans Cinnamon (LEC) strain, and are both required for the CD4+ T-cell deficiency observed in this strain of rats. Deletion of PTPkappa was shown to generate T-helper immunodeficiency in the LEC strain.
By expressing a dominant negative form of PTPkappa or by using short-hairpin RNA for PTPkappa in bone-marrow derived stem cells, Erdenbayer and colleagues demonstrated that CD4(+) T cells development was inhibited. PTPkappa likely regulates T-cell development by positively regulating ERK1/2 phosphorylation via the regulation of MEK1/2 and c-Raf phosphorylation.
## Cadherin-catenin signaling
PTPkappa is localized to cell-cell contact sites, where it colocalizes and co-immunoprecipitates with β-catenin and plakoglobin/γ-catenin β-catenin may be a PTPkappa substrate. The presence of full-length PTPkappa in melanoma cells decreases the level of free-cytosolic β-catenin, which consequently reduces the level of nuclear β-catenin and reduces the expression of the β-catenin-regulated genes, cyclin D1 and c-myc. Expression of ful-length PTPkappa in melanoma cells that normally lack its expression results in reduced cell migration and cell proliferation. Because the presence of PTPkappa at the cell membrane was shown to sequester β-catenin to the plasma membrane, these data suggest that one mechanism whereby PTPkappa functions as a tumor suppressor is by regulating the intracellular localization of free-β-catenin.
The intracellular fragments of PTPkappa, PΔE and PIC, are catalytically active, and can also dephosphorylate β-catenin. Tyrosine phosphorylated β-catenin translocates to the cell nucleus and activates TCF-mediated transcription to promote cell proliferation and migration. While full-length PTPkappa antagonizes TCF-mediated transcription, the PIC fragment augments it, perhaps by regulating other proteins in TCF-mediated transcription. This suggests that phosphatase activity of the PIC fragment opposes that of full-length PTPkappa.
PTPkappa interacts by co-immunoprecipitation with E-cadherin, α-catenin and β-catenin in pancreatic acinar cells prior to the dissolution of adherens junctions in a rat model of pancreatitis. The authors suggest that the presence of PTPkappa at the plasma membrane in association with the cadherin/catenin complex is important for the maintenance of adherens junction in pancreatic acinar cells, much as it was suggested above in melanoma cells.
## EGFR signaling
Use of short interfering RNA (siRNA) of PTPkappa to reduce PTPkappa protein expression in the mammary epithelial cell line, MCF10A, resulted in increased cell proliferation. PTPkappa expression, conversely, was demonstrated to reduce cell proliferation in Chinese hamster ovary cells. The mechanism proposed to explain the influence of PTPkappa on cell proliferation is via PTPkappa dephosphorylation of the EGFR on tyrosines 1068 and 1173 directly. The reduction of PTPkappa expression in CHO cells with PTPkappa siRNA increased EGFR phosphorylation. Therefore, the hypothesis is that PTPkappa functions as a tumor suppressor gene by dephosphorylating and inactivating EGFR.
In addition, glycosylation by N-acetylglucosaminyltransferase-V (GnT-V) has been shown to reduce full-length PTPkappa expression, likely via increasing its cleavage. This aberrant glycosylation has been shown to increase the phosphorylation of EGFR on tyrosine 1068, likely because of reduced plasma-membrane associated PTPkappa expression and hence reduced PTPkappa-mediated dephosphorylation of its membrane associated susbstrates, such as EGFR.
# Structure
PTPkappa possesses an extracellular region, a single transmembrane region, and two tandem catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. PTPkappa is a member of the R2B subfamily of RPTPs, which includes RPTPM, RPTPT, and RPTPU. PTPkappa shares most sequence similarity with PTPmu and PTPrho.
Crystal structure analysis of the first phosphatase domain of PTPkappa demonstrates that it shares many conformational features with PTPmu, including an unhindered open conformation for the catalytically important WPD loop, and a phosphate binding loop for the active-site cysteine (Cys1083). PTPkappa exists as a monomer in solution, with the caveat that dimers of PTPkappa are observed depending on the nature of the buffer used.
# Alternative splicing
Alternative splicing of exons 16, 17a, and 20a has been described for PTPRK. Two novel forms of PTPRK were identified from mouse full-length cDNA sequences and were predicted to result in two PTPkappa splice variants: a secreted form of PTPkappa and a membrane tethered form.
# Homophilic binding
PTPkappa mediates homophilic cell-cell aggregation via its extracellular domain. PTPkappa only mediates binding between cells expressing PTPkappa (i.e. homophilic), and will not mediate cell aggregation between cells expressing PTPkappa, PTPmu or PTPrho (i.e. heterophilic).
# Regulation
## Proteolysis and N-glycosylation
Full-length PTPkappa protein is cleaved by furin to generate two cleaved fragments that remain associated at the plasma membrane, an extracellular (E) subunit and an intracellular phosphatase (P) subunit. In response to high cell density or calcium influx following trifluoperazine (TFP) stimulation, PTPkappa is further cleaved by ADAM 10 to yield a shed extracellular fragment and a membrane tethered intracellular fragment, PΔE. The membrane tethered PΔE fragment is further cleaved by the gamma secretase complex to yield a membrane-released fragment, PIC, that can translocate to the cellular nucleus, where it is catalytically active.
Glycosylation of the extracellular domain of PTPkappa was demonstrated to occur preferentially in WiDr colon cancer cells that over-express N-acetylglucosaminyl transferase V (GnT-V). Over-expression of GnT-V in these cells increased the cleavage and shedding of PTPkappa ectodomain and increased migration of WiDr cells in transwell assays. As a result of glycosylation of PTPkappa by GnT-V, EGFR was phosphorylated on tyrosine 1068 and activated, and is likely the cause of the increased cell migration observed following PTPkappa cleavage.
Shedding of PTPkappa may also be regulated by the presence of galectin-3 binding protein, as has been shown in WiDr cells. The authors suggest that the ratio of galectin-3 binding protein to galectin 3 influences the cleavage and shedding of PTPkappa, although the exact mechanism of how these proteins regulate PTPkappa cleavage was not determined.
## By reactive oxygen species in cancer
One mechanism whereby PTPkappa tyrosine phosphatase activity can be perturbed in cancer is via oxidative inhibition mediated by reactive oxygen species generated by either hydrogen peroxide in vitro or UV irradiation of skin cells in vivo. In cell-free assays, the presence of hydrogen peroxide reduces PTPkappa tyrosine phosphatase activity and increases EGFR tyrosine phosphorylation. UV-irradiation of primary human keratinocytes yields the same results, namely a reduction of PTPkappa tyrosine phosphatase activity and an increase in EGFR tyrosine phosphorylation. EGFR phosphorylation then leads to cell proliferation, suggesting that PTPkappa may function as a tumor suppressor in skin cancer in addition to melanoma.
## Expression
PTPkappa is expressed in human keratinocytes. TGFβ1 is a growth inhibitor in human keratinocytes. Stimulation of the cultured human keratinocyte cell line, HaCaT, with TGFβ1 increases the levels of PTPkappa (PTPRK) mRNA as assayed by northern blot analysis. TGFβ1 also increased PTPkappa mRNA and protein in normal and tumor mammary cell lines. HER2 overexpression reduced PTPkappa mRNA and protein expression.
# Clinical significance
## Melanoma and skin cancer
Expression analysis of PTPkappa mRNA in normal melanocytes and in melanoma cells and tissues demonstrated that PTPkappa is downregulated or absent 20% of the time in melanoma, suggesting that PTPkappa is a tumor suppressor gene in melanoma. A form of PTPkappa with a point mutation in the fourth fibronectin III repeat was identified to be a melanoma specific antigen recognized by CD4+ T cells in a melanoma patient with 10-year tumor-free survival after lymph node resection. This particular mutated form of PTPkappa was not identified in 10 other melanoma cell lines, and may thus represent a unique mutation in one patient.
## Lymphoma
PTPkappa was also identified as the putative tumor suppressor gene commonly deleted in primary central nervous system lymphomas (PCNSLs).
Downregulation of PTPkappa was found to occur following Epstein-Barr Virus (EBV) infection of Hodgkin’s Lymphomas cells.
## Colorectal cancer
Using a transposon-based genetic screen, researchers found that disruption of the PTPRK gene in gastrointestinal tract epithelium resulted in an intestinal lesion, classified as either an intraepithelial neoplasia, an adenocarcinoma or an adenoma.
## Lung cancer
PTPRK mRNA was shown to be significantly reduced by RT-PCR in human lung cancer-derived cell lines.
## Prostate cancer
PTPRK has also been shown to be downregulated in response to androgen stimulation in human LNCaP prostate cancer cells. The mechanism whereby PTPRK is downregulated is via the expression of a microRNA, miR-133b, which is upregulated in response to androgen stimulation.
## Breast cancer
Patients with reduced PTPRK transcript expression have shorter breast cancer survival times and are more likely to have breast cancer metastases or to die from breast cancer. In an experimental model of breast cancer, PTPRK was reduced in breast cancer cell lines with PTPRK ribozymes. In these cells, adhesion to matrigel, transwell migration, and cell growth were all increased following the reduction of PTPRK expression, again supporting a function for PTPRK as a tumor suppressor.
## Glioma
Assem and colleagues identified loss of heterozygosity (LOH) events in malignant glioma specimens, and identified PTPRK as a significant gene candidate in one LOH region. A significant correlation between the presence of PTPRK mutations and short patient survival time was observed. PTPRK was amplified from tumor cDNA to confirm the LOH observed. In these specimens, 6 different mutations were observed, two of which (one in each phosphatase domain) disrupted the enzymatic activity of PTPRK. Expression of wild-type PTPkappa in U87-MG and U251-MG cells resulted in a reduction in cell proliferation, migration and invasion. Expression of the variants of PTPkappa with mutations in the phosphatase domains, however, increased cell proliferation, migration and invasion, supporting a role for the involvement of the mutated variants of PTPkappa in tumorigenicity.
## In development
In situ hybridization localized PTPkappa mRNA to the brain, lung, skeletal muscle, heart, placenta, liver, kidney and intestines during development. PTPkappa was also found to be expressed in the developing retina, in nestin-positive radial progenitor cells and later in development, in the ganglion cell layer, inner plexiform layer and outer segments of photoreceptors. PTPkappa protein is observed in neural progenitor cells and radial glial cells of the developing mouse superior colliculus, as well.
In the adult rat brain, PTPkappa mRNA is highly expressed in regions of the brain with cellular plasticity and growth, such as the olfactory bulb, the hippocampus and the cerebral cortex. PTPkappa mRNA is also observed in the adult mouse cerebellum.
Using a β-galactosidase (β-gal) reporter gene inserted into the phosphatase domain of the murine PTPkappa (PTPRK) gene, Shen and colleagues determined the detailed expression pattern of endogenous PTPRK. β-gal activity was observed in many areas of the adult forebrain, including layers II and IV, and to a lesser extent in layer VI of the cortex. β-gal activity was also observed in apical dendrites of cortical pyramidal cells, the granule layer of the olfactory and accessory olfactory bulbs, the anterior hypothalamus, paraventricular nucleus, and in granule and pyramidal layers of the dentate gyrus and CA 1-3 regions of the hippocampus. In the midbrain, β-gal was observed in the subthalamic nucleus, the superior and inferior colliculi and in the red nucleus. β-gal activity was also observed in the neural retina, in the inner nuclear layer and in small ganglion cells of the ganglion cell layer.
# Interactions
PTPRK has been shown to interact with:
- Beta-catenin,
- E-cadherin (CDH-1),
- Epidermal growth factor receptor (EGFR),
- HER2,
- Plakoglobin, and
- α-catenin. | PTPRK
Receptor-type tyrosine-protein phosphatase kappa is an enzyme that in humans is encoded by the PTPRK gene.[1][2][3] PTPRK is also known as PTPkappa and PTPκ.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
The human PTPRK gene is located on the long arm of chromosome 6, a putative tumor suppressor region of the genome.[4]
## During development
The same reporter construct used by Shen and colleagues, and described above was created by Skarnes et al. during a screen to identify genes important in mouse development.[5] The transgenic mouse was created by combining a β-galactosidase (β-gal) reporter gene with a signal sequence and the transmembrane domain of the type I transmembrane protein CD4. If the transgene was incorporated into a gene with a signal sequence, β-gal activity would remain in the cytosol of the cell and therefore be active. If the reporter gene was incorporated into a gene that lacked a signal sequence, β-gal activity would be in the ER where it would lose β-gal activity. This construct inserted into the phosphatase domain of PTPkappa.[6] Mice generated from these ES cells were viable, suggesting that PTPkappa phosphatase activity is not necessary for embryonic development.[5][6]
Additional studies have suggested a function for PTPkappa during nervous system development. PTPkappa promotes neurite outgrowth from embryonic cerebellar neurons, and thus may be involved in axonal extension or guidance in vivo.[7] Neurites are extensions from neurons that can be considered the in vitro equivalent of axons and dendrites. The extension of cerebellar neurites on purified PTPkappa fusion proteins was demonstrated to require Grb2 and MEK1 activity.[7]
## In T cells
PTPkappa has also been shown to regulate CD4+ positive T cell development.[8] PTPkappa and the THEMIS gene are both deleted in the rat Long-Evans Cinnamon (LEC) strain, and are both required for the CD4+ T-cell deficiency observed in this strain of rats.[8][9] Deletion of PTPkappa was shown to generate T-helper immunodeficiency in the LEC strain.[10]
By expressing a dominant negative form of PTPkappa or by using short-hairpin RNA for PTPkappa in bone-marrow derived stem cells, Erdenbayer and colleagues demonstrated that CD4(+) T cells development was inhibited.[11] PTPkappa likely regulates T-cell development by positively regulating ERK1/2 phosphorylation via the regulation of MEK1/2 and c-Raf phosphorylation.[11]
## Cadherin-catenin signaling
PTPkappa is localized to cell-cell contact sites, where it colocalizes and co-immunoprecipitates with β-catenin and plakoglobin/γ-catenin[2] β-catenin may be a PTPkappa substrate.[2][12] The presence of full-length PTPkappa in melanoma cells decreases the level of free-cytosolic β-catenin, which consequently reduces the level of nuclear β-catenin and reduces the expression of the β-catenin-regulated genes, cyclin D1 and c-myc.[13] Expression of ful-length PTPkappa in melanoma cells that normally lack its expression results in reduced cell migration and cell proliferation. Because the presence of PTPkappa at the cell membrane was shown to sequester β-catenin to the plasma membrane, these data suggest that one mechanism whereby PTPkappa functions as a tumor suppressor is by regulating the intracellular localization of free-β-catenin.[13]
The intracellular fragments of PTPkappa, PΔE and PIC, are catalytically active, and can also dephosphorylate β-catenin.[12] Tyrosine phosphorylated β-catenin translocates to the cell nucleus and activates TCF-mediated transcription to promote cell proliferation and migration. While full-length PTPkappa antagonizes TCF-mediated transcription, the PIC fragment augments it, perhaps by regulating other proteins in TCF-mediated transcription.[12] This suggests that phosphatase activity of the PIC fragment opposes that of full-length PTPkappa.[12]
PTPkappa interacts by co-immunoprecipitation with E-cadherin, α-catenin and β-catenin in pancreatic acinar cells prior to the dissolution of adherens junctions in a rat model of pancreatitis.[14] The authors suggest that the presence of PTPkappa at the plasma membrane in association with the cadherin/catenin complex is important for the maintenance of adherens junction in pancreatic acinar cells, much as it was suggested above in melanoma cells.[14]
## EGFR signaling
Use of short interfering RNA (siRNA) of PTPkappa to reduce PTPkappa protein expression in the mammary epithelial cell line, MCF10A, resulted in increased cell proliferation.[15] PTPkappa expression, conversely, was demonstrated to reduce cell proliferation in Chinese hamster ovary cells.[16] The mechanism proposed to explain the influence of PTPkappa on cell proliferation is via PTPkappa dephosphorylation of the EGFR on tyrosines 1068 and 1173 directly. The reduction of PTPkappa expression in CHO cells with PTPkappa siRNA increased EGFR phosphorylation.[16] Therefore, the hypothesis is that PTPkappa functions as a tumor suppressor gene by dephosphorylating and inactivating EGFR.[16]
In addition, glycosylation by N-acetylglucosaminyltransferase-V (GnT-V) has been shown to reduce full-length PTPkappa expression, likely via increasing its cleavage.[17] This aberrant glycosylation has been shown to increase the phosphorylation of EGFR on tyrosine 1068, likely because of reduced plasma-membrane associated PTPkappa expression and hence reduced PTPkappa-mediated dephosphorylation of its membrane associated susbstrates, such as EGFR.[18]
# Structure
PTPkappa possesses an extracellular region, a single transmembrane region, and two tandem catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats.[19] PTPkappa is a member of the R2B subfamily of RPTPs, which includes RPTPM, RPTPT, and RPTPU. PTPkappa shares most sequence similarity with PTPmu and PTPrho.
Crystal structure analysis of the first phosphatase domain of PTPkappa demonstrates that it shares many conformational features with PTPmu, including an unhindered open conformation for the catalytically important WPD loop, and a phosphate binding loop for the active-site cysteine (Cys1083). PTPkappa exists as a monomer in solution, with the caveat that dimers of PTPkappa are observed depending on the nature of the buffer used.[20]
# Alternative splicing
Alternative splicing of exons 16, 17a, and 20a has been described for PTPRK.[21] Two novel forms of PTPRK were identified from mouse full-length cDNA sequences and were predicted to result in two PTPkappa splice variants: a secreted form of PTPkappa and a membrane tethered form.[22]
# Homophilic binding
PTPkappa mediates homophilic cell-cell aggregation via its extracellular domain.[23] PTPkappa only mediates binding between cells expressing PTPkappa (i.e. homophilic), and will not mediate cell aggregation between cells expressing PTPkappa, PTPmu or PTPrho (i.e. heterophilic).[24][25]
# Regulation
## Proteolysis and N-glycosylation
Full-length PTPkappa protein is cleaved by furin to generate two cleaved fragments that remain associated at the plasma membrane, an extracellular (E) subunit and an intracellular phosphatase (P) subunit.[2][19] In response to high cell density or calcium influx following trifluoperazine (TFP) stimulation, PTPkappa is further cleaved by ADAM 10 to yield a shed extracellular fragment and a membrane tethered intracellular fragment, PΔE.[12] The membrane tethered PΔE fragment is further cleaved by the gamma secretase complex to yield a membrane-released fragment, PIC, that can translocate to the cellular nucleus, where it is catalytically active.[12]
Glycosylation of the extracellular domain of PTPkappa was demonstrated to occur preferentially in WiDr colon cancer cells that over-express N-acetylglucosaminyl transferase V (GnT-V).[17] Over-expression of GnT-V in these cells increased the cleavage and shedding of PTPkappa ectodomain and increased migration of WiDr cells in transwell assays.[17] As a result of glycosylation of PTPkappa by GnT-V, EGFR was phosphorylated on tyrosine 1068 and activated, and is likely the cause of the increased cell migration observed following PTPkappa cleavage.[18]
Shedding of PTPkappa may also be regulated by the presence of galectin-3 binding protein, as has been shown in WiDr cells.[26] The authors suggest that the ratio of galectin-3 binding protein to galectin 3 influences the cleavage and shedding of PTPkappa, although the exact mechanism of how these proteins regulate PTPkappa cleavage was not determined.
## By reactive oxygen species in cancer
One mechanism whereby PTPkappa tyrosine phosphatase activity can be perturbed in cancer is via oxidative inhibition mediated by reactive oxygen species generated by either hydrogen peroxide in vitro or UV irradiation of skin cells in vivo.[27] In cell-free assays, the presence of hydrogen peroxide reduces PTPkappa tyrosine phosphatase activity and increases EGFR tyrosine phosphorylation.[27] UV-irradiation of primary human keratinocytes yields the same results, namely a reduction of PTPkappa tyrosine phosphatase activity and an increase in EGFR tyrosine phosphorylation. EGFR phosphorylation then leads to cell proliferation, suggesting that PTPkappa may function as a tumor suppressor in skin cancer in addition to melanoma.[27]
## Expression
PTPkappa is expressed in human keratinocytes. TGFβ1 is a growth inhibitor in human keratinocytes. Stimulation of the cultured human keratinocyte cell line, HaCaT, with TGFβ1 increases the levels of PTPkappa (PTPRK) mRNA as assayed by northern blot analysis.[28] TGFβ1 also increased PTPkappa mRNA and protein in normal and tumor mammary cell lines.[15] HER2 overexpression reduced PTPkappa mRNA and protein expression.[15]
# Clinical significance
## Melanoma and skin cancer
Expression analysis of PTPkappa mRNA in normal melanocytes and in melanoma cells and tissues demonstrated that PTPkappa is downregulated or absent 20% of the time in melanoma, suggesting that PTPkappa is a tumor suppressor gene in melanoma.[29] A form of PTPkappa with a point mutation in the fourth fibronectin III repeat was identified to be a melanoma specific antigen recognized by CD4+ T cells in a melanoma patient with 10-year tumor-free survival after lymph node resection.[30] This particular mutated form of PTPkappa was not identified in 10 other melanoma cell lines, and may thus represent a unique mutation in one patient.[30]
## Lymphoma
PTPkappa was also identified as the putative tumor suppressor gene commonly deleted in primary central nervous system lymphomas (PCNSLs).[31]
Downregulation of PTPkappa was found to occur following Epstein-Barr Virus (EBV) infection of Hodgkin’s Lymphomas cells.[32]
## Colorectal cancer
Using a transposon-based genetic screen, researchers found that disruption of the PTPRK gene in gastrointestinal tract epithelium resulted in an intestinal lesion, classified as either an intraepithelial neoplasia, an adenocarcinoma or an adenoma.[33]
## Lung cancer
PTPRK mRNA was shown to be significantly reduced by RT-PCR in human lung cancer-derived cell lines.[34]
## Prostate cancer
PTPRK has also been shown to be downregulated in response to androgen stimulation in human LNCaP prostate cancer cells.[35] The mechanism whereby PTPRK is downregulated is via the expression of a microRNA, miR-133b, which is upregulated in response to androgen stimulation.[35]
## Breast cancer
Patients with reduced PTPRK transcript expression have shorter breast cancer survival times and are more likely to have breast cancer metastases or to die from breast cancer.[36] In an experimental model of breast cancer, PTPRK was reduced in breast cancer cell lines with PTPRK ribozymes.[36] In these cells, adhesion to matrigel, transwell migration, and cell growth were all increased following the reduction of PTPRK expression, again supporting a function for PTPRK as a tumor suppressor.[36]
## Glioma
Assem and colleagues identified loss of heterozygosity (LOH) events in malignant glioma specimens, and identified PTPRK as a significant gene candidate in one LOH region.[37] A significant correlation between the presence of PTPRK mutations and short patient survival time was observed.[37] PTPRK was amplified from tumor cDNA to confirm the LOH observed. In these specimens, 6 different mutations were observed, two of which (one in each phosphatase domain) disrupted the enzymatic activity of PTPRK.[38] Expression of wild-type PTPkappa in U87-MG and U251-MG cells resulted in a reduction in cell proliferation, migration and invasion.[38] Expression of the variants of PTPkappa with mutations in the phosphatase domains, however, increased cell proliferation, migration and invasion, supporting a role for the involvement of the mutated variants of PTPkappa in tumorigenicity.[38]
## In development
In situ hybridization localized PTPkappa mRNA to the brain, lung, skeletal muscle, heart, placenta, liver, kidney and intestines during development.[39] PTPkappa was also found to be expressed in the developing retina, in nestin-positive radial progenitor cells and later in development, in the ganglion cell layer, inner plexiform layer and outer segments of photoreceptors.[40] PTPkappa protein is observed in neural progenitor cells and radial glial cells of the developing mouse superior colliculus, as well.[41]
In the adult rat brain, PTPkappa mRNA is highly expressed in regions of the brain with cellular plasticity and growth, such as the olfactory bulb, the hippocampus and the cerebral cortex.[19] PTPkappa mRNA is also observed in the adult mouse cerebellum.[21]
Using a β-galactosidase (β-gal) reporter gene inserted into the phosphatase domain of the murine PTPkappa (PTPRK) gene, Shen and colleagues determined the detailed expression pattern of endogenous PTPRK.[6] β-gal activity was observed in many areas of the adult forebrain, including layers II and IV, and to a lesser extent in layer VI of the cortex. β-gal activity was also observed in apical dendrites of cortical pyramidal cells, the granule layer of the olfactory and accessory olfactory bulbs, the anterior hypothalamus, paraventricular nucleus, and in granule and pyramidal layers of the dentate gyrus and CA 1-3 regions of the hippocampus.[6] In the midbrain, β-gal was observed in the subthalamic nucleus, the superior and inferior colliculi and in the red nucleus. β-gal activity was also observed in the neural retina, in the inner nuclear layer and in small ganglion cells of the ganglion cell layer.[6]
# Interactions
PTPRK has been shown to interact with:
- Beta-catenin,[2][12][14]
- E-cadherin (CDH-1),[14]
- Epidermal growth factor receptor (EGFR),[15]
- HER2,[15]
- Plakoglobin,[2] and
- α-catenin.[14] | https://www.wikidoc.org/index.php/PTPRK | |
f37d1bb3f3e3bf5fd54debd5f71c1a44b2d70cdb | wikidoc | PTPRM | PTPRM
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPs can be both cytosolic and transmembrane.
# Structure
Transmembrane PTPs are known as receptor protein tyrosine phosphatases (RPTPs). RPTPs are single pass transmembrane proteins usually with one or two catalytic domains in their intracellular domain (the part of the protein that is inside the cell) and diverse extracellular structures (the part of the protein that is outside the cell).
PTPmu possesses an extracellular region, a single transmembrane region, a 158 amino acid long juxtamembrane domain and two tandem tyrosine phosphatase domains (referred to as D1 and D2) in its intracellular domain, and thus represents an RPTP.Only the membrane proximal phosphatase domain, D1, is catalytically active. The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. There are other RPTPs that resemble PTPmu. These proteins are all grouped as type IIb RPTPs, and include PTPkappa (κ), PTPrho (ρ), and PCP-2. The structure of type IIb RPTPs classifies them as members of the immunoglobulin superfamily of cell adhesion molecules, in addition to being tyrosine phosphatases. The structure of PTPmu suggests that it can regulate cell adhesion and migration using its extracellular cell adhesion molecule features, while also regulating the level of tyrosine phosphorylation inside of cells using its catalytic tyrosine phosphatase domain. A series of reviews have been written about RPTPs including PTPmu. PTPmu is expressed in different organ tissues in the body, including the lung, heart and brain, pancreas, endothelial cells in capillaries and arteries throughout the body, and in retinal and brain cells. PTPmu has been shown to increase the mRNA of the K+ channel Kv1.5 in cardiac myocytes when CHO cells expressing PTPmu are cultured with cardiac myocytes.
# Homophilic binding
PTPmu protein expressed on the surface of cells is able to mediate binding between two cells, which results in the clustering of the cells, known as cell–cell aggregation. PTPmu accomplishes this by interacting with another PTPmu molecule on an adjacent cell, known as homophilic binding. The Ig domain of PTPmu is responsible for promoting homophilic binding. The Ig domain is also responsible for localizing PTPmu to the plasma membrane surface of the cell. The ability of closely related molecules like PTPmu and PTPkappa to separate themselves to associate only with their identically matched (homologous) molecules, known as sorting, is attributed to the MAM domain. The MAM, Ig, and the first two FNIII repeats are the minimum extracellular domains required for efficient cell–cell adhesion. Crystallographic studies demonstrated that the MAM and Ig domains are tightly associated into one functional entity. Additional crystal structure analysis by Aricescu and colleagues predicted that the adhesive interface between two PTPµ proteins is between the MAM and Ig domains of one PTPµ protein interacts with the first and second FN III domains of the second PTPµ protein. The type IIb RPTPs mediate adhesion, with the exception of PCP-2.
# Tyrosine phosphatase activity
There are a number of ways that RPTP catalytic activity can be regulated (for reviews, see ). Dimerization of identical RPTP proteins at the cell surface leaves the PTP domains either in an open active conformation, as in the case of PTPmu and LAR, or in an inhibited conformation that leaves the catalytic domain inaccessible, in the case of CD45, PTPalpha, and PTPzeta/beta. The binding of different parts of the protein with itself (ex. by folding to interact with itself), known as intramolecular interactions, can affect the activity of RPTPs. The cytoplasmic domains of different RPTPs can interact to yield heterodimers of RPTP proteins, which then influence catalytic activity (for example, see ).
The regulation of PTPmu catalytic activity is complex. Like most RPTPs, the membrane proximal (or D1) phosphatase domain of PTPmu is catalytically active. At high cell density, when PTPmu molecules bind to one another homophilically, phosphotyrosine levels are decreased. This suggests that PTPmu may be catalytically active at high cell density. Substrates of PTPmu (proteins that are dephosphorylated by PTPmu), such as p120catenin, tend to be dephosphorylated at high cell density, supporting the hypothesis that PTPmu is catalytically active when bound homophilically. PTPmu is constitutively dimerized due to its extracellular domain.
Crystal structure analysis of the D1 of PTPmu demonstrated that PTPmu dimers are in an open active conformation. Even though PTPmu dimers may be active, an additional study suggests that the extracellular domain of PTPmu reduces phosphatase activity. In this study, it was shown that the cytoplasmic domain of PTPmu (a PTPmu molecule lacking the extracellular domain) has greater phosphatase activity than the full-length protein in an enzymatic phosphatase assay.
PTPmu has a long juxtamembrane domain, which likely influences catalytic activity. The juxtamembrane domain of PTPmu can bind to either the D1 and/or D2 of PTPmu, but only within the same PTPmu monomer. Removal of the juxtamembrane domain from PTPmu has been suggested to reduce PTPmu phosphatase activity. The D2 domain of PTPmu also regulates its activity. Although originally demonstrated to positively regulate phosphatase activity, the D2 domain has been shown to negatively affect PTPmu catalytic activity. A wedge-shaped motif located by D1 also regulates catalytic activity. Use of a peptide with the same sequence as the wedge motif inhibits PTPmu mediated functions.
Certain stimuli may also influence PTP activity. For example, alteration of cell oxidation induces conformational changes in the cytoplasmic domain of PTPmu, which may affect its tyrosine phosphatase activity or binding of extracellular ligands.
# Cadherin-dependent adhesion
Classical cadherins are important proteins for cells to bind in the body (‘’in vivo’’) where they commonly stabilize cell–cell junctions known as adherens junctions. Cadherins stabilize adherens junctions through the interaction of the cadherin cytoplasmic domains with catenin proteins, such as p120-catenin, beta-catenin and alpha-catenin. Catenins, in turn, bind to the actin cytoskeleton. Binding of these proteins to the actin cytoskeleton prevents actin from growing (a process known as polymerization) and therefore keeps cells stationary. Cadherins regulate cell–cell adhesion during development of the body and in adult tissue. Disruption of cadherin proteins, by genetic alteration or by changes to the structure or function of the protein, has been linked to tumor progression. Notably, PTPmu regulates the adhesion of cells to the classical cadherins. PTPmu likely regulates cadherin-dependent adhesion by interacting with both cadherins and catenins via PTPmu’s cytoplasmic domain. To support this assertion, PTPmu has been shown to interact with and/or dephosphorylate many signaling proteins involved in regulating the cadherin-catenin complex, including p120 catenin, and E-cadherin (CDH1 (gene)) and N-cadherin (CDH2). PTPmu has also been shown to interact with the c-Met hepatocyte growth factor receptor, a protein that is also localized to adherens junctions. Although p120 catenin is a potential substrate of PTPmu, others have suggested that the interaction between PTPmu and catenins is only indirect through E-cadherin. α3β1 integrin and the tetraspanin CD151 regulate PTPmu gene expression to promote E-cadherin-mediated cell–cell adhesion.
In addition to catenins and cadherins, PTPmu dephosphorylates PIPKIγ90 and nectin-3 (PVRL3) to stabilize E-cadherin-based adherens junctions. PTPmu also dephosphorylates another cell junction protein, connexin 43. The interaction between connexin 43 and PTPmu increases gap junction communication.
# Endothelial cell adhesion
PTPµ is expressed in human umbilical cord vein endothelial cells (HUVEC) and in capillaries in the developing brain. The expression of PTPµ in HUVEC cells increases at higher cell density. Studies of PTPµ expression in animal tissues have demonstrated that PTPµ is preferentially expressed in endothelial cells of arteries and capillaries and in cardiac smooth muscle, in addition to brain cells. Because of this specialized expression in arterial endothelial cells, and because PTPµ is found to associate with proteins involved in maintaining endothelial cell–cell junctions, such as VE-cadherin, PTPµ is hypothesized to regulate endothelial cell junction formation or permeability. PTPµ has been shown to be involved in mechanotransduction that results from changes in blood flow to influence endothelial cell-mediated blood vessel dilation, a process induced by “shear stress.” When PTPmu is missing in mice (PTPmu -/- knock-out mice), cannulated mesenteric arteries show reduced flow-induced (or “shear stress” induced) dilation. PTPmu tyrosine phosphatase activity is activated by shear stress. Caveolin 1 is a scaffolding protein enriched in endothelial cell junctions that is also linked to shear stress regulated responses. Caveolin 1 is dephosphorylated on tyrosine 14 in response to shear stress and PTPmu is hypothesized to catalyze this reaction.
# Cell migration
## Neurite outgrowth
PTPmu is expressed in the developing brain and retina. A brain cell, or neuron, has a cell body that contains the nucleus and two types of extensions or processes that grow out from the cell body, the dendrites and axons. Dendrites generally receive input from other neurons, while axons send output to adjacent neurons. These processes are called neurites when grown ‘’in vitro’’ on tissue culture plates, because it is not clear whether they are dendrites or axons. ‘’In vitro’’ growth studies are useful for evaluating the mechanisms that neurons use to grow and function. A neurite outgrowth assay is a type of experiment where neurons are placed on different adhesive substrates on tissue culture plates. A neurite outgrowth assay is meant to mimic how neurons grow inside the body. During development of the nervous system, neuronal axons reach their often-distant targets by reacting to different substrates in their environment, so-called guidance cues, that are attractive, repulsive or simply permissive, meaning these substrates pull axons toward them, away from them, or act in a way that allows growth, respectively. When PTPmu is applied to a dish as an ‘’in vitro’’ substrate, it promotes neurite outgrowth. PTPmu also acts as a guidance cue during development of the nervous system, by repelling neurites of the temporal neural retina, while permitting growth of neurites from the nasal neural retina. Expression of PTPmu protein capable of dephosphorylating tyrosine residues is required for mediating both nasal neurite outgrowth and temporal neurite repulsion. By blocking the expression of PTPmu protein with antisense technology, or by expressing catalytically inactive mutants of PTPmu (molecules of PTPmu that can not dephosphorylate their target proteins) in the developing retina, it was shown that PTPmu is required for the development of the neural retina.
PTPmu also regulates neurite outgrowth on classical cadherins. PTPmu tyrosine phosphatase activity is necessary for neurite outgrowth on the classical cadherins E-, N- and R-cadherin, suggesting that PTPmu dephosphorylates key components of the cadherin-catenin complex to regulate axonal migration. Again, this emphasizes that PTPmu likely regulates cadherin-dependent processes via its cytoplasmic domain.
Various signals required for PTPmu-mediated neurite outgrowth and repulsion have been identified. Some of these signals are proteins that interact with, or bind, to PTPmu, whereas, others may be dephosphorylated by PTPmu. PTPmu interacts with the scaffolding proteins RACK1/GNB2L1, and IQGAP1. IQGAP1 is a scaffold for Rho family of GTPases, E-cadherin, beta-catenin and other proteins. IQGAP1 binding to Rho GTPases is necessary for PTPmu-mediated neurite outgrowth. The growing tip of the neuron, the growth cone, has a distinct appearance depending on what signals are activated inside the growth cone when it touches different substrates. The morphology of the growth cones on PTPmu and the repulsion of temporal neurites are both regulated by the Rho GTPase family member, Cdc42. Inhibition of the Rho GTPase Rac1 permitted neurite outgrowth on PTPmu from neurons in the temporal retina.
The proteins PLCγ1 (PLCG1), PKCδ (PRKCD) and BCCIP are PTPmu substrates. PKCδ activity is required for PTPmu mediated neurite outgrowth and PTPmu-mediated neurite repulsion. Expression of BCCIP is necessary for PTPmu-mediated neurite outgrowth. PTPmu is cleaved in certain brain cancers, which results in nuclear translocation of the cytoplasmic domain of PTPmu (see below). A possible function for the BCCIP-PTPmu interaction may be to shuttle the intracellular PTPmu fragment into the cell nucleus.
In summary, PTPmu dephosphorylates PKCδ, PLCγ1, and BCCIP, and binds to IQGAP1. The expression and/or activity of all these proteins and Cdc42 is necessary for PTPmu-mediated neurite outgrowth. Also, the activity of the GTPase Rac1 promotes PTPmu-mediated neurite repulsion.
## Cancer
PTPmu is downregulated in glioblastoma multiforme (GBM) cells and tissue compared to normal control tissue or cells. The reduction in PTPmu expression in GBM cells has been linked to increased migration of GBM cells.
It was found that PTPmu expression is decreased in GBM cells by proteolysis of the full-length protein into a shed extracellular fragment and a cytoplasmically released intracellular fragment that is capable of translocating into the nucleus. Cleavage of PTPmu is similar to that identified for the Notch signaling pathway. PTPmu is first cleaved to yield two non-covalently associated fragments, likely via a furin-like endo-peptidase in the endoplasmic reticulum (ER), as has been demonstrated for another RPTP, LAR (or PTPRF). Then PTPmu is likely cleaved by an A disintegrin and metalloproteinase (ADAM) protease in the extracellular domain of PTPmu to release the shed extracellular fragment, then by the gamma secretase complex in the transmembrane domain to release the PTPmu intracellular fragment (reviewed in and Cleavage of PTPmu would likely impact the signaling partners that PTPmu would have access to, as has been proposed. (Phillips-Mason, Craig and Brady-Kalnay, 2011). PLCγ1 is a PTPmu substrate. PLCγ1 activity is necessary for mediating GBM cell migration in the absence of PTPmu, thus it seems likely that PTPmu dephosphorylation of PLCγ1 prevents PLCγ1-mediated migration. Cleavage of cell adhesion molecules, like PTPmu, has also been linked to the deregulation of contact inhibition of growth observed in cancer cells. Visualization of the shed extracellular fragment of PTPmu has been proposed to be an effective means of delineating the borders of a GBM tumor ‘’in vivo.’’ Fluorescently tagged PTPmu peptides that bind homophilically to the shed PTPmu extracellular domains are capable of crossing the blood–brain barrier and identifying tumor margins in rodent models of GBM.
# Interactions
PTPRM has been shown to interact with:
- BCCIP,
- c-Met,
- CDH1 E-cadherin (Cadherin-1),
- CDH2 N-cadherin (Cadherin-2),
- CDH4 R-cadherin (cadherin-4),
- CDH5 VE-cadherin (cadherin 5, CDH5),
- CTNND1 (p120catenin),
- GNB2L1/RACK1,
- GJA1 connexin43 (gap junction protein, alpha 1),
- IQGAP1,
- PVRL3 (nectin3),
- PIPKIγ90,
- PRKCD (PKCδ), and
- PLCG1 (PLCγ1). | PTPRM
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases are protein enzymes that remove phosphate moieties from tyrosine residues on other proteins. Tyrosine kinases are enzymes that add phosphates to tyrosine residues, and are the opposing enzymes to PTPs. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPs can be both cytosolic and transmembrane.[4][5]
# Structure
Transmembrane PTPs are known as receptor protein tyrosine phosphatases (RPTPs). RPTPs are single pass transmembrane proteins usually with one or two catalytic domains in their intracellular domain (the part of the protein that is inside the cell) and diverse extracellular structures (the part of the protein that is outside the cell).[6][7]
PTPmu possesses an extracellular region, a single transmembrane region, a 158 amino acid long juxtamembrane domain and two tandem tyrosine phosphatase domains (referred to as D1 and D2) in its intracellular domain, and thus represents an RPTP.[1]Only the membrane proximal phosphatase domain, D1, is catalytically active. The extracellular region contains a meprin-A5 antigen-PTP mu (MAM) domain, an Ig-like domain and four fibronectin type III-like repeats. There are other RPTPs that resemble PTPmu. These proteins are all grouped as type IIb RPTPs, and include PTPkappa (κ), PTPrho (ρ), and PCP-2. The structure of type IIb RPTPs classifies them as members of the immunoglobulin superfamily of cell adhesion molecules, in addition to being tyrosine phosphatases.[6][8] The structure of PTPmu suggests that it can regulate cell adhesion and migration using its extracellular cell adhesion molecule features, while also regulating the level of tyrosine phosphorylation inside of cells using its catalytic tyrosine phosphatase domain. A series of reviews have been written about RPTPs including PTPmu.[6][7][9][10][11][12][13][14][15][16][17] PTPmu is expressed in different organ tissues in the body, including the lung, heart and brain,[18] pancreas,[19] endothelial cells in capillaries and arteries throughout the body,[20][21][22] and in retinal and brain cells.[23][24][25][26][27] PTPmu has been shown to increase the mRNA of the K+ channel Kv1.5 in cardiac myocytes when CHO cells expressing PTPmu are cultured with cardiac myocytes.[28]
# Homophilic binding
PTPmu protein expressed on the surface of cells is able to mediate binding between two cells, which results in the clustering of the cells, known as cell–cell aggregation.[29][30] PTPmu accomplishes this by interacting with another PTPmu molecule on an adjacent cell, known as homophilic binding. The Ig domain of PTPmu is responsible for promoting homophilic binding.[31] The Ig domain is also responsible for localizing PTPmu to the plasma membrane surface of the cell.[32] The ability of closely related molecules like PTPmu and PTPkappa to separate themselves to associate only with their identically matched (homologous) molecules, known as sorting, is attributed to the MAM domain.[33] The MAM, Ig, and the first two FNIII repeats are the minimum extracellular domains required for efficient cell–cell adhesion.[31][32][33][34][35][36][37] Crystallographic studies demonstrated that the MAM and Ig domains are tightly associated into one functional entity.[35] Additional crystal structure analysis by Aricescu and colleagues predicted that the adhesive interface between two PTPµ proteins is between the MAM and Ig domains of one PTPµ protein interacts with the first and second FN III domains of the second PTPµ protein.[36] The type IIb RPTPs mediate adhesion, with the exception of PCP-2.[38]
# Tyrosine phosphatase activity
There are a number of ways that RPTP catalytic activity can be regulated (for reviews, see [7][10][13][39]). Dimerization of identical RPTP proteins at the cell surface leaves the PTP domains either in an open active conformation, as in the case of PTPmu[40] and LAR,[41] or in an inhibited conformation that leaves the catalytic domain inaccessible, in the case of CD45,[42] PTPalpha,[43] and PTPzeta/beta.[44] The binding of different parts of the protein with itself (ex. by folding to interact with itself), known as intramolecular interactions, can affect the activity of RPTPs. The cytoplasmic domains of different RPTPs can interact[45][46] to yield heterodimers of RPTP proteins, which then influence catalytic activity (for example, see [47]).
The regulation of PTPmu catalytic activity is complex. Like most RPTPs, the membrane proximal (or D1) phosphatase domain of PTPmu is catalytically active.[48] At high cell density, when PTPmu molecules bind to one another homophilically, phosphotyrosine levels are decreased.[49] This suggests that PTPmu may be catalytically active at high cell density. Substrates of PTPmu (proteins that are dephosphorylated by PTPmu), such as p120catenin, tend to be dephosphorylated at high cell density,[50] supporting the hypothesis that PTPmu is catalytically active when bound homophilically. PTPmu is constitutively dimerized due to its extracellular domain.[51]
Crystal structure analysis of the D1 of PTPmu demonstrated that PTPmu dimers are in an open active conformation.[40] Even though PTPmu dimers may be active, an additional study suggests that the extracellular domain of PTPmu reduces phosphatase activity. In this study, it was shown that the cytoplasmic domain of PTPmu (a PTPmu molecule lacking the extracellular domain) has greater phosphatase activity than the full-length protein in an enzymatic phosphatase assay.[52]
PTPmu has a long juxtamembrane domain, which likely influences catalytic activity. The juxtamembrane domain of PTPmu can bind to either the D1 and/or D2 of PTPmu, but only within the same PTPmu monomer.[53] Removal of the juxtamembrane domain from PTPmu has been suggested to reduce PTPmu phosphatase activity.[48] The D2 domain of PTPmu also regulates its activity. Although originally demonstrated to positively regulate phosphatase activity,[48] the D2 domain has been shown to negatively affect PTPmu catalytic activity.[54] A wedge-shaped motif located by D1 also regulates catalytic activity.[55] Use of a peptide with the same sequence as the wedge motif inhibits PTPmu mediated functions.[55][56][57][58]
Certain stimuli may also influence PTP activity. For example, alteration of cell oxidation induces conformational changes in the cytoplasmic domain of PTPmu, which may affect its tyrosine phosphatase activity or binding of extracellular ligands.[51]
# Cadherin-dependent adhesion
Classical cadherins are important proteins for cells to bind in the body (‘’in vivo’’) where they commonly stabilize cell–cell junctions known as adherens junctions. Cadherins stabilize adherens junctions through the interaction of the cadherin cytoplasmic domains with catenin proteins, such as p120-catenin, beta-catenin and alpha-catenin. Catenins, in turn, bind to the actin cytoskeleton. Binding of these proteins to the actin cytoskeleton prevents actin from growing (a process known as polymerization) and therefore keeps cells stationary. Cadherins regulate cell–cell adhesion during development of the body and in adult tissue. Disruption of cadherin proteins, by genetic alteration or by changes to the structure or function of the protein, has been linked to tumor progression. Notably, PTPmu regulates the adhesion of cells to the classical cadherins.[59] PTPmu likely regulates cadherin-dependent adhesion by interacting with both cadherins and catenins via PTPmu’s cytoplasmic domain. To support this assertion, PTPmu has been shown to interact with and/or dephosphorylate many signaling proteins involved in regulating the cadherin-catenin complex, including p120 catenin,[50] and E-cadherin (CDH1 (gene)) and N-cadherin (CDH2).[18][60] PTPmu has also been shown to interact with the c-Met hepatocyte growth factor receptor, a protein that is also localized to adherens junctions.[61] Although p120 catenin is a potential substrate of PTPmu,[50] others have suggested that the interaction between PTPmu and catenins is only indirect through E-cadherin.[62] α3β1 integrin and the tetraspanin CD151 regulate PTPmu gene expression to promote E-cadherin-mediated cell–cell adhesion.[63]
In addition to catenins and cadherins, PTPmu dephosphorylates PIPKIγ90 and nectin-3 (PVRL3) to stabilize E-cadherin-based adherens junctions.[64] PTPmu also dephosphorylates another cell junction protein, connexin 43. The interaction between connexin 43 and PTPmu increases gap junction communication.[65]
# Endothelial cell adhesion
PTPµ is expressed in human umbilical cord vein endothelial cells (HUVEC)[66] and in capillaries in the developing brain.[20] The expression of PTPµ in HUVEC cells increases at higher cell density.[66] Studies of PTPµ expression in animal tissues have demonstrated that PTPµ is preferentially expressed in endothelial cells of arteries and capillaries and in cardiac smooth muscle, in addition to brain cells.[21][22] Because of this specialized expression in arterial endothelial cells, and because PTPµ is found to associate with proteins involved in maintaining endothelial cell–cell junctions, such as VE-cadherin,[67] PTPµ is hypothesized to regulate endothelial cell junction formation or permeability. PTPµ has been shown to be involved in mechanotransduction that results from changes in blood flow to influence endothelial cell-mediated blood vessel dilation, a process induced by “shear stress.”[68] When PTPmu is missing in mice (PTPmu -/- knock-out mice), cannulated mesenteric arteries show reduced flow-induced (or “shear stress” induced) dilation.[68] PTPmu tyrosine phosphatase activity is activated by shear stress.[69] Caveolin 1 is a scaffolding protein enriched in endothelial cell junctions that is also linked to shear stress regulated responses.[69] Caveolin 1 is dephosphorylated on tyrosine 14 in response to shear stress and PTPmu is hypothesized to catalyze this reaction.[69]
# Cell migration
## Neurite outgrowth
PTPmu is expressed in the developing brain and retina.[23][24][25][26][27][70] A brain cell, or neuron, has a cell body that contains the nucleus and two types of extensions or processes that grow out from the cell body, the dendrites and axons. Dendrites generally receive input from other neurons, while axons send output to adjacent neurons. These processes are called neurites when grown ‘’in vitro’’ on tissue culture plates, because it is not clear whether they are dendrites or axons. ‘’In vitro’’ growth studies are useful for evaluating the mechanisms that neurons use to grow and function. A neurite outgrowth assay is a type of experiment where neurons are placed on different adhesive substrates on tissue culture plates. A neurite outgrowth assay is meant to mimic how neurons grow inside the body. During development of the nervous system, neuronal axons reach their often-distant targets by reacting to different substrates in their environment, so-called guidance cues, that are attractive, repulsive or simply permissive, meaning these substrates pull axons toward them, away from them, or act in a way that allows growth, respectively. When PTPmu is applied to a dish as an ‘’in vitro’’ substrate, it promotes neurite outgrowth.[23] PTPmu also acts as a guidance cue during development of the nervous system, by repelling neurites of the temporal neural retina, while permitting growth of neurites from the nasal neural retina.[24] Expression of PTPmu protein capable of dephosphorylating tyrosine residues is required for mediating both nasal neurite outgrowth and temporal neurite repulsion.[71] By blocking the expression of PTPmu protein with antisense technology, or by expressing catalytically inactive mutants of PTPmu (molecules of PTPmu that can not dephosphorylate their target proteins) in the developing retina, it was shown that PTPmu is required for the development of the neural retina.[25]
PTPmu also regulates neurite outgrowth on classical cadherins. PTPmu tyrosine phosphatase activity is necessary for neurite outgrowth on the classical cadherins E-, N- and R-cadherin,[23][56][57] suggesting that PTPmu dephosphorylates key components of the cadherin-catenin complex to regulate axonal migration. Again, this emphasizes that PTPmu likely regulates cadherin-dependent processes via its cytoplasmic domain.
Various signals required for PTPmu-mediated neurite outgrowth and repulsion have been identified. Some of these signals are proteins that interact with, or bind, to PTPmu, whereas, others may be dephosphorylated by PTPmu. PTPmu interacts with the scaffolding proteins RACK1/GNB2L1,[72] and IQGAP1.[73] IQGAP1 is a scaffold for Rho family of GTPases, E-cadherin, beta-catenin and other proteins. IQGAP1 binding to Rho GTPases is necessary for PTPmu-mediated neurite outgrowth.[73] The growing tip of the neuron, the growth cone, has a distinct appearance depending on what signals are activated inside the growth cone when it touches different substrates. The morphology of the growth cones on PTPmu and the repulsion of temporal neurites are both regulated by the Rho GTPase family member, Cdc42.[74][75] Inhibition of the Rho GTPase Rac1 permitted neurite outgrowth on PTPmu from neurons in the temporal retina.[75]
The proteins PLCγ1 (PLCG1), PKCδ (PRKCD) and BCCIP are PTPmu substrates.[76] PKCδ activity is required for PTPmu mediated neurite outgrowth[77] and PTPmu-mediated neurite repulsion.[78] Expression of BCCIP is necessary for PTPmu-mediated neurite outgrowth.[79] PTPmu is cleaved in certain brain cancers, which results in nuclear translocation of the cytoplasmic domain of PTPmu (see below). A possible function for the BCCIP-PTPmu interaction may be to shuttle the intracellular PTPmu fragment into the cell nucleus.
In summary, PTPmu dephosphorylates PKCδ, PLCγ1, and BCCIP, and binds to IQGAP1. The expression and/or activity of all these proteins and Cdc42 is necessary for PTPmu-mediated neurite outgrowth. Also, the activity of the GTPase Rac1 promotes PTPmu-mediated neurite repulsion.
## Cancer
PTPmu is downregulated in glioblastoma multiforme (GBM) cells and tissue compared to normal control tissue or cells.[80] The reduction in PTPmu expression in GBM cells has been linked to increased migration of GBM cells.[80][81]
[82][83] It was found that PTPmu expression is decreased in GBM cells by proteolysis of the full-length protein into a shed extracellular fragment[84] and a cytoplasmically released intracellular fragment that is capable of translocating into the nucleus.[58] Cleavage of PTPmu is similar to that identified for the Notch signaling pathway. PTPmu is first cleaved to yield two non-covalently associated fragments,[31][49] likely via a furin-like endo-peptidase in the endoplasmic reticulum (ER), as has been demonstrated for another RPTP, LAR (or PTPRF).[85][86] Then PTPmu is likely cleaved by an A disintegrin and metalloproteinase (ADAM) protease in the extracellular domain of PTPmu to release the shed extracellular fragment, then by the gamma secretase complex in the transmembrane domain to release the PTPmu intracellular fragment (reviewed in [16] and [17] Cleavage of PTPmu would likely impact the signaling partners that PTPmu would have access to, as has been proposed. (Phillips-Mason, Craig and Brady-Kalnay, 2011). PLCγ1 is a PTPmu substrate.[76] PLCγ1 activity is necessary for mediating GBM cell migration in the absence of PTPmu,[76] thus it seems likely that PTPmu dephosphorylation of PLCγ1 prevents PLCγ1-mediated migration. Cleavage of cell adhesion molecules, like PTPmu, has also been linked to the deregulation of contact inhibition of growth observed in cancer cells.[16] Visualization of the shed extracellular fragment of PTPmu has been proposed to be an effective means of delineating the borders of a GBM tumor ‘’in vivo.’’[84] Fluorescently tagged PTPmu peptides that bind homophilically to the shed PTPmu extracellular domains are capable of crossing the blood–brain barrier and identifying tumor margins in rodent models of GBM.[84]
# Interactions
PTPRM has been shown to interact with:
- BCCIP,[79]
- c-Met,[61]
- CDH1 E-cadherin (Cadherin-1),[18][60]
- CDH2 N-cadherin (Cadherin-2),[18][60]
- CDH4 R-cadherin (cadherin-4),[60]
- CDH5 VE-cadherin (cadherin 5, CDH5),[67]
- CTNND1 (p120catenin),[50]
- GNB2L1/RACK1,[72]
- GJA1 connexin43 (gap junction protein, alpha 1),[65]
- IQGAP1,[73]
- PVRL3 (nectin3),[64]
- PIPKIγ90,[64]
- PRKCD (PKCδ),[76] and
- PLCG1 (PLCγ1).[76] | https://www.wikidoc.org/index.php/PTPRM | |
cd80595edba74fba6674378ee73dc25bc04b7861 | wikidoc | PTPRS | PTPRS
Receptor-type tyrosine-protein phosphatase S, also known as R-PTP-S, R-PTP-sigma, or PTPσ, is an enzyme that in humans is encoded by the PTPRS gene.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this protein is composed of multiple Ig-like and fibronectin type III-like domains. Studies of the similar gene in mice suggested that this PTP may be involved in cell-cell interaction, primary axonogenesis, and axon guidance during embryogenesis. This PTP has been also implicated in the molecular control of adult nerve repair. Four alternatively spliced transcript variants, which encode distinct proteins, have been reported.
# Clinical significance
A PTPRS protein mimetic may improve muscular and bladder control in rats with spinal cord injuries.
# Interactions
PTPRS has been shown to interact with:
- chondroitin sulphate proteoglycans,
- PTPRD, glial-derived and
- liprin-alpha-1. | PTPRS
Receptor-type tyrosine-protein phosphatase S, also known as R-PTP-S, R-PTP-sigma, or PTPσ, is an enzyme that in humans is encoded by the PTPRS gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this protein is composed of multiple Ig-like and fibronectin type III-like domains. Studies of the similar gene in mice suggested that this PTP may be involved in cell-cell interaction, primary axonogenesis, and axon guidance during embryogenesis. This PTP has been also implicated in the molecular control of adult nerve repair. Four alternatively spliced transcript variants, which encode distinct proteins, have been reported.[3]
# Clinical significance
A PTPRS protein mimetic may improve muscular and bladder control in rats with spinal cord injuries.[4][5]
# Interactions
PTPRS has been shown to interact with:
- chondroitin sulphate proteoglycans,[4]
- PTPRD,[6] glial-derived and
- liprin-alpha-1.[2][7] | https://www.wikidoc.org/index.php/PTPRS | |
b87c06cfc22bcac866a627f4c41acab4b5e84a91 | wikidoc | PTPRT | PTPRT
Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.
PTPRT is also known as PTPrho, PTPρ and human accelerated region 9. The human accelerated regions are 49 regions of the human genome that are conserved among vertebrates, but in humans show significant distinction from other vertebrates. This region may, therefore, have played a key role in differentiating humans from apes.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer.
# Structure
This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats. PTPrho is a member of the type R2B subfamily of RPTPs, which also includes the RPTPs PTPmu (PTPRM), PTPkappa (PTPRK), and PCP-2 (PTPRU). Comparison of R2B cDNA sequences identified that PTPmu is most closely related to PTPrho. PTPrho is alternatively spliced. Alternative splicing of exons 14, 16, and 22a have been described for PTPrho (PTPRT). Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. The first isoform encodes the larger version of the protein. The second variant lacks a region of the extracellular domain between the fourth FNIII domain and the transmembrane domain and in the juxtamembrane domain.
# Homophilic binding
PTPrho protein mediates homophilic cell-cell adhesion, meaning that when it interacts with a like molecule on an adjacent cell it induces the cells to bind or adhere to one another. PTPrho does not bind to other subfamily members to mediate cell-cell aggregation, similar to other type R2B subfamily members.
The MAM domain, Ig domain and all four fibronectin III domain of PTPrho are necessary for cell-cell aggregation. PTPrho is the most frequently mutated RPTP in colon, lung, skin and stomach cancers. Many of the mutations observed in cancer occur in the extracellular domain of PTPrho, suggesting that defective cell-cell aggregation may contribute to the tumorigenicity of these mutations. When PTPrho proteins are engineered with the different point mutations observed in cancer and then are expressed in non-adherent Sf9 cells, these cells do not mediate comparable levels of cell-cell aggregation to wild-type PTPrho, demonstrating that the mutations observed in cancer are loss of function mutations.
# Tyrosine phosphatase activity
The first catalytic domain of Type R2B RPTPs is considered the active phosphatase domain, whereas the second phosphatase domain is thought to be inactive. Mutations in the second phosphatase domain of PTPrho, however, result in a reduction of phosphatase activity of PTPrho. Deletion of the second tyrosine phosphatase domain in colorectal cancer cells also reduces PTPrho catalytic activity, again demonstrating that the second phosphatase domain of PTPrho does regulate catalytic activity, either directly or indirectly.
Catalytic activity of PTPrho may also be regulated by tyrosine phosphorylation of the wedge domain of the first tyrosine phosphatase domain on tyrosine 912 by Fyn tyrosine kinase. Tyrosine phosphorylation of Y912 results in increased multimerization of PTPrho, likely in cis, with other PTPrho molecules. Based on crystal structure analysis and modeling, the phosphorylated wedge domain is hypothesized to insert into the catalytic domain of a neighboring PTPrho molecule, thus inactivating it. This mechanism has also been proposed to regulate the catalytic activity of RPTPalpha. The crystal structures of PTPmu and LAR suggest a different mechanism for the regulation of their catalytic activity, as these RPTPs are in an open and active conformation when dimerized.
# Regulation of gene expression
Evaluation of the 5’untranslated regions of PTPrho (PTPRT) cDNA indicate a number of transcription factor binding site consensus sequences, including those for AP-2, c-Myb, NF-1, sox-5, and Sp-1, Oct-1, CdxA, C/EBP, En-1, GATA-1, GATA-2, GKLF, HoxA3, Ik-2, Msx-1, Pax-4 and SRY.
(RE1-silencing transcription factor) (REST) is a transcription repressor that binds to REST DNA recognition element (RE-1) in 5’UTRs. A screen of single nucleotide polymorphic genetic changes within the REST binding regions of DNA sequences revealed a polymorphism in the RE-1 of PTPrho (PTPRT). This SNP would result in less REST repressor activity, which could lead to increased expression of PTPrho (PTPRT) in cells that harbored this SNP.
# Expression and function in cancer
PTPrho is the most frequently mutated RPTP in colon, lung, skin and stomach cancers. Evaluation of the cytoplasmic mutations observed in PTPrho in cancer demonstrate that they all reduce catalytic activity, even the mutations located in the second catalytic domain. The frequency of mutations in the cytoplasmic tyrosine phosphatase domain of PTPrho in cancer has been disputed. The PTPrho (PTPRT) promoter was observed to be hypermethylated in colorectal cancer compared to controls, suggesting another mechanism whereby PTPrho function may be reduced in cancer, in this instance by epigenetic silencing.
PTPrho is also upregulated in estrogen receptor alpha positive breast tumor samples versus estrogen receptor alpha negative tumor samples. The authors evaluated 560 selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in estrogen receptor alpha positive tissue and compared it to estrogen receptor alpha negative tissue, and found that PTPrho(PTPRT) was upregulated in the estrogen receptor alpha tissue, suggesting a non-tumor suppressor role for PTPrho.
# Expression and function in the developing nervous system
PTPrho (PTPRT) mRNA is expressed in the developing nervous system. Its expression is first observed in stage 25 in Xenopus embryos in the developing optic vesicles and in nascent motor and interneurons of the spinal cord. At stage 35/36, PTPrho (PTPRT) expression is found in the outer nuclear, or photoreceptor, layer, and in the inner nuclear layer (INL) of the neural retina. The level of PTPrho (PTPRT) transcript decreases in the photoreceptors and increases in the INL, and by stage 41, is restricted to the INL only. PTPrho (PTPRT) transcripts have also been observed in the developing cortex and olfactory bulbs.
PTPrho (PTPRT) is expressed in a very specific subset of neurons in the postnatal cerebellar cortex, the granule cell layer. Specifically, PTPrho (PTPRT) was expressed in postmigratory granule cells of lobules 1 to 6 of the cerebellum.
In adults, PTPrho protein is exclusively expressed in the central nervous system and localizes to synapses between neurons. Over-expression of wild-type and catalytically inactive mutant forms of PTPrho result in an increase in the number of excitatory and inhibitory synapses in cultured neurons in vitro. Knock-down of PTPrho expression decreases the number of synapses in cultured neurons. PTPrho interacts in cis with the extracellular domains of neuroligins and neurexins at synapses. PTPrho is phosphorylated on tyrosine 912 in the wedge region of its first catalytic domain by Fyn tyrosine kinase. Phosphorylation at this site attenuates synapse formation in cultured neurons. When PTPrho is phosphorylated by Fyn, PTPrho appears to form homophilic multimerizations, likely in cis, which appear to decrease PTPrho association with neuroligins and neurexins. The reduction of cis interactions with neuroligins and neurexons is hypothesized to ultimately lead to the reduction in synapse formation.
PTPrho activity has also been demonstrated to be required for the development of neuronal dendrites. It was found to regulate dendritic arborization by dephosphorylating tyrosine 177 of Breakpoint cluster region protein (BCR).
# Substrates
PTPrho associates with members of the cadherin and catenin family of cell adhesion molecules as demonstrated by GST-fusion protein pull-down assays using brain homogenate. Using this technique, the authors identified that PTPrho interacts with alpha-actinin, alpha-catenin, beta-catenin, gamma-catenin/plakoglobin, p120 catenin, desmoglein, E-cadherin, N-cadherin, and VE-cadherin. Purified wild-type PTPrho GST fusion protein was able to dephosphorylate E-cadherin and p120catenin co-immunoprecipitated from a pancreatic beta cell line, MIN6-m9. This suggests that these proteins are PTPrho substrates.
PTPrho also dephosphorylates BCR protein. The ability of PTPrho to dephosphorylate BCR was shown to have functional consequences for the normal development of neuronal dendritic arborization.
PTPrho dephosphorylates STAT3, signal transducer and activator of transcription 3, on tyrosine 705, a residue that is critical for the activation of STAT3. Dephosphorylation by PTPrho in colorectal cancer cells results in a reduction in the total level of transcription of the STAT3 target genes, Bcl-XL and SOCS3. Likewise, expression of wild-type PTPrho decreases the ability of STAT3 to translocate to the nucleus, where it needs to localize to function as a transcription factor.
PTPrho also dephosphorylates paxillin on tyrosine 88. Higher levels of tyrosine 88 phosphorylation of paxillin are observed in colon cancers. When colon cancer cells are engineered to express a mutant form of paxillin that is incapable of being tyrosine phosphorylated, the paxillin Y88F mutant, these cells exhibit reduced tumorigenicity. This suggests that PTPrho may function as a tumor suppressor protein by regulating paxillin phosphorylation.
# Interacting proteins
PTPrho has been shown to interact with:
- alpha-actinin
- Alpha catenin
- Beta-catenin
- Breakpoint cluster region protein (BCR)
- Desmoglein
- E-cadherin
- Fyn
- N-cadherin
- gamma-catenin
- p120-catenin
- Paxillin
- Neuroligin
- Neurexin
- STAT3
- VE-cadherin/Cadherin-5 | PTPRT
Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene.[1][2][3]
PTPRT is also known as PTPrho, PTPρ and human accelerated region 9. The human accelerated regions are 49 regions of the human genome that are conserved among vertebrates, but in humans show significant distinction from other vertebrates. This region may, therefore, have played a key role in differentiating humans from apes.[4]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer.
# Structure
This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats. PTPrho is a member of the type R2B subfamily of RPTPs, which also includes the RPTPs PTPmu (PTPRM), PTPkappa (PTPRK), and PCP-2 (PTPRU). Comparison of R2B cDNA sequences identified that PTPmu is most closely related to PTPrho.[5] PTPrho is alternatively spliced.[5][6] Alternative splicing of exons 14, 16, and 22a have been described for PTPrho (PTPRT).[6] Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported.[3] The first isoform encodes the larger version of the protein. The second variant lacks a region of the extracellular domain between the fourth FNIII domain and the transmembrane domain and in the juxtamembrane domain.[3]
# Homophilic binding
PTPrho protein mediates homophilic cell-cell adhesion, meaning that when it interacts with a like molecule on an adjacent cell it induces the cells to bind or adhere to one another.[7] PTPrho does not bind to other subfamily members to mediate cell-cell aggregation, similar to other type R2B subfamily members.[7][8]
The MAM domain, Ig domain and all four fibronectin III domain of PTPrho are necessary for cell-cell aggregation.[7][8] PTPrho is the most frequently mutated RPTP in colon, lung, skin and stomach cancers.[9] Many of the mutations observed in cancer occur in the extracellular domain of PTPrho, suggesting that defective cell-cell aggregation may contribute to the tumorigenicity of these mutations.[9] When PTPrho proteins are engineered with the different point mutations observed in cancer and then are expressed in non-adherent Sf9 cells, these cells do not mediate comparable levels of cell-cell aggregation to wild-type PTPrho, demonstrating that the mutations observed in cancer are loss of function mutations.[7][8]
# Tyrosine phosphatase activity
The first catalytic domain of Type R2B RPTPs is considered the active phosphatase domain, whereas the second phosphatase domain is thought to be inactive.[10] Mutations in the second phosphatase domain of PTPrho, however, result in a reduction of phosphatase activity of PTPrho.[9] Deletion of the second tyrosine phosphatase domain in colorectal cancer cells also reduces PTPrho catalytic activity, again demonstrating that the second phosphatase domain of PTPrho does regulate catalytic activity, either directly or indirectly.[11]
Catalytic activity of PTPrho may also be regulated by tyrosine phosphorylation of the wedge domain of the first tyrosine phosphatase domain on tyrosine 912 by Fyn tyrosine kinase.[12] Tyrosine phosphorylation of Y912 results in increased multimerization of PTPrho, likely in cis, with other PTPrho molecules. Based on crystal structure analysis and modeling, the phosphorylated wedge domain is hypothesized to insert into the catalytic domain of a neighboring PTPrho molecule, thus inactivating it.[12] This mechanism has also been proposed to regulate the catalytic activity of RPTPalpha.[13] The crystal structures of PTPmu and LAR suggest a different mechanism for the regulation of their catalytic activity, as these RPTPs are in an open and active conformation when dimerized.[14]
# Regulation of gene expression
Evaluation of the 5’untranslated regions of PTPrho (PTPRT) cDNA indicate a number of transcription factor binding site consensus sequences, including those for AP-2, c-Myb, NF-1, sox-5, and Sp-1, Oct-1, CdxA, C/EBP, En-1, GATA-1, GATA-2, GKLF, HoxA3, Ik-2, Msx-1, Pax-4 and SRY.[5]
(RE1-silencing transcription factor) (REST) is a transcription repressor that binds to REST DNA recognition element (RE-1) in 5’UTRs. A screen of single nucleotide polymorphic genetic changes within the REST binding regions of DNA sequences revealed a polymorphism in the RE-1 of PTPrho (PTPRT). This SNP would result in less REST repressor activity, which could lead to increased expression of PTPrho (PTPRT) in cells that harbored this SNP.[15]
# Expression and function in cancer
PTPrho is the most frequently mutated RPTP in colon, lung, skin and stomach cancers.[9] Evaluation of the cytoplasmic mutations observed in PTPrho in cancer demonstrate that they all reduce catalytic activity, even the mutations located in the second catalytic domain.[9] The frequency of mutations in the cytoplasmic tyrosine phosphatase domain of PTPrho in cancer has been disputed.[16] The PTPrho (PTPRT) promoter was observed to be hypermethylated in colorectal cancer compared to controls, suggesting another mechanism whereby PTPrho function may be reduced in cancer, in this instance by epigenetic silencing.[17]
PTPrho is also upregulated in estrogen receptor alpha positive breast tumor samples versus estrogen receptor alpha negative tumor samples.[18] The authors evaluated 560 selected genes by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in estrogen receptor alpha positive tissue and compared it to estrogen receptor alpha negative tissue, and found that PTPrho(PTPRT) was upregulated in the estrogen receptor alpha tissue, suggesting a non-tumor suppressor role for PTPrho.[18]
# Expression and function in the developing nervous system
PTPrho (PTPRT) mRNA is expressed in the developing nervous system.[1][2][19] Its expression is first observed in stage 25 in Xenopus embryos in the developing optic vesicles and in nascent motor and interneurons of the spinal cord.[19] At stage 35/36, PTPrho (PTPRT) expression is found in the outer nuclear, or photoreceptor, layer, and in the inner nuclear layer (INL) of the neural retina. The level of PTPrho (PTPRT) transcript decreases in the photoreceptors and increases in the INL, and by stage 41, is restricted to the INL only.[19] PTPrho (PTPRT) transcripts have also been observed in the developing cortex and olfactory bulbs.[2]
PTPrho (PTPRT) is expressed in a very specific subset of neurons in the postnatal cerebellar cortex, the granule cell layer. Specifically, PTPrho (PTPRT) was expressed in postmigratory granule cells of lobules 1 to 6 of the cerebellum.[1]
In adults, PTPrho protein is exclusively expressed in the central nervous system and localizes to synapses between neurons.[12] Over-expression of wild-type and catalytically inactive mutant forms of PTPrho result in an increase in the number of excitatory and inhibitory synapses in cultured neurons in vitro. Knock-down of PTPrho expression decreases the number of synapses in cultured neurons. PTPrho interacts in cis with the extracellular domains of neuroligins and neurexins at synapses.[12] PTPrho is phosphorylated on tyrosine 912 in the wedge region of its first catalytic domain by Fyn tyrosine kinase. Phosphorylation at this site attenuates synapse formation in cultured neurons. When PTPrho is phosphorylated by Fyn, PTPrho appears to form homophilic multimerizations, likely in cis, which appear to decrease PTPrho association with neuroligins and neurexins. The reduction of cis interactions with neuroligins and neurexons is hypothesized to ultimately lead to the reduction in synapse formation.[12]
PTPrho activity has also been demonstrated to be required for the development of neuronal dendrites. It was found to regulate dendritic arborization by dephosphorylating tyrosine 177 of Breakpoint cluster region protein (BCR).[20]
# Substrates
PTPrho associates with members of the cadherin and catenin family of cell adhesion molecules as demonstrated by GST-fusion protein pull-down assays using brain homogenate. Using this technique, the authors identified that PTPrho interacts with alpha-actinin, alpha-catenin, beta-catenin, gamma-catenin/plakoglobin, p120 catenin, desmoglein, E-cadherin, N-cadherin, and VE-cadherin.[21] Purified wild-type PTPrho GST fusion protein was able to dephosphorylate E-cadherin and p120catenin co-immunoprecipitated from a pancreatic beta cell line, MIN6-m9. This suggests that these proteins are PTPrho substrates.[21]
PTPrho also dephosphorylates BCR protein.[20] The ability of PTPrho to dephosphorylate BCR was shown to have functional consequences for the normal development of neuronal dendritic arborization.
PTPrho dephosphorylates STAT3, signal transducer and activator of transcription 3, on tyrosine 705, a residue that is critical for the activation of STAT3.[11] Dephosphorylation by PTPrho in colorectal cancer cells results in a reduction in the total level of transcription of the STAT3 target genes, Bcl-XL and SOCS3. Likewise, expression of wild-type PTPrho decreases the ability of STAT3 to translocate to the nucleus, where it needs to localize to function as a transcription factor.[11]
PTPrho also dephosphorylates paxillin on tyrosine 88.[22] Higher levels of tyrosine 88 phosphorylation of paxillin are observed in colon cancers. When colon cancer cells are engineered to express a mutant form of paxillin that is incapable of being tyrosine phosphorylated, the paxillin Y88F mutant, these cells exhibit reduced tumorigenicity. This suggests that PTPrho may function as a tumor suppressor protein by regulating paxillin phosphorylation.[22]
# Interacting proteins
PTPrho has been shown to interact with:
- alpha-actinin[21]
- Alpha catenin[21]
- Beta-catenin[21]
- Breakpoint cluster region protein (BCR)[20]
- Desmoglein[21]
- E-cadherin[21]
- Fyn[12]
- N-cadherin[21]
- gamma-catenin[21]
- p120-catenin[21]
- Paxillin[22]
- Neuroligin[12]
- Neurexin[12]
- STAT3[11]
- VE-cadherin/Cadherin-5 [21] | https://www.wikidoc.org/index.php/PTPRT | |
58333a4209a2a7e3bdc628facc8c8a124fbafd5d | wikidoc | PTPRU | PTPRU
Receptor-type tyrosine-protein phosphatase PCP-2 (also known as PTP-pi, PTP lambda, hPTP-J, PTPRO and PTP psi), is an enzyme that in humans is encoded by the PTPRU gene.
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic tyrosine phosphatase domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats, and thus is a member of the type R2B RPTP family. It was cloned by many groups and given different names, including PCP-2, PTP pi, PTP lambda, hPTP-J, PTPRO, and PTP psi. Other type R2B RPTPs include PTPRM, PTPRK, and PTPRT. Analysis of the genomic structure of PCP-2 suggests that it is the most distantly related of the type R2B RPTPS.
RPTPs are able to remove phosphate moieties from tyrosine residues. Although the R2B family of RPTPs are characterized as having two tyrosine phosphatase domains in their intracellular domain, usually only one is catalytically active. A point mutation study suggests that only the first phosphatase domain of PCP-2 is catalytically active and able to dephosphorylate β-catenin. A recombinant protein with both PCP-2 phosphatase domains was also able to dephosphorylate EGFR. However, when each of the two intracellular catalytic tyrosine phosphatase domains are expressed individually as recombinant proteins and assayed in vitro using the artificial substrate ρ-nitrophenol phosphate (pNPP), both the first and second intracellular tyrosine phosphatase domain were able to dephosphorylate pNPP.
# Regulation
PCP-2 mRNA is regulated by phorbol myristate acetate (PMA) or calcium ionophore, okadaic acid, the Ras inhibitor manumycin, and orthovanadate in Jurkat T lymphoma cells.
# Alternative splicing
Four alternatively spliced transcript variants, which encode distinct proteins, have been reported.
Examination of mouse full-length cDNA sequences for alternatively spliced phosphatase genes identified two novel forms of PTPRU predicted to result in two PCP-2 splice variants: a tethered variant of PCP-2, expressing an intact extracellular and transmembrane domain, and a PCP-2 variant that lacked a signal peptide, but encoded intact transmembrane and cytoplasmic domains.
# Homophilic binding
The MAM, Ig and first fibronectin III domain of PCP-2 was shown to mediate bead aggregation in vitro. PCP-2 accomplishes this by binding to another PCP-2 molecule on a fluorescent bead, known as homophilic binding. PCP-2 was unable to mediate aggregation between non-adherent cells when expressed as a full-length protein, however, suggesting that PCP-2 does not mediate homophilic adhesion in cells. The MAM and Ig domains of PCP-2 are capable of mediating weak cell-cell adhesion when swapped into the wild-type PTPrho protein, demonstrating that the MAM and Ig domain can mediate weak cell adhesion, but that they require other functional domains within PTPrho to mediate cell-cell adhesion. The Ig domain of the R2B RPTP, PTPmu, is sufficient to mediate bead aggregation in vitro, therefore, it is possible that the PCP-2 constructs used by Cheng and colleagues were able to mediate bead aggregation due to a functional Ig domain in PCP-2. A functional Ig domain itself would not be sufficient to mediate cell-cell adhesion, however. Similar to other subfamily members, PCP-2 does not mediate heterophilic binding between different R2B RPTPs.
# Regulation of cadherin-dependent adhesion
PCP-2 was localized to cell-cell contact sites using immunohistochemistry, and shown to co-localize with E-cadherin and catenins. PCP-2 was shown to be associated with B-catenin (β-catenin) in cellular lysates.
and to directly bind to β-catenin likely via a sequence in the juxtamembrane domain of PCP-2. β-catenin has since been shown to be a substrate of PCP-2. PCP-2 phosphatase activity antagonizes β-catenin mediated transcription. A consequence of PCP-2 dephosphorylation of β-catenin is to promote E-cadherin mediated cell-cell adhesion, reduce cellular migration, and to reduce cell growth and transformation.
# Role in development
## Tissue distribution
PCP-2 is expressed in the developing mouse nervous system. In specific, it is expressed in the roof plate and floor plate of the developing spinal cord between embryonic days (E) 10.5 and 13.5. At the same developmental time, it is expressed in the ventricular zone in the telecephalon and hindbrain. PCP-2 was also detected in the developing inner nuclear layer of the retina, in the olfactory epithelium of the nasal cavities, and in the meningeal coverings of the brain. In the developing chick nervous system, PCP-2 mRNA is expressed in the ventral midline of the neural tube and in the border between the midbrain and hindbrain, known as the mid-hindbrain boundary. PCP-2 mRNA is also observed in the ventricular zone of the developing chick neural retina.
PCP-2 is expressed in non-neural tissues during development, including the first forming somite in chick, known as S2, the lens fiber cells of the eye, in the esophagus, scleretome, kidneys, lungs, enamel organs (early incisor and molar teeth), and the cochlear ducts of the inner ear. PCP-2 expression in most of these tissue changes over the course of development.
PCP-2 is expressed in meso-diencephalic dopamine (mdDA) neurons
. Its expression here is regulated by the coordinated activity of the orphan nuclear receptor Nurr1 binding to the PCP-2 promoter along with the homeobox transcription factor Pitx3. Both Nurr1 and Pitx3 are required for the development of mdDA neurons in the brain. This suggests that PCP-2 is also an important downstream gene for the development of mdDA neurons.
## Function
Using morpholinos to reduce PCP-2 (PTP psi) protein expression in zebrafish embryos, Aerne and Ish-Horowicz demonstrated that PCP-2 was required for somite, or body segment, formation during zebrafish development. Reduction of PCP-2 expression resulted in the loss of boundaries between somites, shortening of the body axis, and disruption of anteroposterior polarity within developing somites. Ultimately, PCP-2 was shown to reduce the expression of the somitogenesis clock genes her1, her7 and delta C, suggesting to the authors that PCP-2 is involved either upstream or in parallel with the Notch-delta signaling pathway during zebrafish development.
PCP-2 is expressed in megakaryocytic cell lines. PCP-2 protein expression in these cell lines is increased by PMA stimulation. PCP-2 and the c-Kit tyrosine kinase receptor interact constitutively in these cells, and PCP-2 was shown to be tyrosine phosphorylated upon stimulation with the c-Kit ligand, SCF. Antisense oligonucleotide treatment of megakaryocyte cells to reduce PCP-2 protein expression resulted in a significant reduction in megakaryocyte progenitor proliferation.
# Role in cancer
PCP-2 is predicted to be a tumor suppressor gene because of its reduced expression in melanoma tissue and cell lines.
# Interactions
PCP-2 interacts with the following proteins:
- β-catenin
- Adaptor protein-3 (AP3; AP3B1, AP3B2, AP3D1, AP3M1, AP3S1, AP3S2)
- Sorting nexin 3 (SNX3)
- C-Kit receptor | PTPRU
Receptor-type tyrosine-protein phosphatase PCP-2 (also known as PTP-pi, PTP lambda, hPTP-J, PTPRO and PTP psi), is an enzyme that in humans is encoded by the PTPRU gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic tyrosine phosphatase domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats, and thus is a member of the type R2B RPTP family. It was cloned by many groups and given different names, including PCP-2,[1] PTP pi,[4] PTP lambda,[5] hPTP-J,[6] PTPRO,[2] and PTP psi.[7] Other type R2B RPTPs include PTPRM, PTPRK, and PTPRT. Analysis of the genomic structure of PCP-2 suggests that it is the most distantly related of the type R2B RPTPS.[8]
RPTPs are able to remove phosphate moieties from tyrosine residues. Although the R2B family of RPTPs are characterized as having two tyrosine phosphatase domains in their intracellular domain, usually only one is catalytically active.[9][10] A point mutation study suggests that only the first phosphatase domain of PCP-2 is catalytically active and able to dephosphorylate β-catenin.[11] A recombinant protein with both PCP-2 phosphatase domains was also able to dephosphorylate EGFR.[4] However, when each of the two intracellular catalytic tyrosine phosphatase domains are expressed individually as recombinant proteins and assayed in vitro using the artificial substrate ρ-nitrophenol phosphate (pNPP), both the first and second intracellular tyrosine phosphatase domain were able to dephosphorylate pNPP.[4]
# Regulation
PCP-2 mRNA is regulated by phorbol myristate acetate (PMA) or calcium ionophore, okadaic acid, the Ras inhibitor manumycin, and orthovanadate in Jurkat T lymphoma cells.[6][12]
# Alternative splicing
Four alternatively spliced transcript variants, which encode distinct proteins, have been reported.[3]
Examination of mouse full-length cDNA sequences for alternatively spliced phosphatase genes identified two novel forms of PTPRU predicted to result in two PCP-2 splice variants: a tethered variant of PCP-2, expressing an intact extracellular and transmembrane domain, and a PCP-2 variant that lacked a signal peptide, but encoded intact transmembrane and cytoplasmic domains.[13]
# Homophilic binding
The MAM, Ig and first fibronectin III domain of PCP-2 was shown to mediate bead aggregation in vitro.[5] PCP-2 accomplishes this by binding to another PCP-2 molecule on a fluorescent bead, known as homophilic binding. PCP-2 was unable to mediate aggregation between non-adherent cells when expressed as a full-length protein, however, suggesting that PCP-2 does not mediate homophilic adhesion in cells.[14] The MAM and Ig domains of PCP-2 are capable of mediating weak cell-cell adhesion when swapped into the wild-type PTPrho protein, demonstrating that the MAM and Ig domain can mediate weak cell adhesion, but that they require other functional domains within PTPrho to mediate cell-cell adhesion.[14] The Ig domain of the R2B RPTP, PTPmu, is sufficient to mediate bead aggregation in vitro,[15] therefore, it is possible that the PCP-2 constructs used by Cheng and colleagues were able to mediate bead aggregation due to a functional Ig domain in PCP-2.[14] A functional Ig domain itself would not be sufficient to mediate cell-cell adhesion, however. Similar to other subfamily members, PCP-2 does not mediate heterophilic binding between different R2B RPTPs.[14]
# Regulation of cadherin-dependent adhesion
PCP-2 was localized to cell-cell contact sites using immunohistochemistry, and shown to co-localize with E-cadherin and catenins.[6] PCP-2 was shown to be associated with B-catenin (β-catenin) in cellular lysates.[5][6]
and to directly bind to β-catenin likely via a sequence in the juxtamembrane domain of PCP-2.[11][16] β-catenin has since been shown to be a substrate of PCP-2.[11] PCP-2 phosphatase activity antagonizes β-catenin mediated transcription.[17] A consequence of PCP-2 dephosphorylation of β-catenin is to promote E-cadherin mediated cell-cell adhesion, reduce cellular migration,[11] and to reduce cell growth and transformation.[17]
# Role in development
## Tissue distribution
PCP-2 is expressed in the developing mouse nervous system. In specific, it is expressed in the roof plate and floor plate of the developing spinal cord between embryonic days (E) 10.5 and 13.5.[18] At the same developmental time, it is expressed in the ventricular zone in the telecephalon and hindbrain.[18][19] PCP-2 was also detected in the developing inner nuclear layer of the retina, in the olfactory epithelium of the nasal cavities, and in the meningeal coverings of the brain.[19] In the developing chick nervous system, PCP-2 mRNA is expressed in the ventral midline of the neural tube and in the border between the midbrain and hindbrain, known as the mid-hindbrain boundary.[7][20] PCP-2 mRNA is also observed in the ventricular zone of the developing chick neural retina.[20]
PCP-2 is expressed in non-neural tissues during development, including the first forming somite in chick, known as S2,[7] the lens fiber cells of the eye, in the esophagus, scleretome, kidneys, lungs, enamel organs (early incisor and molar teeth), and the cochlear ducts of the inner ear.[18][19] PCP-2 expression in most of these tissue changes over the course of development.[19]
PCP-2 is expressed in meso-diencephalic dopamine (mdDA) neurons[21]
. Its expression here is regulated by the coordinated activity of the orphan nuclear receptor Nurr1 binding to the PCP-2 promoter along with the homeobox transcription factor Pitx3.[21] Both Nurr1 and Pitx3 are required for the development of mdDA neurons in the brain. This suggests that PCP-2 is also an important downstream gene for the development of mdDA neurons.[21]
## Function
Using morpholinos to reduce PCP-2 (PTP psi) protein expression in zebrafish embryos, Aerne and Ish-Horowicz demonstrated that PCP-2 was required for somite, or body segment, formation during zebrafish development.[22] Reduction of PCP-2 expression resulted in the loss of boundaries between somites, shortening of the body axis, and disruption of anteroposterior polarity within developing somites. Ultimately, PCP-2 was shown to reduce the expression of the somitogenesis clock genes her1, her7 and delta C, suggesting to the authors that PCP-2 is involved either upstream or in parallel with the Notch-delta signaling pathway during zebrafish development.[22]
PCP-2 is expressed in megakaryocytic cell lines.[23] PCP-2 protein expression in these cell lines is increased by PMA stimulation.[23] PCP-2 and the c-Kit tyrosine kinase receptor interact constitutively in these cells, and PCP-2 was shown to be tyrosine phosphorylated upon stimulation with the c-Kit ligand, SCF.[23] Antisense oligonucleotide treatment of megakaryocyte cells to reduce PCP-2 protein expression resulted in a significant reduction in megakaryocyte progenitor proliferation.[23]
# Role in cancer
PCP-2 is predicted to be a tumor suppressor gene because of its reduced expression in melanoma tissue and cell lines.[24]
# Interactions
PCP-2 interacts with the following proteins:
- β-catenin[6][11][16]
- Adaptor protein-3 (AP3; AP3B1, AP3B2, AP3D1, AP3M1, AP3S1, AP3S2)[25]
- Sorting nexin 3 (SNX3)[25]
- C-Kit receptor[23] | https://www.wikidoc.org/index.php/PTPRU | |
4c5fd65f046dcff4955dd8256bf4b7b06d82c32d | wikidoc | PTTG1 | PTTG1
Securin is a protein that in humans is encoded by the PTTG1 gene.
# Function
The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus.
# Interactions
PTTG1 has been shown to interact with:
- DNAJA1,
- Ku70
- P53,
- PTTG1IP, and
- RPS10.
# Regulation
During Mitosis CDK1 phosphorylate PTTG1 at Ser-165.PTTG1 is down-regulated in melanoma cells in response to the cyclin-dependent kinase inhibitor PHA-848125. | PTTG1
Securin is a protein that in humans is encoded by the PTTG1 gene.[1][2][3]
# Function
The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus.[3]
# Interactions
PTTG1 has been shown to interact with:
- DNAJA1,[4]
- Ku70[5]
- P53,[6]
- PTTG1IP,[7] and
- RPS10.[4]
# Regulation
During Mitosis CDK1 phosphorylate PTTG1 at Ser-165.[8]PTTG1 is down-regulated in melanoma cells in response to the cyclin-dependent kinase inhibitor PHA-848125.[9] | https://www.wikidoc.org/index.php/PTTG1 | |
0ecd6c07417856fe8bb4e67382800f4300820496 | wikidoc | PUS7L | PUS7L
Pseudouridylate synthase 7 homolog-like protein is an enzyme that in humans is encoded by the PUS7L gene.
# Model organisms
Model organisms have been used in the study of PUS7L function. A conditional knockout mouse line, called Pus7ltm2a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on homozygous mutant mice and one significant abnormality was observed: an increased susceptibility to bacterial infection. | PUS7L
Pseudouridylate synthase 7 homolog-like protein is an enzyme that in humans is encoded by the PUS7L gene.[1][2]
# Model organisms
Model organisms have been used in the study of PUS7L function. A conditional knockout mouse line, called Pus7ltm2a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty three tests were carried out on homozygous mutant mice and one significant abnormality was observed: an increased susceptibility to bacterial infection.[5] | https://www.wikidoc.org/index.php/PUS7L | |
a141cb6fe6333423935f2682456e49ea109b3e99 | wikidoc | PYCR2 | PYCR2
Pyrroline-5-carboxylate reductase family, member 2 is a protein that in humans is encoded by the PYCR2 gene.
# Function
This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Loss of PYCR2 does not lead to a gross defect in mitochondrial protein synthesis, but loss of function of PYCR2 leads to increased apoptosis under oxidative stress.
# Clinical significance
Mutations in the PYCR2 gene have been identified as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Hypomyelination and the absence of wrinkly skin makes this condition distinct from that caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development. This is substantiated by the fact that PYCR2 mRNA is moderately expressed in the developing human brain, and in much higher forms than either of the other two isoforms. Although PYCR2 is an enzyme for proline biosynthesis, systemic deprivation of proline does not appear to be the pathogenetic mechanism of this condition, given that plasma amino acid analysis in two affected individuals did not show low proline levels. Furthermore, mitochondrial protein synthesis was not affected in PYCR2-deficient cells. Therefore, deficiency of proline, as a building block of proteins, might not be the major pathophysiology. However, proline has been reported as a non-enzymatic antioxidant that suppresses apoptosis, and therefore local proline biosynthesis in neurons might be important for neuronal protection against oxidative stress.
The PYCR family also has been correlated with melanoma cells. PYCR2 as well as PYCR are abundant in melanoma cells but not detected in melanocytes. | PYCR2
Pyrroline-5-carboxylate reductase family, member 2 is a protein that in humans is encoded by the PYCR2 gene.[1]
# Function
This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis.[1] Loss of PYCR2 does not lead to a gross defect in mitochondrial protein synthesis, but loss of function of PYCR2 leads to increased apoptosis under oxidative stress.[2]
# Clinical significance
Mutations in the PYCR2 gene have been identified as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Hypomyelination and the absence of wrinkly skin makes this condition distinct from that caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development. This is substantiated by the fact that PYCR2 mRNA is moderately expressed in the developing human brain, and in much higher forms than either of the other two isoforms. Although PYCR2 is an enzyme for proline biosynthesis, systemic deprivation of proline does not appear to be the pathogenetic mechanism of this condition, given that plasma amino acid analysis in two affected individuals did not show low proline levels. Furthermore, mitochondrial protein synthesis was not affected in PYCR2-deficient cells. Therefore, deficiency of proline, as a building block of proteins, might not be the major pathophysiology. However, proline has been reported as a non-enzymatic antioxidant that suppresses apoptosis, and therefore local proline biosynthesis in neurons might be important for neuronal protection against oxidative stress.[2]
The PYCR family also has been correlated with melanoma cells. PYCR2 as well as PYCR are abundant in melanoma cells but not detected in melanocytes.[3] | https://www.wikidoc.org/index.php/PYCR2 | |
84fcc4ff6b343e2b399f199868faddfa47d1675a | wikidoc | Taxus | Taxus
Taxus is a genus of yews, small coniferous trees or shrubs in the yew family Taxaceae. They are relatively slow growing and can be very long-lived, and reach heights of 1-40 m, with trunk diameters of up to 4 m. They have reddish bark, lanceolate, flat, dark-green leaves 1-4 cm long and 2-3 mm broad, arranged spirally on the stem, but with the leaf bases twisted to align the leaves in two flat rows either side of the stem.
The seed cones are highly modified, each cone containing a single seed 4-7 mm long partly surrounded by a modified scale which develops into a soft, bright red berry-like structure called an aril, 8-15 mm long and wide and open at the end. The arils are mature 6-9 months after pollination, and with the seed contained are eaten by thrushes, waxwings and other birds, which disperse the hard seeds undamaged in their droppings; maturation of the arils is spread over 2-3 months, increasing the chances of successful seed dispersal. The male cones are globose, 3-6 mm diameter, and shed their pollen in early spring. Yews are mostly dioecious, but occasional individuals can be variably monoecious, or change sex with time.
All of the yews are very closely related to each other, and some botanists treat them all as subspecies or varieties of just one widespread species; under this treatment, the species name used is Taxus baccata, the first yew described scientifically.
The most distinct is the Sumatran Yew (T. sumatrana, native from Sumatra and Celebes north to southernmost China), distinguished by its sparse, sickle-shaped yellow-green leaves. The Mexican Yew (T. globosa, native to eastern Mexico south to Honduras) is also relatively distinct with foliage intermediate between Sumatran Yew and the other species. The Florida Yew, Mexican Yew and Pacific Yew are all rare species listed as threatened or endangered.
All species of yew contain highly poisonous alkaloids known as taxanes, with some variation in the exact formula of the alkaloid between the species. All parts of the tree except the arils contain the alkaloid. The arils are edible and sweet, but the seed is dangerously poisonous; unlike birds, the human stomach can break down the seed coat and release the taxanes into the body. This can have fatal results if yew 'berries' are eaten without removing the seeds first. Grazing animals, particularly cattle and horses, are also sometimes found dead near yew trees after eating the leaves, though deer are able to break down the poisons and will eat yew foliage freely. In the wild, deer browsing of yews is often so extensive that wild yew trees are commonly restricted to cliffs and other steep slopes inaccessible to deer. The foliage is also eaten by the larvae of some Lepidopteran insects including Willow Beauty.
# Uses and traditions
Yew wood is reddish brown (with whiter sapwood), and is very springy. It was traditionally used to make bows, especially the longbow. Ötzi, the Chalcolithic mummy found in 1991 in the Austrian alps, carried an unfinished longbow made of yew wood. Consequently, it is not surprising that, in Norse mythology, the god of the bow, Ullr's abode had the name Ydalir (Yew dales). Most longbow wood used in northern Europe was imported from Iberia, where climatic conditions are better for growing the knot-free yew wood required. The Eihwaz rune ᛇ is named after the yew, and sometimes also associated with the "evergreen" World tree, Yggdrasil.
Yews are widely used in landscaping and ornamental horticulture. Over 400 cultivars of yews have been named, the vast majority of these being derived from European Yew, Japanese Yew and the hybrid between them (Taxus x media). The most popular of these are the "Irish Yew" (Taxus baccata 'Fastigiata'), a fastigiate cultivar of the European Yew, and the several variants with yellow leaves, collectively known as golden yew.
The Pacific Yew Taxus brevifolia, native to the Pacific Northwest of North America, and Canada Yew Taxus canadensis are the sources of paclitaxel, a chemotherapeutic drug used in breast and lung cancer treatment and, more recently, in the production of the Taxus drug eluting stent by Boston Scientific. Over-harvesting of the Pacific Yew for this drug has resulted in it becoming an endangered species, though the drug is now produced semi-synthetically from cultivated yews, without the need to further endanger the wild populations. The more common Canada yew, Taxus canadensis, is also being successfully harvested in northern Ontario, Québec and New Brunswick, and has become another major source of paclitaxel. Other yew species contain similar compounds with similar biochemical activity. Docetaxel, an analogue of paclitaxel, is derived from the Taxus baccata.
The yew tree can often be found in church graveyards and is symbolic of sadness. Such a representation appears in Lord Alfred Tennyson's poem "In Memoriam A.H.H." (2.61-64).
The yew tree is a frequent symbol in the Christian poetry of T. S. Eliot, especially his Four Quartets.
On January 18, 2008, the Botanic Gardens Conservation International (representing botanic gardens in 120 countries) stated that "400 medicinal plants are at risk of extinction, from over-collection and deforestation, threatening the discovery of future cures for disease." These included Yew trees (the bark is used for cancer drugs, paclitaxel); Hoodia (from Namibia, source of weight loss drugs); half of Magnolias (used as Chinese medicine for 5,000 years to fight cancer, dementia and heart disease); and Autumn crocus (for gout). The group also found that 5 billion people benefit from traditional plant-based medicine for health care | Taxus
Taxus is a genus of yews, small coniferous trees or shrubs in the yew family Taxaceae. They are relatively slow growing and can be very long-lived, and reach heights of 1-40 m, with trunk diameters of up to 4 m. They have reddish bark, lanceolate, flat, dark-green leaves 1-4 cm long and 2-3 mm broad, arranged spirally on the stem, but with the leaf bases twisted to align the leaves in two flat rows either side of the stem.
The seed cones are highly modified, each cone containing a single seed 4-7 mm long partly surrounded by a modified scale which develops into a soft, bright red berry-like structure called an aril, 8-15 mm long and wide and open at the end. The arils are mature 6-9 months after pollination, and with the seed contained are eaten by thrushes, waxwings and other birds, which disperse the hard seeds undamaged in their droppings; maturation of the arils is spread over 2-3 months, increasing the chances of successful seed dispersal. The male cones are globose, 3-6 mm diameter, and shed their pollen in early spring. Yews are mostly dioecious, but occasional individuals can be variably monoecious, or change sex with time.
All of the yews are very closely related to each other, and some botanists treat them all as subspecies or varieties of just one widespread species; under this treatment, the species name used is Taxus baccata, the first yew described scientifically.
The most distinct is the Sumatran Yew (T. sumatrana, native from Sumatra and Celebes north to southernmost China), distinguished by its sparse, sickle-shaped yellow-green leaves. The Mexican Yew (T. globosa, native to eastern Mexico south to Honduras) is also relatively distinct with foliage intermediate between Sumatran Yew and the other species. The Florida Yew, Mexican Yew and Pacific Yew are all rare species listed as threatened or endangered.
All species of yew contain highly poisonous alkaloids known as taxanes, with some variation in the exact formula of the alkaloid between the species. All parts of the tree except the arils contain the alkaloid. The arils are edible and sweet, but the seed is dangerously poisonous; unlike birds, the human stomach can break down the seed coat and release the taxanes into the body. This can have fatal results if yew 'berries' are eaten without removing the seeds first. Grazing animals, particularly cattle and horses, are also sometimes found dead near yew trees after eating the leaves, though deer are able to break down the poisons and will eat yew foliage freely. In the wild, deer browsing of yews is often so extensive that wild yew trees are commonly restricted to cliffs and other steep slopes inaccessible to deer. The foliage is also eaten by the larvae of some Lepidopteran insects including Willow Beauty.
## Uses and traditions
Yew wood is reddish brown (with whiter sapwood), and is very springy. It was traditionally used to make bows, especially the longbow. Ötzi, the Chalcolithic mummy found in 1991 in the Austrian alps, carried an unfinished longbow made of yew wood. Consequently, it is not surprising that, in Norse mythology, the god of the bow, Ullr's abode had the name Ydalir (Yew dales). Most longbow wood used in northern Europe was imported from Iberia, where climatic conditions are better for growing the knot-free yew wood required. The Eihwaz rune ᛇ is named after the yew, and sometimes also associated with the "evergreen" World tree, Yggdrasil.
Yews are widely used in landscaping and ornamental horticulture. Over 400 cultivars of yews have been named, the vast majority of these being derived from European Yew, Japanese Yew and the hybrid between them (Taxus x media). The most popular of these are the "Irish Yew" (Taxus baccata 'Fastigiata'), a fastigiate cultivar of the European Yew, and the several variants with yellow leaves, collectively known as golden yew.
The Pacific Yew Taxus brevifolia, native to the Pacific Northwest of North America, and Canada Yew Taxus canadensis are the sources of paclitaxel, a chemotherapeutic drug used in breast and lung cancer treatment and, more recently, in the production of the Taxus drug eluting stent by Boston Scientific. Over-harvesting of the Pacific Yew for this drug has resulted in it becoming an endangered species, though the drug is now produced semi-synthetically from cultivated yews, without the need to further endanger the wild populations. The more common Canada yew, Taxus canadensis, is also being successfully harvested in northern Ontario, Québec and New Brunswick, and has become another major source of paclitaxel. Other yew species contain similar compounds with similar biochemical activity. Docetaxel, an analogue of paclitaxel, is derived from the Taxus baccata.
The yew tree can often be found in church graveyards and is symbolic of sadness. Such a representation appears in Lord Alfred Tennyson's poem "In Memoriam A.H.H." (2.61-64).
The yew tree is a frequent symbol in the Christian poetry of T. S. Eliot, especially his Four Quartets.
On January 18, 2008, the Botanic Gardens Conservation International (representing botanic gardens in 120 countries) stated that "400 medicinal plants are at risk of extinction, from over-collection and deforestation, threatening the discovery of future cures for disease." These included Yew trees (the bark is used for cancer drugs, paclitaxel); Hoodia (from Namibia, source of weight loss drugs); half of Magnolias (used as Chinese medicine for 5,000 years to fight cancer, dementia and heart disease); and Autumn crocus (for gout). The group also found that 5 billion people benefit from traditional plant-based medicine for health care[1] | https://www.wikidoc.org/index.php/Pacific_yew | |
992d0d5f8937cb7dff99ed7b914c532ac2649ec5 | wikidoc | Panic | Panic
Panic is a sudden fear which dominates or replaces thinking and often affects groups of people or animals. Panics typically occur in disaster situations, or violent situations (such as robbery, home invasion, a shooting rampage, etc.) which may endanger the overall health of the affected group. The word panic derives from the name of the Greek god Pan, who was said to have the ability to cause extreme, irrational fear, especially in lonely or open places.
Prehistoric man used mass panic as a technique when hunting animals, especially ruminants. Herds reacting to unusually strong sounds or unfamiliar visual effects were directed towards cliffs, where they eventually jumped to their deaths when cornered.
Humans are also vulnerable to panic and it is often considered infectious, in the sense one person's panic may easily spread to other people nearby and soon the entire group acts irrationally, but people also have the ability to prevent and/or control their own and other's panic by disciplined thinking or training (such as disaster drills). Architects and city planners try to accommodate the symptoms of panic, such as herd behavior, during design and planning, often using simulations to determine the best way to lead people to a safe exit and prevent congestion (stampedes). The most effective methods are often nonintuitive. A tall column, approximately 1 ft (300 mm) in diameter, placed in front of the door exit at a precisely calculated distance, may speed up the evacuation of a large room by up to 30%, as the obstacle divides the congestion well ahead of the choke point.
In sociology, precipitate and irrational actions of a group are often referred to as panics, as for example "sex panic", "stock market panic". (See hysteria.) Panic is usually understood to mean active, but senseless behaviour (e.g. trying to flee in a random direction or suddenly attacking others without consideration), while hysteria often carries a more passive notion (as in crying uncontrollably). An influential theoretical treatment of panic by a sociologist is found in Neil J. Smelser's, Theory of Collective Behavior.
The science of panic management has found important practical applications in the armed forces and emergency services of the world.
Many highly publicized cases of deadly panic occurred during massive public events.
The layout of Mecca was extensively redesigned by Saudi authorities in an attempt to eliminate frequent stampedes, which kill an average of 250 pilgrims every year.
Football stadiums have seen deadly crowd rushes and stampedes, such as at Hillsborough stadium in Sheffield, England, in 1989. This led to controlled entry gates and stricter rules by the end of the 1980s to regulate seating arrangements.
# Etymology
"Panic" comes from Greek panikon, "pertaining to Pan." Pan is the god of woods and fields who was the source of mysterious sounds that caused contagious, groundless fear in herds and crowds, or in people in lonely spots.
# Panic and the law
Most jurisdictions limit the freedom of speech in order to deter people from creating potentially dangerous panic situations, especially a false alarm (the classic example is shouting "Fire!" in a crowded theatre when in fact nothing is burning).
Some criminal defendants attempt to evade or reduce the severity of their conviction by claiming their violence was induced by a sense of panic. Certain jurisdiction may limit punishment in case one's actions for self-defense were excessively powerful because of panic reaction.
Panic experienced by air travellers during the last minutes of their lives aboard crashing commercial flights has been the basis of several multi-million dollar lawsuits brought against airlines, based on the legal concept of emotional suffering. | Panic
Template:Disputed
Panic is a sudden fear which dominates or replaces thinking and often affects groups of people or animals. Panics typically occur in disaster situations, or violent situations (such as robbery, home invasion, a shooting rampage, etc.) which may endanger the overall health of the affected group. The word panic derives from the name of the Greek god Pan, who was said to have the ability to cause extreme, irrational fear, especially in lonely or open places.
Prehistoric man used mass panic as a technique when hunting animals, especially ruminants. Herds reacting to unusually strong sounds or unfamiliar visual effects were directed towards cliffs, where they eventually jumped to their deaths when cornered.[citation needed]
Humans are also vulnerable to panic and it is often considered infectious, in the sense one person's panic may easily spread to other people nearby and soon the entire group acts irrationally, but people also have the ability to prevent and/or control their own and other's panic by disciplined thinking or training (such as disaster drills). Architects and city planners try to accommodate the symptoms of panic, such as herd behavior, during design and planning, often using simulations to determine the best way to lead people to a safe exit and prevent congestion (stampedes). The most effective methods are often nonintuitive. A tall column, approximately 1 ft (300 mm) in diameter, placed in front of the door exit at a precisely calculated distance, may speed up the evacuation of a large room by up to 30%, as the obstacle divides the congestion well ahead of the choke point.[citation needed]
In sociology, precipitate and irrational actions of a group are often referred to as panics, as for example "sex panic", "stock market panic". (See hysteria.) Panic is usually understood to mean active, but senseless behaviour (e.g. trying to flee in a random direction or suddenly attacking others without consideration), while hysteria often carries a more passive notion (as in crying uncontrollably). An influential theoretical treatment of panic by a sociologist is found in Neil J. Smelser's, Theory of Collective Behavior.
The science of panic management has found important practical applications in the armed forces and emergency services of the world.
Many highly publicized cases of deadly panic occurred during massive public events.
The layout of Mecca was extensively redesigned by Saudi authorities in an attempt to eliminate frequent stampedes, which kill an average of 250 pilgrims every year. [1]
Football stadiums have seen deadly crowd rushes and stampedes, such as at Hillsborough stadium in Sheffield, England, in 1989. This led to controlled entry gates and stricter rules by the end of the 1980s to regulate seating arrangements.
# Etymology
"Panic" comes from Greek panikon, "pertaining to Pan." Pan is the god of woods and fields who was the source of mysterious sounds that caused contagious, groundless fear in herds and crowds, or in people in lonely spots.
# Panic and the law
Most jurisdictions limit the freedom of speech in order to deter people from creating potentially dangerous panic situations, especially a false alarm (the classic example is shouting "Fire!" in a crowded theatre when in fact nothing is burning).
Some criminal defendants attempt to evade or reduce the severity of their conviction by claiming their violence was induced by a sense of panic. Certain jurisdiction may limit punishment in case one's actions for self-defense were excessively powerful because of panic reaction.
Panic experienced by air travellers during the last minutes of their lives aboard crashing commercial flights has been the basis of several multi-million dollar lawsuits brought against airlines, based on the legal concept of emotional suffering[citation needed]. | https://www.wikidoc.org/index.php/Panic | |
d7e3145e6526cac0b2ccd2c6c1febb68ccf2a003 | wikidoc | Pecan | Pecan
# Overview
The pecan (/pˈkɑːn/, /pˈkæn/, or /ˈpiːkæn/), Carya illinoinensis, is a species of hickory, native to south-central North America, in Mexico from Coahuila south to Jalisco and Veracruz, in the United States from southern Iowa, Illinois, Missouri, and Indiana to Virginia, southwestern Ohio, south through Georgia, Alabama, Mississippi, Louisiana, Texas, Oklahoma, Arkansas, and Florida, and west into New Mexico.
"Pecan" is from an Algonquian word, meaning a nut requiring a stone to crack.
## Cultivation
Pecans were one of the most recently domesticated major crops. Although wild pecans were well-known among the colonial Americans as a delicacy, the commercial growing of pecans in the United States did not begin until the 1880s. Today, the U.S. produces between 80% and 95% of the world's pecans, with an annual crop of 150–200 thousand tons from more than 10 million trees. The nut harvest for growers is typically around mid-October. Historically, the leading pecan-producing state in the U.S. has been Georgia, followed by Texas, New Mexico and Oklahoma; they are also grown in Arizona, South Carolina and Hawaii. Outside the United States, pecans are grown in Australia, Brazil, China, Israel, Mexico, Peru and South Africa. They can be grown approximately from USDA hardiness zones 5 to 9, provided summers are also hot and humid.
Pecan trees may live and bear edible nuts for more than 300 years. They are mostly self-incompatible, because most cultivars, being clones derived from wild trees, show incomplete dichogamy. Generally, two or more trees of different cultivars must be present to pollinate each other.
Choosing cultivars can be a complex practice, based on the Alternate Bearing Index and their period of pollinating. Commercial planters are most concerned with the Alternate Bearing Index, which describes a cultivar's likelihood to bear on an alternating years (index of 1.0 signifies highest likelihood of bearing little to nothing every other year). The period of pollination groups all cultivars into two families: those that shed pollen before they can receive pollen (protandrous), and those that shed pollen after becoming receptive to pollen (protogynous). Planting cultivars from both families within 250 feet is recommended for proper pollination.
## Diseases
In the southeastern United States, nickel deficiency in C. Illinoinensis produces a disorder called mouse-ear in trees fertilized with urea. An enzyme within the leaves uses nickel during the conversion of urea to ammonia, and a deficiency results in the toxic accumulation of urea. Symptoms of mouse-ear include rounded or blunt leaflet tips which produces smaller leaflets, dwarfing of tree organs, poorly developed root systems, rosetting, delayed bud break, loss of apical dominance, and necrosis of leaflet tips. Mouse-ear can be treated with foliar sprays of nickel.
A similar condition results from a zinc deficiency, which also can be treated by foliar sprays.
## Nutrition
Pecans are a good source of protein and unsaturated fats. Like walnuts (which pecans resemble), pecans are rich in omega-6 fatty acids, although pecans contain about half as much omega-6 as walnuts.
A diet rich in nuts can lower the risk of gallstones in women. The antioxidants and plant sterols found in pecans reduce high cholesterol by reducing the "bad" LDL cholesterol levels.
Clinical research published in the Journal of Nutrition (September 2001) found that eating about a handful of pecans each day may help lower cholesterol levels similar to what is often seen with cholesterol-lowering medications. Research conducted at the University of Georgia has also confirmed that pecans contain plant sterols, which are known for their cholesterol-lowering ability. Pecans may also play a role in neurological health. Eating pecans daily may delay age-related muscle nerve degeneration, according to a study conducted at the University of Massachusetts and published in Current Topics in Nutraceutical Research.
The Lazy Magnolia Brewing Company from Kiln, Mississippi has produced a variety of beer using pecans rather than hops.
## Evolutionary development
The pecan, Carya illinoinensis, is a member of the Juglandaceae family. Juglandaceae are represented worldwide by between seven and 10 extant genera and more than 60 species. Most of these species are concentrated in the Northern Hemisphere of the New World, but can be found on every continent except for Antarctica. The first fossil examples of the family appear during the Cretaceous. Differentiation between the subfamilies of Engelhardioideae and Juglandioideae occurred during the early Paleogene, about 64 million years ago. Extant examples of Engelharioideae are generally tropical and evergreen, while those of Juglandioideae are deciduous and found in more temperate zones. The second major step in the development of the pecan was a change from wind-dispersed fruits to animal dispersion. This dispersal strategy coincides with the development of a husk around the fruit and a drastic change in the relative concentrations of fatty acids. The ratio of oleic to linoleic acids are inverted between wind- and animal-dispersed seeds. Further differentiation from other species of Juglandaceae occurred about 44 million years ago during the Eocene. The fruits of the pecan genus Carya differ from those of the walnut genus Juglans only in the formation of the husk of the fruit. The husks of walnuts develop from the bracts, bracteoles, and sepals, or sepals only. The husks of pecans develop from the bracts and the bracteoles only.
## History
Before European settlement, pecans were widely consumed and traded by Native Americans. As a food source, pecans are a natural choice for preagricultural society. They can provide two to five times more calories per unit weight than wild game, and require no preparation. As a wild forage, the fruit of the previous growing season are commonly still edible when found on the ground. Hollow tree trunks, found in abundance in pecan stands, offer ideal storage of pecans by humans and squirrels alike.
Pecans first became known to Europeans in the 16th century. The first Europeans to come into contact with pecans were Spanish explorers in what is now Mexico, Texas, and Louisiana. The genus Carya does not exist in the Old World. Because of their familiarity with the genus Juglans, these early explorers referred to the nuts as nogales and nueces, the Spanish terms for "walnut trees" and "fruit of the walnut." They noted the particularly thin shell and acorn-like shape of the fruit, indicating they were indeed referring to pecans. The Spaniards brought the pecan into Europe, Asia, and Africa beginning in the 16th century. In 1792, William Bartram reported in his botanical book, Travels, a nut tree, Juglans exalata that some botanists today argue was the American pecan tree, but others argue was hickory, Carya ovata. Pecan trees are native to the United States, and writing about the pecan tree goes back to the nation's founders. Thomas Jefferson planted pecan trees, Carya illinoinensis (Illinois nuts), in his nut orchard at his home, Monticello, in Virginia. George Washington reported in his journal that Thomas Jefferson gave him "Illinois nuts", pecans, which George Washington then grew at Mount Vernon, his Virginia home.
## Breeding and breeding programs
Active breeding and selection programs are carried out by USDA-ARS with growing locations at Brownwood and College Station, Texas. While selection work has been done since the late 1800s, most acreage of pecans grown today are of older cultivars, such as 'Stuart', 'Schley', 'Desirable', with known flaws but also with known production potential. The long cycle time for pecan trees plus financial considerations dictate that new varieties go through an extensive vetting process before being widely planted. Numerous examples of varieties produce well in Texas, but fail in the Southeastern U.S. due to increased disease pressure. Selection programs are ongoing at the state level, with Alabama, Arkansas, Georgia, Kansas, Florida, Missouri and others having trial plantings.
Varieties that are adapted from the southern tier of States up through some parts of Iowa and even into southern Canada are available from nurseries. Production potential drops significantly when planted further north than Tennessee. Most breeding efforts for northern-adapted varieties have not been on a large enough scale to significantly impact production. Varieties that are available and adapted (e.g., 'Major', 'Martzahn', 'Witte', 'Greenriver', and 'Posey') in zones 6 and further north are almost entirely selections from wild stands. A northern-adapted variety must be grafted onto a northern rootstock to avoid freeze damage.
The pecan is a 32-chromosome species, and can hybridize with other 32-chromosome members of the Carya genus, such as Carya ovata, Carya laciniosa, and Carya cordiformis. Most such hybrids are unproductive, though a few second-generation hybrids have potential for producing hickory-flavored nuts with pecan nut structure. Such hybrids are referred to as "hicans" to indicate their hybrid origin.
## Symbolism
In 1906, Texas Governor James Stephen Hogg asked that a pecan tree be planted at his grave instead of a traditional headstone, requesting that the nuts be distributed throughout the state to make Texas a "Land of Trees". His wish was carried out and this brought more attention to pecan trees. In 1919, the 36th Texas Legislature made the pecan tree the state tree of Texas.
In Groves, Texas the Texas Pecan Festival is celebrated every year. There is also an annual Pecan Festival in Colfax, Louisiana in the month of November. | Pecan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The pecan (/[invalid input: 'icon']p[invalid input: 'ɨ']ˈkɑːn/, /p[invalid input: 'ɨ']ˈkæn/, or /ˈpiːkæn/), Carya illinoinensis, is a species of hickory, native to south-central North America, in Mexico from Coahuila south to Jalisco and Veracruz,[1][2] in the United States from southern Iowa, Illinois, Missouri, and Indiana to Virginia, southwestern Ohio, south through Georgia, Alabama, Mississippi, Louisiana, Texas, Oklahoma, Arkansas, and Florida, and west into New Mexico.
"Pecan" is from an Algonquian word, meaning a nut requiring a stone to crack.[3]
## Cultivation
Pecans were one of the most recently domesticated major crops. Although wild pecans were well-known among the colonial Americans as a delicacy, the commercial growing of pecans in the United States did not begin until the 1880s.[4] Today, the U.S. produces between 80% and 95% of the world's pecans, with an annual crop of 150–200 thousand tons [5] from more than 10 million trees.[6] The nut harvest for growers is typically around mid-October. Historically, the leading pecan-producing state in the U.S. has been Georgia, followed by Texas, New Mexico and Oklahoma; they are also grown in Arizona, South Carolina and Hawaii. Outside the United States, pecans are grown in Australia, Brazil, China, Israel, Mexico, Peru and South Africa. They can be grown approximately from USDA hardiness zones 5 to 9, provided summers are also hot and humid.
Pecan trees may live and bear edible nuts for more than 300 years. They are mostly self-incompatible, because most cultivars, being clones derived from wild trees, show incomplete dichogamy. Generally, two or more trees of different cultivars must be present to pollinate each other.
Choosing cultivars can be a complex practice, based on the Alternate Bearing Index and their period of pollinating. Commercial planters are most concerned with the Alternate Bearing Index, which describes a cultivar's likelihood to bear on an alternating years (index of 1.0 signifies highest likelihood of bearing little to nothing every other year).[7] The period of pollination groups all cultivars into two families: those that shed pollen before they can receive pollen (protandrous), and those that shed pollen after becoming receptive to pollen (protogynous).[8] Planting cultivars from both families within 250 feet is recommended for proper pollination.
## Diseases
In the southeastern United States, nickel deficiency in C. Illinoinensis produces a disorder called mouse-ear in trees fertilized with urea.[9] An enzyme within the leaves uses nickel during the conversion of urea to ammonia, and a deficiency results in the toxic accumulation of urea. Symptoms of mouse-ear include rounded or blunt leaflet tips which produces smaller leaflets, dwarfing of tree organs, poorly developed root systems, rosetting, delayed bud break, loss of apical dominance, and necrosis of leaflet tips. Mouse-ear can be treated with foliar sprays of nickel.
A similar condition results from a zinc deficiency, which also can be treated by foliar sprays.[10]
## Nutrition
Template:Nutritional value
Template:American cuisine
Pecans are a good source of protein and unsaturated fats. Like walnuts (which pecans resemble), pecans are rich in omega-6 fatty acids, although pecans contain about half as much omega-6 as walnuts.[11][12]
A diet rich in nuts can lower the risk of gallstones in women.[13] The antioxidants and plant sterols found in pecans reduce high cholesterol by reducing the "bad" LDL cholesterol levels.[14]
Clinical research published in the Journal of Nutrition (September 2001) found that eating about a handful of pecans each day may help lower cholesterol levels similar to what is often seen with cholesterol-lowering medications.[15] Research conducted at the University of Georgia has also confirmed that pecans contain plant sterols, which are known for their cholesterol-lowering ability.[16] Pecans may also play a role in neurological health. Eating pecans daily may delay age-related muscle nerve degeneration, according to a study conducted at the University of Massachusetts and published in Current Topics in Nutraceutical Research.[17]
The Lazy Magnolia Brewing Company from Kiln, Mississippi has produced a variety of beer using pecans rather than hops.
## Evolutionary development
The pecan, Carya illinoinensis, is a member of the Juglandaceae family. Juglandaceae are represented worldwide by between seven and 10 extant genera and more than 60 species. Most of these species are concentrated in the Northern Hemisphere of the New World, but can be found on every continent except for Antarctica. The first fossil examples of the family appear during the Cretaceous. Differentiation between the subfamilies of Engelhardioideae and Juglandioideae occurred during the early Paleogene, about 64 million years ago. Extant examples of Engelharioideae are generally tropical and evergreen, while those of Juglandioideae are deciduous and found in more temperate zones. The second major step in the development of the pecan was a change from wind-dispersed fruits to animal dispersion. This dispersal strategy coincides with the development of a husk around the fruit and a drastic change in the relative concentrations of fatty acids. The ratio of oleic to linoleic acids are inverted between wind- and animal-dispersed seeds.[18][19] Further differentiation from other species of Juglandaceae occurred about 44 million years ago during the Eocene. The fruits of the pecan genus Carya differ from those of the walnut genus Juglans only in the formation of the husk of the fruit. The husks of walnuts develop from the bracts, bracteoles, and sepals, or sepals only. The husks of pecans develop from the bracts and the bracteoles only.[19]
## History
Before European settlement, pecans were widely consumed and traded by Native Americans. As a food source, pecans are a natural choice for preagricultural society. They can provide two to five times more calories per unit weight than wild game, and require no preparation. As a wild forage, the fruit of the previous growing season are commonly still edible when found on the ground. Hollow tree trunks, found in abundance in pecan stands, offer ideal storage of pecans by humans and squirrels alike.[6]
Pecans first became known to Europeans in the 16th century. The first Europeans to come into contact with pecans were Spanish explorers in what is now Mexico, Texas, and Louisiana. The genus Carya does not exist in the Old World. Because of their familiarity with the genus Juglans, these early explorers referred to the nuts as nogales and nueces, the Spanish terms for "walnut trees" and "fruit of the walnut." They noted the particularly thin shell and acorn-like shape of the fruit, indicating they were indeed referring to pecans.[6] The Spaniards brought the pecan into Europe, Asia, and Africa beginning in the 16th century. In 1792, William Bartram reported in his botanical book, Travels, a nut tree, Juglans exalata that some botanists today argue was the American pecan tree, but others argue was hickory, Carya ovata.[20] Pecan trees are native to the United States, and writing about the pecan tree goes back to the nation's founders. Thomas Jefferson planted pecan trees, Carya illinoinensis (Illinois nuts), in his nut orchard at his home, Monticello, in Virginia. George Washington reported in his journal that Thomas Jefferson gave him "Illinois nuts", pecans, which George Washington then grew at Mount Vernon, his Virginia home.
## Breeding and breeding programs
Active breeding and selection programs are carried out by USDA-ARS[21] with growing locations at Brownwood and College Station, Texas. While selection work has been done since the late 1800s, most acreage of pecans grown today are of older cultivars, such as 'Stuart', 'Schley', 'Desirable', with known flaws but also with known production potential. The long cycle time for pecan trees plus financial considerations dictate that new varieties go through an extensive vetting process before being widely planted. Numerous examples of varieties produce well in Texas, but fail in the Southeastern U.S. due to increased disease pressure. Selection programs are ongoing at the state level, with Alabama, Arkansas, Georgia, Kansas, Florida, Missouri and others having trial plantings.
Varieties that are adapted from the southern tier of States up through some parts of Iowa and even into southern Canada are available from nurseries. Production potential drops significantly when planted further north than Tennessee. Most breeding efforts for northern-adapted varieties have not been on a large enough scale to significantly impact production. Varieties that are available and adapted (e.g., 'Major', 'Martzahn', 'Witte', 'Greenriver', and 'Posey') in zones 6 and further north are almost entirely selections from wild stands. A northern-adapted variety must be grafted onto a northern rootstock to avoid freeze damage.
The pecan is a 32-chromosome species, and can hybridize with other 32-chromosome members of the Carya genus, such as Carya ovata, Carya laciniosa, and Carya cordiformis. Most such hybrids are unproductive, though a few second-generation hybrids have potential for producing hickory-flavored nuts with pecan nut structure. Such hybrids are referred to as "hicans" to indicate their hybrid origin.
## Symbolism
In 1906, Texas Governor James Stephen Hogg asked that a pecan tree be planted at his grave instead of a traditional headstone, requesting that the nuts be distributed throughout the state to make Texas a "Land of Trees".[5] His wish was carried out and this brought more attention to pecan trees. In 1919, the 36th Texas Legislature made the pecan tree the state tree of Texas.
In Groves, Texas the Texas Pecan Festival is celebrated every year. There is also an annual Pecan Festival in Colfax, Louisiana in the month of November. | https://www.wikidoc.org/index.php/Pecan | |
49ae4d2009fd44178f581130fb648abbd0642795 | wikidoc | Penis | Penis
The penis (plural penises, penes) is an external sexual organ of certain biologically male organisms. The penis is a reproductive organ and, for mammals, additionally serves as the external organ of urination.
# Structure
The human penis is made up of three columns of tissue: two corpora cavernosa lie next to each other on the dorsal side and one corpus spongiosum lies between them on the ventral side.
The end of the corpus spongiosum is enlarged and bulbous-shaped and forms the glans penis. The glans supports the foreskin or prepuce, a loose fold of skin that in adults can retract to expose the glans. The area on the underside of the penis, where the foreskin is attached, is called the frenum (or frenulum).
The urethra, which is the last part of the urinary tract, traverses the corpus spongiosum and its opening, known as the meatus, lies on the tip of the glans penis. It is a passage both for urine and for the ejaculation of semen. Sperm is produced in the testes and stored in the attached epididymis. During ejaculation, sperm are propelled up the vas deferens, two ducts that pass over and behind the bladder. Fluids are added by the seminal vesicles and the vas deferens turns into the ejaculatory ducts which join the urethra inside the prostate gland. The prostate as well as the bulbourethral glands add further secretions, and the semen is expelled through the penis.
The raphe is the visible ridge between the lateral halves of the penis, found on the ventral or underside of the penis, running from the meatus (opening of the urethra) across the scrotum to the perineum (area between scrotum and anus).
The human penis differs from those of most other mammals. It has no baculum, or erectile bone; instead it relies entirely on engorgement with blood to reach its erect state. It cannot be withdrawn into the groin, and is larger than average in the animal kingdom in proportion to body mass.
# Linguistics
## Etymology
The word "penis" was taken from Latin and originally meant "tail." Some derive that from Indo-European *pesnis, and the Greek word πεος = "penis" from Indo-European *pesos. Prior to the adoption of the Latin word in English the penis was referred to as a "yard". The Oxford English Dictionary cites an examples of the word yard used in this sense from 1379, and notes that in his Physical Dictionary of 1684, Steven Blankaart defined the word penis as "the Yard, made up of two nervous Bodies, the Channel, Nut, Skin, and Fore-skin, etc."
The Latin word "phallus" (from Greek φαλλος) is sometimes used to describe the penis, although "phallus" originally was used to describe images, pictorial or carved, of the penis.
## Slang
As with nearly any aspect of the human body that is involved in sexual or excretory functions, the word penis is considered inherently funny from a juvenile perspective and there are many slang words for the penis, including "dick", "wang" or "cock". Many of these are noted in the bathroom humor article.
"Penii" is sometimes facetiously or mistakenly used as a plural form of "penis" instead of "penes" or "penises," its correct forms.
# Puberty
When a boy enters puberty, after the testicles begin to develop, the penis begins to enlarge, alongside the rest of the genitals. The penis grows longer until about the age of 16, and growth in width begins at roughly the age of 11. During the process, pubic hair grows above and around the penis.
# Sexual homology
In short, this is a known list of sex organs that evolve from the same tissue in a human life.
The glans of the penis is homologous to the clitoral glans; the corpora cavernosa are homologous to the body of the clitoris; the corpus spongiosum is homologous to the vestibular bulbs beneath the labia minora; the scrotum, homologous to the labia minora and labia majora; and the foreskin, homologous to the clitoral hood. The raphe does not exist in females, because there, the two halves are not connected.
# Erection
An erection is the stiffening and rising of the penis, which occurs during sexual arousal, though it can also happen in non-sexual situations. The primary physiological mechanism that brings about erection is the autonomic dilation of arteries supplying blood to the penis, which allows more blood to fill the three spongy erectile tissue chambers in the penis, causing it to lengthen and stiffen. The now-engorged erectile tissue presses against and constricts the veins that carry blood away from the penis. More blood enters than leaves the penis until an equilibrium is reached where an equal volume of blood flows into the dilated arteries and out of the constricted veins; a constant erectile size is achieved at this equilibrium.
Erection facilitates sexual intercourse though it is not essential for various other sexual activities. Although many erect penises point upwards (see illustration), it is common and normal for the erect penis to point nearly vertically upwards or nearly vertically downwards or even horizontally straightforward, all depending on the tension of the suspensory ligament that holds it in position. Stiffness or erectile angle can vary.
# Size
As a general rule, an animal's penis is proportional to its body size, but this varies greatly between species — even between closely related species. For example, an adult gorilla's erect penis is about 4 cm (1.5 in) in length; an adult chimpanzee, significantly smaller (in body size) than a gorilla, has a penis size about double that of the gorilla. In comparison, the human penis is larger than that of any other primate, both in proportion to body size and in absolute terms.
While results vary across studies, the consensus is that the average human penis is approximately 12.7-15 cm (5-5.9 in) in length and 12.3 cm (4.85 in) in circumference when fully erect. The average penis size is slightly larger than the median size. Most of these studies were performed on subjects of primarily European descent; worldwide averages may vary.
A research project, summarizing dozens of published studies conducted by physicians of different nationalities, shows that worldwide, erect-penis size averages vary between 9.6 cm (3.7 in) and 16 cm (6.2 in). It has been suggested that this difference is caused not only by genetics, but also by environmental factors such as culture, diet, chemical/pollution exposure, etc.
As with any other bodily attribute, the length and girth of the penis can be highly variable between individuals of the same species. In many animals, especially mammals, the size of a flaccid penis is much smaller than its erect size. In humans and some other species, flaccid vs. erect penis size varies greatly between individuals, such that penis size when flaccid is not a reliable predictor of size when erect.
Except for extreme cases at either end of the size spectrum, penis size does not correspond strongly to reproductive ability in almost any species.
# Normal variations
Depending on temperature, a flaccid (not erect) penis of average size can withdraw almost completely within the body. During erection the penis will return to its normal (erect) size.
- Other variations:
- Pearly penile papules are raised bumps of somewhat paler color around the base of the glans and are normal.
- Fordyce's spots are small, raised, yellowish-white spots 1-2 mm in diameter that may appear on the penis.
- Sebaceous prominences are raised bumps similar to Fordyce's spots on the shaft of the penis, located at the sebaceous glands and are normal.
- Phimosis is an inability to retract the foreskin fully, is harmless in infancy and pre-pubescence, occurring in about 8% of boys at age 10. According to the British Medical Association, treatment (steroid cream, manual stretching) does not need to be considered until age 19.
- Curvature: few penises are completely straight with curves commonly seen in all directions (up, down, left, right). Sometimes the curve is very prominent but it rarely inhibits sexual intercourse. Curvature as great as 30° is considered normal and medical treatment is rarely considered unless the angle exceeds 45°. Changes to the curvature of a penis may be caused by Peyronie's disease.
# Disorders affecting the penis
Edema (swelling) of the foreskin can result from sexual activity, including masturbation.
Paraphimosis is an inability to move the foreskin forward, over the glans. It can result from fluid trapped in a foreskin which is left retracted, perhaps following a medical procedure, or accumulation of fluid in the foreskin because of friction during vigorous sexual activity.
In Peyronie's disease, anomalous scar tissue grows in the soft tissue of the penis, causing curvature. Severe cases can benefit from surgical correction.
A thrombosis can occur during periods of frequent and prolonged sexual activity, especially fellatio. It is usually harmless and self-corrects within a few weeks.
Infection with the Herpes virus can occur after sexual contact with an infected carrier; this may lead to the development of herpes sores.
Pudendal nerve entrapment is a condition characterized by pain on sitting and loss of penile (or clitoral) sensation and orgasm. Occasionally there is a total loss of sensation and orgasm. The pudendal nerve can be damaged by narrow hard bicycle seats and accidents.
Penile fracture can occur if the erect penis is bent excessively. A popping or cracking sound and pain is normally associated with this event. Emergency medical assistance should be obtained. Prompt medical attention lowers likelihood of permanent penile curvature.
In diabetes, peripheral neuropathy can cause tingling in the penile skin and possibly reduced or completely absent sensation. The reduced sensations can lead to injuries for either partner and their absence can make it impossible to have sexual pleasure through stimulation of the penis. Since the problems are caused by permanent nerve damage, preventive treatment through good control of the diabetes is the primary treatment. Some limited recovery may be possible through improved diabetes control.
Erectile dysfunction or impotence is the inability to have and maintain an erection sufficiently firm for satisfactory sexual performance. Diabetes is a leading cause, as is natural aging. A variety of treatments exist, including drugs, such as sildenafil citrate (marketed as Viagra) which works by vasodilation.
Priapism is a painful and potentially harmful medical condition in which the erect penis does not return to its flaccid state. The causative mechanisms are poorly understood but involve complex neurological and vascular factors. Potential complications include ischaemia, thrombosis, and impotence. In serious cases the condition may result in gangrene, which may necessitate amputation.
Lymphangiosclerosis is a hardened lymph vessel, although it can feel like a hardened, almost calcified or fibrous, vein. It tend to not share the common blue tint with a vein however. It can be felt as a hardened lump or "vein" even when the penis is flaccid, and is even more prominent during an erection. It is considered a benign physical condition. It is fairly common and can follow a particularly vigorous sexual activity for men and tend to go away if given rest and more gentle care, for example by use of lubricants.
### Developmental disorders of the penis
Hypospadias is a developmental disorder where the meatus is positioned wrongly at birth. Hypospadias can also occur iatrogenically by the downward pressure of an indwelling urethral catheter. It is usually corrected by surgery. The Intersex Society of North America classifies hypospadias as an intersex condition. They believe in halting all medically unnecessary surgeries, including many of those done on people with hypospadias.
A micropenis is a very small penis caused by developmental or congenital problems. Diphallia, or penile duplication (PD), is the condition of having two penises. However, this disorder is exceedingly rare.
### Alleged and observed psychological disorders
- penis panic (koro in Malaysian/Indonesian) - delusion of shrinkage of the penis and retraction into the body. This appears to be culturally conditioned and largely limited to Sudan, China, Japan, and Southeast Asia.
- penis envy - the contested Freudian belief of a woman envying men for having a penis.
- small penis syndrome - disorder when men believe that their penis is smaller than average
## Altering the genitalia
The most prevalent form of genital alteration in some countries is circumcision: removal of part or all of the foreskin for various cultural, religious, and more rarely medical reasons. In many cases, such as in some United States hospitals, the frenulum and part of the shaft skin is also removed.
Less commonly, the penis is sometimes pierced or decorated by other body art. Other than circumcision, genital alterations are almost universally elective and usually for the purpose of aesthetics or increased sensitivity. Piercings of the penis include the Prince Albert piercing, the apadravya piercing, the ampallang piercing, the dydoe piercing, and the frenum piercing. Foreskin restoration or stretching is a further form of body modification.
Other practices which alter the penis are also performed, although they are rare in Western societies without a diagnosed medical condition. Apart from a penectomy, perhaps the most radical of these is subincision, in which the urethra is split along the underside of the penis. Subincision originated among Australian Aborigines, although it is now done by some in the U.S. and Europe.
# Penis replacement
The first successful penis allotransplant surgery was done on September 2005 in a military hospital in Guangzhou, China. A man at 44 sustained an injury after an accident and his penis was severed; urination became difficult as his urethra was partly blocked. A newly brain-dead man, at 23, was tracked down and his penis selected for the transplant. Despite atrophy of blood vessels and nerves, the arteries, veins, nerves and the corpora spongiosa were successfully matched. On September 19th, the surgery was reversed because of a severe psychological problem of the recipient and his wife.
# Non-human penises
Most marsupials, except for the two largest species of kangaroos, have a bifurcated penis. That is, it separates into two columns, and so the penis has two ends. Urban legend alleges that the dolphin has prehensile control over his penis (it is true, however, that whales and dolphins can move and to a certain degree bend their penis tips to facilitate mating). In the realm of absolute size, the smallest vertebrate penis belongs to the common shrew (5 mm or 0.2 inches). The largest penis belongs to the blue whale estimated at over 2 m (more than 6½ feet). Accurate measurements are difficult to take because the whale's erect length can only be observed during mating. Gorillas have relatively small penises, so it is an often used subtle insult in some countries to insinuate or directly state that one is 'hung like a gorilla'.
The Icelandic Phallological Museum is devoted entirely to collecting penis specimens from all sorts of land and sea mammals. The museum has received a legally-certified gift token for a future specimen belonging to Homo sapiens.
Among birds, only paleognathes (tinamous and ratites) and Anatidae (ducks, geese and swans) possess a penis. It is different in structure from mammal penises, being an erectile expansion of the cloacal wall and being erected by lymph, not blood. It is usually partially feathered and in some species features spines and brush-like filaments, and in flaccid state curled up inside the cloaca. The Argentine Blue-bill has the largest penis in relation to body size of all vertebrates; while usually about half the body size (20 cm), a specimen with a remarkable 42.5 cm-long penis is documented.
Male specimens of the Squamata order of reptiles have two paired organs called hemipenes. In fish, the gonopodium, andropodium, and claspers are various organs developed from modified fins. In male insects, the structure homologous to a penis is known as aedeagus. The male copulatory organ of various lower invertebrate animals is often called the cirrus.
# Cultural aspects involving penises
## Uses of animal penises
- Culinary, e.g., in Chinese gastronomy
- Magical and therapeutic, in medicine and/or superstition, especially as an alleged aphrodisiac or even cure for impotence
- Also used for punitive implements and dog toys, such as the bull pizzle
## Uses of human penises in cultural traditions
- Aesthetical, e.g., Body modification
- For the symbolic and artistic use, see under phallus; in heraldry, the term is pizzle
- In humor, considered indecent or completely taboo in various cultures | Penis
Template:Infobox Anatomy
Editor-in-Chief: Joel Gelman, M.D. [1], Director of the Center for Reconstructive Urology and Associate Clinical Professor in the Department of Urology at the University of California, Irvine
The penis (plural penises, penes) is an external sexual organ of certain biologically male organisms. The penis is a reproductive organ and, for mammals, additionally serves as the external organ of urination.
# Structure
The human penis is made up of three columns of tissue: two corpora cavernosa lie next to each other on the dorsal side and one corpus spongiosum lies between them on the ventral side.
The end of the corpus spongiosum is enlarged and bulbous-shaped and forms the glans penis. The glans supports the foreskin or prepuce, a loose fold of skin that in adults can retract to expose the glans. The area on the underside of the penis, where the foreskin is attached, is called the frenum (or frenulum).
The urethra, which is the last part of the urinary tract, traverses the corpus spongiosum and its opening, known as the meatus, lies on the tip of the glans penis. It is a passage both for urine and for the ejaculation of semen. Sperm is produced in the testes and stored in the attached epididymis. During ejaculation, sperm are propelled up the vas deferens, two ducts that pass over and behind the bladder. Fluids are added by the seminal vesicles and the vas deferens turns into the ejaculatory ducts which join the urethra inside the prostate gland. The prostate as well as the bulbourethral glands add further secretions, and the semen is expelled through the penis.
The raphe is the visible ridge between the lateral halves of the penis, found on the ventral or underside of the penis, running from the meatus (opening of the urethra) across the scrotum to the perineum (area between scrotum and anus).
The human penis differs from those of most other mammals. It has no baculum, or erectile bone; instead it relies entirely on engorgement with blood to reach its erect state. It cannot be withdrawn into the groin, and is larger than average in the animal kingdom in proportion to body mass.[citation needed]
# Linguistics
## Etymology
The word "penis" was taken from Latin and originally meant "tail." Some derive that from Indo-European *pesnis, and the Greek word πεος = "penis" from Indo-European *pesos. Prior to the adoption of the Latin word in English the penis was referred to as a "yard". The Oxford English Dictionary cites an examples of the word yard used in this sense from 1379,[1] and notes that in his Physical Dictionary of 1684, Steven Blankaart defined the word penis as "the Yard, made up of two nervous Bodies, the Channel, Nut, Skin, and Fore-skin, etc."[2]
The Latin word "phallus" (from Greek φαλλος) is sometimes used to describe the penis, although "phallus" originally was used to describe images, pictorial or carved, of the penis.[3]
## Slang
As with nearly any aspect of the human body that is involved in sexual or excretory functions, the word penis is considered inherently funny from a juvenile perspective and there are many slang words for the penis, including "dick", "wang" or "cock". Many of these are noted in the bathroom humor article.
"Penii" is sometimes facetiously or mistakenly used as a plural form of "penis" instead of "penes" or "penises," its correct forms.
# Puberty
When a boy enters puberty, after the testicles begin to develop, the penis begins to enlarge, alongside the rest of the genitals. The penis grows longer until about the age of 16, and growth in width begins at roughly the age of 11. During the process, pubic hair grows above and around the penis.
# Sexual homology
In short, this is a known list of sex organs that evolve from the same tissue in a human life.
The glans of the penis is homologous to the clitoral glans; the corpora cavernosa are homologous to the body of the clitoris; the corpus spongiosum is homologous to the vestibular bulbs beneath the labia minora; the scrotum, homologous to the labia minora and labia majora; and the foreskin, homologous to the clitoral hood. The raphe does not exist in females, because there, the two halves are not connected.
# Erection
An erection is the stiffening and rising of the penis, which occurs during sexual arousal, though it can also happen in non-sexual situations. The primary physiological mechanism that brings about erection is the autonomic dilation of arteries supplying blood to the penis, which allows more blood to fill the three spongy erectile tissue chambers in the penis, causing it to lengthen and stiffen. The now-engorged erectile tissue presses against and constricts the veins that carry blood away from the penis. More blood enters than leaves the penis until an equilibrium is reached where an equal volume of blood flows into the dilated arteries and out of the constricted veins; a constant erectile size is achieved at this equilibrium.
Erection facilitates sexual intercourse though it is not essential for various other sexual activities. Although many erect penises point upwards (see illustration), it is common and normal for the erect penis to point nearly vertically upwards or nearly vertically downwards or even horizontally straightforward, all depending on the tension of the suspensory ligament that holds it in position. Stiffness or erectile angle can vary.
# Size
As a general rule, an animal's penis is proportional to its body size, but this varies greatly between species — even between closely related species. For example, an adult gorilla's erect penis is about 4 cm (1.5 in) in length; an adult chimpanzee, significantly smaller (in body size) than a gorilla, has a penis size about double that of the gorilla. In comparison, the human penis is larger than that of any other primate, both in proportion to body size and in absolute terms.
While results vary across studies, the consensus is that the average human penis is approximately 12.7-15 cm (5-5.9 in) in length and 12.3 cm (4.85 in) in circumference when fully erect. The average penis size is slightly larger than the median size. Most of these studies were performed on subjects of primarily European descent; worldwide averages may vary.
A research project, summarizing dozens of published studies conducted by physicians of different nationalities, shows that worldwide, erect-penis size averages vary between 9.6 cm (3.7 in) and 16 cm (6.2 in). It has been suggested that this difference is caused not only by genetics, but also by environmental factors such as culture, diet, chemical/pollution exposure[4][5], etc.
As with any other bodily attribute, the length and girth of the penis can be highly variable between individuals of the same species. In many animals, especially mammals, the size of a flaccid penis is much smaller than its erect size. In humans and some other species, flaccid vs. erect penis size varies greatly between individuals, such that penis size when flaccid is not a reliable predictor of size when erect.
Except for extreme cases at either end of the size spectrum, penis size does not correspond strongly to reproductive ability in almost any species.
# Normal variations
Depending on temperature, a flaccid (not erect) penis of average size can withdraw almost completely within the body[citation needed]. During erection the penis will return to its normal (erect) size.
- Other variations:
- Pearly penile papules are raised bumps of somewhat paler color around the base of the glans and are normal.
- Fordyce's spots are small, raised, yellowish-white spots 1-2 mm in diameter that may appear on the penis.
- Sebaceous prominences are raised bumps similar to Fordyce's spots on the shaft of the penis, located at the sebaceous glands and are normal.
- Phimosis is an inability to retract the foreskin fully, is harmless in infancy and pre-pubescence, occurring in about 8% of boys at age 10. According to the British Medical Association, treatment (steroid cream, manual stretching) does not need to be considered until age 19.
- Curvature: few penises are completely straight with curves commonly seen in all directions (up, down, left, right). Sometimes the curve is very prominent but it rarely inhibits sexual intercourse. Curvature as great as 30° is considered normal and medical treatment is rarely considered unless the angle exceeds 45°. Changes to the curvature of a penis may be caused by Peyronie's disease.
# Disorders affecting the penis
Edema (swelling) of the foreskin can result from sexual activity, including masturbation.
Paraphimosis is an inability to move the foreskin forward, over the glans. It can result from fluid trapped in a foreskin which is left retracted, perhaps following a medical procedure, or accumulation of fluid in the foreskin because of friction during vigorous sexual activity.
In Peyronie's disease, anomalous scar tissue grows in the soft tissue of the penis, causing curvature. Severe cases can benefit from surgical correction.
A thrombosis can occur during periods of frequent and prolonged sexual activity, especially fellatio. It is usually harmless and self-corrects within a few weeks.
Infection with the Herpes virus can occur after sexual contact with an infected carrier; this may lead to the development of herpes sores.
Pudendal nerve entrapment is a condition characterized by pain on sitting and loss of penile (or clitoral) sensation and orgasm. Occasionally there is a total loss of sensation and orgasm. The pudendal nerve can be damaged by narrow hard bicycle seats and accidents.
Penile fracture can occur if the erect penis is bent excessively. A popping or cracking sound and pain is normally associated with this event. Emergency medical assistance should be obtained. Prompt medical attention lowers likelihood of permanent penile curvature.
In diabetes, peripheral neuropathy can cause tingling in the penile skin and possibly reduced or completely absent sensation. The reduced sensations can lead to injuries for either partner and their absence can make it impossible to have sexual pleasure through stimulation of the penis. Since the problems are caused by permanent nerve damage, preventive treatment through good control of the diabetes is the primary treatment. Some limited recovery may be possible through improved diabetes control.
Erectile dysfunction or impotence is the inability to have and maintain an erection sufficiently firm for satisfactory sexual performance. Diabetes is a leading cause, as is natural aging. A variety of treatments exist, including drugs, such as sildenafil citrate (marketed as Viagra) which works by vasodilation.
Priapism is a painful and potentially harmful medical condition in which the erect penis does not return to its flaccid state. The causative mechanisms are poorly understood but involve complex neurological and vascular factors. Potential complications include ischaemia, thrombosis, and impotence. In serious cases the condition may result in gangrene, which may necessitate amputation.
Lymphangiosclerosis is a hardened lymph vessel, although it can feel like a hardened, almost calcified or fibrous, vein. It tend to not share the common blue tint with a vein however. It can be felt as a hardened lump or "vein" even when the penis is flaccid, and is even more prominent during an erection. It is considered a benign physical condition. It is fairly common and can follow a particularly vigorous sexual activity for men and tend to go away if given rest and more gentle care, for example by use of lubricants.
### Developmental disorders of the penis
Hypospadias is a developmental disorder where the meatus is positioned wrongly at birth. Hypospadias can also occur iatrogenically by the downward pressure of an indwelling urethral catheter.[6] It is usually corrected by surgery. The Intersex Society of North America classifies hypospadias as an intersex condition. They believe in halting all medically unnecessary surgeries, including many of those done on people with hypospadias.
A micropenis is a very small penis caused by developmental or congenital problems. Diphallia, or penile duplication (PD), is the condition of having two penises. However, this disorder is exceedingly rare.
### Alleged and observed psychological disorders
- penis panic (koro in Malaysian/Indonesian) - delusion of shrinkage of the penis and retraction into the body. This appears to be culturally conditioned and largely limited to Sudan, China, Japan, and Southeast Asia.
- penis envy - the contested Freudian belief of a woman envying men for having a penis.
- small penis syndrome - disorder when men believe that their penis is smaller than average
## Altering the genitalia
The most prevalent form of genital alteration in some countries is circumcision: removal of part or all of the foreskin for various cultural, religious, and more rarely medical reasons. In many cases, such as in some United States hospitals, the frenulum and part of the shaft skin is also removed.
Less commonly, the penis is sometimes pierced or decorated by other body art. Other than circumcision, genital alterations are almost universally elective and usually for the purpose of aesthetics or increased sensitivity. Piercings of the penis include the Prince Albert piercing, the apadravya piercing, the ampallang piercing, the dydoe piercing, and the frenum piercing. Foreskin restoration or stretching is a further form of body modification.
Other practices which alter the penis are also performed, although they are rare in Western societies without a diagnosed medical condition. Apart from a penectomy, perhaps the most radical of these is subincision, in which the urethra is split along the underside of the penis. Subincision originated among Australian Aborigines, although it is now done by some in the U.S. and Europe.
# Penis replacement
The first successful penis allotransplant surgery was done on September 2005 in a military hospital in Guangzhou, China.[7] A man at 44 sustained an injury after an accident and his penis was severed; urination became difficult as his urethra was partly blocked. A newly brain-dead man, at 23, was tracked down and his penis selected for the transplant. Despite atrophy of blood vessels and nerves, the arteries, veins, nerves and the corpora spongiosa were successfully matched. On September 19th, the surgery was reversed because of a severe psychological problem of the recipient and his wife.[8]
# Non-human penises
Most marsupials, except for the two largest species of kangaroos, have a bifurcated penis. That is, it separates into two columns, and so the penis has two ends. Urban legend alleges that the dolphin has prehensile control over his penis (it is true, however, that whales and dolphins can move and to a certain degree bend their penis tips to facilitate mating). In the realm of absolute size, the smallest vertebrate penis belongs to the common shrew (5 mm or 0.2 inches). The largest penis belongs to the blue whale estimated at over 2 m (more than 6½ feet). Accurate measurements are difficult to take because the whale's erect length can only be observed during mating. Gorillas have relatively small penises, so it is an often used subtle insult in some countries to insinuate or directly state that one is 'hung like a gorilla'.
The Icelandic Phallological Museum is devoted entirely to collecting penis specimens from all sorts of land and sea mammals. The museum has received a legally-certified gift token for a future specimen belonging to Homo sapiens.
Among birds, only paleognathes (tinamous and ratites) and Anatidae (ducks, geese and swans) possess a penis. It is different in structure from mammal penises, being an erectile expansion of the cloacal wall and being erected by lymph, not blood. It is usually partially feathered and in some species features spines and brush-like filaments, and in flaccid state curled up inside the cloaca. The Argentine Blue-bill has the largest penis in relation to body size of all vertebrates; while usually about half the body size (20 cm), a specimen with a remarkable 42.5 cm-long penis is documented.
Male specimens of the Squamata order of reptiles have two paired organs called hemipenes. In fish, the gonopodium, andropodium, and claspers are various organs developed from modified fins. In male insects, the structure homologous to a penis is known as aedeagus. The male copulatory organ of various lower invertebrate animals is often called the cirrus.
# Cultural aspects involving penises
## Uses of animal penises
- Culinary, e.g., in Chinese gastronomy
- Magical and therapeutic, in medicine and/or superstition, especially as an alleged aphrodisiac or even cure for impotence
- Also used for punitive implements and dog toys, such as the bull pizzle
## Uses of human penises in cultural traditions
- Aesthetical, e.g., Body modification
- For the symbolic and artistic use, see under phallus; in heraldry, the term is pizzle
- In humor, considered indecent or completely taboo in various cultures | https://www.wikidoc.org/index.php/Penile_disease | |
afeed61fd83e0f52f43f8edbe66aa3e7a261dddf | wikidoc | Renin | Renin
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the renin–angiotensin–aldosterone axis—that mediates the volume of extracellular fluid (blood plasma, lymph and interstitial fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.
Renin can also be referred to as a hormone, as it has a receptor, the (pro)renin receptor, also known as the renin receptor and prorenin receptor (see also below) as well as enzymatic activity with which it hydrolyzes angiotensinogen to angiotensin I.
# Biochemistry and physiology
## Structure
The primary structure of renin precursor consists of 406 amino acids with a pre- and a pro-segment carrying 20 and 46 amino acids, respectively. Mature renin contains 340 amino acids and has a mass of 37 kDa.
## Secretion
The enzyme renin is secreted by pericytes (mural cells) (1) in the vicinity of the afferent arterioles and similar microvessels of the kidney from specialized cells of the juxtaglomerular apparatus—the juxtaglomerular cells, in response to three stimuli:
- A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
- A decrease in sodium load delivered to the distal tubule. This load is measured by the macula densa of the juxtaglomerular apparatus.
- Sympathetic nervous system activity, which also controls blood pressure, acting through the β1 adrenergic receptors.
Human renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of the precursor prorenin and a regulated pathway for the secretion of mature renin.
## Renin–angiotensin system
File:Renin-angiotensin system in man shadow.svg
The renin enzyme circulates in the blood stream and hydrolyzes (breaks down) angiotensinogen secreted from the liver into the peptide angiotensin I.
Angiotensin I is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the most vasoactive peptide. Angiotensin II is a potent constrictor of all blood vessels. It acts on the smooth muscle and, therefore, raises the resistance posed by these arteries to the heart. The heart, trying to overcome this increase in its 'load', works more vigorously, causing the blood pressure to rise. Angiotensin II also acts on the adrenal glands and releases aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, and water, leading to raised blood volume and raised blood pressure. The RAS also acts on the CNS to increase water intake by stimulating thirst, as well as conserving blood volume, by reducing urinary loss through the secretion of vasopressin from the posterior pituitary gland.
The normal concentration of renin in adult human plasma is 1.98–24.6 ng/L in the upright position.
# Function
Renin activates the renin–angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin–converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. Renin's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
Renin is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the macula densa. The macula densa senses changes in sodium delivery to the distal tubule, and responds to a drop in tubular sodium load by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.
Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through beta-2 adrenergic receptor (β1 adrenoreceptor) activation.
The (pro)renin receptor to which renin and prorenin bind is encoded by the gene ATP6ap2, ATPase H(+)-transporting lysosomal accessory protein 2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin as well as non-hydrolytic activation of prorenin via a conformational change in prorenin which exposes the catalytic site to angiotensinogen substrate. In addition, renin and prorenin binding results in phosphorylation of serine and tyrosine residues of ATP6AP2.
The level of renin mRNA appears to be modulated by the binding of HADHB, HuR and CP1 to a regulatory region in the 3' UTR.
# Genetics
The gene for renin, REN, spans 12 kb of DNA and contains 8 introns. It produces several mRNA that encode different REN isoforms.
Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease, so far found to be present in only 2 families. This disease is autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for dialysis or kidney transplantation. Many—but not all—patients and families with this disease suffer from an elevation in serum potassium and unexplained anemia relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40s while others may not go on dialysis until into their 70s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.
## Model organisms
Model organisms have been used in the study of REN function. A knockout mouse line, called Ren1Ren-1c Enhancer KO was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to bacterial infection. A more detailed analysis of this line indicated plasma creatinine was also increased and males had lower mean arterial pressure than controls.
# Clinical applications
An over-active renin-angiotension system leads to vasoconstriction and retention of sodium and water. These effects lead to hypertension. Therefore, renin inhibitors can be used for the treatment of hypertension. This is measured by the plasma renin activity (PRA).
In current medical practice, the renin–angiotensin–aldosterone system's overactivity (and resultant hypertension) is more commonly reduced using either ACE inhibitors (such as ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor. ACE inhibitors or ARBs are also part of the standard treatment after a heart attack.
The differential diagnosis of kidney cancer in a young patient with hypertension includes juxtaglomerular cell tumor (reninoma), Wilms' tumor, and renal cell carcinoma, all of which may produce renin.
## Measurement
Renin is usually measured as the plasma renin activity (PRA). PRA is measured specially in case of certain diseases that present with hypertension or hypotension. PRA is also raised in certain tumors. A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.
# Discovery and naming
The name renin = ren + -in, "kidney" + "compound". The most common pronunciation in English is /ˈriːnɪn/ (long e); /ˈrɛnɪn/ (short e) is also common, but using /ˈriːnɪn/ allows one to reserve /ˈrɛnɪn/ for rennin. Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology, and his student, Per Bergman, at the Karolinska Institute in Stockholm. | Renin
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the renin–angiotensin–aldosterone axis—that mediates the volume of extracellular fluid (blood plasma, lymph and interstitial fluid), and arterial vasoconstriction. Thus, it regulates the body's mean arterial blood pressure.
Renin can also be referred to as a hormone, as it has a receptor, the (pro)renin receptor, also known as the renin receptor and prorenin receptor [1] (see also below) as well as enzymatic activity with which it hydrolyzes angiotensinogen to angiotensin I.
# Biochemistry and physiology
## Structure
The primary structure of renin precursor consists of 406 amino acids with a pre- and a pro-segment carrying 20 and 46 amino acids, respectively. Mature renin contains 340 amino acids and has a mass of 37 kDa.[2]
## Secretion
The enzyme renin is secreted by pericytes (mural cells) (1) in the vicinity of the afferent arterioles and similar microvessels of the kidney from specialized cells of the juxtaglomerular apparatus—the juxtaglomerular cells, in response to three stimuli:
- A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways).
- A decrease in sodium load delivered to the distal tubule. This load is measured by the macula densa of the juxtaglomerular apparatus.
- Sympathetic nervous system activity, which also controls blood pressure, acting through the β1 adrenergic receptors.
Human renin is secreted by at least 2 cellular pathways: a constitutive pathway for the secretion of the precursor prorenin and a regulated pathway for the secretion of mature renin.[3]
## Renin–angiotensin system
File:Renin-angiotensin system in man shadow.svg
The renin enzyme circulates in the blood stream and hydrolyzes (breaks down) angiotensinogen secreted from the liver into the peptide angiotensin I.
Angiotensin I is further cleaved in the lungs by endothelial-bound angiotensin-converting enzyme (ACE) into angiotensin II, the most vasoactive peptide.[5][6] Angiotensin II is a potent constrictor of all blood vessels. It acts on the smooth muscle and, therefore, raises the resistance posed by these arteries to the heart. The heart, trying to overcome this increase in its 'load', works more vigorously, causing the blood pressure to rise. Angiotensin II also acts on the adrenal glands and releases aldosterone, which stimulates the epithelial cells in the distal tubule and collecting ducts of the kidneys to increase re-absorption of sodium, exchanging with potassium to maintain electrochemical neutrality, and water, leading to raised blood volume and raised blood pressure. The RAS also acts on the CNS to increase water intake by stimulating thirst, as well as conserving blood volume, by reducing urinary loss through the secretion of vasopressin from the posterior pituitary gland.
The normal concentration of renin in adult human plasma is 1.98–24.6 ng/L in the upright position.[7]
# Function
Renin activates the renin–angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin–converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. Renin's primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
Renin is secreted from juxtaglomerular kidney cells, which sense changes in renal perfusion pressure, via stretch receptors in the vascular walls. The juxtaglomerular cells are also stimulated to release renin by signaling from the macula densa. The macula densa senses changes in sodium delivery to the distal tubule, and responds to a drop in tubular sodium load by stimulating renin release in the juxtaglomerular cells. Together, the macula densa and juxtaglomerular cells comprise the juxtaglomerular complex.
Renin secretion is also stimulated by sympathetic nervous stimulation, mainly through beta-2 adrenergic receptor (β1 adrenoreceptor) activation.
The (pro)renin receptor to which renin and prorenin bind is encoded by the gene ATP6ap2, ATPase H(+)-transporting lysosomal accessory protein 2, which results in a fourfold increase in the conversion of angiotensinogen to angiotensin I over that shown by soluble renin as well as non-hydrolytic activation of prorenin via a conformational change in prorenin which exposes the catalytic site to angiotensinogen substrate. In addition, renin and prorenin binding results in phosphorylation of serine and tyrosine residues of ATP6AP2.[8]
The level of renin mRNA appears to be modulated by the binding of HADHB, HuR and CP1 to a regulatory region in the 3' UTR.[9]
# Genetics
The gene for renin, REN, spans 12 kb of DNA and contains 8 introns.[10] It produces several mRNA that encode different REN isoforms.
Mutations in the REN gene can be inherited, and are a cause of a rare inherited kidney disease, so far found to be present in only 2 families. This disease is autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and is a slowly progressive chronic kidney disease that leads to the need for dialysis or kidney transplantation. Many—but not all—patients and families with this disease suffer from an elevation in serum potassium and unexplained anemia relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their 40s while others may not go on dialysis until into their 70s. This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.[11]
## Model organisms
Model organisms have been used in the study of REN function. A knockout mouse line, called Ren1Ren-1c Enhancer KO was generated.[17] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][18] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a decreased heart rate and an increased susceptibility to bacterial infection.[15] A more detailed analysis of this line indicated plasma creatinine was also increased and males had lower mean arterial pressure than controls.[17]
# Clinical applications
An over-active renin-angiotension system leads to vasoconstriction and retention of sodium and water. These effects lead to hypertension. Therefore, renin inhibitors can be used for the treatment of hypertension.[19][20] This is measured by the plasma renin activity (PRA).
In current medical practice, the renin–angiotensin–aldosterone system's overactivity (and resultant hypertension) is more commonly reduced using either ACE inhibitors (such as ramipril and perindopril) or angiotensin II receptor blockers (ARBs, such as losartan, irbesartan or candesartan) rather than a direct oral renin inhibitor. ACE inhibitors or ARBs are also part of the standard treatment after a heart attack.
The differential diagnosis of kidney cancer in a young patient with hypertension includes juxtaglomerular cell tumor (reninoma), Wilms' tumor, and renal cell carcinoma, all of which may produce renin.[21]
## Measurement
Renin is usually measured as the plasma renin activity (PRA). PRA is measured specially in case of certain diseases that present with hypertension or hypotension. PRA is also raised in certain tumors.[22] A PRA measurement may be compared to a plasma aldosterone concentration (PAC) as a PAC/PRA ratio.
# Discovery and naming
The name renin = ren + -in, "kidney" + "compound". The most common pronunciation in English is /ˈriːnɪn/ (long e); /ˈrɛnɪn/ (short e) is also common, but using /ˈriːnɪn/ allows one to reserve /ˈrɛnɪn/ for rennin. Renin was discovered, characterized, and named in 1898 by Robert Tigerstedt, Professor of Physiology, and his student, Per Bergman, at the Karolinska Institute in Stockholm.[23][24] | https://www.wikidoc.org/index.php/Plasma_renin_activity | |
99aa0108f48726423c5b6fe52f472206044bb5b8 | wikidoc | Plunc | Plunc
Palate, lung, and nasal epithelium clone protein (PLUNC) is a gene encoding a secretory protein. It is also called Secretory protein in upper respiratory tracts (SPURT). In humans, it is encoded by the BPIFA1 gene, previously called PLUNC.
# Function
This gene is the human homolog of murine plunc, and like the mouse gene, is specifically expressed in the airways and nasopharyngeal regions. Plunc inhibits the epithelial sodium channel (ENaC), and also has anti-microbial functions. As such, plunc is believed to play a role in innate immune defense in the airways. PLUNC's ability to regulate ENaC is pH-sensitive and fails in acidic cystic fibrosis airways. Thus, defective PLUNC1 function is thought to contribute to the development of lung pathology in cystic fibrosis patients.
It may also serve as a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer. | Plunc
Palate, lung, and nasal epithelium clone protein[1] (PLUNC) is a gene encoding a secretory protein. It is also called Secretory protein in upper respiratory tracts (SPURT). In humans, it is encoded by the BPIFA1 gene, previously called PLUNC.[2][3]
# Function
This gene is the human homolog of murine plunc, and like the mouse gene, is specifically expressed in the airways and nasopharyngeal regions. Plunc inhibits the epithelial sodium channel (ENaC),[4] and also has anti-microbial functions.[5] As such, plunc is believed to play a role in innate immune defense in the airways. PLUNC's ability to regulate ENaC is pH-sensitive and fails in acidic cystic fibrosis airways.[6] Thus, defective PLUNC1 function is thought to contribute to the development of lung pathology in cystic fibrosis patients.
It may also serve as a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer.[7] | https://www.wikidoc.org/index.php/Plunc | |
6dfe8aef3651d2f7bb1c4b47b830717dcf5b356b | wikidoc | Poppy | Poppy
A poppy is any of a number of showy flowers, typically with
-ne per stem, belonging to the poppy family. They include a number of attractive wildflower species with showy flowers found growing singularly or in large groups; many species are also grown in gardens. Those that are grown in gardens include large plants used in a mixed herbaceous boarder and small plants that are grown in rock or alpine gardens.
The flower color of poppy species include: white, pink, yellow, orange, red and blue; some have dark center markings. The species that have been cultivated for many years also include many other colors ranging from dark solid colors to soft pastel shades. The center of the flower has a whorl of stamens surrounded by a cup- or bowl-shaped collection of four to six petals. Prior to blooming, the petals are crumpled in bud, and as blooming finishes, the petals often lie flat before falling away.
Poppies may be found in the genera:
- Meconopsis —— Himalayan poppy, Welsh poppy and relatives.
- Papaver —— Iceland poppy, Oriental poppy, Opium poppy, corn poppy and about 120 other species.
- Romneya —— Matilija poppy and relatives.
- Eschscholzia —— California poppy and relatives.
- Stylophorum —— Celandine-poppy, mock poppy, yellow-poppy, wood-poppy.
- Argemone —— Prickly-poppy
- Canbya —— Pygmy-poppy
- Stylomecon —— Wind-poppy
- Arctomecon —— Desert bearclaw-poppy
- Hunnemannia —— Tulip poppy
- Dendromecon —— Tree poppy
The pollen of the oriental poppy, Papaver orientale, is dark blue. The pollen of the field poppy or corn poppy (Papaver rhoeas) is dark blue to grey. Bees will use poppies as a pollen source.
The opium poppy, Papaver somniferum, is grown for opium, opiates or seeds to be used in cooking and baking, eg., Hungarian poppy seed rolls.
# Symbolism
Poppies have long been used as a symbol of both sleep and death: sleep because of the opium extracted from them, and death because of their (commonly) blood-red color. In Greco-Roman myths, poppies were used as offerings to the dead. Poppies are used as emblems on tombstones to symbolize eternal sleep. This aspect was used, fictionally, in The Wonderful Wizard of Oz to create magical poppy fields, dangerous because they caused those who passed through them to sleep forever.
A second meaning for the depiction and use of poppies in Greco-Roman myths is the symbolism of the bright scarlet colour as signifying the promise of resurrection after death.
The poppy of wartime remembrance is the red corn poppy, Papaver rhoeas. This poppy is a common weed in Europe and is found in many locations, including Flanders Fields. This is because the corn poppy was one of the only plants that grew on the battlefield. It thrives in disturbed soil, which was abundant on the battlefield due to intensive shelling. During the few weeks the plant blossomed, the battlefield was coloured blood red, not just from the red flower that grew in great numbers but also from the actual blood of the dead soldiers that lay scattered and untended to on the otherwise barren battlegrounds. Thus the plant became a symbol for the dead World War I soldiers. In many Commonwealth countries, artificial, paper versions of this poppy are worn to commemorate the sacrifice of veterans and civilians in World War I and other wars, during the weeks preceding Remembrance Day on November 11. It has been adopted as a symbol by The Royal British Legion in their Poppy Appeal.
In North America, poppies are known as Clown Shoes by the Royal Canadian Legion, who sell them each fall prior to Remembrance Day. The design of the Canadian poppy has changed recently. formerly the poppy was red plastic with a felt lining with a green centre held on by a pin. The green was to represent the green fields of France. In 2002 the design was changed with some small controversy to a black centre. This is to reflect the actual colour of the French poppy.
In New Zealand and Australia, paper poppies are widely distributed by the Returned Services Association leading up to ANZAC day (April 25th).
The golden poppy, Eschscholzia californica, is the state flower of California.
# False positive drug tests
Although the drug opium is produced by "milking" latex from the unripe fruits ("seed pods") rather than from the seeds, all parts of the plant can contain or carry the opium alkaloids, especially morphine and codeine. This means that eating foods (e.g., muffins) that contain poppy seeds can result in a false positive for opiates in a drug test.
While made popular in the sitcom Seinfeld, this was considered "confirmed" by the presenters of the television program MythBusters. One participant, Adam Savage, who ate an entire loaf of poppy seed cake, tested positive for opiates just half an hour later. A second participant, Jamie Hyneman, who ate three poppy seed bagels, first tested positive two hours after eating. Both tested positive for the remainder of the day, but were clean eighteen hours later. The show Brainiac: Science Abuse also did experiments where a priest ate several poppy seed bagels and gave a sample, which also resulted in a false positive.
The results of this experiment are inconclusive, because a test was used with an opiate cutoff level of 300 ng/mL instead of the current SAMHSA recommended cutoff level used in the NIDA 5 test, which was raised from 300 ng/mL to 2,000 ng/mL in 1998 in order to avoid false positives from poppy seeds . However, according to an article published in the Medical Science Law Journal, after ingesting "a curry meal or two containing various amounts of washed seeds" where total morphine levels were in the range 58.4 to 62.2 µg/g seeds, the urinary morphine levels were found to range as high as 1.27 µg/mL (1,270 ng/mL) urine . Another article in the Journal of Forensic Science reports that concentration of morphine in some batches of seeds may be as high as 251 µg/g . In both studies codeine was also present in the seeds in smaller concentrations. Therefore it is possible to cross the current standard 2,000 ng/mL limit of detection, depending on seed potency and quantity ingested. Some toxicology labs still continue to use a cutoff level of 300 ng/mL .
The sale of poppy seeds from Papaver somniferum is banned in Singapore due to the morphine content. Poppy seeds are also banned in Saudi Arabia due to various religious and drug control reasons.
# Food and drink
Poppy is widely consumed in many parts of Central and Eastern Europe. The sugared, milled mature seeds are eaten with pasta, or they are boiled with milk and used as filling or topping on various kinds of sweet pastry.
Poppy seeds are widely used in Bengali cuisine and in Oriya cuisine.
In Mexico, Grupo Modelo, the makers of Corona beer, until the 60s used red poppy flowers in its advertising, where almost any image it used had poppy flowers somewhere in the image.
# The poppy in literature
What may be the most famous literary use of the poppy occurs both in L. Frank Baum's The Wonderful Wizard of Oz and in MGM's classic 1939 film based on the novel.
In the novel, while on their way to the Emerald City, Dorothy, the Scarecrow, the Tin Man and the Cowardly Lion walk through a field of poppies, and the opium from the flowers puts both Dorothy and the Lion to sleep. The Scarecrow and the Tin Man, not being made of flesh and blood, are unaffected. They carry Dorothy to safety and place her on the ground beyond the poppy field. While they are considering how to help the Lion, a field mouse runs in front of them, fleeing a cougar. The Tin Man beheads the cougar with his axe, and the field mouse pledges her eternal gratitude. Being the Queen of the Field Mice, she gathers all her subjects together. The Tin Man cuts down several trees, and builds a wagon. The Lion is pushed onto it, and the mice pull the wagon safely out of the poppy field.
In the 1939 film, the sequence is considerably altered. The poppy field is conjured up by the Wicked Witch of the West, and it appears directly in front of the Emerald City, preventing the four travelers from reaching it. As in the novel, Dorothy and the Cowardly Lion fall asleep, but in a direct reversal of the book, the Scarecrow and the Tin Man are unable to carry Dorothy. Glinda, who has been watching over them, conjures up a snowfall which kills the poppies and enables Dorothy and the Lion to awaken. Unfortunately, the Tin Man has been weeping in despair, and the combination of his tears and the wet snow has caused him to rust. After he is oiled by Dorothy, the four skip happily toward the Emerald City.
# Gallery
- Close-up of an Oriental poppy (Papaver orientale). Ontario, Canada. June 2002.
Close-up of an Oriental poppy (Papaver orientale). Ontario, Canada. June 2002.
- A poppy bud and plant.
A poppy bud and plant.
- Immature crowning Opium Poppy, top view.
Immature crowning Opium Poppy, top view.
- A poppy bud opening.
A poppy bud opening.
- Papaver somniferum seeds.
Papaver somniferum seeds.
- Papaver rhoeas.
Papaver rhoeas.
- Closeup of a poppy flower in private garden, Derbyshire, England, UK, May 2007.
Closeup of a poppy flower in private garden, Derbyshire, England, UK, May 2007.
- Close up view of a poppy bloom (and buds in the background). Papaver somniferum. See Opium Poppy.
Close up view of a poppy bloom (and buds in the background). Papaver somniferum. See Opium Poppy.
- Closeup of a poppy flower at the Monastery of Lorch, Baden-Württemberg, Germany.
Closeup of a poppy flower at the Monastery of Lorch, Baden-Württemberg, Germany.
- California Poppy.
California Poppy.
- Field of poppies, from a photograph by Sergei Mikhailovich Prokudin-Gorskii, taken ca. 1912.
Field of poppies, from a photograph by Sergei Mikhailovich Prokudin-Gorskii, taken ca. 1912.
- A wild field of poppies, above the Wye Valley, UK, in June 2006.
A wild field of poppies, above the Wye Valley, UK, in June 2006.
- Poppies near Kelling, North Norfolk, UK, in June 2002
Poppies near Kelling, North Norfolk, UK, in June 2002 | Poppy
Template:This
A poppy is any of a number of showy flowers, typically with
one per stem, belonging to the poppy family. They include a number of attractive wildflower species with showy flowers found growing singularly or in large groups; many species are also grown in gardens. Those that are grown in gardens include large plants used in a mixed herbaceous boarder and small plants that are grown in rock or alpine gardens.
The flower color of poppy species include: white, pink, yellow, orange, red and blue; some have dark center markings. The species that have been cultivated for many years also include many other colors ranging from dark solid colors to soft pastel shades. The center of the flower has a whorl of stamens surrounded by a cup- or bowl-shaped collection of four to six petals. Prior to blooming, the petals are crumpled in bud, and as blooming finishes, the petals often lie flat before falling away.
Poppies may be found in the genera:
- Meconopsis —— Himalayan poppy, Welsh poppy and relatives.
- Papaver —— Iceland poppy, Oriental poppy, Opium poppy, corn poppy and about 120 other species.
- Romneya —— Matilija poppy and relatives.
- Eschscholzia —— California poppy and relatives.
- Stylophorum —— Celandine-poppy, mock poppy, yellow-poppy, wood-poppy.
- Argemone —— Prickly-poppy
- Canbya —— Pygmy-poppy
- Stylomecon —— Wind-poppy
- Arctomecon —— Desert bearclaw-poppy
- Hunnemannia —— Tulip poppy
- Dendromecon —— Tree poppy
The pollen of the oriental poppy, Papaver orientale, is dark blue. The pollen of the field poppy or corn poppy (Papaver rhoeas) is dark blue to grey. Bees will use poppies as a pollen source.
The opium poppy, Papaver somniferum, is grown for opium, opiates or seeds to be used in cooking and baking, eg., Hungarian poppy seed rolls.
# Symbolism
Poppies have long been used as a symbol of both sleep and death: sleep because of the opium extracted from them, and death because of their (commonly) blood-red color. In Greco-Roman myths, poppies were used as offerings to the dead.[1] Poppies are used as emblems on tombstones to symbolize eternal sleep. This aspect was used, fictionally, in The Wonderful Wizard of Oz to create magical poppy fields, dangerous because they caused those who passed through them to sleep forever.[2]
A second meaning for the depiction and use of poppies in Greco-Roman myths is the symbolism of the bright scarlet colour as signifying the promise of resurrection after death. [3]
The poppy of wartime remembrance is the red corn poppy, Papaver rhoeas. This poppy is a common weed in Europe and is found in many locations, including Flanders Fields. This is because the corn poppy was one of the only plants that grew on the battlefield. It thrives in disturbed soil, which was abundant on the battlefield due to intensive shelling. During the few weeks the plant blossomed, the battlefield was coloured blood red, not just from the red flower that grew in great numbers but also from the actual blood of the dead soldiers that lay scattered and untended to on the otherwise barren battlegrounds.[citation needed] Thus the plant became a symbol for the dead World War I soldiers. In many Commonwealth countries, artificial, paper versions of this poppy are worn to commemorate the sacrifice of veterans and civilians in World War I and other wars, during the weeks preceding Remembrance Day on November 11. It has been adopted as a symbol by The Royal British Legion in their Poppy Appeal.
In North America, poppies are known as Clown Shoes by the Royal Canadian Legion, who sell them each fall prior to Remembrance Day. The design of the Canadian poppy has changed recently. formerly the poppy was red plastic with a felt lining with a green centre held on by a pin. The green was to represent the green fields of France. In 2002 the design was changed with some small controversy to a black centre. This is to reflect the actual colour of the French poppy.
In New Zealand and Australia, paper poppies are widely distributed by the Returned Services Association leading up to ANZAC day (April 25th).
The golden poppy, Eschscholzia californica, is the state flower of California.
# False positive drug tests
Although the drug opium is produced by "milking" latex from the unripe fruits ("seed pods") rather than from the seeds, all parts of the plant can contain or carry the opium alkaloids, especially morphine and codeine. This means that eating foods (e.g., muffins) that contain poppy seeds can result in a false positive for opiates in a drug test.
While made popular in the sitcom Seinfeld, this was considered "confirmed" by the presenters of the television program MythBusters. One participant, Adam Savage, who ate an entire loaf of poppy seed cake, tested positive for opiates just half an hour later. A second participant, Jamie Hyneman, who ate three poppy seed bagels, first tested positive two hours after eating. Both tested positive for the remainder of the day, but were clean eighteen hours later. The show Brainiac: Science Abuse also did experiments where a priest ate several poppy seed bagels and gave a sample, which also resulted in a false positive.
The results of this experiment are inconclusive, because a test was used with an opiate cutoff level of 300 ng/mL instead of the current SAMHSA recommended cutoff level used in the NIDA 5 test, which was raised from 300 ng/mL to 2,000 ng/mL in 1998 in order to avoid false positives from poppy seeds [1]. However, according to an article published in the Medical Science Law Journal, after ingesting "a curry meal or two containing various amounts of washed seeds" where total morphine levels were in the range 58.4 to 62.2 µg/g seeds, the urinary morphine levels were found to range as high as 1.27 µg/mL (1,270 ng/mL) urine [2]. Another article in the Journal of Forensic Science reports that concentration of morphine in some batches of seeds may be as high as 251 µg/g [3]. In both studies codeine was also present in the seeds in smaller concentrations. Therefore it is possible to cross the current standard 2,000 ng/mL limit of detection, depending on seed potency and quantity ingested. Some toxicology labs still continue to use a cutoff level of 300 ng/mL [4].
The sale of poppy seeds from Papaver somniferum is banned in Singapore due to the morphine content. Poppy seeds are also banned in Saudi Arabia due to various religious and drug control reasons.[4]
# Food and drink
Poppy is widely consumed in many parts of Central and Eastern Europe. The sugared, milled mature seeds are eaten with pasta, or they are boiled with milk and used as filling or topping on various kinds of sweet pastry.
Poppy seeds are widely used in Bengali cuisine and in Oriya cuisine.
In Mexico, Grupo Modelo, the makers of Corona beer, until the 60s used red poppy flowers in its advertising, where almost any image it used had poppy flowers somewhere in the image.
# The poppy in literature
What may be the most famous literary use of the poppy occurs both in L. Frank Baum's The Wonderful Wizard of Oz and in MGM's classic 1939 film based on the novel.
In the novel, while on their way to the Emerald City, Dorothy, the Scarecrow, the Tin Man and the Cowardly Lion walk through a field of poppies, and the opium from the flowers puts both Dorothy and the Lion to sleep. The Scarecrow and the Tin Man, not being made of flesh and blood, are unaffected. They carry Dorothy to safety and place her on the ground beyond the poppy field. While they are considering how to help the Lion, a field mouse runs in front of them, fleeing a cougar. The Tin Man beheads the cougar with his axe, and the field mouse pledges her eternal gratitude. Being the Queen of the Field Mice, she gathers all her subjects together. The Tin Man cuts down several trees, and builds a wagon. The Lion is pushed onto it, and the mice pull the wagon safely out of the poppy field.
In the 1939 film, the sequence is considerably altered. The poppy field is conjured up by the Wicked Witch of the West, and it appears directly in front of the Emerald City, preventing the four travelers from reaching it. As in the novel, Dorothy and the Cowardly Lion fall asleep, but in a direct reversal of the book, the Scarecrow and the Tin Man are unable to carry Dorothy. Glinda, who has been watching over them, conjures up a snowfall which kills the poppies and enables Dorothy and the Lion to awaken. Unfortunately, the Tin Man has been weeping in despair, and the combination of his tears and the wet snow has caused him to rust. After he is oiled by Dorothy, the four skip happily toward the Emerald City.
# Gallery
- Close-up of an Oriental poppy (Papaver orientale). Ontario, Canada. June 2002.
Close-up of an Oriental poppy (Papaver orientale). Ontario, Canada. June 2002.
- A poppy bud and plant.
A poppy bud and plant.
- Immature crowning Opium Poppy, top view.
Immature crowning Opium Poppy, top view.
- A poppy bud opening.
A poppy bud opening.
- Papaver somniferum seeds.
Papaver somniferum seeds.
- Papaver rhoeas.
Papaver rhoeas.
- Closeup of a poppy flower in private garden, Derbyshire, England, UK, May 2007.
Closeup of a poppy flower in private garden, Derbyshire, England, UK, May 2007.
- Close up view of a poppy bloom (and buds in the background). Papaver somniferum. See Opium Poppy.
Close up view of a poppy bloom (and buds in the background). Papaver somniferum. See Opium Poppy.
- Closeup of a poppy flower at the Monastery of Lorch, Baden-Württemberg, Germany.
Closeup of a poppy flower at the Monastery of Lorch, Baden-Württemberg, Germany.
- California Poppy.
California Poppy.
- Field of poppies, from a photograph by Sergei Mikhailovich Prokudin-Gorskii, taken ca. 1912.
Field of poppies, from a photograph by Sergei Mikhailovich Prokudin-Gorskii, taken ca. 1912.
- A wild field of poppies, above the Wye Valley, UK, in June 2006.
A wild field of poppies, above the Wye Valley, UK, in June 2006.
- Poppies near Kelling, North Norfolk, UK, in June 2002
Poppies near Kelling, North Norfolk, UK, in June 2002 | https://www.wikidoc.org/index.php/Poppy | |
ef8fdddaa929193803eb20dc829bc9e81f7656cd | wikidoc | Prion | Prion
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A prion (Template:IPAEng — short for proteinaceous infectious particle (-on by analogy to virion) — is an infectious agent composed only of protein. They cause a number of diseases in a variety of animals, including BSE in cattle and CJD in humans. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and fatal. Mice genetically modified to avoid the symptoms are important models of study. In general usage, prion can refer to both the theoretical unit of infection or the specific protein (e.g., PrP) that is thought to be the infective agent, whether or not it is in an infective state. Prion diseases can result from modification of a host-encoded glycoprotein (i.e. PrP)("protease resistant protein") which disrupts normal synaptic function.
Prions are believed to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. However, the term in itself does not preclude other mechanisms of transmission. All known prions induce the formation of an amyloid fold, in which the protein polymerizes into a fiber with a core consisting of tightly packed beta sheets. Other mechanisms may exist in yet undiscovered infectious protein particles. This altered structure renders them quite resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult; even so, infectivity may be reduced by these treatments to a degree.
Proteins showing prion behaviour are also found in some fungi. Some fungal prions may not be associated with any disease; it is unknown whether these prions represent an evolutionary advantage for their hosts.
# Discovery
Radiation biologist Tikvah Alper and physicist J.S. Griffith developed the theory in the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent made solely of protein. This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet radiation (which breaks down nucleic acids - present in viruses and all living things) yet responded to agents that disrupt proteins.
Francis Crick recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his famous "Central dogma of molecular biology" (Nature. 1970 Aug 8;227(5258):561-3). While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded" by the dogma, he noted that Griffith's hypothesis was a potential difficulty (although it was not so promoted by Griffith). As the revised "dogma" was formulated, in part, to accommodate the then recent discovery of reverse transcription by Howard Temin and David Baltimore (Nobel Prize, 1975), proof of the protein-only hypothesis might have been seen as a sure bet for a future Prize.
Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified infectious material and that the infectious agent consisted mainly of a specific protein, although they had not managed to satisfactorily isolate the protein until two years after making his announcement.
Prusiner coined the word "prion" as a name for the infectious agent, by combining the first two syllables of the words proteinaceous and infectious. While the infectious agent was named a prion, the specific protein that the prion was made of was named PrP, an abbreviation for "protease-resistant protein". Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.
# Structure
## Isoforms
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.
### PrPC
PrPC is a normal protein found on the membranes of cells. Several topological forms of it exist; one cell surface form anchored via glycolipid and two transmembrane forms, however its function has not been fully resolved. PrPC is readily digested by proteinase K and can be liberated from the cell surface by the enzyme phosphatidyl inositol-specific phospholipase C, which cleaves the phosphatidyl inositol glycolipid anchor. A typical yeast prion protein contains a core region (domain) with many repeats of the amino acids glutamine and asparagine. Normal yeast prion domains are flexible and lack a defined structure.
### PrPSc
The infectious isoform of PrPC, known as PrPSc, is able to catalyse the formation of other normal PrPC proteins into the infectious isoform by changing their conformation.
Although the exact 3D structure of PrPSc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix. Aggregations of these abnormal isoforms forms a highly structured amyloid fiber. The end of the fiber acts as a template for the free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber. The mammalian prion proteins do not resemble the prion proteins of yeast in their amino acid sequence, however, they are still known as PrPC and PrPSc and share basic structural features.
# Function
## PrP and long-term memory
There is evidence that PrP may have a normal function in maintenance of long term memory. Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP.
# Prion disease
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterised by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons. Other histological changes include astrogliosis and the absence of an inflammatory reaction. While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE, building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.
Prions are able to affect a variety of different species, however the prions involved are somewhat species-specific: they are similar but not identical. However overlap may occur; the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.
Metal ion interactions with prion proteins might be relevant to the progression of prion-mediated disease, based on epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper.
The following diseases are believed to be caused by prions.
- In animals:
Scrapie in sheep and goats
Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease)
Transmissible mink encephalopathy (TME) in mink
Chronic wasting disease (CWD) in elk and mule deer
Feline spongiform encephalopathy in cats
Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu
Spongiform encephalopathy of the ostrich
- Scrapie in sheep and goats
- Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease)
- Transmissible mink encephalopathy (TME) in mink
- Chronic wasting disease (CWD) in elk and mule deer
- Feline spongiform encephalopathy in cats
- Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu
- Spongiform encephalopathy of the ostrich
- In humans:
Creutzfeldt-Jakob disease (CJD) and its varieties: iatrogenic Creutzfeldt-Jakob disease (iCJD), variant Creutzfeldt-Jakob disease (vCJD), familial Creutzfeldt-Jakob disease (fCJD), and sporadic Creutzfeldt-Jakob disease (sCJD)
Gerstmann-Sträussler-Scheinker syndrome (GSS)
Fatal familial insomnia (fFI)
Sporadic fatal insomnia (sFI)
Kuru
Alpers syndrome
- Creutzfeldt-Jakob disease (CJD) and its varieties: iatrogenic Creutzfeldt-Jakob disease (iCJD), variant Creutzfeldt-Jakob disease (vCJD), familial Creutzfeldt-Jakob disease (fCJD), and sporadic Creutzfeldt-Jakob disease (sCJD)
- Gerstmann-Sträussler-Scheinker syndrome (GSS)
- Fatal familial insomnia (fFI)
- Sporadic fatal insomnia (sFI)
- Kuru
- Alpers syndrome
## Transmission
Although the identity and general properties of prions are now well-understood, the mechanism of prion infection and propagation remains mysterious. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.
Current research suggests that the primary method of infection is through ingestion. Prions are deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They linger in the soil for at least three years by binding to clay and other minerals. This process in many cases makes the disease more transmissible.
## Sterilization
Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions however, are infectious by their effect on normal versions of the protein. Therefore, sterilizing prions involves the denaturation of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins. However, prions are generally quite resistant to denaturation by proteases, heat, radiation, and formalin treatments, although their infectivity can be reduced by such treatments.
Prions can be denatured by subjecting them to a temperatures of 134 degrees Celsius for 18 minutes in a pressurised steam autoclave. Ozone sterilization is currently being studied as a potential method for prion deactivation. Renaturation of a completely denatured prion to infectious status has not yet been achieved, however partially denatured prions can be renatured to an infective status under certain artificial conditions.
## Debate
### Protein-only hypothesis
Prior to the discovery of prions, it was thought that all pathogens used nucleic acids to direct their replication. The "protein-only hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was initially controversial as it contradicts the so-called "central dogma of modern biology," which describes nucleic acid as the central form of replicative information.
Evidence in favor of a protein-only hypothesis include:
- No virus particles have been conclusively associated with prion diseases
- No nucleic acid has been conclusively associated with infectivity; agent is resistant to degradation by nucleases
- No immune response to infection
- PrPSc experimentally transmitted between one species and another results in PrPSc with the amino-acid sequence of the recipient species, suggesting that replication of the donor agent does not occur
- Level of infectivity is associated with levels of PrPSc
- PrPSc and PrPC do not differ in amino-acid sequence, therefore a PrPSc-specific nucleic acid is a redundant concept
- Familial prion disease occurs in families with a mutation in the PrP gene, and mice with PrP mutations develop prion disease despite controlled conditions where transmission is prevented
- PrPSc has been shown to arise from exposure of PrPC to molecules of PrPSc
### Viral hypothesis
The protein-only hypothesis was initially met with skepticism and still has critics. For more than a decade, Yale University neuropathologist Laura Manuelidis has been proposing that prion diseases are caused instead by an unidentifiable "slow virus". In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science reporting to have found the virus in 10%, or less, of their scrapie-infected cells in culture.
Evidence in favor of a viral hypothesis include:
- No bacteria or other living organisms have been found in prion-affected organisms, defaulting to the idea that a virus must be involved
- The long incubation and rapid onset of symptoms resembles some viral infections, such as HIV-induced AIDS
- Differences in prion infectivity, incubation, symptomology and progression among species resembles the "strain variation" seen between viruses, especially RNA viruses
- Familial prion disease is proposed to be due to genetic predisposition to the viral agent
### Heavy Metal Poisoning hypothesis
Mark Purdey and Dr. David R. Brown have suggested that prions be accepted in the role of anti-oxidant molecules in conjunction with copper. Brown suggests that manganese can degrade the protein. This would be relevant to calling it a protein ion and declaring it an enzyme or ionophore. Purdey cited epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper as evidence.
Brown, an Oxford professor, agrees that banning cannibalism in cows was a justifiable course of action. It also follows from his work that carnivorous animals may be hazardous, because the pathogen may only show up as disease in animals with a long life.
Evidence in favor of a pollutant cause:
- Compounds of carbon and nitrogen vaporize at one thousand degrees Fahrenheit, but the agent for causing scrapie in sheep does not.
- Alzheimer's disease has similar symptoms, and has been attributed to excessive Aluminum.
- Copper deficiency and Manganese proficiency have been found in the environment of affected cattle.
# Genetics
A gene for the normal protein has been isolated: the PRNP gene. Some prion diseases can be inherited, and in all inherited cases there is a mutation in the PRNP gene. Many different PRNP mutations have been identified and it is thought that the mutations somehow make PrPC more likely to spontaneously change into the abnormal PrPSc form. Prion diseases are the only known diseases that can be sporadic, genetic, or infectious.
It should be noted that the same gene is responsible for spongiform encephalopathies which are not known to be transmissible, as well as some non-neurological diseases. Some require a mutation for transmission to occur, and there are respective mutations which can prevent or protect against transmission for most of the TSEs (eg. mutations leading to total absence of the PRNP gene or heterozygosity at codon 129 of the same gene). The normal role of the prion gene has yet to be found, and so it is an area of considerable active research. Indeed gene knockout mice lacking the prion gene only exhibit subtle differences and seem to be incapable of acquiring spongiforme encephalopathy.
# Prions in yeast and other fungi
Prion-like proteins that behave in a similar way to PrP are found naturally in some fungi and non-mammalian animals. A group at the Whitehead Institute has argued that some of the fungal prions are not associated with any disease state and may have a useful role; however, researchers at the NIH have also provided strong arguments demonstrating that fungal prions should be considered a diseased state. Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, as it has been demonstrated that seeds extracted from cells with the prion state, can convert the normal form of the protein into the infectious form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions. | Prion
Template:DiseaseDisorder infobox
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A prion (Template:IPAEng[1] — short for proteinaceous infectious particle (-on by analogy to virion) — is an infectious agent composed only of protein. They cause a number of diseases in a variety of animals, including BSE in cattle and CJD in humans. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and fatal. Mice genetically modified to avoid the symptoms are important models of study.[2] In general usage, prion can refer to both the theoretical unit of infection or the specific protein (e.g., PrP) that is thought to be the infective agent, whether or not it is in an infective state. Prion diseases can result from modification of a host-encoded glycoprotein (i.e. PrP)("protease resistant protein") which disrupts normal synaptic function.[3]
Prions are believed to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. However, the term in itself does not preclude other mechanisms of transmission. All known prions induce the formation of an amyloid fold, in which the protein polymerizes into a fiber with a core consisting of tightly packed beta sheets. Other mechanisms may exist in yet undiscovered infectious protein particles. This altered structure renders them quite resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult; even so, infectivity may be reduced by these treatments to a degree.
Proteins showing prion behaviour are also found in some fungi. Some fungal prions may not be associated with any disease; it is unknown whether these prions represent an evolutionary advantage for their hosts.
# Discovery
Radiation biologist Tikvah Alper and physicist J.S. Griffith developed the theory in the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent made solely of protein.[4][5] This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet radiation (which breaks down nucleic acids - present in viruses and all living things) yet responded to agents that disrupt proteins.
Francis Crick recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his famous "Central dogma of molecular biology" (Nature. 1970 Aug 8;227(5258):561-3). While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded" by the dogma, he noted that Griffith's hypothesis was a potential difficulty (although it was not so promoted by Griffith). As the revised "dogma" was formulated, in part, to accommodate the then recent discovery of reverse transcription by Howard Temin and David Baltimore (Nobel Prize, 1975), proof of the protein-only hypothesis might have been seen as a sure bet for a future Prize.
Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified infectious material and that the infectious agent consisted mainly of a specific protein, although they had not managed to satisfactorily isolate the protein until two years after making his announcement.[6]
Prusiner coined the word "prion" as a name for the infectious agent, by combining the first two syllables of the words proteinaceous and infectious.[7] While the infectious agent was named a prion, the specific protein that the prion was made of was named PrP, an abbreviation for "protease-resistant protein". Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.[8]
# Structure
## Isoforms
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.
### PrPC
PrPC is a normal protein found on the membranes of cells. Several topological forms of it exist; one cell surface form anchored via glycolipid and two transmembrane forms,[9] however its function has not been fully resolved.[10] PrPC is readily digested by proteinase K and can be liberated from the cell surface by the enzyme phosphatidyl inositol-specific phospholipase C, which cleaves the phosphatidyl inositol glycolipid anchor.[11] A typical yeast prion protein contains a core region (domain) with many repeats of the amino acids glutamine and asparagine. Normal yeast prion domains are flexible and lack a defined structure.[12]
### PrPSc
The infectious isoform of PrPC, known as PrPSc, is able to catalyse the formation of other normal PrPC proteins into the infectious isoform by changing their conformation.
Although the exact 3D structure of PrPSc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix.[13] Aggregations of these abnormal isoforms forms a highly structured amyloid fiber. The end of the fiber acts as a template for the free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber. The mammalian prion proteins do not resemble the prion proteins of yeast in their amino acid sequence, however, they are still known as PrPC and PrPSc and share basic structural features.
# Function
## PrP and long-term memory
There is evidence that PrP may have a normal function in maintenance of long term memory.[14] Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP.[15]
# Prion disease
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterised by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.[16] Other histological changes include astrogliosis and the absence of an inflammatory reaction.[17] While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death.[18] Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal.[19] However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections.[20] Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE,[21] building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.[22]
Prions are able to affect a variety of different species, however the prions involved are somewhat species-specific: they are similar but not identical.[23] However overlap may occur; the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.[24]
Metal ion interactions with prion proteins might be relevant to the progression of prion-mediated disease, based on epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper.[25]
The following diseases are believed to be caused by prions.
- In animals:
Scrapie in sheep and goats[26]
Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease)[26]
Transmissible mink encephalopathy (TME) in mink[26]
Chronic wasting disease (CWD) in elk and mule deer[26]
Feline spongiform encephalopathy in cats[26]
Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu[26]
Spongiform encephalopathy of the ostrich[27]
- Scrapie in sheep and goats[26]
- Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease)[26]
- Transmissible mink encephalopathy (TME) in mink[26]
- Chronic wasting disease (CWD) in elk and mule deer[26]
- Feline spongiform encephalopathy in cats[26]
- Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu[26]
- Spongiform encephalopathy of the ostrich[27]
- In humans:
Creutzfeldt-Jakob disease (CJD)[26] and its varieties: iatrogenic Creutzfeldt-Jakob disease (iCJD), variant Creutzfeldt-Jakob disease (vCJD), familial Creutzfeldt-Jakob disease (fCJD), and sporadic Creutzfeldt-Jakob disease (sCJD)
Gerstmann-Sträussler-Scheinker syndrome (GSS)[26]
Fatal familial insomnia (fFI)[26]
Sporadic fatal insomnia (sFI)[28]
Kuru[26]
Alpers syndrome[27]
- Creutzfeldt-Jakob disease (CJD)[26] and its varieties: iatrogenic Creutzfeldt-Jakob disease (iCJD), variant Creutzfeldt-Jakob disease (vCJD), familial Creutzfeldt-Jakob disease (fCJD), and sporadic Creutzfeldt-Jakob disease (sCJD)
- Gerstmann-Sträussler-Scheinker syndrome (GSS)[26]
- Fatal familial insomnia (fFI)[26]
- Sporadic fatal insomnia (sFI)[28]
- Kuru[26]
- Alpers syndrome[27]
## Transmission
Although the identity and general properties of prions are now well-understood, the mechanism of prion infection and propagation remains mysterious. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.[29]
Current research suggests that the primary method of infection is through ingestion. Prions are deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They linger in the soil for at least three years by binding to clay and other minerals. This process in many cases makes the disease more transmissible.[30]
## Sterilization
Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions however, are infectious by their effect on normal versions of the protein. Therefore, sterilizing prions involves the denaturation of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins. However, prions are generally quite resistant to denaturation by proteases, heat, radiation, and formalin treatments,[31] although their infectivity can be reduced by such treatments.
Prions can be denatured by subjecting them to a temperatures of 134 degrees Celsius for 18 minutes in a pressurised steam autoclave.[32] Ozone sterilization is currently being studied as a potential method for prion deactivation.[33] Renaturation of a completely denatured prion to infectious status has not yet been achieved, however partially denatured prions can be renatured to an infective status under certain artificial conditions.[34]
## Debate
### Protein-only hypothesis
Prior to the discovery of prions, it was thought that all pathogens used nucleic acids to direct their replication. The "protein-only hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was initially controversial as it contradicts the so-called "central dogma of modern biology," which describes nucleic acid as the central form of replicative information.
Evidence in favor of a protein-only hypothesis include:[35]
- No virus particles have been conclusively associated with prion diseases
- No nucleic acid has been conclusively associated with infectivity; agent is resistant to degradation by nucleases
- No immune response to infection
- PrPSc experimentally transmitted between one species and another results in PrPSc with the amino-acid sequence of the recipient species, suggesting that replication of the donor agent does not occur
- Level of infectivity is associated with levels of PrPSc
- PrPSc and PrPC do not differ in amino-acid sequence, therefore a PrPSc-specific nucleic acid is a redundant concept
- Familial prion disease occurs in families with a mutation in the PrP gene, and mice with PrP mutations develop prion disease despite controlled conditions where transmission is prevented
- PrPSc has been shown to arise from exposure of PrPC to molecules of PrPSc
### Viral hypothesis
The protein-only hypothesis was initially met with skepticism and still has critics. For more than a decade, Yale University neuropathologist Laura Manuelidis has been proposing that prion diseases are caused instead by an unidentifiable "slow virus". In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science reporting to have found the virus in 10%, or less, of their scrapie-infected cells in culture.[36][37]
Evidence in favor of a viral hypothesis include:[35]
- No bacteria or other living organisms have been found in prion-affected organisms, defaulting to the idea that a virus must be involved
- The long incubation and rapid onset of symptoms resembles some viral infections, such as HIV-induced AIDS
- Differences in prion infectivity, incubation, symptomology and progression among species resembles the "strain variation" seen between viruses, especially RNA viruses
- Familial prion disease is proposed to be due to genetic predisposition to the viral agent
### Heavy Metal Poisoning hypothesis
Mark Purdey and Dr. David R. Brown have suggested that prions be accepted in the role of anti-oxidant molecules in conjunction with copper. Brown suggests that manganese can degrade the protein. This would be relevant to calling it a protein ion and declaring it an enzyme or ionophore.[38] Purdey cited epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper as evidence.
Brown, an Oxford professor, agrees that banning cannibalism in cows was a justifiable course of action. It also follows from his work that carnivorous animals may be hazardous, because the pathogen may only show up as disease in animals with a long life.
Evidence in favor of a pollutant cause:
- Compounds of carbon and nitrogen vaporize at one thousand degrees Fahrenheit, but the agent for causing scrapie in sheep does not.
- Alzheimer's disease has similar symptoms, and has been attributed to excessive Aluminum.
- Copper deficiency and Manganese proficiency have been found in the environment of affected cattle.
# Genetics
A gene for the normal protein has been isolated: the PRNP gene.[39] Some prion diseases can be inherited, and in all inherited cases there is a mutation in the PRNP gene. Many different PRNP mutations have been identified and it is thought that the mutations somehow make PrPC more likely to spontaneously change into the abnormal PrPSc form. Prion diseases are the only known diseases that can be sporadic, genetic, or infectious.
It should be noted that the same gene is responsible for spongiform encephalopathies which are not known to be transmissible, as well as some non-neurological diseases. Some require a mutation for transmission to occur, and there are respective mutations which can prevent or protect against transmission for most of the TSEs (eg. mutations leading to total absence of the PRNP gene or heterozygosity at codon 129 of the same gene).[16] The normal role of the prion gene has yet to be found, and so it is an area of considerable active research. Indeed gene knockout mice lacking the prion gene only exhibit subtle differences and seem to be incapable of acquiring spongiforme encephalopathy.
# Prions in yeast and other fungi
Prion-like proteins that behave in a similar way to PrP are found naturally in some fungi and non-mammalian animals. A group at the Whitehead Institute has argued that some of the fungal prions are not associated with any disease state and may have a useful role; however, researchers at the NIH have also provided strong arguments demonstrating that fungal prions should be considered a diseased state. Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, as it has been demonstrated that seeds extracted from cells with the prion state, can convert the normal form of the protein into the infectious form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions. | https://www.wikidoc.org/index.php/Prion | |
95a23844f7ef1ca94f6bed4c35e537653b2e3204 | wikidoc | Vulva | Vulva
The vulva (from Latin, vulva, plural vulvae or vulvas; see etymology) is the region of the external genital organs of the female, including the labia majora, mons pubis, labia minora, clitoris, bulb of the vestibule, vestibule of the vagina, greater and lesser vestibular glands, and vaginal orifice.
The vulva has many major and minor anatomical structures. Its development occurs during several phases, chiefly the fetal and pubertal periods. The vulva protects the vaginal opening by a "double door": the labia majora and the labia minora as well as a vulval vestibule, and a normal microbial flora that flows from the inside out. Normal external cleanliness is usually sufficient to assure good vulvovaginal health, without recourse to any internal cleansing. The vulva is more susceptible to infections than the penis.
These external body structures also have a sexual function; they are richly innervated and provide pleasure during sexual intercourse when properly stimulated. Since the origin of human society, in various branches of art the vulva has been depicted as the organ that has the power both "to give life" (i.e., often confused and associated with the vagina in pre-historic periods and antiquity, decreasingly as science has progressed), and to give sexual pleasure to humankind.
In common speech, the term vagina is often used to refer to the vulva or female genitals generally, although, strictly speaking, the vagina is a specific internal structure, whereas the vulva is the exterior genitalia.
This article deals with the human vulva, although the structures are similar for other mammals.
# Linguistics
## Etymology
The word "vulva" was taken from Middle Latin volva or vulva "womb, female genitals", probably from Latin volvere "to roll" (lit. "wrapper"). Similar to Sanskrit ulva "womb".
An alternate term, also from Latin, is genitalia feminina externa.
## Slang
As with nearly any aspect of the human body that is involved in sexual or excretory functions, there are many slang words for the vulva.
# Sexual homology
Most male and female sex organs originate from the same tissues in the development of a foetus. The vulva is no different. The anatomy of the vulva is related to the anatomy of the male genitalia by a shared developmental biology. Organs that have a common developmental ancestry in this way are said to be homologous.
The clitoral glans is homologous to the glans penis in males, and the clitoral body and the clitoral crura are homologous to the corpora cavernosa of the penis. The labia majora, labia minora and clitoral hood are homologous to the scrotum, shaft skin of the penis, and the foreskin, respectively. The vestibular bulbs beneath the skin of the labia minora are homologous to the corpus spongiosum, the tissue of the penis surrounding the urethra. The Bartholin's glands are homologous to Cowper's glands in males.
# Structures
In human beings, major structures of the vulva are:
- the mons pubis
- the labia, consisting of the labia majora and the labia minora
- the external portion of the clitoris and the clitoral hood
- the vulval vestibule
- the frenulum labiorum pudendi or the fourchette
- the opening (or urinary meatus)
- the opening (or introitus) of the vagina
- the hymen and
Other structures:
- the perineum
- the Sebaceous glands on labia majora
- the vaginal glands:
Bartholin's glands
Paraurethral glands called Skene's glands
- Bartholin's glands
- Paraurethral glands called Skene's glands
The soft mound at the front of the vulva is formed by fatty tissue covering the pubic bone, and is called the mons pubis. The term mons pubis is Latin for "pubic mound", and is gender non-specific. In human females, the mons pubis is often referred to as the mons veneris, Latin for "mound of Venus" or "mound of love". The mons pubis separates into two folds of skin called the labia majora, literally "major (or large) lips". The cleft between the labia majora is called the pudendal cleft, or cleft of Venus, and it contains and protects the other, more delicate structures of the vulva. The labia majora meet again at a flat area between the pudendal cleft and the anus called the perineum. The colour of the outside skin of the labia majora is usually close to the overall skin colour of the individual, although there is considerable variation. The inside skin and mucus membrane are often pink or brownish. After the onset of puberty, the mons pubis and the labia majora become covered by pubic hair. This hair sometimes extends to the inner thighs and perineum, but the density, texture, and extent of pubic hair coverage varies considerably. The practice of cosmetic trimming and shaping the edge of the so-called "bikini line" is common, but a trend toward the severe reduction, or even complete removal, of pubic hair has gained popularity in recent years.
The labia minora are two soft folds of skin within the labia majora. While labia minora translates as "minor (or small) lips", often the "minora" are of considerable size, and protrude outside the "majora". Much of the variation between vulvae lies in the significant variation in the size, shape, and color of the labia minora.
The clitoris is located at the front of the vulva, where the labia minora meet. The visible portion of the clitoris is the clitoral glans. Typically, the clitoral glans is roughly the size and shape of a pea, although it can be significantly larger or smaller. The clitoral glans is highly sensitive, containing as many nerve endings as the analogous organ in males, the glans penis. The point where the labia minora attach to the clitoris is called the frenulum clitoridis. A prepuce, the clitoral hood, normally covers and protects the clitoris, however in women with particularly large clitorises or small prepuces, the clitoris may be partially or wholly exposed at all times. Often the clitoral hood is only partially hidden inside of the pudendal cleft.
The area between the labia minora is called the vulval vestibule, and it contains the vaginal and urethral openings. The urethral opening (meatus) is located below the clitoris and just in front of the vagina. This is where urine passes from the bladder to the outside of the body.
The opening of the vagina is located at the bottom of the vulval vestibule, towards the perineum. The term introitus is more technically correct than "opening", since the vagina is collapsed, with the opening closed, unless something is inserted into it. The introitus is sometimes partly covered by a membrane called the hymen. The hymen will rupture during the first episode of vigorous sex, and the blood produced by this rupture is often used as a sign of virginity. However, the hymen may also rupture spontaneously during exercise, or be stretched by normal activities such as the use of tampons, or be so minor as to not be noticeable. In some rare cases, the hymen may completely cover the vaginal opening, requiring surgical separation. Slightly below and to the left and right of the vaginal opening are two Bartholin glands which produce a waxy, pheromone-containing substance, the purpose of which is not fully known.
The appearance of the vulva and the size of the various parts varies a great deal from one female to another, and it is common for the left and right sides to differ in appearance.
# Development
## Fetus
During the first eight weeks of life, both male and female fetuses have the same rudimentary reproductive and sexual organs, and maternal hormones control their development. Male and female organs begin to become distinct when the fetus is able to begin producing its own hormones, although visible determination of the sex is difficult until after the twelfth week.
During the sixth week, the genital tubercle develops in front of the cloacal membrane. The tubercle contains a groove termed the urethral groove. The urogenital sinus (forerunner of the bladder) opens into this groove. On either side of the grove are the urogenital folds. Beside the tubercle are a pair of ridges called the labioscrotal swellings.
Beginning in the third month of development, the genital tubercle becomes the clitoris. The urogenital folds become the labia minora, and the labioscrotal swellings become the labia majora.
## Childhood
At birth, the neonate's vulva (and breasts) may be swollen or enlarged as a result of having been exposed, via the placenta, to her mother's increased levels of hormones. The clitoris is proportionally larger than it is likely to be later in life. Within a short period of time as these hormones wear off, the vulva will shrink in size.
From one year of age until the onset of puberty, the vulva does not undergo any change in appearance, other than growing in proportion with the rest of the body.
## Puberty
The onset of puberty produces a number of changes. The structures of the vulva become proportionately larger and may become more pronounced. Coloration may change and pubic hair develops, first on the labia majora, and later spreading to the mons pubis, and sometimes the inner thighs and perineum.
In pre-adolescent girls, the vulva appears to be positioned further forward than in adults, showing a larger percentage of the labia majora and pudendal cleft when standing. During puberty the mons pubis enlarges, pushing the forward portion of the labia majora away from the pubic bone, and parallel to the ground (when standing). Variations in body fat levels affect the extent to which this occurs.
## Childbirth
During childbirth, the vagina and vulva must stretch to accommodate the baby's head (approximately 9.5 cm or 3.7 in). This can result in tears in the vaginal opening, labia, and clitoris. An episiotomy (surgical pre-emptive cutting of the perineum) is sometimes performed to limit tearing, but its appropriateness as a routine procedure is under debate.
Some of the changes that occur during pregnancy may be permanent.
## Post-menopause
During menopause, hormone levels decrease, and along with them tissues sensitive to these hormones also decrease. The mons pubis, labia, and clitoris may reduce in size, although not usually to pre-puberty proportions.
# Sexual arousal
Sexual arousal results in a number of physical changes in the vulva. Arousal may be broken up into four somewhat arbitrary phases: Excitement, Plateau, Orgasm, and Resolution.
## Excitement
Vaginal lubrication begins first. This is caused as a result of the vasocongestion of the vaginal walls. Increased blood pooling there causes moisture to seep from the walls. These droplets collect together and flow out of the vagina, moistening the vulva. The labia majora flatten and spread apart, and the clitoris and labia minora increase in size.
Unlike in men, where sexual excitement produces large and readily apparent changes, namely an erection, women are not necessarily aware that vaginal lubrication and blood engorgement of their vulva has occurred.
## Plateau
Increased vasocongestion in the vagina causes it to swell, decreasing the size of the vaginal opening by about 30%. The clitoris becomes increasingly erect, and the glans moves towards the pubic bone, becoming concealed by the hood. The labia minora increase considerably in thickness, approximately 2–3 times, causing them to spread apart, displaying the vaginal opening. The labia minora change considerably in color, (in Caucasians) going from pink to red in women who have not borne a child, or red to wine in those that have.
A woman is not fully ready for vaginal intercourse until the plateau stage.
## Orgasm
Immediately prior to orgasm, the clitoris becomes exceptionally engorged, causing the glans to appear to retract into the clitoral hood. This is thought to protect the sensitive glans during orgasm. However, there is some doubt that this is the case, since the same engorgement prior to orgasm occurs in the male homologous structure, the penis, the function of which is thought to be to extend the penis as close to the cervix as possible prior to ejaculation.
Rhythmic muscle contractions occur in the outer third of the vagina, as well as the uterus and anus. They occur initially at a rate of about one every 0.8 seconds, becoming less intense and more randomly spaced as the orgasm continues. An orgasm may have as few as one or as many as 15 or more contractions, depending on intensity. Orgasm may be accompanied by female ejaculation, causing liquid from either the Skene's gland or bladder to be expelled through the urethra.
Immediately after orgasm the clitoris may be so sensitive that any stimulation is uncomfortable.
## Resolution
The pooled blood begins to dissipate, although at a much slower rate if orgasm has not occurred. The vagina and vaginal opening return to their normal relaxed state, and the rest of the vulva returns to its normal size, position and color.
# Fluids and odour
There are a number of different secretions associated with the vulva, including urine, sweat, menses, skin oils (sebum), Bartholin's and Skene's gland secretions, and vaginal wall secretions. These secretions contain a mix of chemicals, including pyridine, squalene, urea, acetic acid, lactic acid, complex alcohols, glycols, ketones, and aldehydes. A secretion associated with ovulation is known as "spinnbarkeit".
## Smegma
Smegma is a white substance formed from a combination of dead cells, skin oils, moisture and naturally occurring bacteria, that forms in mammalian genitalia. In females it collects around the clitoris and labial folds.
## Aliphatic acids
Approximately one third of women produce aliphatic acids. These acids are a pungent class of chemicals which other primate species produce as sexual-olfactory signals. While there is some debate, researchers often refer to them as human pheromones. These acids are produced by natural bacteria resident on the skin. The acid content varies with the menstrual cycle, rising from one day after menstruation, and peaking mid-cycle, just before ovulation.
# Disorders affecting the vulva
Gynaecology is the branch of medicine dealing with the diagnosis and treatment of the diseases and disorders associated with the vulva. Regular examinations are necessary to detect any abnormal changes in the vulvar region. Several pathologies are defined, a complete descriptive listing may be found in Chapter XIV of the list of ICD-10 codes; the most significant disorders include:
## Blemishes and cysts
- Epidermal cysts
- Angiomas
- Moles
- Freckles
- Lentigos
## Infections
- Candidiasis (thrush)
- Bacterial vaginosis (BV)
- Warts (due to HPV or condyloma acuminata)
- Molluscum contagiosum
- Herpes simplex (genital herpes)
- Herpes zoster (shingles)
- Tinea (fungus)
- Hidradenitis suppurativa
## Inflammatory diseases
- Eczema/Dermatitis
- Lichen simplex (chronic eczema)
- Psoriasis
- Lichen sclerosus
- Lichen planus
- zoons vulvitis (zoons balanitis in men)
- Pemphigus vulgaris
- Pemphigoid (mucous membrane pemphigoid, cicratricial pemphigoid, bullous pemphigoid)
## Pain syndromes
- Vulvodynia and vulvular vestibulitis
- Vaginismus
## Vulvar cancer
- Squamous cell carcinoma (the most common kind)
- Basal cell carcinoma
- Melanoma
- Vulvar cancer
Symptoms of vulvar cancer include itching, a lump or sore on the vulva which doesn't heal and/or goes larger, and sometimes discomfort/pain/swelling in the vulval area. Treatments include vulvectomy – removal of all or part of the vulva.
## Ulcers
- Aphthous ulcer
- Behcet's Disease
## Developmental disorders
- Septate vagina
- Vaginal opening extremely close to the urethra or anus
- An imperforate hymen
- Various stages of genital masculinization including fused labia, an absent or partially-formed vagina, urethra located on the clitoris.
- Hermaphroditism
## Other
- Vulvar lymphangioma
- Extramammary Paget's disease
- Vulvar intraepithelial neoplasia (VIN)
- Bowen's disease
- Bowenoid papulosis
- Vulvar varicose veins
- Labial adhesions
- Perineodynia (perineal pain)
- Desquamative Inflammatory Vaginitis (DIV)
- Childbirth tears and Episiotomy related changes
# Altering the female genitalia
The most prevalent form of genital alteration in some countries is female genital cutting: removal of any part of the female genitalia for cultural, religious or other non-medical reasons. This practice is highly controversial as it is often done to non-consenting minors and for debatable (often misogynistic) reasons.
In some cases, people elect to have their genitals pierced, tattooed or otherwise altered for aesthetic or other reasons. Female genital enhancement surgery includes laser resurfacing of the labia to remove wrinkles, clitoral repositioning for those not achieving optimum stimulation, labiaplasty (reducing the size of the labia) and vaginal tightening.
# Cultural attitudes
Many peoples have no or few taboos on exposure of the breasts, but the vulva and pubic triangle are always the first areas to be covered. Saartjie Baartman, the so-called "Hottentot Venus" who was exhibited in London at the beginning of the nineteenth century, was paid to display her large buttocks, but she never revealed her vulva. Khoisan women were said to have elongated labia, leading to questions about, and requests to exhibit, their sinus pudoris, "curtain of shame", or tablier (the French word for "apron"). To quote Stephen Jay Gould, "The labia minora, or inner lips, of the ordinary female genitalia are greatly enlarged in Khoi-San women, and may hang down three or four inches below the vagina when women stand, thus giving the impression of a separate and enveloping curtain of skin". Saartjie never allowed this trait to be exhibited while she was alive.
In some cultures, including modern Western culture, some women have shaved or otherwise depilated part or all of the vulva. This is a fairly recent phenomenon in the United States, Canada, and western Europe, but has been prevalent, usually in the form of waxing, in many eastern European and Middle Eastern cultures for centuries, usually for the belief that it is more hygienic. High-cut swimsuits compelled their wearers to shave the sides of their pubic triangles. Shaving may include all or nearly all of the hair. Some styles retain a "racing stripe" (on either side of the labia) or "landing strip" (directly above and in line with the vulva). See the article on pubic hair.
Since the early days of Islam, Muslim women and men have followed a tradition to "pluck the armpit hairs and shave the pubic hairs". This is a preferred practice rather than an obligation, and could be carried out by shaving, waxing, cutting, clipping or any other method. This is a regular practice that is considered in some more devout Muslim cultures as a form of worship, not a shameful practice, while in other less devout regions it is a practice for the purpose of good hygiene. The reasons behind removing this hair could also be applied to the hair on the scrotum and around the anus, because the purpose is to be completely clean and pure and keep away from anything that may cause dirt and impurities.
## Health and function
- Menopause
- Orgasm
- Vulvovaginal health
- Gonad | Vulva
Template:Infobox Anatomy
The vulva (from Latin, vulva, plural vulvae or vulvas; see etymology) is the region of the external genital organs of the female, including the labia majora, mons pubis, labia minora, clitoris, bulb of the vestibule, vestibule of the vagina, greater and lesser vestibular glands, and vaginal orifice.[1]
The vulva has many major and minor anatomical structures. Its development occurs during several phases, chiefly the fetal and pubertal periods. The vulva protects the vaginal opening by a "double door": the labia majora and the labia minora as well as a vulval vestibule, and a normal microbial flora that flows from the inside out. Normal external cleanliness is usually sufficient to assure good vulvovaginal health, without recourse to any internal cleansing. The vulva is more susceptible to infections than the penis.
These external body structures also have a sexual function; they are richly innervated and provide pleasure during sexual intercourse when properly stimulated. Since the origin of human society, in various branches of art the vulva has been depicted as the organ that has the power both "to give life" (i.e., often confused and associated with the vagina in pre-historic periods and antiquity, decreasingly as science has progressed), and to give sexual pleasure to humankind.[2]
In common speech, the term vagina is often used to refer to the vulva or female genitals generally, although, strictly speaking, the vagina is a specific internal structure, whereas the vulva is the exterior genitalia.[3]
This article deals with the human vulva, although the structures are similar for other mammals.
# Linguistics
## Etymology
The word "vulva" was taken from Middle Latin volva or vulva "womb, female genitals", probably from Latin volvere "to roll" (lit. "wrapper"). Similar to Sanskrit ulva "womb".[4]
An alternate term, also from Latin, is genitalia feminina externa.[5]
## Slang
As with nearly any aspect of the human body that is involved in sexual or excretory functions, there are many slang words for the vulva.[6]
# Sexual homology
Most male and female sex organs originate from the same tissues in the development of a foetus. The vulva is no different. The anatomy of the vulva is related to the anatomy of the male genitalia by a shared developmental biology. Organs that have a common developmental ancestry in this way are said to be homologous.
The clitoral glans is homologous to the glans penis in males, and the clitoral body and the clitoral crura are homologous to the corpora cavernosa of the penis. The labia majora, labia minora and clitoral hood are homologous to the scrotum, shaft skin of the penis, and the foreskin, respectively. The vestibular bulbs beneath the skin of the labia minora are homologous to the corpus spongiosum, the tissue of the penis surrounding the urethra. The Bartholin's glands are homologous to Cowper's glands in males.
# Structures
In human beings, major structures of the vulva are:[7]
- the mons pubis
- the labia, consisting of the labia majora and the labia minora
- the external portion of the clitoris and the clitoral hood
- the vulval vestibule
- the frenulum labiorum pudendi or the fourchette
- the opening (or urinary meatus)
- the opening (or introitus) of the vagina
- the hymen and
Other structures:
- the perineum
- the Sebaceous glands on labia majora
- the vaginal glands:
Bartholin's glands
Paraurethral glands called Skene's glands
- Bartholin's glands
- Paraurethral glands called Skene's glands
The soft mound at the front of the vulva is formed by fatty tissue covering the pubic bone, and is called the mons pubis. The term mons pubis is Latin for "pubic mound", and is gender non-specific. In human females, the mons pubis is often referred to as the mons veneris, Latin for "mound of Venus" or "mound of love". The mons pubis separates into two folds of skin called the labia majora, literally "major (or large) lips". The cleft between the labia majora is called the pudendal cleft, or cleft of Venus, and it contains and protects the other, more delicate structures of the vulva. The labia majora meet again at a flat area between the pudendal cleft and the anus called the perineum. The colour of the outside skin of the labia majora is usually close to the overall skin colour of the individual, although there is considerable variation. The inside skin and mucus membrane are often pink or brownish. After the onset of puberty, the mons pubis and the labia majora become covered by pubic hair. This hair sometimes extends to the inner thighs and perineum, but the density, texture, and extent of pubic hair coverage varies considerably. The practice of cosmetic trimming and shaping the edge of the so-called "bikini line" is common, but a trend toward the severe reduction, or even complete removal, of pubic hair has gained popularity in recent years.
The labia minora are two soft folds of skin within the labia majora. While labia minora translates as "minor (or small) lips", often the "minora" are of considerable size, and protrude outside the "majora". Much of the variation between vulvae lies in the significant variation in the size, shape, and color of the labia minora.
The clitoris is located at the front of the vulva, where the labia minora meet. The visible portion of the clitoris is the clitoral glans. Typically, the clitoral glans is roughly the size and shape of a pea, although it can be significantly larger or smaller. The clitoral glans is highly sensitive, containing as many nerve endings as the analogous organ in males, the glans penis. The point where the labia minora attach to the clitoris is called the frenulum clitoridis. A prepuce, the clitoral hood, normally covers and protects the clitoris, however in women with particularly large clitorises or small prepuces, the clitoris may be partially or wholly exposed at all times. Often the clitoral hood is only partially hidden inside of the pudendal cleft.
The area between the labia minora is called the vulval vestibule, and it contains the vaginal and urethral openings. The urethral opening (meatus) is located below the clitoris and just in front of the vagina. This is where urine passes from the bladder to the outside of the body.
The opening of the vagina is located at the bottom of the vulval vestibule, towards the perineum. The term introitus is more technically correct than "opening", since the vagina is collapsed, with the opening closed, unless something is inserted into it. The introitus is sometimes partly covered by a membrane called the hymen. The hymen will rupture during the first episode of vigorous sex, and the blood produced by this rupture is often used as a sign of virginity. However, the hymen may also rupture spontaneously during exercise, or be stretched by normal activities such as the use of tampons, or be so minor as to not be noticeable. In some rare cases, the hymen may completely cover the vaginal opening, requiring surgical separation. Slightly below and to the left and right of the vaginal opening are two Bartholin glands which produce a waxy, pheromone-containing substance, the purpose of which is not fully known.
The appearance of the vulva and the size of the various parts varies a great deal from one female to another, and it is common for the left and right sides to differ in appearance.
# Development
## Fetus
During the first eight weeks of life, both male and female fetuses have the same rudimentary reproductive and sexual organs, and maternal hormones control their development. Male and female organs begin to become distinct when the fetus is able to begin producing its own hormones, although visible determination of the sex is difficult until after the twelfth week.
During the sixth week, the genital tubercle develops in front of the cloacal membrane. The tubercle contains a groove termed the urethral groove. The urogenital sinus (forerunner of the bladder) opens into this groove. On either side of the grove are the urogenital folds. Beside the tubercle are a pair of ridges called the labioscrotal swellings.
Beginning in the third month of development, the genital tubercle becomes the clitoris. The urogenital folds become the labia minora, and the labioscrotal swellings become the labia majora.
## Childhood
At birth, the neonate's vulva (and breasts) may be swollen or enlarged as a result of having been exposed, via the placenta, to her mother's increased levels of hormones. The clitoris is proportionally larger than it is likely to be later in life. Within a short period of time as these hormones wear off, the vulva will shrink in size.
From one year of age until the onset of puberty, the vulva does not undergo any change in appearance, other than growing in proportion with the rest of the body.
## Puberty
The onset of puberty produces a number of changes. The structures of the vulva become proportionately larger and may become more pronounced. Coloration may change and pubic hair develops, first on the labia majora, and later spreading to the mons pubis, and sometimes the inner thighs and perineum.
In pre-adolescent girls, the vulva appears to be positioned further forward than in adults, showing a larger percentage of the labia majora and pudendal cleft when standing. During puberty the mons pubis enlarges, pushing the forward portion of the labia majora away from the pubic bone, and parallel to the ground (when standing). Variations in body fat levels affect the extent to which this occurs.
## Childbirth
During childbirth, the vagina and vulva must stretch to accommodate the baby's head (approximately 9.5 cm or 3.7 in). This can result in tears in the vaginal opening, labia, and clitoris. An episiotomy (surgical pre-emptive cutting of the perineum) is sometimes performed to limit tearing, but its appropriateness as a routine procedure is under debate.
Some of the changes that occur during pregnancy may be permanent.
## Post-menopause
During menopause, hormone levels decrease, and along with them tissues sensitive to these hormones also decrease. The mons pubis, labia, and clitoris may reduce in size, although not usually to pre-puberty proportions.
# Sexual arousal
Sexual arousal results in a number of physical changes in the vulva. Arousal may be broken up into four somewhat arbitrary phases: Excitement, Plateau, Orgasm, and Resolution.
## Excitement
Vaginal lubrication begins first. This is caused as a result of the vasocongestion of the vaginal walls. Increased blood pooling there causes moisture to seep from the walls. These droplets collect together and flow out of the vagina, moistening the vulva. The labia majora flatten and spread apart, and the clitoris and labia minora increase in size.
Unlike in men, where sexual excitement produces large and readily apparent changes, namely an erection, women are not necessarily aware that vaginal lubrication and blood engorgement of their vulva has occurred.
## Plateau
Increased vasocongestion in the vagina causes it to swell, decreasing the size of the vaginal opening by about 30%. The clitoris becomes increasingly erect, and the glans moves towards the pubic bone, becoming concealed by the hood. The labia minora increase considerably in thickness, approximately 2–3 times, causing them to spread apart, displaying the vaginal opening. The labia minora change considerably in color, (in Caucasians) going from pink to red in women who have not borne a child, or red to wine in those that have.
A woman is not fully ready for vaginal intercourse until the plateau stage.
## Orgasm
Immediately prior to orgasm, the clitoris becomes exceptionally engorged, causing the glans to appear to retract into the clitoral hood. This is thought to protect the sensitive glans during orgasm. However, there is some doubt that this is the case, since the same engorgement prior to orgasm occurs in the male homologous structure, the penis, the function of which is thought to be to extend the penis as close to the cervix as possible prior to ejaculation.
Rhythmic muscle contractions occur in the outer third of the vagina, as well as the uterus and anus. They occur initially at a rate of about one every 0.8 seconds, becoming less intense and more randomly spaced as the orgasm continues. An orgasm may have as few as one or as many as 15 or more contractions, depending on intensity. Orgasm may be accompanied by female ejaculation, causing liquid from either the Skene's gland or bladder to be expelled through the urethra.
Immediately after orgasm the clitoris may be so sensitive that any stimulation is uncomfortable.
## Resolution
The pooled blood begins to dissipate, although at a much slower rate if orgasm has not occurred. The vagina and vaginal opening return to their normal relaxed state, and the rest of the vulva returns to its normal size, position and color.
# Fluids and odour
There are a number of different secretions associated with the vulva, including urine, sweat, menses, skin oils (sebum), Bartholin's and Skene's gland secretions, and vaginal wall secretions. These secretions contain a mix of chemicals, including pyridine, squalene, urea, acetic acid, lactic acid, complex alcohols, glycols, ketones, and aldehydes. A secretion associated with ovulation is known as "spinnbarkeit".
## Smegma
Smegma is a white substance formed from a combination of dead cells, skin oils, moisture and naturally occurring bacteria, that forms in mammalian genitalia. In females it collects around the clitoris and labial folds.
## Aliphatic acids
Approximately one third of women produce aliphatic acids. These acids are a pungent class of chemicals which other primate species produce as sexual-olfactory signals. While there is some debate, researchers often refer to them as human pheromones. These acids are produced by natural bacteria resident on the skin. The acid content varies with the menstrual cycle, rising from one day after menstruation, and peaking mid-cycle, just before ovulation.
# Disorders affecting the vulva
Gynaecology is the branch of medicine dealing with the diagnosis and treatment of the diseases and disorders associated with the vulva. Regular examinations are necessary to detect any abnormal changes in the vulvar region. Several pathologies are defined, a complete descriptive listing may be found in Chapter XIV of the list of ICD-10 codes; the most significant disorders include:
## Blemishes and cysts
- Epidermal cysts
- Angiomas
- Moles
- Freckles
- Lentigos
## Infections
- Candidiasis (thrush)
- Bacterial vaginosis (BV)
- Warts (due to HPV or condyloma acuminata)
- Molluscum contagiosum
- Herpes simplex (genital herpes)
- Herpes zoster (shingles)
- Tinea (fungus)
- Hidradenitis suppurativa
## Inflammatory diseases
- Eczema/Dermatitis
- Lichen simplex (chronic eczema)
- Psoriasis
- Lichen sclerosus
- Lichen planus
- zoons vulvitis (zoons balanitis in men)
- Pemphigus vulgaris
- Pemphigoid (mucous membrane pemphigoid, cicratricial pemphigoid, bullous pemphigoid)
## Pain syndromes
- Vulvodynia and vulvular vestibulitis
- Vaginismus
## Vulvar cancer
- Squamous cell carcinoma (the most common kind)
- Basal cell carcinoma
- Melanoma
- Vulvar cancer
Symptoms of vulvar cancer include itching, a lump or sore on the vulva which doesn't heal and/or goes larger, and sometimes discomfort/pain/swelling in the vulval area. Treatments include vulvectomy – removal of all or part of the vulva.
## Ulcers
- Aphthous ulcer
- Behcet's Disease
## Developmental disorders
- Septate vagina
- Vaginal opening extremely close to the urethra or anus
- An imperforate hymen
- Various stages of genital masculinization including fused labia, an absent or partially-formed vagina, urethra located on the clitoris.
- Hermaphroditism
## Other
- Vulvar lymphangioma
- Extramammary Paget's disease
- Vulvar intraepithelial neoplasia (VIN)
- Bowen's disease
- Bowenoid papulosis
- Vulvar varicose veins
- Labial adhesions
- Perineodynia (perineal pain)
- Desquamative Inflammatory Vaginitis (DIV)
- Childbirth tears and Episiotomy related changes
# Altering the female genitalia
The most prevalent form of genital alteration in some countries is female genital cutting: removal of any part of the female genitalia for cultural, religious or other non-medical reasons. This practice is highly controversial as it is often done to non-consenting minors and for debatable (often misogynistic) reasons.
In some cases, people elect to have their genitals pierced, tattooed or otherwise altered for aesthetic or other reasons. Female genital enhancement surgery includes laser resurfacing of the labia to remove wrinkles, clitoral repositioning for those not achieving optimum stimulation, labiaplasty (reducing the size of the labia) and vaginal tightening.
# Cultural attitudes
Many peoples have no or few taboos on exposure of the breasts, but the vulva and pubic triangle are always the first areas to be covered. Saartjie Baartman, the so-called "Hottentot Venus" who was exhibited in London at the beginning of the nineteenth century, was paid to display her large buttocks, but she never revealed her vulva. Khoisan women were said to have elongated labia, leading to questions about, and requests to exhibit, their sinus pudoris, "curtain of shame", or tablier (the French word for "apron"). To quote Stephen Jay Gould, "The labia minora, or inner lips, of the ordinary female genitalia are greatly enlarged in Khoi-San women, and may hang down three or four inches below the vagina when women stand, thus giving the impression of a separate and enveloping curtain of skin". [8] Saartjie never allowed this trait to be exhibited while she was alive.[9]
In some cultures, including modern Western culture, some women have shaved or otherwise depilated part or all of the vulva. This is a fairly recent phenomenon in the United States, Canada, and western Europe, but has been prevalent, usually in the form of waxing, in many eastern European and Middle Eastern cultures for centuries, usually for the belief that it is more hygienic. High-cut swimsuits compelled their wearers to shave the sides of their pubic triangles. Shaving may include all or nearly all of the hair. Some styles retain a "racing stripe" (on either side of the labia) or "landing strip" (directly above and in line with the vulva). See the article on pubic hair.
Since the early days of Islam, Muslim women and men have followed a tradition to "pluck the armpit hairs and shave the pubic hairs". This is a preferred practice rather than an obligation, and could be carried out by shaving, waxing, cutting, clipping or any other method. This is a regular practice that is considered in some more devout Muslim cultures as a form of worship, not a shameful practice, while in other less devout regions it is a practice for the purpose of good hygiene. The reasons behind removing this hair could also be applied to the hair on the scrotum and around the anus, because the purpose is to be completely clean and pure and keep away from anything that may cause dirt and impurities.[10]
## Health and function
- Menopause
- Orgasm
- Vulvovaginal health
- Gonad | https://www.wikidoc.org/index.php/Pudendum | |
92412a5d37b7229a2d30b28ac3bf41cd6b0825cc | wikidoc | QSER1 | QSER1
Glutamine Serine Rich Protein 1 or QSER1 is a protein encoded by the QSER1 gene.
The function of this protein is currently unknown. QSER1 has one alias, FLJ21924.
# Gene
## Location
The QSER1 gene is found on the short arm of chromosome 11 (11p13), beginning at 32,914,792 bp and ending at 33,001,816 bp. It is 87,024 bp in length. It is located between the genes DEPDC7 and PRRG4 and is 500,000 bp downstream from the Wilms Tumor 1 gene (WT1), which is implicated in multiple pathologies.
## Homology
### Orthologs
QSER1 is highly conserved in most species of the clade Chordata. Orthologs have been found in primates, birds, reptiles, amphibians, and fish as far back as the coelacanth, which diverged 414.9 million years ago.
### Paralogs
QSER1 has one paralog in humans, Proline-rich 12, or PRR12. PRR12 is found on chromosome 9 at 9q13.33, which does not have known function. PRR12 is found in most chordate species as far back as the coelacanth. The duplication event likely occurred sometime in the chordate lineage near the divergence of the coelacanth. Both PRR12 and QSER1 contain the conserved DUF4211 domain near the 3’ ends of the genes.
# mRNA
## Promoter and transcription factors
The promoter region for QSER1 is 683 bp in length and is found on chromosome 11 between 32,914,224 bp and 32,914,906. There is some overlap between the promoter region and the 5’ UTR of QSER1. Predicted transcription factors with conservation include (but are not limited to) EGR1, p53, E2F3, E2F4, PLAG1, NeuroD2, Myf5, IKAROS1, SMAD3, KRAB, MZF1, and c-Myb.
## Expression
### Normal expression
Expression of QSER1 is seen at levels lower than 50% in many tissues. However, notable expression is seen in skeletal muscle, the appendix, trigeminal ganglia, cerebellum peduncles, pons, spinal cord, ciliary ganglion, globus pallidus, subthalamic nucleus, dorsal root ganglion, fetal liver, adrenal gland, ovary, uterus corpus, cardiac myocytes, the atrioventricular node, skin, pituitary gland, tongue, early erythroid progenitors, and tonsil.
### Differential expression
A notable decrease in QSER1 expression has been noted in renal mesangial cells in response to treatment with 25 mM glucose. This condition was studied as differential expression of genes involved in cell cycle regulation had been noted in these cells in response to high glucose levels seen with diabetes mellitus.
A different study noted overexpression of QSER1 in pathological cardiomyopathy. This condition is associated with altered expression of genes involved in immune responses, signaling, cell growth, and proliferation as well as infiltration of B lymphocytes.
Differential expression of QSER1 is seen in multiple cancer conditions. Overexpression of QSER1 was noted in Burkitt’s Lymphoma. QSER1 expression also increases with increasing Gleason score (more advanced stages) of prostate cancer. In a study on breast cancer response to paclitaxel and fluorouracil‐doxorubicin‐cyclophosphamide chemotherapy, it was noted that breast cancer lines with higher levels of QSER1 were more likely to respond to treatment than those with underexpression of QSER1.
Greater expression of QSER1 was also noted in mammary epithelial cells of immortalized cell lines than in mammary epithelial cells from cell lines with finite lifespan.
## 3’ UTR
Over 20 stem loops are predicted in the 3’ UTR of QSER1. 16 stem loops are found within the first 800 bp of 3’ UTR. The 3’ UTR is almost entirely conserved in mammals with less conservation seen in other organisms.
# Protein
## General properties
QSER1 protein is 1735 amino acids in length. The composition of the peptide is significantly high in serine and glutamine: 14.7% serine residues and 8.9% glutamine.
## Conservation
QSER1 protein is highly conserved in chordate species.
The table below shows information on the protein orthologs.
## Domains and motifs
QSER1 protein contains two high conserved domains found not only in QSER1 but also in other protein products. These include the PHA02939 domain from amino acid 1380-1440 and the DUF4211 domain from amino acid 1522-1642.
Nuclear localization was predicted by pSORT. This property was conserved from the human QSER1 to the coelacanth QSER1. Multiple conserved nuclear localization signals were also predicted within the QSER1 protein by pSORT.
## Structure
Predictions of the QSER1 protein structure indicate that the protein contains many alpha helices. NCBI cBLAST predicted structural similarity between the QSER1 protein and the Schizosaccharomyces pombe (fission yeast) RNA Polymerase II A chain. The two regions of similarity occur between amino acids 56-194 and 322-546. This first region (56-194) is a regulatory region in both the human and yeast RNA Polymerase II containing multiple repeats of the sequence YSPTSPSYS. Phosphorylation of serine residues in this region regulates progression through the steps of gene transcription. A 3D structure was provided for this region. The structurally similar region is on the exterior of the protein molecule and forms part of the DNA binding cleft.
Further structural similarity to a viral RNA Polymerase binding protein was predicted by Phyre2. This structure is found at the very end of the protein between amino acids 1671-1735. The structure has a long region of alpha helices that were also predicted by SDSC Biology Workbench PELE. An image of the structurally similar region and sequence alignment is shown on the right. Regions before the identified structurally similar domain show two other alpha helices predicted with high confidence.
## Post translational modifications
### Phosphorylation
There are 12 confirmed phosphorylation sites on the QSER1 protein. Eight are phosphoserines, one phosphotyrosine, and three phosphothreonines. Three of these sites have been shown to be phosphorylated by ATM and ATR in response in DNA damage. 123 other possible phosphorylation sites have been predicted using the ExPASy NetPhos tool.
### SUMOylation
Interaction of QSER1 protein with SUMO has been noted in multiple proteome-wide studies. Predicted SUMOylation sites have been found in QSER1 protein. Highly conserved SUMOylation sites occur with the sequence MKMD at amino acid 794, VKIE at 1057, VKTG at 1145, LKSG at 1157, VKQP at 1487, and VKAE at 1492 .
## Interactions
### ATM/ATR
Phosphorylation of QSER1 at three serine residues, S1228, S1231, and S1239, by ATM and ATR in response to DNA damage was found in a proteome-wide study.
### SUMO
Interaction of QSER1 with SUMO has been confirmed in multiple studies. The role of SUMOylation in QSER1 function is unclear. However, there may be a connection between QSER1 and SUMO in response to endoplasmic reticulum stress (often caused by accumulation of misfolded proteins). In a study on ER stress, QSER1 was tagged as an ER stress response gene with altered expression. Further, in a study on SUMOylation in response to accumulated misfolded proteins and ER stress found QSER1 to be a SUMO interactant in this situation. Any connection between these two activities is unstudied and unconfirmed.
### RNA polymerase II
Direct interaction of QSER1 with RNA polymerase II was found in a study performed by Moller, et al. Interaction was shown to occur with the DNA-directed RNA polymerase II subunit, RPB1, of RNA polymerase II during both mitosis and interphase. Colocalization/interaction of QSER1 was shown to the regulatory region of RPB1 with 52 heptapeptide (YSPTSPSYS) repeats.
### NANOG and TET1
Interaction between homeobox protein NANOG and Tet methylcytosine dioxygenase 1 (TET1) has been shown to be important in establishing pluripotency during the generation of induced pluripotent stem cells. QSER1 protein was shown to interact with both NANOG and TET1.
### Ubiquitin
QSER1 was found to interact with ubiquitin in two proteome-wide substrate studies. Specific details about this interaction have not been studied.
# Pathology
Altered expression of QSER1 is noted in pathological cardiomyopathy, Burkitt's Lymphoma, prostate cancer, and some breast cancers mentioned above. NCBI AceView lists multiple mutations associated with other pathologies including an eight base pair and 13 base pair deletion in QSER1 associated with leiomyosarcoma of the uterus, and 57 base pair difference in a neuroblastoma. Also listed are multiple splice variants with truncated 5' and/or 3' ends often noted in cancerous conditions. Further, according to the NCBI OMIM database, multiple pathologies are associated with alterations in the 11p13 region and therefore may implicate QSER1. These include Exudative Vitreoretinopathy 3, Familial Candidiasis 3, Centralopathic Epilepsy, and Autosomal Recessive Deafness 51.
QSER1 was also noted as a susceptibility gene for Parkinson's Disease. | QSER1
Glutamine Serine Rich Protein 1 or QSER1 is a protein encoded by the QSER1 gene.[1]
The function of this protein is currently unknown. QSER1 has one alias, FLJ21924.[1]
# Gene
## Location
The QSER1 gene is found on the short arm of chromosome 11 (11p13), beginning at 32,914,792 bp and ending at 33,001,816 bp. It is 87,024 bp in length. It is located between the genes DEPDC7 and PRRG4 and is 500,000 bp downstream from the Wilms Tumor 1 gene (WT1), which is implicated in multiple pathologies.[1][2]
## Homology
### Orthologs
QSER1 is highly conserved in most species of the clade Chordata. Orthologs have been found in primates, birds, reptiles, amphibians, and fish as far back as the coelacanth, which diverged 414.9 million years ago.[1][2]
### Paralogs
QSER1 has one paralog in humans, Proline-rich 12, or PRR12. PRR12 is found on chromosome 9 at 9q13.33, which does not have known function. PRR12 is found in most chordate species as far back as the coelacanth.[3] The duplication event likely occurred sometime in the chordate lineage near the divergence of the coelacanth. Both PRR12 and QSER1 contain the conserved DUF4211 domain near the 3’ ends of the genes.[1][3]
# mRNA
## Promoter and transcription factors
The promoter region for QSER1 is 683 bp in length and is found on chromosome 11 between 32,914,224 bp and 32,914,906. There is some overlap between the promoter region and the 5’ UTR of QSER1. Predicted transcription factors with conservation include (but are not limited to) EGR1, p53, E2F3, E2F4, PLAG1, NeuroD2, Myf5, IKAROS1, SMAD3, KRAB, MZF1, and c-Myb.[4]
## Expression
### Normal expression
Expression of QSER1 is seen at levels lower than 50% in many tissues. However, notable expression is seen in skeletal muscle, the appendix, trigeminal ganglia, cerebellum peduncles, pons, spinal cord, ciliary ganglion, globus pallidus, subthalamic nucleus, dorsal root ganglion, fetal liver, adrenal gland, ovary, uterus corpus, cardiac myocytes, the atrioventricular node, skin, pituitary gland, tongue, early erythroid progenitors, and tonsil.[5][6]
### Differential expression
A notable decrease in QSER1 expression has been noted in renal mesangial cells in response to treatment with 25 mM glucose. This condition was studied as differential expression of genes involved in cell cycle regulation had been noted in these cells in response to high glucose levels seen with diabetes mellitus.[7][8]
A different study noted overexpression of QSER1 in pathological cardiomyopathy. This condition is associated with altered expression of genes involved in immune responses, signaling, cell growth, and proliferation as well as infiltration of B lymphocytes.[9][10]
Differential expression of QSER1 is seen in multiple cancer conditions. Overexpression of QSER1 was noted in Burkitt’s Lymphoma.[5] QSER1 expression also increases with increasing Gleason score (more advanced stages) of prostate cancer.[11] In a study on breast cancer response to paclitaxel and fluorouracil‐doxorubicin‐cyclophosphamide chemotherapy, it was noted that breast cancer lines with higher levels of QSER1 were more likely to respond to treatment than those with underexpression of QSER1.[12]
Greater expression of QSER1 was also noted in mammary epithelial cells of immortalized cell lines than in mammary epithelial cells from cell lines with finite lifespan.[13]
## 3’ UTR
Over 20 stem loops are predicted in the 3’ UTR of QSER1. 16 stem loops are found within the first 800 bp of 3’ UTR.[14] The 3’ UTR is almost entirely conserved in mammals with less conservation seen in other organisms.[15]
# Protein
## General properties
QSER1 protein is 1735 amino acids in length.[16] The composition of the peptide is significantly high in serine and glutamine: 14.7% serine residues and 8.9% glutamine.[17]
## Conservation
QSER1 protein is highly conserved in chordate species.
The table below shows information on the protein orthologs.
## Domains and motifs
QSER1 protein contains two high conserved domains found not only in QSER1 but also in other protein products. These include the PHA02939 domain from amino acid 1380-1440 and the DUF4211 domain from amino acid 1522-1642.[19][20]
Nuclear localization was predicted by pSORT. This property was conserved from the human QSER1 to the coelacanth QSER1. Multiple conserved nuclear localization signals were also predicted within the QSER1 protein by pSORT.[21]
## Structure
Predictions of the QSER1 protein structure indicate that the protein contains many alpha helices.[22][23][24] NCBI cBLAST predicted structural similarity between the QSER1 protein and the Schizosaccharomyces pombe (fission yeast) RNA Polymerase II A chain. The two regions of similarity occur between amino acids 56-194 and 322-546.[23] This first region (56-194) is a regulatory region in both the human and yeast RNA Polymerase II containing multiple repeats of the sequence YSPTSPSYS. Phosphorylation of serine residues in this region regulates progression through the steps of gene transcription.[25] A 3D structure was provided for this region. The structurally similar region is on the exterior of the protein molecule and forms part of the DNA binding cleft.
Further structural similarity to a viral RNA Polymerase binding protein was predicted by Phyre2.[24] This structure is found at the very end of the protein between amino acids 1671-1735. The structure has a long region of alpha helices that were also predicted by SDSC Biology Workbench PELE. An image of the structurally similar region and sequence alignment is shown on the right. Regions before the identified structurally similar domain show two other alpha helices predicted with high confidence.[24]
## Post translational modifications
### Phosphorylation
There are 12 confirmed phosphorylation sites on the QSER1 protein. Eight are phosphoserines, one phosphotyrosine, and three phosphothreonines. Three of these sites have been shown to be phosphorylated by ATM and ATR in response in DNA damage.[26] 123 other possible phosphorylation sites have been predicted using the ExPASy NetPhos tool.[27]
### SUMOylation
Interaction of QSER1 protein with SUMO has been noted in multiple proteome-wide studies.[28][29] Predicted SUMOylation sites have been found in QSER1 protein. Highly conserved SUMOylation sites occur with the sequence MKMD at amino acid 794, VKIE at 1057, VKTG at 1145, LKSG at 1157, VKQP at 1487, and VKAE at 1492 .[30]
## Interactions
### ATM/ATR
Phosphorylation of QSER1 at three serine residues, S1228, S1231, and S1239, by ATM and ATR in response to DNA damage was found in a proteome-wide study.[26]
### SUMO
Interaction of QSER1 with SUMO has been confirmed in multiple studies.[28][29] The role of SUMOylation in QSER1 function is unclear. However, there may be a connection between QSER1 and SUMO in response to endoplasmic reticulum stress (often caused by accumulation of misfolded proteins). In a study on ER stress, QSER1 was tagged as an ER stress response gene with altered expression.[31] Further, in a study on SUMOylation in response to accumulated misfolded proteins and ER stress found QSER1 to be a SUMO interactant in this situation.[28] Any connection between these two activities is unstudied and unconfirmed.
### RNA polymerase II
Direct interaction of QSER1 with RNA polymerase II was found in a study performed by Moller, et al. Interaction was shown to occur with the DNA-directed RNA polymerase II subunit, RPB1, of RNA polymerase II during both mitosis and interphase. Colocalization/interaction of QSER1 was shown to the regulatory region of RPB1 with 52 heptapeptide (YSPTSPSYS) repeats.[25]
### NANOG and TET1
Interaction between homeobox protein NANOG and Tet methylcytosine dioxygenase 1 (TET1) has been shown to be important in establishing pluripotency during the generation of induced pluripotent stem cells. QSER1 protein was shown to interact with both NANOG and TET1.[32]
### Ubiquitin
QSER1 was found to interact with ubiquitin in two proteome-wide substrate studies.[33][34] Specific details about this interaction have not been studied.
# Pathology
Altered expression of QSER1 is noted in pathological cardiomyopathy, Burkitt's Lymphoma, prostate cancer, and some breast cancers mentioned above.[4][5][9][11] NCBI AceView lists multiple mutations associated with other pathologies including an eight base pair and 13 base pair deletion in QSER1 associated with leiomyosarcoma of the uterus, and 57 base pair difference in a neuroblastoma. Also listed are multiple splice variants with truncated 5' and/or 3' ends often noted in cancerous conditions.[35] Further, according to the NCBI OMIM database, multiple pathologies are associated with alterations in the 11p13 region and therefore may implicate QSER1.[36] These include Exudative Vitreoretinopathy 3,[37] Familial Candidiasis 3,[38] Centralopathic Epilepsy,[39] and Autosomal Recessive Deafness 51.[40]
QSER1 was also noted as a susceptibility gene for Parkinson's Disease.[31] | https://www.wikidoc.org/index.php/QSER1 | |
0fed385c790930deb99fc47dc06149e78ff64eca | wikidoc | Qanat | Qanat
A qanat (from Template:Lang-ar) or kareez (from Template:Lang-fa) is a water management system used to provide a reliable supply of water to human settlements or for irrigation in hot, arid and semi-arid climates. The widespread distribution of qanat known in different places in their local names has confounded the question of its origin, but the earliest evidence of this technology dates back to ancient Persia, and spread during the Arab Muslim conquests, to the Iberian peninsula, southern Italy and North Africa.
# Qanats and settlement patterns
Qanats are constructed as a series of well-like vertical shafts, connected by gently sloping tunnels. This technique:
- Taps into a subterranean water in a manner that efficiently delivers large quantities of water to the surface without need for pumping. The water drains relying on gravity, with the destination lower than the source, which is typically an upland aquifer.
- Allows water to be transported long distances in hot dry climates without losing a large proportion of the source water to seepage and evaporation.
It is very common in the construction of a qanat for the water source to be found below ground at the foot of a range of foothills of mountains, where the water table is closest to the surface. From this point, the slope of the qanat is maintained closer to level than the surface above, until the water finally flows out of the qanat above ground. To reach an underground aquifer qanats must often be of extreme length.
## Features common to regions which use qanat technology
The qanat technology was used most extensively in areas with the following characteristics:
- An absence of larger rivers with year-round flows sufficient to support irrigation.
- Proximity of potentially fertile areas to precipitation-rich mountains or mountain ranges.
- Arid climate with its high surface evaporation rates so that surface reservoirs and canals would result in high losses
- An aquifer at the potentially fertile area which is too deep for convenient use of simple wells.
The investment and organization required by the construction and the maintenance of a qanat is typically provided by local merchants or landowners in small groups. In the middle of the twentieth century, it is estimated that approximately 50,000 qanats were in use in Iran, each commissioned and maintained by local users. The qanat system has the advantage of being relatively immune to natural disasters (earthquakes, floods…) and human destruction in war. Further it is relatively insensitive to the levels of precipitation; a qanat typically delivers a relatively constant flow with only gradual variations from wet to dry years.
## Settlement patterns
A typical town or city in Iran and elsewhere where the qanat is used has more than one qanat. Fields and gardens are located both over the qanats a short distance before they emerge from the ground and after the surface outlet. Water from the qanats defines both the social regions in the city and the layout of the city.
The water is freshest, cleanest, and coolest in the upper reaches and more prosperous people live at the outlet or immediately upstream of the outlet. When the qanat is still below grade, the water is drawn to the surface via Ater-wells or animal driven Persian wells. Private subterranean reservoirs could supply houses and buildings for domestic use and garden irrigation as well. Further, air flow from the qanat is used to cool an underground summer room (shabestan) found in many older houses and buildings.
Downstream of the outlet, the water runs through surface canals called jubs (jūbs) which run downhill, with lateral branches to carry water to the neighborhood, gardens and fields. The streets normally parallel the jubs and their lateral branches. As a result, the cities and towns are oriented consistent with the gradient of the land; what is sometimes viewed as chaotic to the western eye is a practical response to efficient water distribution over varying terrain.
The lower reaches of the canals are less desirable for both residences and agriculture. The water grows progressively more polluted as it passes downstream. In dry years the lower reaches are the most likely to see substantial reductions in flow.
# Construction
Traditionally qanats are built by a group of skilled laborers, muqannīs, with hand labor. The profession historically paid well and was typically handed down from father to son.
## Preparations
The critical, initial step in qanat construction is identification of an appropriate water source. The search begins at the point where the alluvial fan meets the mountains or foothills; water is more abundant in the mountains because of orographic lifting and excavation in the alluvial fan is relatively easy. The muqannīs follow the track of the main water courses coming from the mountains or foothills to identify evidence of subsurface water such as deep-rooted vegetation or seasonal seeps. A trial well is then dug to determine the location of the water table and determine whether a sufficient flow is available to justify construction. If these prerequisites are met, then the route is laid out aboveground.
Equipment must be assembled. The equipment is straightforward: containers (usually leather bags), ropes, reels to raise the container to the surface at the shaft head, hatchets and shovels for excavation, lights, spirit levels or plumb bobs and string. Depending upon the soil type, qanat liners (usually fired clay hoops) may also be required.
Although the construction methods are simple, the construction of a qanat requires a detailed understanding of subterranean geology and a degree of engineering sophistication. The gradient of the qanat must be carefully controlled—too shallow a gradient yields no flow—too steep a gradient will result in excessive erosion, collapsing the qanat. And misreading the soil conditions leads to collapses which at best require extensive rework and, at worst, can be fatal for the crew.
## Excavation
Construction of a qanat is usually performed by a crew of 3-4 muqannīs. For a shallow qanat, one worker typically digs the horizontal shaft, one raises the excavated earth from the shaft and one distributes the excavated earth at the top.
The crew typically begins from the destination to which the water will be delivered into the soil and works toward the source (the test well). Vertical shafts are excavated along the route, separated at a distance of 20-35 m. The separation of the shafts is a balance between the amount of work required to excavate them and the amount of effort required to excavate the space between them, as well as the ultimate maintenance effort. In general, the shallower the qanat, the closer the vertical shafts. If the qanat is long, excavation may begin from both ends at once. Tributary channels are sometimes also constructed to supplement the water flow.
Most qanats in Iran run less than 5 km. The overall length of the qanat often runs up to 16 km, while some have been measured at ~70 km in length near Kerman. The vertical shafts usually range from 20 to 200 meters in depth, although in Iran qanats in the province of Khorasan have been recorded with vertical shafts of up to 275 m. The vertical shafts support construction and maintenance of the underground channel as well as air interchange. Deep shafts require intermediate platforms to simplify the process of removing spoils.
The qanat's water-carrying channel is 50-100 cm wide and 90-150 cm high. The channel must have a sufficient downward slope that water flows easily. However the downward gradient must not be so great as to create conditions under which the water transitions between supercritical and subcritical flow; if this occurs, the waves which are established result in severe erosion and can damage or destroy the qanat. In shorter qanats the downward gradient varies between 1:1000 and 1:1500, while in longer qanats it may be almost horizontal. Such precision is routinely obtained with a spirit level and string.
In cases where the gradient is steeper, underground waterfalls may be constructed with appropriate design features (usually linings) to absorb the energy with minimal erosion. In some cases the water power has been harnessed to drive underground mills. If it is not possible to bring the outlet of the qanat out near the settlement, it is necessary to run a jub or canal overgound. This is avoided when possible to limit pollution, warming and water loss due to evaporation.
The construction speed depends on the depth. At 20 meters depth, a crew of 4 people can excavate a horizontal length of 40 meters per day. When the vertical shaft reaches 40 meters, they can only excavate 20 meters horizontally per day and at 60 meters in depth this drops below 5 horizontal meters per day. Deep, long qanats (which many are) require years and even decades to construct.
The excavated material is usually transported by means of leather bags up the vertical shafts. It is mounded around the vertical shaft exit, providing a barrier that prevents windblown or rain driven debris from entering the shafts. From the air, these shafts look like a string of bomb craters.
## Maintenance
The vertical shafts may be covered to minimize in-blown sand. The channels of qanats must be periodically inspected for erosion or cave-ins, cleaned of sand and mud and otherwise repaired. Air flow must be assured before entry for human safety.
## Value
The value of a qanat is directly related to the quality, volume and regularity of the water flow. Much of the population of Iran historically depended upon the water from qanats; the areas of population corresponded closely to the areas where qanats are possible. Although a qanat was expensive to construct, its long-term value to the community, and therefore to the group who invested in building and maintaining it, was substantial.
# Other applications for qanats
## Distribution systems
Qanats were frequently split into an underground distribution network of smaller canals called kariz when reaching a major city. Like Qanats, these smaller canals were below ground to avoid contamination.
## Water storage
An Ab Anbar is a traditional qanat fed reservoir for drinking water in Persian antiquity.
## Cooling
Qanats used in conjunction with a wind tower can provide cooling as well as a water supply. A wind tower is a chimney-like structure positioned above the house to catch the prevailing wind. The tower catches the wind, driving a hot, dry breeze into the house; the flow of the incoming air is then directed across the vertical shaft from the qanat. The air flow across the vertical shaft opening creates a lower pressure (see Bernoulli effect) and draws cool air up from the qanat tunnel, mixing with it. The air from the qanat was drawn into the tunnel at some distance away and is cooled both by contact with the cool tunnel walls/water and by the giving up latent heat of evaporation as water evaporates into the air stream. In dry desert climates this can result in a greater than 15°C reduction in the air temperature coming from the qanat; the mixed air still feels dry, so the basement is cool and only comfortably moist (not damp). Wind tower and qanat cooling have been used in desert climates for over 1000 years.
## Ice storage
In 400 BC Persian engineers had already mastered the technique of storing ice in the middle of summer in the desert. The ice was brought in during the winters from nearby mountains in large quantities, and stored in specially designed, naturally cooled refrigerators called yakhchal (meaning ice pits). A large underground space with thick insulated walls was connected to a qanat, and a system of windcatchers was used to draw cool subterranean air up from the qanat to maintain temperatures inside the space at low levels, even during hot summer days. As a result, the ice melted slowly and ice was available year-round.
# Common terms
Qanat is from the Persian word qanāt, pronounced as ‘kanat’ in Arabic and ‘karez’ in Pashto. A qanat is referred to by different names in different regions: qanat (Iran); karez (Afghanistan and Pakistan); karez (China); qanat romani (Jordan and Syria); khettara (Morocco); galeria (Spain); falaj (United Arab Emirates and Oman); Kahn (Baloch). foggara/fughara is the French translation of the Arabic qanat, used in North Africa although the origin of the name is unknown. Alternative terms for Qanats in Asia and North Africa are kakuriz, chin-avulz, and mayun.
Common variant spellings/transliterations of qanat in English include kanat, khanat, kunut, kona, konait, ghanat, ghundat.
Closely related to such structures is the karez.
# Qanats in practical application
## Asia
### China
An oasis at Turpan in the deserts of northwestern China uses water provided by qanat (locally karez). Turfan has long been the center of a fertile oasis and an important trade center along the Silk Road's northern route, at which time it was adjacent to the kingdoms of Korla and Karashahr to the southwest. The historical record of the karez system extends back to the Han Dynasty. The Turfan Water Museum (see photos on this page) is a Protected Area of the People's Republic of China because of the importance of the local karez system to the history of the area. The number of karez systems in the area is slightly below 1,000 and the total length of the canals is about 5,000 kilometers in length.
### Pakistan
The Chagai district is in the north west corner of Balochistan, Pakistan, bordering with Afghanistan and Iran. Karez's are found more broadly in this region. They are spread from Chaghai district all the way up to Zhob district. A number of them are present in Qilla Abduallah and Pishin districts. Karez's are also extensively found in the neighbouring areas of Afghanistan like Kandahar. The remains of qanats (called karezes) found in different parts of the district are attributed to the Arabs.
### Iran
About four-fifths of the water used in the plateau regions of Iran is brought to use in this way. However, because agriculture is less and less practiced in Iran, the qanats that are being made now are not as effective as those made in the past because knowledge of how to make them is being lost. Also, the construction and maintenance of a qanat is unpleasant and dangerous, and modern technology allows water to be pumped from a drilled well. Hence although qanats still exist, they are falling out of use.
The oldest and largest known qanat is in the Iranian city of Gonabad which after 2700 years still provides drinking and agricultural water to nearly 40,000 people. Its main well depth is more than 360 meters and its length is 45 kilometers. Yazd and Kerman are the also known zones for their dependence with an extensive system of qanats.
In traditional Persian architecture, a Kariz (کاریز) is a small Qanat, usually within a network inside an urban setting. Kariz is what distributes the Qanat into its final destinations. (see also Traditional water sources of Persian antiquity and Ab Anbar)
### Syria
Qanats were found over much of Syria. The widespread installation of groundwater pumps has lowered the water table and antiquated the old qanat system. Qanats have gone dry and been abandoned across the country.
## Arabian Peninsula
### United Arab Emirates
The oasis of Al Ain in the United Arab Emirates continues traditional falaj (qanat) irrigations for the palm-groves and gardens. Evidence suggests the technology has been in use for 3000 years here.
### Oman
A ribbon of oases, watered by wells and underground channels (falaj), extends the length of the Oman plain, extending about ten kilometers inland. Nizwa was the capital city of Oman proper was built around a falaj (qanat) which is in use to this day.
In July 2006, the five representative examples of this irrigation system were inscribed as a World Heritage Site.
## North Africa
### Egypt
There are 4 main oases in the Egyptian desert. The Kharga Oasis is one of them which has been extensively studied. As early as the second half of the 5th century BC there is evidence that water was being used via qanats. The qanat is excavated through water-bearing sandstone rock which seeps into the channel to collect in a basin behind a small dam at the end. The width is approximately 60 cm, but the height ranges from 5 to 9 meters; it is likely that the qanat was deepened to enhance seepage when the water table dropped (as is also seen in Iran). From there the water was used to irrigate fields.
There is another instructive structure located at the Kharga Oasis. A well which apparently dried up was improved by driving a side shaft through the easily penetrated sandstone (presumably in the direction of greatest water seepage) into the hill of Ayn-Manâwîr to allow collection of additional water. After this side shaft had been extended, another vertical shaft was driven to intersect the side shaft. Side chambers were built and holes bored into the rock—presumably at points where water seeped from the rocks—are evident.
### Libya
David Mattingley reports foggara extending for hundreds of miles in the Garamantes area near Jarma in Libya: "The channels were generally very narrow - less than 2 feet wide and 5 high - but some were several miles long, and in total some 600 foggara extended for hundreds of miles underground. The channels were dug out and maintained using a series of regularly-spaced vertical shafts, one every 30 feet or so, 100,000 in total, averaging 30 feet in depth, but sometimes reaching 130." ("The 153 Club Newsletter", July 2007 No. 112, pp.14-19; reprinted from Current world Archaeology.
### Tunisia
The foggara water management system in Tunisia, used to create oases, is similar to that of the Iranian qanat. The foggara is dug into the foothills of a fairly steep mountain range such as the eastern ranges of the Atlas mountains. Rainfall in the mountains enters the aquifer and moves toward the Saharan region to the south. The foggara, 1 to 3 km in length, penetrates the aquifer and collects water. Families maintain the foggara and own the land it irrigates over a ten meter wide, with width only by the size of plot that the available water will irrigate.
### Algeria
Qanats (designated foggaras in Algeria) are the source of water for irrigation at large oases like that at Gourara. The foggaras are also found at Touat (an area of Adrar 200 km from Gourara). The length of the foggaras in this region is estimated to be thousands of kilometers.
Although sources suggest that the foggaras may have been in use as early as 200 AD, they were clearly in use by the 11th century after the Arabs took possession of the oases in the 10th century and imposed the Islamic religion upon the residents.
The water is metered to the various users through the use of distribution weirs which meter flow to the various canals, each for a separate user.
The humidity of the oases is also used to supplement the water supply to the foggara. The temperature gradient in the vertical shafts causes air to rise by natural convection, causing a draft to enter the foggara. The moist air of the agricultural area is drawn into the foggara in the opposite direction to the water run-off. In the foggara it condenses on the tunnel walls and the air passed out of the vertical shafts. This condensed moisture is available for reuse.
### Morocco
In southern Morocco the qanat (locally khettara) is also used. On the margins of the Sahara Desert, the isolated oases of the Draa River valley and Tafilalt have relied on qanat water for irrigation since the late-14th century. In Marrakech and the Haouz plain the qanats have been abandoned since the early 1970s as they've dried; in the Tafilaft area half of the 400 khettaras are still in use. The Hassan Adahkil Dam's impacts on local water tables is said to be one of the many reasons given for the loss of half of the khettara.
The black berbers of the south are the hereditary class of qanat diggers in Morocco who build and repair these systems. Their work is hazardous.
## Europe
### Spain
There are still many examples of galeria or qanat systems in Spain, most likely brought to the area by the Moors during their occupation of the Iberian peninsula. Turrillas in Andalusia on the north facing slopes of the Sierra de Alhamilla has evidence of a qanat system. Granada is another site with an extensive qanat system.
### Italy
The entire ancient town of Palermo in Sicily has been built over a huge qanat system built during the Arab period (827-1072). Many of the qanat are now mapped and some can be visited. An interesting building is the famous Scirocco room, which has an air refreshing system using the flux of waters of a qanat and a "wind tower", a structure able to catch the wind and direct it into the room.
## The Americas
Qanats in the Americas can be found in the Atacama regions of Peru, and Chile at Nazca and Pica. The Spanish introduced qanats into Mexico in 1520 AD. | Qanat
Template:Globalize
A qanat (from Template:Lang-ar) or kareez (from Template:Lang-fa) is a water management system used to provide a reliable supply of water to human settlements or for irrigation in hot, arid and semi-arid climates. The widespread distribution of qanat known in different places in their local names has confounded the question of its origin,[1] but the earliest evidence of this technology dates back to ancient Persia,[2] and spread during the Arab Muslim conquests, to the Iberian peninsula, southern Italy and North Africa.[3]
# Qanats and settlement patterns
Qanats are constructed as a series of well-like vertical shafts, connected by gently sloping tunnels. This technique:
- Taps into a subterranean water in a manner that efficiently delivers large quantities of water to the surface without need for pumping. The water drains relying on gravity, with the destination lower than the source, which is typically an upland aquifer.
- Allows water to be transported long distances in hot dry climates without losing a large proportion of the source water to seepage and evaporation.
It is very common in the construction of a qanat for the water source to be found below ground at the foot of a range of foothills of mountains, where the water table is closest to the surface. From this point, the slope of the qanat is maintained closer to level than the surface above, until the water finally flows out of the qanat above ground. To reach an underground aquifer qanats must often be of extreme length.[4]
## Features common to regions which use qanat technology
The qanat technology was used most extensively in areas with the following characteristics:
- An absence of larger rivers with year-round flows sufficient to support irrigation.
- Proximity of potentially fertile areas to precipitation-rich mountains or mountain ranges.
- Arid climate with its high surface evaporation rates so that surface reservoirs and canals would result in high losses
- An aquifer at the potentially fertile area which is too deep for convenient use of simple wells.
The investment and organization required by the construction and the maintenance of a qanat is typically provided by local merchants or landowners in small groups. In the middle of the twentieth century, it is estimated that approximately 50,000 qanats were in use in Iran[4], each commissioned and maintained by local users[5]. The qanat system has the advantage of being relatively immune to natural disasters (earthquakes, floods…) and human destruction in war. Further it is relatively insensitive to the levels of precipitation; a qanat typically delivers a relatively constant flow with only gradual variations from wet to dry years.
## Settlement patterns
A typical town or city in Iran and elsewhere where the qanat is used has more than one qanat. Fields and gardens are located both over the qanats a short distance before they emerge from the ground and after the surface outlet. Water from the qanats defines both the social regions in the city and the layout of the city.[4]
The water is freshest, cleanest, and coolest in the upper reaches and more prosperous people live at the outlet or immediately upstream of the outlet. When the qanat is still below grade, the water is drawn to the surface via Ater-wells or animal driven Persian wells. Private subterranean reservoirs could supply houses and buildings for domestic use and garden irrigation as well. Further, air flow from the qanat is used to cool an underground summer room (shabestan) found in many older houses and buildings.[4]
Downstream of the outlet, the water runs through surface canals called jubs (jūbs) which run downhill, with lateral branches to carry water to the neighborhood, gardens and fields. The streets normally parallel the jubs and their lateral branches. As a result, the cities and towns are oriented consistent with the gradient of the land; what is sometimes viewed as chaotic to the western eye is a practical response to efficient water distribution over varying terrain.[4]
The lower reaches of the canals are less desirable for both residences and agriculture. The water grows progressively more polluted as it passes downstream. In dry years the lower reaches are the most likely to see substantial reductions in flow[4].
# Construction
Traditionally qanats are built by a group of skilled laborers, muqannīs, with hand labor. The profession historically paid well and was typically handed down from father to son.[4]
## Preparations
The critical, initial step in qanat construction is identification of an appropriate water source. The search begins at the point where the alluvial fan meets the mountains or foothills; water is more abundant in the mountains because of orographic lifting and excavation in the alluvial fan is relatively easy. The muqannīs follow the track of the main water courses coming from the mountains or foothills to identify evidence of subsurface water such as deep-rooted vegetation or seasonal seeps. A trial well is then dug to determine the location of the water table and determine whether a sufficient flow is available to justify construction. If these prerequisites are met, then the route is laid out aboveground.[6][4]
Equipment must be assembled. The equipment is straightforward: containers (usually leather bags), ropes, reels to raise the container to the surface at the shaft head, hatchets and shovels for excavation, lights, spirit levels or plumb bobs and string. Depending upon the soil type, qanat liners (usually fired clay hoops) may also be required.[6][4]
Although the construction methods are simple, the construction of a qanat requires a detailed understanding of subterranean geology and a degree of engineering sophistication. The gradient of the qanat must be carefully controlled—too shallow a gradient yields no flow—too steep a gradient will result in excessive erosion, collapsing the qanat. And misreading the soil conditions leads to collapses which at best require extensive rework and, at worst, can be fatal for the crew.[6]
## Excavation
Construction of a qanat is usually performed by a crew of 3-4 muqannīs. For a shallow qanat, one worker typically digs the horizontal shaft, one raises the excavated earth from the shaft and one distributes the excavated earth at the top.[6]
The crew typically begins from the destination to which the water will be delivered into the soil and works toward the source (the test well). Vertical shafts are excavated along the route, separated at a distance of 20-35 m. The separation of the shafts is a balance between the amount of work required to excavate them and the amount of effort required to excavate the space between them, as well as the ultimate maintenance effort. In general, the shallower the qanat, the closer the vertical shafts. If the qanat is long, excavation may begin from both ends at once. Tributary channels are sometimes also constructed to supplement the water flow.[6][4]
Most qanats in Iran run less than 5 km. The overall length of the qanat often runs up to 16 km, while some have been measured at ~70 km in length near Kerman. The vertical shafts usually range from 20 to 200 meters in depth, although in Iran qanats in the province of Khorasan have been recorded with vertical shafts of up to 275 m. The vertical shafts support construction and maintenance of the underground channel as well as air interchange. Deep shafts require intermediate platforms to simplify the process of removing spoils.[6][4]
The qanat's water-carrying channel is 50-100 cm wide and 90-150 cm high. The channel must have a sufficient downward slope that water flows easily. However the downward gradient must not be so great as to create conditions under which the water transitions between supercritical and subcritical flow; if this occurs, the waves which are established result in severe erosion and can damage or destroy the qanat. In shorter qanats the downward gradient varies between 1:1000 and 1:1500, while in longer qanats it may be almost horizontal. Such precision is routinely obtained with a spirit level and string.[6][4]
In cases where the gradient is steeper, underground waterfalls may be constructed with appropriate design features (usually linings) to absorb the energy with minimal erosion. In some cases the water power has been harnessed to drive underground mills. If it is not possible to bring the outlet of the qanat out near the settlement, it is necessary to run a jub or canal overgound. This is avoided when possible to limit pollution, warming and water loss due to evaporation.[6][4]
The construction speed depends on the depth. At 20 meters depth, a crew of 4 people can excavate a horizontal length of 40 meters per day. When the vertical shaft reaches 40 meters, they can only excavate 20 meters horizontally per day and at 60 meters in depth this drops below 5 horizontal meters per day. Deep, long qanats (which many are) require years and even decades to construct.[6][4]
The excavated material is usually transported by means of leather bags up the vertical shafts. It is mounded around the vertical shaft exit, providing a barrier that prevents windblown or rain driven debris from entering the shafts. From the air, these shafts look like a string of bomb craters.[6]
## Maintenance
The vertical shafts may be covered to minimize in-blown sand. The channels of qanats must be periodically inspected for erosion or cave-ins, cleaned of sand and mud and otherwise repaired. Air flow must be assured before entry for human safety.
## Value
The value of a qanat is directly related to the quality, volume and regularity of the water flow. Much of the population of Iran historically depended upon the water from qanats; the areas of population corresponded closely to the areas where qanats are possible. Although a qanat was expensive to construct, its long-term value to the community, and therefore to the group who invested in building and maintaining it, was substantial. [4]
# Other applications for qanats
## Distribution systems
Qanats were frequently split into an underground distribution network of smaller canals called kariz when reaching a major city. Like Qanats, these smaller canals were below ground to avoid contamination.
## Water storage
An Ab Anbar is a traditional qanat fed reservoir for drinking water in Persian antiquity.
## Cooling
Qanats used in conjunction with a wind tower can provide cooling as well as a water supply. A wind tower is a chimney-like structure positioned above the house to catch the prevailing wind. The tower catches the wind, driving a hot, dry breeze into the house; the flow of the incoming air is then directed across the vertical shaft from the qanat. The air flow across the vertical shaft opening creates a lower pressure (see Bernoulli effect) and draws cool air up from the qanat tunnel, mixing with it. The air from the qanat was drawn into the tunnel at some distance away and is cooled both by contact with the cool tunnel walls/water and by the giving up latent heat of evaporation as water evaporates into the air stream. In dry desert climates this can result in a greater than 15°C reduction in the air temperature coming from the qanat; the mixed air still feels dry, so the basement is cool and only comfortably moist (not damp). Wind tower and qanat cooling have been used in desert climates for over 1000 years.[7]
## Ice storage
In 400 BC Persian engineers had already mastered the technique of storing ice in the middle of summer in the desert. The ice was brought in during the winters from nearby mountains in large quantities, and stored in specially designed, naturally cooled refrigerators called yakhchal (meaning ice pits). A large underground space with thick insulated walls was connected to a qanat, and a system of windcatchers was used to draw cool subterranean air up from the qanat to maintain temperatures inside the space at low levels, even during hot summer days. As a result, the ice melted slowly and ice was available year-round.
# Common terms
Qanat is from the Persian word qanāt, pronounced as ‘kanat’ in Arabic and ‘karez’ in Pashto. A qanat is referred to by different names in different regions: qanat (Iran); karez (Afghanistan and Pakistan); karez (China); qanat romani (Jordan and Syria); khettara (Morocco); galeria (Spain); falaj (United Arab Emirates and Oman); Kahn (Baloch). foggara/fughara is the French translation of the Arabic qanat, used in North Africa although the origin of the name is unknown.[8] Alternative terms for Qanats in Asia and North Africa are kakuriz, chin-avulz, and mayun.
Common variant spellings/transliterations of qanat in English include kanat, khanat, kunut, kona, konait, ghanat, ghundat.
Closely related to such structures is the karez.
# Qanats in practical application
## Asia
### China
An oasis at Turpan in the deserts of northwestern China uses water provided by qanat (locally karez). Turfan has long been the center of a fertile oasis and an important trade center along the Silk Road's northern route, at which time it was adjacent to the kingdoms of Korla and Karashahr to the southwest. The historical record of the karez system extends back to the Han Dynasty. The Turfan Water Museum (see photos on this page) is a Protected Area of the People's Republic of China because of the importance of the local karez system to the history of the area. The number of karez systems in the area is slightly below 1,000 and the total length of the canals is about 5,000 kilometers in length.[9]
### Pakistan
The Chagai district is in the north west corner of Balochistan, Pakistan, bordering with Afghanistan and Iran. Karez's are found more broadly in this region. They are spread from Chaghai district all the way up to Zhob district. A number of them are present in Qilla Abduallah and Pishin districts. Karez's are also extensively found in the neighbouring areas of Afghanistan like Kandahar. The remains of qanats (called karezes) found in different parts of the district are attributed to the Arabs.
### Iran
About four-fifths of the water used in the plateau regions of Iran is brought to use in this way. However, because agriculture is less and less practiced in Iran, the qanats that are being made now are not as effective as those made in the past because knowledge of how to make them is being lost. Also, the construction and maintenance of a qanat is unpleasant and dangerous, and modern technology allows water to be pumped from a drilled well. Hence although qanats still exist, they are falling out of use.
The oldest and largest known qanat is in the Iranian city of Gonabad which after 2700 years still provides drinking and agricultural water to nearly 40,000 people. Its main well depth is more than 360 meters and its length is 45 kilometers. Yazd and Kerman are the also known zones for their dependence with an extensive system of qanats.
In traditional Persian architecture, a Kariz (کاریز) is a small Qanat, usually within a network inside an urban setting. Kariz is what distributes the Qanat into its final destinations. (see also Traditional water sources of Persian antiquity and Ab Anbar)
### Syria
Qanats were found over much of Syria. The widespread installation of groundwater pumps has lowered the water table and antiquated the old qanat system. Qanats have gone dry and been abandoned across the country.[10]
## Arabian Peninsula
### United Arab Emirates
The oasis of Al Ain in the United Arab Emirates continues traditional falaj (qanat) irrigations for the palm-groves and gardens. Evidence suggests the technology has been in use for 3000 years here.[11]
### Oman
A ribbon of oases, watered by wells and underground channels (falaj), extends the length of the Oman plain, extending about ten kilometers inland. Nizwa was the capital city of Oman proper was built around a falaj (qanat) which is in use to this day.
In July 2006, the five representative examples of this irrigation system were inscribed as a World Heritage Site.
## North Africa
### Egypt
There are 4 main oases in the Egyptian desert. The Kharga Oasis is one of them which has been extensively studied. As early as the second half of the 5th century BC there is evidence that water was being used via qanats. The qanat is excavated through water-bearing sandstone rock which seeps into the channel to collect in a basin behind a small dam at the end. The width is approximately 60 cm, but the height ranges from 5 to 9 meters; it is likely that the qanat was deepened to enhance seepage when the water table dropped (as is also seen in Iran). From there the water was used to irrigate fields.
[12][6]
There is another instructive structure located at the Kharga Oasis. A well which apparently dried up was improved by driving a side shaft through the easily penetrated sandstone (presumably in the direction of greatest water seepage) into the hill of Ayn-Manâwîr to allow collection of additional water. After this side shaft had been extended, another vertical shaft was driven to intersect the side shaft. Side chambers were built and holes bored into the rock—presumably at points where water seeped from the rocks—are evident.[12]
### Libya
David Mattingley reports foggara extending for hundreds of miles in the Garamantes area near Jarma in Libya: "The channels were generally very narrow - less than 2 feet wide and 5 high - but some were several miles long, and in total some 600 foggara extended for hundreds of miles underground. The channels were dug out and maintained using a series of regularly-spaced vertical shafts, one every 30 feet or so, 100,000 in total, averaging 30 feet in depth, but sometimes reaching 130." ("The 153 Club Newsletter", July 2007 No. 112, pp.14-19; reprinted from Current world Archaeology.
### Tunisia
The foggara water management system in Tunisia, used to create oases, is similar to that of the Iranian qanat. The foggara is dug into the foothills of a fairly steep mountain range such as the eastern ranges of the Atlas mountains. Rainfall in the mountains enters the aquifer and moves toward the Saharan region to the south. The foggara, 1 to 3 km in length, penetrates the aquifer and collects water. Families maintain the foggara and own the land it irrigates over a ten meter wide, with width only by the size of plot that the available water will irrigate.[13]
### Algeria
Qanats (designated foggaras in Algeria) are the source of water for irrigation at large oases like that at Gourara. The foggaras are also found at Touat (an area of Adrar 200 km from Gourara). The length of the foggaras in this region is estimated to be thousands of kilometers.
Although sources suggest that the foggaras may have been in use as early as 200 AD, they were clearly in use by the 11th century after the Arabs took possession of the oases in the 10th century and imposed the Islamic religion upon the residents.
The water is metered to the various users through the use of distribution weirs which meter flow to the various canals, each for a separate user.
The humidity of the oases is also used to supplement the water supply to the foggara. The temperature gradient in the vertical shafts causes air to rise by natural convection, causing a draft to enter the foggara. The moist air of the agricultural area is drawn into the foggara in the opposite direction to the water run-off. In the foggara it condenses on the tunnel walls and the air passed out of the vertical shafts. This condensed moisture is available for reuse. [14]
### Morocco
In southern Morocco the qanat (locally khettara) is also used. On the margins of the Sahara Desert, the isolated oases of the Draa River valley and Tafilalt have relied on qanat water for irrigation since the late-14th century. In Marrakech and the Haouz plain the qanats have been abandoned since the early 1970s as they've dried; in the Tafilaft area half of the 400 khettaras are still in use. The Hassan Adahkil Dam's impacts on local water tables is said to be one of the many reasons given for the loss of half of the khettara.[10]
The black berbers of the south are the hereditary class of qanat diggers in Morocco who build and repair these systems. Their work is hazardous.[8]
## Europe
### Spain
There are still many examples of galeria or qanat systems in Spain, most likely brought to the area by the Moors during their occupation of the Iberian peninsula. Turrillas in Andalusia on the north facing slopes of the Sierra de Alhamilla has evidence of a qanat system. Granada is another site with an extensive qanat system.[15]
### Italy
The entire ancient town of Palermo in Sicily has been built over a huge qanat system built during the Arab period (827-1072). Many of the qanat are now mapped and some can be visited. An interesting building is the famous Scirocco room, which has an air refreshing system using the flux of waters of a qanat and a "wind tower", a structure able to catch the wind and direct it into the room.
## The Americas
Qanats in the Americas can be found in the Atacama regions of Peru, and Chile at Nazca and Pica.[10] The Spanish introduced qanats into Mexico in 1520 AD.[16] | https://www.wikidoc.org/index.php/Qanat | |
f889d69ecb31f0df7d4e9d552e460e69dbd9fdbe | wikidoc | Quark | Quark
A quark (Template:IPAEng, Template:IPAEng or Template:IPAEng) is a generic type of physical particle that forms one of the two basic constituents of matter, the other being the lepton. Various species of quarks combine in specific ways to form protons and neutrons, in each case taking exactly three quarks to make the composite particle in question.
There are six different types of quark, usually known as flavors: up, down, charm, strange, top, and bottom. (Their names were chosen arbitrarily based on the need to name them something that could be easily remembered and used.) The up and down varieties are abundant, and are distinguished by (among other things) their electric charge. It is this which makes the difference when quarks clump together to form protons or neutrons: a proton is made up of two up quarks and one down quark, yielding a net charge of +1; while a neutron contains one up quark and two down quarks, yielding a net charge of 0. Quarks are the only fundamental particles that interact through all four of the fundamental forces. Antiparticles of quarks are called antiquarks. Isolated quarks are never found naturally; they are almost always found in groups of two (mesons) or groups of three (baryons) called hadrons. This is a direct consequence of confinement.
# Properties
The following table summarizes the key properties of the six known quarks:
- Top quark mass from the Tevatron Electroweak Working Group
- Other quark masses from Particle Data Group; these masses are given in the MS-bar scheme.
- The quantum numbers of the top and bottom quarks are sometimes known as truth and beauty respectively, as an alternative to topness and bottomness.
## Flavor
Each quark is assigned a baryon number, B = 1/3, and a vanishing lepton number L = 0. They have fractional electric charge, Q, either Q = +2/3 or Q = −1/3. The former are called up-type quarks, the latter, down-type quarks. Each quark is assigned a weak isospin: Tz = +1/2 for an up-type quark and Tz = −1/2 for a down-type quark. Each doublet of weak isospin defines a generation of quarks. There are three generations, and hence six flavors of quarks — the up-type quark flavors are up, charm and top; the down-type quark flavors are down, strange, and bottom (each list is in the order of increasing mass).
The number of generations of quarks and leptons are equal in the standard model. The number of generations of leptons with a light neutrino is strongly constrained by experiments at the LEP in CERN and by observations of the abundance of helium in the universe. Precision measurement of the lifetime of the Z boson at LEP constrains the number of light neutrino generations to be three. Astronomical observations of helium abundance give consistent results. Results of direct searches for a fourth generation give limits on the mass of the lightest possible fourth generation quark. The most stringent limit comes from analysis of results from the Tevatron collider at Fermilab, and shows that the mass of a fourth-generation quark must be greater than 190 GeV. Additional limits on extra quark generations come from measurements of quark mixing performed by the experiments Belle and BaBar.
Each flavor defines a quantum number which is conserved under the strong interactions, but not the weak interactions. The magnitude of flavor changing in the weak interaction is encoded into a structure called the CKM matrix. This also encodes the CP violation allowed in the Standard Model. The flavor quantum numbers are described in detail in the article on flavor.
## Spin
Quantum numbers corresponding to non-Abelian symmetries like rotations require more care in extraction, since they are not additive. In the quark model one builds mesons out of a quark and an antiquark, whereas baryons are built from three quarks. Since mesons are bosons (having integer spins) and baryons are fermions (having half-integer spins), the quark model implies that quarks are fermions. Further, the fact that the lightest baryons have spin-1/2 implies that each quark can have spin S = 1/2. The spins of excited mesons and baryons are completely consistent with this assignment.
## Color
Since quarks are fermions, the Pauli exclusion principle implies that the three valence quarks must be in an antisymmetric combination in a baryon. However, the charge Q = 2 baryon, Template:SubatomicParticle (which is one of four isospin Iz = 3/2 baryons) can only be made of three Template:SubatomicParticle quarks with parallel spins. Since this configuration is symmetric under interchange of the quarks, it implies that there exists another internal quantum number, which would then make the combination antisymmetric. This is given the name "color", although it has nothing to do with the perception of the frequency (or wavelength) of light, which is the usual meaning of color. This quantum number is the charge involved in the gauge theory called quantum chromodynamics (QCD).
The only other colored particle is the gluon, which is the gauge boson of QCD. Like all other non-Abelian gauge theories (and unlike quantum electrodynamics) the gauge bosons interact with one another by the same force that affects the quarks.
Color is a gauged SU(3) symmetry. Quarks are placed in the fundamental representation, 3, and hence come in three colors (red, green, and blue). Gluons are placed in the adjoint representation, 8, and hence come in eight varieties.
# Confinement and quark properties
Every subatomic particle is completely described by a small set of observables such as mass m and quantum numbers, such as spin b and parity r. Usually these properties are directly determined by experiments. However, confinement makes it impossible to measure these properties of quarks. Instead, they must be inferred from measurable properties of the composite particles which are made up of quarks. Such inferences are usually most easily made for certain additive quantum numbers called flavors.
The composite particles made of quarks and antiquarks are the hadrons. These include the mesons which get their quantum numbers from a quark and an antiquark, and the baryons, which get theirs from three quarks. The quarks (and antiquarks) which impart quantum numbers to hadrons are called valence quarks. Apart from these, any hadron may contain an indefinite number of virtual quarks, antiquarks and gluons which together contribute nothing to their quantum numbers. Such virtual quarks are called sea quarks.
It is now believed that so-called "neutron stars", collapsed remnants of a massive star in which the protons and electrons degenerate and combine to form neutrons, might actually exist instead in the form of up, down and strange quarks as a single "atom" in what is called a quark star.
## Free quarks
No search for free quarks or fractional electric charges has returned convincing evidence. The absence of free quarks has therefore been incorporated into the notion of confinement, which, it is believed, the theory of quarks must possess. This was expounded upon by Frank Wilczek, H. David Politzer and David Gross who concluded that the more quarks separated, the greater the attraction due to the strong force, making it impossible to separate the quarks into free particles. This has been called asymptotic freedom, for which Wilczek was awarded the Nobel Prize in Physics in 2004.
Confinement began as an experimental observation, and is expected to follow from the modern theory of strong interactions, called quantum chromodynamics (QCD). Although there is no mathematical derivation of confinement in QCD, it is easy to show using lattice gauge theory.
However, it may be possible to change the confinement by creating dense or hot quark matter. These new phases of QCD matter have been predicted theoretically, and experimental searches for them have now started at the RHIC. Under some theories, sufficient energy input to the Editor of Scientific American in 1999. However, he concluded that there likely should be no cause for concern, as most theories show such strangelets to be positively charged, and would repulse normal nuclei due to the charge repulsion of Coulomb's law.
# Quark masses
Although one speaks of quark mass in the same way as the mass of any other particle, the notion of mass for quarks is complicated by the fact that quarks cannot be found free in nature. As a result, the notion of a quark mass is a theoretical construct, which makes sense only when one specifies exactly the procedure used to define it.
## Current quark mass
The approximate chiral symmetry of quantum chromodynamics, for example, allows one to define the ratio between various (up, down and strange) quark masses through combinations of the masses of the pseudo-scalar meson octet in the quark model through chiral perturbation theory, giving
The fact that the up quark has mass is important, since there would be no strong CP problem if it were massless. The absolute values of the masses are currently determined from QCD sum rules (also called spectral function sum rules) and lattice QCD. Masses determined in this manner are called current quark masses. The connection between different definitions of the current quark masses needs the full machinery of renormalization for its specification.
## Valence quark mass
Another, older, method of specifying the quark masses was to use the Gell-Mann-Nishijima mass formula in the quark model, which connect hadron masses to quark masses. The masses so determined are called constituent quark masses, and are significantly different from the current quark masses defined above. The constituent masses do not have any further dynamical meaning.
## Heavy quark masses
The masses of the heavy charm and bottom quarks are obtained from the masses of hadrons containing a single heavy quark (and one light antiquark or two light quarks) and from the analysis of quarkonia. Lattice QCD computations using the heavy quark effective theory (HQET) or non-relativistic quantum chromodynamics (NRQCD) are currently used to determine these quark masses.
The top quark is sufficiently heavy that perturbative QCD can be used to determine its mass. Before its discovery in 1995, the best theoretical estimates of the top quark mass are obtained from global analysis of precision tests of the Standard Model. The top quark, however, is unique amongst quarks in that it decays before having a chance to hadronize. Thus, its mass can be directly measured from the resulting decay products. This can only be done at the Tevatron which is the only particle accelerator energetic enough to produce top quarks in abundance.
# Antiquarks
The additive quantum numbers of antiquarks are equal in magnitude and opposite in sign to those of the quarks. CPT symmetry forces them to have the same spin and mass as the corresponding quark. Tests of CPT symmetry cannot be performed directly on quarks and antiquarks, due to confinement, but can be performed on hadrons. Notation of antiquarks follows that of antimatter in general: an up quark is denoted by Template:SubatomicParticle, and an up antiquark is denoted by Template:SubatomicParticle.
# Substructure
Some extensions of the Standard Model begin with the assumption that quarks and leptons have substructure. In other words, these models assume that the elementary particles of the Standard Model are in fact composite particles, made of some other elementary constituents. Such an assumption is open to experimental tests, and these theories are severely constrained by data. At present there is no evidence for such substructure. For more details see the article on preons.
# History
The notion of quarks evolved out of a classification of hadrons developed independently in 1961 by Murray Gell-Mann and Kazuhiko Nishijima, which nowadays goes by the name of the quark model. The scheme grouped together particles with isospin and strangeness using a unitary symmetry derived from current algebra, which we today recognize as part of the approximate chiral symmetry of QCD. This is a global flavor SU(3) symmetry, which should not be confused with the gauge symmetry of QCD.
In this scheme the lightest mesons (spin-0) and baryons (spin-½) are grouped together into octets, 8, of flavor symmetry. A classification of the spin-3/2 baryons into the representation 10 yielded a prediction of a new particle, Template:SubatomicParticle, the discovery of which in 1964 led to wide acceptance of the model. The missing representation 3 was identified with quarks.
This scheme was called the eightfold way by Gell-Mann, a clever conflation of the octets of the model with the eightfold way of Buddhism. He also chose the name quark and attributed it to the sentence “Three quarks for Muster Mark” in James Joyce's Finnegans Wake. In reply to the common claim that he did not actually believe that quarks were real physical entities, Gell-Mann has been quoted as saying - "That is baloney. I have explained so many times that I believed from the beginning that quarks were confined inside objects like neutrons and protons, and in my early papers on quarks I described how they could be confined either by an infinite mass and infinite binding energy, or by a potential rising to infinity, which is what we believe today to be correct. Unfortunately, I referred to confined quarks as 'fictitious', meaning that they could not emerge to be utilized for applications such as catalysing nuclear fusion."
Analysis of certain properties of high energy reactions of hadrons led Richard Feynman to postulate substructures of hadrons, which he called partons (since they form part of hadrons). A scaling of deep inelastic scattering cross sections derived from current algebra by James Bjorken received an explanation in terms of partons. When Bjorken scaling was verified in an experiment in 1969, it was immediately realized that partons and quarks could be the same thing. With the proof of asymptotic freedom in QCD in 1973 by David Gross, Frank Wilczek and David Politzer the connection was firmly established.
The charm quark was postulated by Sheldon Glashow, John Iliopoulos and Luciano Maiani in 1970 to prevent unphysical flavor changes in weak decays which would otherwise occur in the standard model. The discovery in 1974 of the meson which came to be called the J/ψ led to the recognition that it was made of a charm quark and its antiquark.
The existence of a third generation of quarks was predicted by Makoto Kobayashi and Toshihide Maskawa in 1973 who realized that the observed violation of CP symmetry by neutral kaons could not be accommodated into the Standard Model with two generations of quarks. The bottom quark was discovered in 1977 and the top quark in 1996 at the Tevatron collider in Fermilab.
# Origin of the word
The word was originally coined by Murray Gell-Mann as a nonsense word rhyming with "pork", but without a spelling. Later, he found the word "quark" in James Joyce's book Finnegans Wake, and used the spelling but not the pronunciation:
In this context, the word rhymes with "mark", and "bark", but the physics term is pronounced "kwork". Gell-Mann's own explanation:
The phrase "three quarks" is a particularly good fit (as mentioned in the above quote), as at the time, there were only three known quarks, and since quarks appear in groups of three in baryons.
In Joyce's use, it is seabirds giving "three quarks", akin to three cheers, "quark" having a meaning of the cry of a gull (probably onomatopoeia, like "quack" for ducks). The word is also a pun on the relationship between Munster and its provincial capital, Cork. | Quark
Template:Tfd
A quark (Template:IPAEng, Template:IPAEng or Template:IPAEng[1]) is a generic type of physical particle that forms one of the two basic constituents of matter, the other being the lepton. Various species of quarks combine in specific ways to form protons and neutrons, in each case taking exactly three quarks to make the composite particle in question.
There are six different types of quark, usually known as flavors: up, down, charm, strange, top, and bottom. (Their names were chosen arbitrarily based on the need to name them something that could be easily remembered and used.) The up and down varieties are abundant, and are distinguished by (among other things) their electric charge. It is this which makes the difference when quarks clump together to form protons or neutrons: a proton is made up of two up quarks and one down quark, yielding a net charge of +1; while a neutron contains one up quark and two down quarks, yielding a net charge of 0. Quarks are the only fundamental particles that interact through all four of the fundamental forces. Antiparticles of quarks are called antiquarks. Isolated quarks are never found naturally; they are almost always found in groups of two (mesons) or groups of three (baryons) called hadrons. This is a direct consequence of confinement.
# Properties
The following table summarizes the key properties of the six known quarks:
- Top quark mass from the Tevatron Electroweak Working Group
- Other quark masses from Particle Data Group; these masses are given in the MS-bar scheme.
- The quantum numbers of the top and bottom quarks are sometimes known as truth and beauty respectively, as an alternative to topness and bottomness.
## Flavor
Each quark is assigned a baryon number, B = 1/3, and a vanishing lepton number L = 0. They have fractional electric charge, Q, either Q = +2/3 or Q = −1/3. The former are called up-type quarks, the latter, down-type quarks. Each quark is assigned a weak isospin: Tz = +1/2 for an up-type quark and Tz = −1/2 for a down-type quark. Each doublet of weak isospin defines a generation of quarks. There are three generations, and hence six flavors of quarks — the up-type quark flavors are up, charm and top; the down-type quark flavors are down, strange, and bottom (each list is in the order of increasing mass).
The number of generations of quarks and leptons are equal in the standard model. The number of generations of leptons with a light neutrino is strongly constrained by experiments at the LEP in CERN and by observations of the abundance of helium in the universe. Precision measurement of the lifetime of the Z boson at LEP constrains the number of light neutrino generations to be three. Astronomical observations of helium abundance give consistent results. Results of direct searches for a fourth generation give limits on the mass of the lightest possible fourth generation quark. The most stringent limit comes from analysis of results from the Tevatron collider at Fermilab, and shows that the mass of a fourth-generation quark must be greater than 190 GeV. Additional limits on extra quark generations come from measurements of quark mixing performed by the experiments Belle and BaBar.
Each flavor defines a quantum number which is conserved under the strong interactions, but not the weak interactions. The magnitude of flavor changing in the weak interaction is encoded into a structure called the CKM matrix. This also encodes the CP violation allowed in the Standard Model. The flavor quantum numbers are described in detail in the article on flavor.
## Spin
Quantum numbers corresponding to non-Abelian symmetries like rotations require more care in extraction, since they are not additive. In the quark model one builds mesons out of a quark and an antiquark, whereas baryons are built from three quarks. Since mesons are bosons (having integer spins) and baryons are fermions (having half-integer spins), the quark model implies that quarks are fermions. Further, the fact that the lightest baryons have spin-1/2 implies that each quark can have spin S = 1/2. The spins of excited mesons and baryons are completely consistent with this assignment.
## Color
Since quarks are fermions, the Pauli exclusion principle implies that the three valence quarks must be in an antisymmetric combination in a baryon. However, the charge Q = 2 baryon, Template:SubatomicParticle (which is one of four isospin Iz = 3/2 baryons) can only be made of three Template:SubatomicParticle quarks with parallel spins. Since this configuration is symmetric under interchange of the quarks, it implies that there exists another internal quantum number, which would then make the combination antisymmetric. This is given the name "color", although it has nothing to do with the perception of the frequency (or wavelength) of light, which is the usual meaning of color. This quantum number is the charge involved in the gauge theory called quantum chromodynamics (QCD).
The only other colored particle is the gluon, which is the gauge boson of QCD. Like all other non-Abelian gauge theories (and unlike quantum electrodynamics) the gauge bosons interact with one another by the same force that affects the quarks.
Color is a gauged SU(3) symmetry. Quarks are placed in the fundamental representation, 3, and hence come in three colors (red, green, and blue). Gluons are placed in the adjoint representation, 8, and hence come in eight varieties.
# Confinement and quark properties
Every subatomic particle is completely described by a small set of observables such as mass m and quantum numbers, such as spin b and parity r. Usually these properties are directly determined by experiments. However, confinement makes it impossible to measure these properties of quarks. Instead, they must be inferred from measurable properties of the composite particles which are made up of quarks. Such inferences are usually most easily made for certain additive quantum numbers called flavors.
The composite particles made of quarks and antiquarks are the hadrons. These include the mesons which get their quantum numbers from a quark and an antiquark, and the baryons, which get theirs from three quarks. The quarks (and antiquarks) which impart quantum numbers to hadrons are called valence quarks. Apart from these, any hadron may contain an indefinite number of virtual quarks, antiquarks and gluons which together contribute nothing to their quantum numbers. Such virtual quarks are called sea quarks.
It is now believed that so-called "neutron stars", collapsed remnants of a massive star in which the protons and electrons degenerate and combine to form neutrons, might actually exist instead in the form of up, down and strange quarks as a single "atom" in what is called a quark star.
## Free quarks
No search for free quarks or fractional electric charges has returned convincing evidence. The absence of free quarks has therefore been incorporated into the notion of confinement, which, it is believed, the theory of quarks must possess. This was expounded upon by Frank Wilczek, H. David Politzer and David Gross who concluded that the more quarks separated, the greater the attraction due to the strong force, making it impossible to separate the quarks into free particles. This has been called asymptotic freedom, for which Wilczek was awarded the Nobel Prize in Physics in 2004.[citation needed]
Confinement began as an experimental observation, and is expected to follow from the modern theory of strong interactions, called quantum chromodynamics (QCD). Although there is no mathematical derivation of confinement in QCD, it is easy to show using lattice gauge theory.
However, it may be possible to change the confinement by creating dense or hot quark matter. These new phases of QCD matter have been predicted theoretically, and experimental searches for them have now started at the RHIC. Under some theories, sufficient energy input [by high-speed relativistic collisions such as at the RHIC and planned at the LHC might also generate strange quarks arising from the vacuum, which could recombine with the up and down quarks to form a new type of nucleon called a strangelet or strange quark matter. Wilczek cautioned that there might be concern for an "ice-9" type reaction, in which a strangelet engaged in runaway fusion with normal nuclei, in a Letter[3] to the Editor of Scientific American in 1999. However, he concluded that there likely should be no cause for concern, as most theories[4][5] show such strangelets to be positively charged, and would repulse normal nuclei due to the charge repulsion of Coulomb's law.
# Quark masses
Although one speaks of quark mass in the same way as the mass of any other particle, the notion of mass for quarks is complicated by the fact that quarks cannot be found free in nature. As a result, the notion of a quark mass is a theoretical construct, which makes sense only when one specifies exactly the procedure used to define it.
## Current quark mass
The approximate chiral symmetry of quantum chromodynamics, for example, allows one to define the ratio between various (up, down and strange) quark masses through combinations of the masses of the pseudo-scalar meson octet in the quark model through chiral perturbation theory, giving
The fact that the up quark has mass is important, since there would be no strong CP problem if it were massless. The absolute values of the masses are currently determined from QCD sum rules (also called spectral function sum rules) and lattice QCD. Masses determined in this manner are called current quark masses. The connection between different definitions of the current quark masses needs the full machinery of renormalization for its specification.
## Valence quark mass
Another, older, method of specifying the quark masses was to use the Gell-Mann-Nishijima mass formula in the quark model, which connect hadron masses to quark masses. The masses so determined are called constituent quark masses, and are significantly different from the current quark masses defined above. The constituent masses do not have any further dynamical meaning.
## Heavy quark masses
The masses of the heavy charm and bottom quarks are obtained from the masses of hadrons containing a single heavy quark (and one light antiquark or two light quarks) and from the analysis of quarkonia. Lattice QCD computations using the heavy quark effective theory (HQET) or non-relativistic quantum chromodynamics (NRQCD) are currently used to determine these quark masses.
The top quark is sufficiently heavy that perturbative QCD can be used to determine its mass. Before its discovery in 1995, the best theoretical estimates of the top quark mass are obtained from global analysis of precision tests of the Standard Model. The top quark, however, is unique amongst quarks in that it decays before having a chance to hadronize. Thus, its mass can be directly measured from the resulting decay products. This can only be done at the Tevatron which is the only particle accelerator energetic enough to produce top quarks in abundance.
# Antiquarks
The additive quantum numbers of antiquarks are equal in magnitude and opposite in sign to those of the quarks. CPT symmetry forces them to have the same spin and mass as the corresponding quark. Tests of CPT symmetry cannot be performed directly on quarks and antiquarks, due to confinement, but can be performed on hadrons. Notation of antiquarks follows that of antimatter in general: an up quark is denoted by Template:SubatomicParticle, and an up antiquark is denoted by Template:SubatomicParticle.
# Substructure
Some extensions of the Standard Model begin with the assumption that quarks and leptons have substructure. In other words, these models assume that the elementary particles of the Standard Model are in fact composite particles, made of some other elementary constituents. Such an assumption is open to experimental tests, and these theories are severely constrained by data. At present there is no evidence for such substructure. For more details see the article on preons.
# History
The notion of quarks evolved out of a classification of hadrons developed independently in 1961 by Murray Gell-Mann and Kazuhiko Nishijima, which nowadays goes by the name of the quark model. The scheme grouped together particles with isospin and strangeness using a unitary symmetry derived from current algebra, which we today recognize as part of the approximate chiral symmetry of QCD. This is a global flavor SU(3) symmetry, which should not be confused with the gauge symmetry of QCD.
In this scheme the lightest mesons (spin-0) and baryons (spin-½) are grouped together into octets, 8, of flavor symmetry. A classification of the spin-3/2 baryons into the representation 10 yielded a prediction of a new particle, Template:SubatomicParticle, the discovery of which in 1964 led to wide acceptance of the model. The missing representation 3 was identified with quarks.
This scheme was called the eightfold way by Gell-Mann, a clever conflation of the octets of the model with the eightfold way of Buddhism. He also chose the name quark and attributed it to the sentence “Three quarks for Muster Mark” in James Joyce's Finnegans Wake.[6] In reply to the common claim that he did not actually believe that quarks were real physical entities, Gell-Mann has been quoted as saying - "That is baloney. I have explained so many times that I believed from the beginning that quarks were confined inside objects like neutrons and protons, and in my early papers on quarks I described how they could be confined either by an infinite mass and infinite binding energy, or by a potential rising to infinity, which is what we believe today to be correct. Unfortunately, I referred to confined quarks as 'fictitious', meaning that they could not emerge to be utilized for applications such as catalysing nuclear fusion."[7]
Analysis of certain properties of high energy reactions of hadrons led Richard Feynman to postulate substructures of hadrons, which he called partons (since they form part of hadrons). A scaling of deep inelastic scattering cross sections derived from current algebra by James Bjorken received an explanation in terms of partons. When Bjorken scaling was verified in an experiment in 1969, it was immediately realized that partons and quarks could be the same thing. With the proof of asymptotic freedom in QCD in 1973 by David Gross, Frank Wilczek and David Politzer the connection was firmly established.
The charm quark was postulated by Sheldon Glashow, John Iliopoulos and Luciano Maiani in 1970 to prevent unphysical flavor changes in weak decays which would otherwise occur in the standard model. The discovery in 1974 of the meson which came to be called the J/ψ led to the recognition that it was made of a charm quark and its antiquark.
The existence of a third generation of quarks was predicted by Makoto Kobayashi and Toshihide Maskawa in 1973 who realized that the observed violation of CP symmetry by neutral kaons could not be accommodated into the Standard Model with two generations of quarks. The bottom quark was discovered in 1977 and the top quark in 1996 at the Tevatron collider in Fermilab.
# Origin of the word
The word was originally coined by Murray Gell-Mann as a nonsense word rhyming with "pork"[8], but without a spelling. Later, he found the word "quark" in James Joyce's book Finnegans Wake, and used the spelling but not the pronunciation:
In this context, the word rhymes with "mark", and "bark", but the physics term is pronounced "kwork". Gell-Mann's own explanation:[9][10]
The phrase "three quarks" is a particularly good fit (as mentioned in the above quote), as at the time, there were only three known quarks, and since quarks appear in groups of three in baryons.
In Joyce's use, it is seabirds giving "three quarks", akin to three cheers, "quark" having a meaning of the cry of a gull (probably onomatopoeia, like "quack" for ducks). The word is also a pun on the relationship between Munster and its provincial capital, Cork. | https://www.wikidoc.org/index.php/Quark | |
e040e4f228f8879859dfe1d507fd2dd63539cf76 | wikidoc | RAB23 | RAB23
Ras-related protein Rab-23 is a protein that in humans is encoded by the RAB23 gene. Alternative splicing occurs at this gene locus and two transcript variants encoding the same protein have been identified.
# Function
RAB23 belongs to the small GTPase superfamily, Rab family. It may be involved in small GTPase mediated signal transduction and intracellular protein transportation.
RAB23 is an essential negative regulator of the Sonic hedgehog signaling pathway. The first understanding of biological processes requiring the Rab23 gene came from 2 independent mouse mutations in the gene and an epistasis analysis with mutations in the mouse shh gene. These studies showed that the gene is required for normal development of the brain and spinal cord and that the morphological defects seen in mutant embryos, such as failure to close dorsal regions of the neural tube during development, appeared secondary to expansion of ventral and reduction of dorsal identities in the developing neural tube. These same mutations implicated the RAB23 gene in development of digits and eyes. The mouse open brain (opb) and Sonic hedgehog (Shh) genes have opposing roles in neural patterning: opb is required for dorsal cell types and Shh is required for ventral cell types in the spinal cord. | RAB23
Ras-related protein Rab-23 is a protein that in humans is encoded by the RAB23 gene.[1][2][3] Alternative splicing occurs at this gene locus and two transcript variants encoding the same protein have been identified.[4]
# Function
RAB23 belongs to the small GTPase superfamily, Rab family. It may be involved in small GTPase mediated signal transduction and intracellular protein transportation.[4]
RAB23 is an essential negative regulator of the Sonic hedgehog signaling pathway.[2] The first understanding of biological processes requiring the Rab23 gene came from 2 independent mouse mutations in the gene [5][6] and an epistasis analysis with mutations in the mouse shh gene.[2] These studies showed that the gene is required for normal development of the brain and spinal cord and that the morphological defects seen in mutant embryos, such as failure to close dorsal regions of the neural tube during development, appeared secondary to expansion of ventral and reduction of dorsal identities in the developing neural tube. These same mutations implicated the RAB23 gene in development of digits and eyes. The mouse open brain (opb) and Sonic hedgehog (Shh) genes have opposing roles in neural patterning: opb is required for dorsal cell types and Shh is required for ventral cell types in the spinal cord.[2] | https://www.wikidoc.org/index.php/RAB23 | |
5b6e0d53c3fcbdfd20fb9b6fafcb2b84db14eb2b | wikidoc | RAB27 | RAB27
Rab27 is a member of the Rab subfamily of GTPases. Rab27 is post translationally modified by the addition of two geranylgeranyl groups on the two C-terminal cysteines.
# Pathology
Mutations that prevent the expression of Rab27 ('knock out' mutations) cause the hypopigmentation and immunodefficiency disorder known as type II Griscelli syndrome, while a decrease in Rab27 prenylation is thought to be involved in choroideremia.
The symptoms of type II Griscelli syndrome have shown that Rab27 is involved in melanosome transport in melanocytes and in cytotoxic killing activity in cytotoxic T lymphoblasts. In melanocytes Rab27 binds the melanosome. The melanosome is transported along the microtubule. Rab27 then recruits Slac2A and myosin Va, these enzymes are essential for the transfer of the melanosomes from the microtubules to actin filaments. The melanosomes can now continue on their path towards the cell periphery. If either Rab27, Slac2A or myosin Va are absent then the melansomes remain in the perinuclear region of the cell. This disruption in pigmentation results in the hypopigmentation seen in the silvery hair colour of patients with Griscelli syndrome. | RAB27
Rab27 is a member of the Rab subfamily of GTPases. Rab27 is post translationally modified by the addition of two geranylgeranyl groups on the two C-terminal cysteines.
# Pathology
Mutations that prevent the expression of Rab27 ('knock out' mutations) cause the hypopigmentation and immunodefficiency disorder known as type II Griscelli syndrome, while a decrease in Rab27 prenylation is thought to be involved in choroideremia.
The symptoms of type II Griscelli syndrome have shown that Rab27 is involved in melanosome transport in melanocytes and in cytotoxic killing activity in cytotoxic T lymphoblasts. In melanocytes Rab27 binds the melanosome. The melanosome is transported along the microtubule. Rab27 then recruits Slac2A and myosin Va, these enzymes are essential for the transfer of the melanosomes from the microtubules to actin filaments. The melanosomes can now continue on their path towards the cell periphery. If either Rab27, Slac2A or myosin Va are absent then the melansomes remain in the perinuclear region of the cell. This disruption in pigmentation results in the hypopigmentation seen in the silvery hair colour of patients with Griscelli syndrome.
# External links
- RAB27A+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- RAB27B+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH) | https://www.wikidoc.org/index.php/RAB27 | |
c0286b85e94551ddeca1010a61b6082ab57bf0fe | wikidoc | RAB7A | RAB7A
Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.
Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the cell membrane around a substance outside of the cell (for example a protein) and then forms a vesicle. The vesicle is then brought into the cell and cleaved from the cell membrane. RAB7A plays an important role in the movement of vesicles into the cell as well as with vesicle trafficking.
Various mutations of RAB7A are associated with Hereditary sensory neuropathy type 1C (HSN IC), also known as Charcot-Marie-Tooth syndrome type 2B (CMT2B).
# Function
Members of the RAB family of RAS-related GTP-binding proteins are important regulators of vesicular transport and are located in specific intracellular compartments. RAB7 has been localized to late endosomes and shown to be important in the late endocytic pathway. In addition, it has been shown to have a fundamental role in the cellular vacuolation induced by the cytotoxin VacA of Helicobacter pylori.
RAB7A functions as a key regulator in endo-lysosomal trafficking, governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positions, and endosome-lysosome transport through different protein-protein interaction cascades.
RAB7A is also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes through modulation of SOX10 and the oncogene MYC. Mutations in the lysosomal pathway result in tumor progression in melanoma cells.
# Tissue distribution
RAB7 is widely expressed; high expression found in skeletal muscle as it plays a role in the long-range retrograde transport of signalling endosomes in the axons.
# Gene
The RAB7A gene is located on chromosome 3 in humans, specifically on the long q arm from base pair 128,726,135 to 128,814,797. The location was found using mapping which was first done by Davies et al. in 1997 to map the RAB7A gene to chromosome 3 using PCR analysis. In 1995 it had been mapped to chromosome 9 in mice by Barbosa et al. Finally, using fluorescence in situ hybridization (FISH), Kashuba et al. were able to map the RAB7A gene to 3q21 in 1997.
RAB7a was cloned by screening a human placenta cDNA library with a rat Rab7 cDNA to show that the RAB7a cDNA encodes a 207-amino acid protein whose sequence is 99% identical to those of mouse, rat, and dog Rab7a and 61% identical to that of yeast Rab7a. Using Northern Blot Analysis, Vitelli et al. (1996) found that RAB7a was expressed as 1.7- and 2.5-kb transcripts in all cell lines examined but that there was a large difference in the total amount of RAB7a mRNA among the cell lines.
# Regulation
It is linked that RAB7a levels and function were independent of melanocyte lineage-specific transcription factors (MITF) but recent research has shown that SOX10 (a neuroectodermal master modulator) and MYC (an oncogene) are the major regulators. Rab7a is regulated by SOX10 and MYC respectively in a lineage-specific wiring. Studies show that RAB7a can be specifically up regulated through MITF-independent manners like changing levels of SOX10 or MYC to affect tumor proliferation especially in melanoma.
In studies using antisense RNA, downregulation of RAB7 gene expression in HeLa cells using antisense RNA induces severe cell vacuolation that resembles the phenotype seen in fibroblasts from patients with Chédiak–Higashi syndrome.
In the presence of growth factor, growth factor inhibition of mammalian Rab7 had no effect on nutrient transporter expression in mouse pro-B-lymphocytic cells. In growth factor-deprived cells, however, blocking Rab7 function prevented the clearance of glucose and amino acid transporter proteins from the cell surface. When Rab7 was inhibited, growth factor-deprived cells maintained their mitochondrial membrane potential and displayed prolonged, growth factor-independent, nutrient-dependent cell survival. The authors concluded that RAB7 functions as a proapoptotic protein by limiting cell-autonomous nutrient uptake.
# Interactions
RAB7A has been shown to interact with RILP and CHM. RILP has been shown to have a key role in the control of transport to degradative compartments along with Rab7 and may link Rab7 function to the cytoskeleton. RILP plays the role of a downstream effector for Rab7 and together both of these proteins act to regulate late endocytic traffic.
Other key interactions include RAC1 (By similarity), NTRK1/TRKA (By similarity), C9orf72 (By similarity), CHM (the substrate-binding subunit of the Rab geranylgeranyltransferase complex), and RILP, as well as PSMA7, RNF115 and FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4 complex. The GTP-bound form interacts with OSBPL1A and CLN3. Rab7A was also shown to interact with the Retromer Complex, most likely through the Vps35 subunit.
# Clinical significance
RAB7 is a small GTPase that has the potential of causing malignancy from over 35 tumor types. It is found that RAB7 is an early induced melanoma driver whose levels can define metastatic risk. The RAB7A gene belongs to the RAB family of genes, which is a member of the RAS oncogene family. These genes in the RAB family provides the instructions that are necessary for making proteins for vesicle trafficking. These proteins are GTPases and act like switch which is turned on and off by GTP and GDP molecules.
## Melanoma
Melanoma cells retain a developmental memory that reflects a unique wiring of vesicles trafficking pathways. Rab7 is seen to control the proliferative and invasive potential of these aggressive tumors upon identification of melanoma enriched endolysosomal gene cluster. Lysosomal-associated degradation, a universal feature of eukaryotic cells, can be hijacked in a tumor-type- and stage –dependent manner. Finding that RAB7 is controlled by SOX10 and MYC in a MITF-independent manner has important basic and translational implications. Sox10 is not inhibited by mechanisms that downregulate MITF, some of which including BRAF mutations, are relatively frequent in malignant melanomas. This may ensure a developmental memory in the expression of RAB7. It is speculated that downregulation of RAB7 in the invasive front of aggressive melanomas is modulated by epithelial-to-mesenchymal-like mechanisms, such as those recently described to underlie the transcriptional switch associated with prometastatic phenotypes. In otherwords, there is an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF and instead, the neuroectodermal master modulator SOX10 and the oncogene MYC are key RAB7a regulators.
## Charcot-Marie-Tooth 2B
Also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA). This is a genetically and clinically heterogeneous group of inherited disorders, characterized by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement. Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 23,000 people in the United Kingdom and 125,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy. | RAB7A
Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.[1][2]
Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the cell membrane around a substance outside of the cell (for example a protein) and then forms a vesicle. The vesicle is then brought into the cell and cleaved from the cell membrane. RAB7A plays an important role in the movement of vesicles into the cell as well as with vesicle trafficking.[3]
Various mutations of RAB7A are associated with Hereditary sensory neuropathy type 1C (HSN IC), also known as Charcot-Marie-Tooth syndrome type 2B (CMT2B).[4]
# Function
Members of the RAB family of RAS-related GTP-binding proteins are important regulators of vesicular transport and are located in specific intracellular compartments. RAB7 has been localized to late endosomes and shown to be important in the late endocytic pathway. In addition, it has been shown to have a fundamental role in the cellular vacuolation induced by the cytotoxin VacA of Helicobacter pylori.[5]
RAB7A functions as a key regulator in endo-lysosomal trafficking, governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positions, and endosome-lysosome transport through different protein-protein interaction cascades.
RAB7A is also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes through modulation of SOX10 and the oncogene MYC. Mutations in the lysosomal pathway result in tumor progression in melanoma cells.
# Tissue distribution
RAB7 is widely expressed; high expression found in skeletal muscle[6] as it plays a role in the long-range retrograde transport of signalling endosomes in the axons.
# Gene
The RAB7A gene is located on chromosome 3 in humans, specifically on the long q arm from base pair 128,726,135 to 128,814,797. The location was found using mapping which was first done by Davies et al. in 1997 to map the RAB7A gene to chromosome 3 using PCR analysis.[1] In 1995 it had been mapped to chromosome 9 in mice by Barbosa et al. Finally, using fluorescence in situ hybridization (FISH), Kashuba et al. were able to map the RAB7A gene to 3q21 in 1997.[2]
RAB7a was cloned by screening a human placenta cDNA library with a rat Rab7 cDNA to show that the RAB7a cDNA encodes a 207-amino acid protein whose sequence is 99% identical to those of mouse, rat, and dog Rab7a and 61% identical to that of yeast Rab7a. Using Northern Blot Analysis, Vitelli et al. (1996) found that RAB7a was expressed as 1.7- and 2.5-kb transcripts in all cell lines examined but that there was a large difference in the total amount of RAB7a mRNA among the cell lines.[7]
# Regulation
It is linked that RAB7a levels and function were independent of melanocyte lineage-specific transcription factors (MITF) but recent research has shown that SOX10 (a neuroectodermal master modulator) and MYC (an oncogene) are the major regulators. Rab7a is regulated by SOX10 and MYC respectively in a lineage-specific wiring. Studies show that RAB7a can be specifically up regulated through MITF-independent manners like changing levels of SOX10 or MYC to affect tumor proliferation especially in melanoma[14].
In studies using antisense RNA, downregulation of RAB7 gene expression in HeLa cells using antisense RNA induces severe cell vacuolation that resembles the phenotype seen in fibroblasts from patients with Chédiak–Higashi syndrome.[8]
In the presence of growth factor, growth factor inhibition of mammalian Rab7 had no effect on nutrient transporter expression in mouse pro-B-lymphocytic cells. In growth factor-deprived cells, however, blocking Rab7 function prevented the clearance of glucose and amino acid transporter proteins from the cell surface. When Rab7 was inhibited, growth factor-deprived cells maintained their mitochondrial membrane potential and displayed prolonged, growth factor-independent, nutrient-dependent cell survival. The authors concluded that RAB7 functions as a proapoptotic protein by limiting cell-autonomous nutrient uptake.[9]
# Interactions
RAB7A has been shown to interact with RILP[10][11] and CHM.[12][13] RILP has been shown to have a key role in the control of transport to degradative compartments along with Rab7 and may link Rab7 function to the cytoskeleton. RILP plays the role of a downstream effector for Rab7 and together both of these proteins act to regulate late endocytic traffic.[14]
Other key interactions include RAC1 (By similarity), NTRK1/TRKA (By similarity), C9orf72 (By similarity), CHM (the substrate-binding subunit of the Rab geranylgeranyltransferase complex), and RILP,[15] as well as PSMA7, RNF115 and FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4 complex. The GTP-bound form interacts with OSBPL1A and CLN3.[16] Rab7A was also shown to interact with the Retromer Complex, most likely through the Vps35 subunit.[17]
# Clinical significance
RAB7 is a small GTPase that has the potential of causing malignancy from over 35 tumor types. It is found that RAB7 is an early induced melanoma driver whose levels can define metastatic risk. The RAB7A gene belongs to the RAB family of genes, which is a member of the RAS oncogene family. These genes in the RAB family provides the instructions that are necessary for making proteins for vesicle trafficking. These proteins are GTPases and act like switch which is turned on and off by GTP and GDP molecules.[3]
## Melanoma
Melanoma cells retain a developmental memory that reflects a unique wiring of vesicles trafficking pathways. Rab7 is seen to control the proliferative and invasive potential of these aggressive tumors upon identification of melanoma enriched endolysosomal gene cluster. Lysosomal-associated degradation, a universal feature of eukaryotic cells, can be hijacked in a tumor-type- and stage –dependent manner. Finding that RAB7 is controlled by SOX10 and MYC in a MITF-independent manner has important basic and translational implications.[18] Sox10 is not inhibited by mechanisms that downregulate MITF, some of which including BRAF mutations, are relatively frequent in malignant melanomas. This may ensure a developmental memory in the expression of RAB7. It is speculated that downregulation of RAB7 in the invasive front of aggressive melanomas is modulated by epithelial-to-mesenchymal-like mechanisms, such as those recently described to underlie the transcriptional switch associated with prometastatic phenotypes. In otherwords, there is an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF and instead, the neuroectodermal master modulator SOX10 and the oncogene MYC are key RAB7a regulators.[18]
## Charcot-Marie-Tooth 2B
Also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA). This is a genetically and clinically heterogeneous group of inherited disorders, characterized by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement.[19][20] Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 23,000 people in the United Kingdom and 125,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy.[21] | https://www.wikidoc.org/index.php/RAB7A | |
fb4a4f0dfc205d09f656fd91a84e9799e02b2241 | wikidoc | RAD18 | RAD18
E3 ubiquitin-protein ligase RAD18 is an enzyme that in humans is encoded by the RAD18 gene.
# Function
The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is a ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens.
# Animal models
Model organisms have been used in the study of RAD18 function. A conditional knockout mouse line, called Rad18tm1a(EUCOMM)Wtsi, was generated as part of the EUCOMM program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Mice lacking Rad18 had no significant defects in viability or fertility, therefore male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.
Twenty five tests were carried out and four significant phenotypes were reported:
- Mutant male mice had a decreased body weight compared to wildtype control mice.
- Mutant male mice showed increased activity, VO2 and energy expenditure, determined by indirect calorimetry.
- Dual-energy X-ray absorptiometry (DEXA) showed mutant male mice had a decrease in fat mass.
- A micronucleus test found a potential increase in DNA damage in mutant mice.
A knockout in a human colorectal cancer cell line, HCT116, has also been created.
# Interactions
RAD18 has been shown to interact with HLTF, UBE2B and UBE2A. | RAD18
E3 ubiquitin-protein ligase RAD18 is an enzyme that in humans is encoded by the RAD18 gene.[1][2][3]
# Function
The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is a ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens.[3]
# Animal models
Model organisms have been used in the study of RAD18 function. A conditional knockout mouse line, called Rad18tm1a(EUCOMM)Wtsi,[4] was generated as part of the EUCOMM program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[5][6][7][8][9] Mice lacking Rad18 had no significant defects in viability or fertility,[10][11] therefore male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][12][13]
Twenty five tests were carried out and four significant phenotypes were reported:[13]
- Mutant male mice had a decreased body weight compared to wildtype control mice.
- Mutant male mice showed increased activity, VO2 and energy expenditure, determined by indirect calorimetry.
- Dual-energy X-ray absorptiometry (DEXA) showed mutant male mice had a decrease in fat mass.
- A micronucleus test found a potential increase in DNA damage in mutant mice.
A knockout in a human colorectal cancer cell line, HCT116, has also been created.[21]
# Interactions
RAD18 has been shown to interact with HLTF,[22] UBE2B[1][2] and UBE2A.[1][2] | https://www.wikidoc.org/index.php/RAD18 | |
194960a03cc7c267cb7e4e7e1517fa244abd0d42 | wikidoc | RAD51 | RAD51
RAD51 is a eukaryotic gene. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.
# Variants
Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. Transcript variants utilizing alternative polyA signals exist.
# Family
In mammals, seven recA-like genes have been identified: Rad51, Rad51L1/B, Rad51L2/C, Rad51L3/D, XRCC2, XRCC3, and DMC1/Lim15. All of these proteins, with the exception of meiosis-specific DMC1, are essential for development in mammals. Rad51 is a member of the RecA-like NTPases.
# Function
In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2 and RAD52.
The structural basis for Rad51 filament formation and its functional mechanism still remain poorly understood. However, recent studies using fluorescent labeled Rad51 have indicated that Rad51 fragments elongate via multiple nucleation events followed by growth, with the total fragment terminating when it reaches about 2 μm in length. Disassociation of Rad51 from dsDNA, however, is slow and incomplete, suggesting that there is a separate mechanism that accomplishes this.
# RAD51 expression in cancer
In eukaryotes, RAD51 protein has a central role in homologous recombinational repair. RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (see homologous recombination models).
Numerous studies report that RAD51 is over-expressed in different cancers (see Table 1). In many of these studies, elevated expression of RAD51 is correlated with decreased patient survival. There are also some reports of under-expression of RAD51 in cancers (see Table 1).
Where RAD51 expression was measured in conjunction with BRCA1 expression, an inverse correlation was found. This was interpreted as selection for increased RAD51 expression and thus increased homologous recombinational repair (HRR) (by the HRR RAD52-RAD51 back-up pathway) to compensate for the added DNA damages remaining when BRCA1 was deficient.
Many cancers have epigenetic deficiencies in various DNA repair genes (see Frequencies of epimutations in DNA repair genes in cancers), likely causing increased unrepaired DNA damages. The over expression of RAD51 seen in many cancers may reflect compensatory RAD51 over expression (as in BRCA1 deficiency) and increased HRR to at least partially deal with such excess DNA damages.
Under-expression of RAD51 would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis), would lead to increased mutations and cancer.
# In double-strand break repair
Double-strand break (DSB) repair by homologous recombination is initiated by 5' to 3' strand resection (DSB resection). In humans, the DNA2 nuclease cuts back the 5'-to-3' strand at the DSB to generate a 3' single-strand DNA overhang strand.
A number of paralogs (see Figure) of RAD51 are essential for RAD51 protein recruitment or stabilization at damage sites in vertebrates.
In vertebrates and plants, five paralogs of RAD51 are expressed in somatic cells, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and with each other.
Outside of plants and vertebrates, a much broader diversity of Rad51 recombinase paralog proteins exists. In budding yeast, Saccharomyces cerevisiae, the paralogs Rad55 and Rad57 are present, which form a complex that associates with yeast Rad51 to ssDNA. The recombinase paralog rfs-1 is found in the round worm Caenorhabditis elegans, where it is not essential for homologous recombination. Among archaea the RadB and RadC recombinase paralogs are found in many organisms belonging to Euryarchaeota while a broader diversity of related recombinase paralogs seem to be found in the Crenarchaea including Ral1, Ral2, Ral3, RadC, RadC1, and RadC2.
The RAD51 paralogs contribute to efficient DNA double-strand break repair by homologous recombination and depletion of any paralog often results in significant decreases in homologous recombination frequency.
The paralogs form two identified complexes: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. The CX3 complex acts downstream of RAD51 recruitment to damage sites.
Another complex, the BRCA1-PALB2-BRCA2 complex, and the RAD51 paralogs cooperate to load RAD51 onto ssDNA coated with RPA to form the essential recombination intermediate, the RAD51-ssDNA filament.
In mice and humans, the BRCA2 complex primarily mediates orderly assembly of RAD51 on ssDNA, the form that is active for homologous pairing and strand invasion. BRCA2 also redirects RAD51 from dsDNA and prevents dissociation from ssDNA. However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair, though with lower efficiency than BRCA2.
Further steps are detailed in the article Homologous recombination.
# MicroRNA control of RAD51 expression
In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. Some miRNAs also undergo methylation-associated silencing in cancer cells. If a repressive miRNA is silenced by hypermethylation or deletion, then a gene it is targeting becomes over-expressed.
At least eight miRNAs have been identified that repress RAD51 expression, and five of them appear to be important in cancer. For instance, in triple negative breast cancers (TNBC), over-expression of miR-155 occurs together with repression of RAD51. Further tests directly showed that transfecting breast cancer cells with a vector over-expressing miR-155 represses RAD51, causing decreased homologous recombination and increased sensitivity to ionizing radiation.
Four further miRNAs that repress RAD51 (miR-148b- and miR-193b*, miR-506, and miR-34a) are under-expressed in cancers, presumably leading to induction of RAD51.
Under-expression of miR-148b- and miR-193b- cause an observed induction of RAD51 expression. Deletions of 148b- and miR-193b- in serous ovarian tumors correlate with increased incidences of (possibly carcinogenic) losses of heterozygosity (LOH). This excess LOH was thought to be due to excess recombination caused by induced expression of RAD51.
Under-expression of miR-506 is associated with early time to recurrence (and reduced survival) for epithelial ovarian cancer patients.
Methylation of the promoter of miR-34a, resulting in under-expression of miR-34a, is observed in 79% of prostate cancers and 63% of primary melanomas. Under-expressed levels of miR-34a are also seen in 63% of non-small cell lung cancers, and 36% of colon cancers. miR-34a is also generally under-expressed in primary neuroblastoma tumors.
Table 2 summarizes these five microRNAs, their over or under expression, and the cancers in which their altered expression was noted to occur.
The information summarized in Table 2 suggests that under-expression of microRNAs (causing induction of RAD51) occurs frequently in cancers. Over-expression of a microRNA that causes repression of RAD51 appears to be less frequent. The data in Table 1 (above) indicates that, in general, over-expression of RAD51 is more frequent in cancers than under-expression.
Three other microRNAs were identified, by various criteria, as likely to repress RAD51 (miR-96, miR-203, and miR-103/107). These microRNAs were then tested by over-expressing them in cells in vitro, and they were found to indeed repress RAD51. This repression was generally associated with decreased HR and increased sensitivity of the cells to DNA damaging agents.
# Pathology
This protein is also found to interact with PALB2 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis.
Several alterations of the Rad51 gene have been associated with an increased risk of developing breast cancer. The breast cancer susceptibility protein BRCA2 and PALB2 controls the function of Rad51 in the pathway for DNA repair by homologous recombination.
In addition to the data listed in Table 1, increased RAD51 expression levels have been identified in metastatic canine mammary carcinoma, indicating that genomic instability plays an important role in the carcinogenesis of this tumor type.
# Interactions
RAD51 has been shown to interact with:
- Abl gene,
- Ataxia telangiectasia mutated,
- BARD1,
- BRCA1,
- BRCA2,
- BRCC3,
- BRE,
- Bloom syndrome protein,
- DMC1,
- RAD54,
- P53
- RAD52,
- RAD54B, and
- UBE2I. | RAD51
RAD51 is a eukaryotic gene. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51.[1][2] The protein is highly conserved in most eukaryotes, from yeast to humans.[3]
# Variants
Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. Transcript variants utilizing alternative polyA signals exist.
# Family
In mammals, seven recA-like genes have been identified: Rad51, Rad51L1/B, Rad51L2/C, Rad51L3/D, XRCC2, XRCC3, and DMC1/Lim15.[4] All of these proteins, with the exception of meiosis-specific DMC1, are essential for development in mammals. Rad51 is a member of the RecA-like NTPases.
# Function
In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.[5]
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[6] and RAD52.
The structural basis for Rad51 filament formation and its functional mechanism still remain poorly understood. However, recent studies using fluorescent labeled Rad51[7] have indicated that Rad51 fragments elongate via multiple nucleation events followed by growth, with the total fragment terminating when it reaches about 2 μm in length. Disassociation of Rad51 from dsDNA, however, is slow and incomplete, suggesting that there is a separate mechanism that accomplishes this.
# RAD51 expression in cancer
In eukaryotes, RAD51 protein has a central role in homologous recombinational repair. RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (see homologous recombination models).
Numerous studies report that RAD51 is over-expressed in different cancers (see Table 1). In many of these studies, elevated expression of RAD51 is correlated with decreased patient survival. There are also some reports of under-expression of RAD51 in cancers (see Table 1).
Where RAD51 expression was measured in conjunction with BRCA1 expression, an inverse correlation was found.[8][9] This was interpreted as selection for increased RAD51 expression and thus increased homologous recombinational repair (HRR) (by the HRR RAD52-RAD51 back-up pathway[10]) to compensate for the added DNA damages remaining when BRCA1 was deficient.[8][9][11]
Many cancers have epigenetic deficiencies in various DNA repair genes (see Frequencies of epimutations in DNA repair genes in cancers), likely causing increased unrepaired DNA damages. The over expression of RAD51 seen in many cancers may reflect compensatory RAD51 over expression (as in BRCA1 deficiency) and increased HRR to at least partially deal with such excess DNA damages.
Under-expression of RAD51 would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis), would lead to increased mutations and cancer.
# In double-strand break repair
Double-strand break (DSB) repair by homologous recombination is initiated by 5' to 3' strand resection (DSB resection). In humans, the DNA2 nuclease cuts back the 5'-to-3' strand at the DSB to generate a 3' single-strand DNA overhang strand.[22][23]
A number of paralogs (see Figure) of RAD51 are essential for RAD51 protein recruitment or stabilization at damage sites in vertebrates.
In vertebrates and plants, five paralogs of RAD51 are expressed in somatic cells, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and with each other.[24]
Outside of plants and vertebrates, a much broader diversity of Rad51 recombinase paralog proteins exists. In budding yeast, Saccharomyces cerevisiae, the paralogs Rad55 and Rad57 are present, which form a complex that associates with yeast Rad51 to ssDNA. The recombinase paralog rfs-1 is found in the round worm Caenorhabditis elegans, where it is not essential for homologous recombination. Among archaea the RadB and RadC recombinase paralogs are found in many organisms belonging to Euryarchaeota while a broader diversity of related recombinase paralogs seem to be found in the Crenarchaea including Ral1, Ral2, Ral3, RadC, RadC1, and RadC2.
The RAD51 paralogs contribute to efficient DNA double-strand break repair by homologous recombination and depletion of any paralog often results in significant decreases in homologous recombination frequency.[25]
The paralogs form two identified complexes: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[25] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. The CX3 complex acts downstream of RAD51 recruitment to damage sites.[25]
Another complex, the BRCA1-PALB2-BRCA2 complex, and the RAD51 paralogs cooperate to load RAD51 onto ssDNA coated with RPA to form the essential recombination intermediate, the RAD51-ssDNA filament.[26]
In mice and humans, the BRCA2 complex primarily mediates orderly assembly of RAD51 on ssDNA, the form that is active for homologous pairing and strand invasion.[27] BRCA2 also redirects RAD51 from dsDNA and prevents dissociation from ssDNA.[27] However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair,[28] though with lower efficiency than BRCA2.
Further steps are detailed in the article Homologous recombination.
# MicroRNA control of RAD51 expression
In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes.[29] Some miRNAs also undergo methylation-associated silencing in cancer cells.[30][31] If a repressive miRNA is silenced by hypermethylation or deletion, then a gene it is targeting becomes over-expressed.
At least eight miRNAs have been identified that repress RAD51 expression, and five of them appear to be important in cancer. For instance, in triple negative breast cancers (TNBC), over-expression of miR-155 occurs together with repression of RAD51.[32] Further tests directly showed that transfecting breast cancer cells with a vector over-expressing miR-155 represses RAD51, causing decreased homologous recombination and increased sensitivity to ionizing radiation.[32]
Four further miRNAs that repress RAD51 (miR-148b* and miR-193b*,[33] miR-506,[34] and miR-34a[35]) are under-expressed in cancers, presumably leading to induction of RAD51.
Under-expression of miR-148b* and miR-193b* cause an observed induction of RAD51 expression.[33] Deletions of 148b* and miR-193b* in serous ovarian tumors correlate with increased incidences of (possibly carcinogenic) losses of heterozygosity (LOH). This excess LOH was thought to be due to excess recombination caused by induced expression of RAD51.[33]
Under-expression of miR-506 is associated with early time to recurrence (and reduced survival) for epithelial ovarian cancer patients.[36]
Methylation of the promoter of miR-34a, resulting in under-expression of miR-34a, is observed in 79% of prostate cancers and 63% of primary melanomas.[37] Under-expressed levels of miR-34a are also seen in 63% of non-small cell lung cancers,[38] and 36% of colon cancers.[39] miR-34a is also generally under-expressed in primary neuroblastoma tumors.[40]
Table 2 summarizes these five microRNAs, their over or under expression, and the cancers in which their altered expression was noted to occur.
The information summarized in Table 2 suggests that under-expression of microRNAs (causing induction of RAD51) occurs frequently in cancers. Over-expression of a microRNA that causes repression of RAD51 appears to be less frequent. The data in Table 1 (above) indicates that, in general, over-expression of RAD51 is more frequent in cancers than under-expression.
Three other microRNAs were identified, by various criteria, as likely to repress RAD51 (miR-96,[41] miR-203,[42] and miR-103/107[43]). These microRNAs were then tested by over-expressing them in cells in vitro, and they were found to indeed repress RAD51. This repression was generally associated with decreased HR and increased sensitivity of the cells to DNA damaging agents.
# Pathology
This protein is also found to interact with PALB2[6] and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis.[44]
Several alterations of the Rad51 gene have been associated with an increased risk of developing breast cancer. The breast cancer susceptibility protein BRCA2 and PALB2 controls the function of Rad51 in the pathway for DNA repair by homologous recombination.[6][45]
In addition to the data listed in Table 1, increased RAD51 expression levels have been identified in metastatic canine mammary carcinoma, indicating that genomic instability plays an important role in the carcinogenesis of this tumor type.[46][47][48][49]
# Interactions
RAD51 has been shown to interact with:
- Abl gene,[50]
- Ataxia telangiectasia mutated,[50]
- BARD1,[51]
- BRCA1,[51][52][53][54]
- BRCA2,[45][51][52][55][56][57][58][59][60][61][62][63][64]
- BRCC3,[51]
- BRE,[51]
- Bloom syndrome protein,[65]
- DMC1,[66]
- RAD54,[67]
- P53[51][68][69]
- RAD52,[50]
- RAD54B,[70] and
- UBE2I.[71][72] | https://www.wikidoc.org/index.php/RAD51 | |
52d4eea252eb295443fabb703126cf9c2715ed4a | wikidoc | RAD52 | RAD52
RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.
# Function
The protein encoded by this gene shares similarity with Saccharomyces cerevisiae Rad52, a protein important for DNA double-strand break repair and homologous recombination. This gene product was shown to bind single-stranded DNA ends, and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. It was also found to interact with DNA recombination protein RAD51, which suggested its role in RAD51-related DNA recombination and repair.
# Role in DNA recombination repair
RAD52 mediates RAD51 function in homologous recombinational repair (HRR) in both yeast Saccharomyces cerevisiae and in mammalian cells of mice and humans. However, the RAD52 protein has distinctly different functions in HRR of yeast and humans. In S. cerevisae, Rad52 protein, acting alone, facilitates the loading of Rad51 protein onto single-stranded DNA pre-coated with replication protein A in the presynaptic phase of recombination.
In mice and humans, however, BRCA2 primarily mediates orderly assembly of RAD51 on ssDNA, the form that is active for homologous pairing and strand invasion. BRCA2 also redirects RAD51 from dsDNA and prevents dissociation from ssDNA. In addition, the four paralogs of RAD51, consisting of RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 form a complex called the BCDX2 complex. This complex participates in RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair, though with lower efficiency than BRCA2.
In addition, human RAD52, in combination with ERCC1, promotes the error-prone homologous DNA repair pathway of single-strand annealing. Though error prone, this repair pathway may be needed for survival of cells with DNA damage that is not otherwise repairable.
Human RAD52 also has an important role in repair of DNA double-strand breaks at active transcription sites during the G0/G1 phase of the cell cycle. Repair of these double-strand breaks appears to use an RNA template-based recombination mechanism dependent on RAD52. The Cockayne Syndrome B protein (CSB) (coded for by ERCC6) localizes at double-strand breaks at sites of active transcription, followed by RAD51, RAD51C and RAD52 to carry out homologous recombinational repair using the newly synthesized RNA as a template.
# microRNAs and cancer risk
Three prime untranslated regions (3'UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that can cause post-transcriptional RNA silencing. Such 3'-UTRs often contain binding sites for microRNAs (miRNAs). By binding to specific sites within the 3'-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript.
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of protein coding genes of the human genome. One microRNA, miR-210, represses RAD52. As noted by Devlin et al., miR-210 is up-regulated in most solid tumors and negatively affects the clinical outcome.
The 3'-UTR of RAD52 also has a binding site for the microRNA let-7. Women with a single-nucleotide polymorphism (SNP) in the binding site for let-7 (rs7963551), that causes reduced binding of let-7, likely have increased expression of RAD52 (as was shown for this SNP in liver). Women with this SNP in the 3'UTR of RAD52 showed a reduced breast cancer risk with an odds ratio of 0.84, 95% confidence interval of 0.75-0.95.
In a Han Chinese population, the same SNP as above in the 3'-UTR of RAD52 binding site for let-7 (rs7963551) reduced the risk of glioma. The risk of glioma associated with the RAD52 rs7963551 genotype had an odds ratio (compared to those without the SNP) of 0.44 for those older than 41 years, and an odds ratio of 0.58 for those 41 years or younger.
Li et al. found significantly decreased hepatic cellular carcinoma risk among individuals with the RAD52 rs7963551 CC genotype (the same SNP as above) compared with those with the AA genotype in a Chinese population. They also found that in 44 normal human liver tissue samples, presence of the rs7963551 SNP was associated with a significant increase of RAD52 mRNA expression.
Thus increased RAD52 expression is protective against various cancers.
Another study of altered microRNA binding sites in RAD52 and their effects on cancer susceptibility was carried out by Naccarati et al. They found two RAD52 microRNA binding sites that were frequently altered and had an effect on colon cancer risk. Individuals with a homozygous or heterozygous SNP in rs1051669 were at increased risk of colon cancer (OR 1.78, 95% CI 1.13–2.80, p = 0.01 for homozygotes and OR 1.72, 95% CI 1.10–2.692, p = 0.02 for heterozygotes). Heterozygous carriers of the other RAD52 SNP (rs11571475) were at decreased risk of colon cancer (OR 0.76, 95% CI 0.58–1.00, p = 0.05). Of 21 genes in the homologous recombinational repair pathway and 7 genes in the non-homologous end joining pathway examined, the only SNPs found in microRNA binding regions which were both at high enough frequency to evaluate and which affected risks of colon cancer, were the two in RAD52 and one in MRE11A.
DNA damage appears to be the primary underlying cause of cancer, and deficiencies in DNA repair appear to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer. The frequent microRNA-induced increase or deficiency of RAD52-mediated DNA repair due to microRNA binding alterations likely contributes to either the prevention or progression of breast, brain, liver or colon cancers.
# Interactions
RAD52 has been shown to interact with RAD51. The Rad52 will ease the loading of Rad51 on ssDNA by interfering with the RPA protein. | RAD52
RAD52 homolog (S. cerevisiae), also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.[1][2]
# Function
The protein encoded by this gene shares similarity with Saccharomyces cerevisiae Rad52, a protein important for DNA double-strand break repair and homologous recombination. This gene product was shown to bind single-stranded DNA ends, and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. It was also found to interact with DNA recombination protein RAD51, which suggested its role in RAD51-related DNA recombination and repair.[2]
# Role in DNA recombination repair
RAD52 mediates RAD51 function in homologous recombinational repair (HRR) in both yeast Saccharomyces cerevisiae and in mammalian cells of mice and humans. However, the RAD52 protein has distinctly different functions in HRR of yeast and humans. In S. cerevisae, Rad52 protein, acting alone, facilitates the loading of Rad51 protein onto single-stranded DNA pre-coated with replication protein A in the presynaptic phase of recombination.[3][4]
In mice and humans, however, BRCA2 primarily mediates orderly assembly of RAD51 on ssDNA, the form that is active for homologous pairing and strand invasion.[5] BRCA2 also redirects RAD51 from dsDNA and prevents dissociation from ssDNA.[5] In addition, the four paralogs of RAD51, consisting of RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 form a complex called the BCDX2 complex. This complex participates in RAD51 recruitment or stabilization at damage sites.[6] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair,[7] though with lower efficiency than BRCA2.
In addition, human RAD52, in combination with ERCC1, promotes the error-prone homologous DNA repair pathway of single-strand annealing.[8] Though error prone, this repair pathway may be needed for survival of cells with DNA damage that is not otherwise repairable.
Human RAD52 also has an important role in repair of DNA double-strand breaks at active transcription sites during the G0/G1 phase of the cell cycle. Repair of these double-strand breaks appears to use an RNA template-based recombination mechanism dependent on RAD52.[9] The Cockayne Syndrome B protein (CSB) (coded for by ERCC6) localizes at double-strand breaks at sites of active transcription, followed by RAD51, RAD51C and RAD52 to carry out homologous recombinational repair using the newly synthesized RNA as a template.[9]
# microRNAs and cancer risk
Three prime untranslated regions (3'UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that can cause post-transcriptional RNA silencing. Such 3'-UTRs often contain binding sites for microRNAs (miRNAs). By binding to specific sites within the 3'-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript.
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of protein coding genes of the human genome.[10] One microRNA, miR-210, represses RAD52.[11] As noted by Devlin et al., miR-210 is up-regulated in most solid tumors and negatively affects the clinical outcome.[12]
The 3'-UTR of RAD52 also has a binding site for the microRNA let-7. Women with a single-nucleotide polymorphism (SNP) in the binding site for let-7 (rs7963551), that causes reduced binding of let-7, likely have increased expression of RAD52 (as was shown for this SNP in liver[13]). Women with this SNP in the 3'UTR of RAD52 showed a reduced breast cancer risk with an odds ratio of 0.84, 95% confidence interval of 0.75-0.95.[14]
In a Han Chinese population, the same SNP as above in the 3'-UTR of RAD52 binding site for let-7 (rs7963551) reduced the risk of glioma. The risk of glioma associated with the RAD52 rs7963551 genotype had an odds ratio (compared to those without the SNP) of 0.44 for those older than 41 years, and an odds ratio of 0.58 for those 41 years or younger.[15]
Li et al.[13] found significantly decreased hepatic cellular carcinoma risk among individuals with the RAD52 rs7963551 CC genotype (the same SNP as above) compared with those with the AA genotype in a Chinese population. They also found that in 44 normal human liver tissue samples, presence of the rs7963551 SNP was associated with a significant increase of RAD52 mRNA expression.
Thus increased RAD52 expression is protective against various cancers.
Another study of altered microRNA binding sites in RAD52 and their effects on cancer susceptibility was carried out by Naccarati et al.[16] They found two RAD52 microRNA binding sites that were frequently altered and had an effect on colon cancer risk. Individuals with a homozygous or heterozygous SNP in rs1051669 were at increased risk of colon cancer (OR 1.78, 95% CI 1.13–2.80, p = 0.01 for homozygotes and OR 1.72, 95% CI 1.10–2.692, p = 0.02 for heterozygotes). Heterozygous carriers of the other RAD52 SNP (rs11571475) were at decreased risk of colon cancer (OR 0.76, 95% CI 0.58–1.00, p = 0.05). Of 21 genes in the homologous recombinational repair pathway and 7 genes in the non-homologous end joining pathway examined, the only SNPs found in microRNA binding regions which were both at high enough frequency to evaluate and which affected risks of colon cancer, were the two in RAD52 and one in MRE11A.
DNA damage appears to be the primary underlying cause of cancer,[17][18] and deficiencies in DNA repair appear to underlie many forms of cancer.[19] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[20][21] Such mutations and epigenetic alterations may give rise to cancer. The frequent microRNA-induced increase or deficiency of RAD52-mediated DNA repair due to microRNA binding alterations likely contributes to either the prevention or progression of breast, brain, liver or colon cancers.
# Interactions
RAD52 has been shown to interact with RAD51.[22] The Rad52 will ease the loading of Rad51 on ssDNA by interfering with the RPA protein. | https://www.wikidoc.org/index.php/RAD52 | |
78712a34908debf95dd0f74bc2a56df4ea094627 | wikidoc | RAD9A | RAD9A
Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the RAD9A gene.Rad9 has been shown to induce G2 arrest in the cell cycle in response to DNA damage in yeast cells. Rad9 was originally found in budding yeast cells but a human homolog has also been found and studies have suggested that the molecular mechanisms of the S and G2 checkpoints are conserved in eukaryotes. Thus, what is found in yeast cells are likely to be similar in human cells.
# Function
This gene product is highly similar to S. pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair in response to DNA damage. This protein is found to possess 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with Rad1 and Hus1. This is also known as the Rad9-Rad1-Hus1 or 9-1-1 complex. This complex is recruited by checkpoint protein Rad17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Use of alternative polyA sites has been noted for this gene. This complex plays a role in DNA base excision repair. Hus1 binds and stimulates MYH DNA glycosylase which stimulates base excision repair. Rad9 binds with the strongest affinity to DNA which attaches the complex to damaged DNA. Rad1 recruits other base excision factors. Previous research has suggested that Rad9 is not necessary to repair DNA, but it does not mean it can still play a role in DNA damage repair. If Rad9 is mutated there may be other pathways or mechanisms in DNA repair that can compensate for a loss of function.
# History
Rad9 was first found as a gene that promotes G2 cell cycle arrest in response to DNA damage in Saccharomyces cerevisiae by Weinert et al. The group irradiated yeast cells to induce DNA damage and tested many different mutants. They tested 7 rad mutants and all of the mutants underwent G2 arrest as normal, except for one, the rad9 mutant. The rad9 mutant did not undergo G2 arrest and instead proceeded through the cell cycle and many of the cells died because the DNA was never repaired. From this they suspected that Rad9 is necessary to invoke G2 cell cycle arrest. To confirm this they tested a double mutant of rad9 with DNA repair deficient-strain rad52 and found that the cell failed to arrest in G2 further proving that a functioning Rad9 gene is needed to induce G2 arrest. They then used MBC, a microtubule inhibitor, to synthetically arrest the cell in G2 in order to test if the Rad9 gene was necessary to also repair DNA. The found that when the rad9 mutant was arrested in G2, irradiated to induce DNA damage, and left arrested in G2 by MBC for 4 hours, the cell was able to repair DNA and divide normally. This result suggested that Rad9 is not necessary to repair DNA. They concluded that Rad9 is an important gene that is crucial to arrest the cell in G2 and ensures fidelity of chromosome transmission but is not necessary to repair DNA.
# Interactions
Rad9 is activated by multiple phosphorylations by cyclin dependent kinases and activates Rad53 through Mec1 downstream. Mrc1 has also been shown to work cooperatively to recruit Rad53 to damaged DNA. After the 9-1-1 complex Rad9 is extensively phosphorylated by Mec1 which can trigger self-association of more Rad9 oligomers on the chromosomes. Further phosphorylation generates binding sites for Rad53 which also gets activated by Mec1 to pursue its target in the cell cycle control system. Rad9 doesn’t do the DNA repair itself, it is just an adaptor protein that sends the signal.
Rad9 has also been shown to interact with p53 and can even mimic certain functions of p53.
Rad9 has been shown to be able to bind to the same promoter region as p53 that transactivates p21, which halts progression of the cell cycle by inhibiting cyclins and CDK’s. In addition to transactivating p21, Rad9 can also regulate transcription of the base excision repair gene NEIL by binding p53-like response elements in the gene promoter.
RAD9A has been shown to interact with:
- Abl gene,
- Androgen receptor,
- BCL2-like 1,
- Bcl-2,
- DNAJC7,
- HDAC1,
- HUS1
- RAD1 homolog,
- RAD17, and
- TOPBP1.
# Structure
The Rad9 protein contains a carboxy-terminal tandem repeat of the BRCT (BRCA1 carboxyl terminus) motif, which is found in many proteins involved in DNA damage repair. This motif is necessary for Rad9 to function. When the BRCT motif was removed, cell survival severely decreased compared to wild type Rad9. Rad9 is normally hyperphosphorylated after DNA damage. and the rad9 mutants without the BRCT motif displayed no phosphorylation so it is possible that the phosphorylation sites are located on this domain. The same mutant was also not able to phosphorylate Rad53 downstream. | RAD9A
Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the RAD9A gene.[1]Rad9 has been shown to induce G2 arrest in the cell cycle in response to DNA damage in yeast cells. Rad9 was originally found in budding yeast cells but a human homolog has also been found and studies have suggested that the molecular mechanisms of the S and G2 checkpoints are conserved in eukaryotes.[2] Thus, what is found in yeast cells are likely to be similar in human cells.
# Function
This gene product is highly similar to S. pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair in response to DNA damage. This protein is found to possess 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with Rad1 and Hus1. This is also known as the Rad9-Rad1-Hus1 or 9-1-1 complex. This complex is recruited by checkpoint protein Rad17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Use of alternative polyA sites has been noted for this gene.[3] This complex plays a role in DNA base excision repair. Hus1 binds and stimulates MYH DNA glycosylase which stimulates base excision repair.[4] Rad9 binds with the strongest affinity to DNA which attaches the complex to damaged DNA. Rad1 recruits other base excision factors. Previous research has suggested that Rad9 is not necessary to repair DNA,[5] but it does not mean it can still play a role in DNA damage repair. If Rad9 is mutated there may be other pathways or mechanisms in DNA repair that can compensate for a loss of function.[4]
# History
Rad9 was first found as a gene that promotes G2 cell cycle arrest in response to DNA damage in Saccharomyces cerevisiae by Weinert et al.[5] The group irradiated yeast cells to induce DNA damage and tested many different mutants. They tested 7 rad mutants and all of the mutants underwent G2 arrest as normal, except for one, the rad9 mutant. The rad9 mutant did not undergo G2 arrest and instead proceeded through the cell cycle and many of the cells died because the DNA was never repaired.[5] From this they suspected that Rad9 is necessary to invoke G2 cell cycle arrest. To confirm this they tested a double mutant of rad9 with DNA repair deficient-strain rad52 and found that the cell failed to arrest in G2 further proving that a functioning Rad9 gene is needed to induce G2 arrest. They then used MBC, a microtubule inhibitor, to synthetically arrest the cell in G2 in order to test if the Rad9 gene was necessary to also repair DNA. The found that when the rad9 mutant was arrested in G2, irradiated to induce DNA damage, and left arrested in G2 by MBC for 4 hours, the cell was able to repair DNA and divide normally.[5] This result suggested that Rad9 is not necessary to repair DNA. They concluded that Rad9 is an important gene that is crucial to arrest the cell in G2 and ensures fidelity of chromosome transmission but is not necessary to repair DNA.
# Interactions
Rad9 is activated by multiple phosphorylations by cyclin dependent kinases and activates Rad53 through Mec1 downstream.[6] Mrc1 has also been shown to work cooperatively to recruit Rad53 to damaged DNA.[7] After the 9-1-1 complex Rad9 is extensively phosphorylated by Mec1 which can trigger self-association of more Rad9 oligomers on the chromosomes. Further phosphorylation generates binding sites for Rad53 which also gets activated by Mec1 to pursue its target in the cell cycle control system. Rad9 doesn’t do the DNA repair itself, it is just an adaptor protein that sends the signal.[8]
Rad9 has also been shown to interact with p53 and can even mimic certain functions of p53.[2]
Rad9 has been shown to be able to bind to the same promoter region as p53 that transactivates p21, which halts progression of the cell cycle by inhibiting cyclins and CDK’s. In addition to transactivating p21, Rad9 can also regulate transcription of the base excision repair gene NEIL by binding p53-like response elements in the gene promoter.[2]
RAD9A has been shown to interact with:
- Abl gene,[9]
- Androgen receptor,[10]
- BCL2-like 1,[11][12]
- Bcl-2,[12]
- DNAJC7,[13]
- HDAC1,[14]
- HUS1[15][16][17][18]
- RAD1 homolog,[15][16][17][18][19]
- RAD17,[15][19][20][21] and
- TOPBP1.[22]
# Structure
The Rad9 protein contains a carboxy-terminal tandem repeat of the BRCT (BRCA1 carboxyl terminus) motif, which is found in many proteins involved in DNA damage repair.[23] This motif is necessary for Rad9 to function. When the BRCT motif was removed, cell survival severely decreased compared to wild type Rad9. Rad9 is normally hyperphosphorylated after DNA damage.[24] and the rad9 mutants without the BRCT motif displayed no phosphorylation so it is possible that the phosphorylation sites are located on this domain. The same mutant was also not able to phosphorylate Rad53 downstream.[24] | https://www.wikidoc.org/index.php/RAD9A | |
c20bf758e869c8c327d2d0b4fa1b6330afad579c | wikidoc | RANKL | RANKL
Receptor activator of nuclear factor kappa-.mw-parser-output .polytonic{font-family:"SBL BibLit","SBL Greek",Athena,"EB Garamond 12","Foulis Greek",Cardo,"Gentium Plus",Gentium,Garamond,"Palatino Linotype","DejaVu Sans","DejaVu Serif",FreeSerif,FreeSans,"Arial Unicode MS","Lucida Sans Unicode","Lucida Grande",Code2000,sans-serif}Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.
RANKL is known as a type II membrane protein and is a member of the tumor necrosis factor (TNF) superfamily. RANKL has been identified to affect the immune system and control bone regeneration and remodeling. RANKL is an apoptosis regulator gene, a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK and controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1. RANKL is expressed in several tissues and organs including: skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoblast, mammary gland epithelial cells, prostate and pancreas. Variation in concentration levels of RANKL throughout several organs reconfirms the importance of RANKL in tissue growth (particularly bone growth) and immune functions within the body.
# Tissue expression
The level of RANKL expression does not linearly correlate to the effect of this ligand. High protein expression of RANKL is commonly detected in the lungs, thymus and lymph nodes. Low protein expression is found in bone marrow, the stomach, peripheral blood, the spleen, the placenta, leukocytes, the heart, the thyroid, and skeletal muscle. While bone marrow expresses low levels of RANKL, RANKL plays a critical role for adequate bone metabolism. This surface-bound molecule (also known as CD254), found on osteoblasts, serves to activate osteoclasts, which are critically involved in bone resorption. Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound receptor activator of nuclear factor kappa-B (RANK). Recent studies suggest that in postnatal bones, the osteocyte is the major source of RANKL regulating bone remodeling. RANKL derived from other cell types contributes to bone loss in conditions involving inflammation such as rheumatoid arthritis, and in lytic lesions caused by cancer, such as in multiple myeloma.
# Gene and expression
RANKL can be expressed in three different molecular forms consisting of either a: (1) trimeric transmembrane protein, (2) primary secreted form, and (3) truncated ectodomain. RANKL is identified as a part of the TNF family; RANKL is specifically categorized under the TNFSF11, the TNF ligand superfamily member. RANKL is composed of 314 amino acids and was originally described to have a gene sequence containing 5 exons. Among the exons, Exon 1 encoded the intracellular and transmembrane protein domains and Exon 2-5 encoded the extracellular domains. RANKL’s extracellular domains are similar to other TNF family members in regards to the structural homology and are able to cleave from the cell surface. While the function and significance of A kinase anchor protein 11(AKAP11) is presently unknown, AKAP11 is immediately upstream from RANKL for all species that has a RANKL gene. The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.
# Function
RANKL is a member of the tumor necrosis factor (TNF) cytokine family, it binds to RANK on cells of the myeloid lineage and functions as a key factor for osteoclast differentiation and activation. RANKL may also bind to osteoprotegerin, a protein secreted mainly by cells of the osteoblast lineage which is a potent inhibitor of osteoclast formation by preventing binding of RANKL to RANK. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor 6 (TRAF6), which indicated this protein may have a role in the regulation of cell apoptosis.
# Animal models
Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. Deficient mice, with an inactivation of RANKL or its receptor RANK, exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy.
It was observed that during pregnancy, RANK-RANKL signaling played a critical role in regulating skeletal calcium release; in which contributed to the hormone response that stimulated proliferation in the mammary cells. Ultimately, impaired lobuloalveolar mammary structures resulted in death of the fetus. Those who suffer from osteoporosis often have a cardiovascular defect, such as heart failure. Some studies suggest, since RANK-RANKL pathway regulates calcium release and homeostasis, RANK-RANKL signal could invertedly affect the cardiovascular system; thus, an explanation for the positive correlation between osteoporosis and cardiovascular deficiencies.
# Role in cancer
Primary tumors will commonly metastasize into the bone. Breast and prostate cancers typically have a greater chance of inducing secondary cancers within bone. Stephen Paget's seed and soil theory suggests, the microenvironment in bone creates a sufficient ‘soil’ for secondary tumors to grow in. Some studies suggest the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (i.e. chronic lymphocytic leukemia (CLL) and multiple myeloma). Among patients with multiple myeloma, RANKL activity was greatly increased. In fact RANKL surface expression and secreted RANKL expression was reported to be increased, 80% and 50% respectively. Therefore, RANKL is considered to be a key signal regulator for cancer-induced bone loss.
According to the vicious cycle hypothesis, after secondary tumors cells have migrated to bone, the tumor cell will secrete cytokines and growth factors that can act on osteoblast lineage cells. Since osteoblasts control the regulation of RANKL, the stimulation via cytokines and growth factors will then stimulate osteoblasts to increase the expression of RANKL, often while simultaneously reducing bone formation. The additional RANKL-mediated osteoclast frequency and activity will in turn increase secretion of growth factors, or matrix derived factors, which can ultimately increase tumor growth and bone destruction activity.
# Clinical significance
RANKL, through its ability to stimulate osteoclast formation and activity, is a critical mediator of bone resorption and overall bone density. Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis. In addition to degenerative bone diseases, bone metastases can also induce pain and other abnormal health complexities that can significantly reduce a cancer patient’s quality of life. Some examples of these complications that are a consequence of bone metastasis are: hypercalcemia, pathological fractures and spinal cord compression. Some findings also suggest that some cancer cells, particularly prostate cancer cells, can activate an increase in bone remodeling and ultimately increase overall bone production. This increase in bone remodeling and bone production increases the overall growth of bone metastasizes. The overall control of bone remodeling is regulated by the binding of RANKL with its receptor or its decoy receptor, respectively, RANK and OPG.
## Denosumab
Denosumab is an FDA-approved fully human monoclonal antibody to RANKL and during pre-clinical trials was first used to treat postmenopausal patients suffering with osteoporosis (PMO). In denosumab's third stage of the FDA's clinical trial, it was shown to: (1) decrease bone turnover, (2) reduce fractures in the PMO population, and (3) increase bone mineral density. The anti-RANKL antibody, denosumab, is also approved for use in cancer settings, and in those indications, it is branded as Xgeva. In both prostate and breast cancer, denosumab has been shown to reduce cancer treatment–induced bone loss.
### Prostate cancer
The HALT-prostate cancer trial (also known as NCT00089674) included 1468 non-metastatic prostate cancer patients who were currently receiving androgen deprivation therapy. Randomly selected patients were given either 60 mg of denosumab or calcium and vitamin D supplements. This was done to measure the effectiveness of preventing treatment-induced bone loss. The patients who received 60 mg of denosumab showed a +5.6% increased in bone mineral density and a 1.5% decrease in bone fracture rates.
Another clinical trial (NCT00321620) was established to determine the safety and effectiveness of using denosumab compared to zoledronic acid. In this trial, they used 1901 bone metastatic prostate patients whom were also suffering with other complication of bone diseases. Again, patients were randomized and some were given either 120 mg of denosumab or 4 mg of zoledronic acid. Patients who were given 120 mg of denosumab (in comparison to those who were given 4 mg of zoledronic acid) showed a greater increase in hypocalcemia, a greater resistance to bone turnover markers uNTx, a delay response in both pathological fractures and spinal cord compression. However, survival rates for both clinical groups were comparable.
### Breast cancer
Hormone receptor positive breast cancer patients have a significant increased risk of complications such as osteopenia and osteoporosis. About two out of every three breast cancer patients are hormone receptor positive. In the past several years, denosumab has been used in clinical trials, primarily because a large population is affected by bone complication among those who have breast cancer.
252 patients enlisted in the HALT-BC clinical trial (also known as NCT00089661). In addition to receiving vitamin D and calcium supplements, half of the patients were randomly given 60 mg of denosumab while the other half were given a placebo. Patients given denosumab had an increase in lumbar spine bone mineral density, a decrease in bone turnover markers, with no significant change in survival rates.
NCT00321464 was another phase III RCT. Similar to NCT00321620 (prostate), this trial measured the safety and efficacy of denosumab versus zoledronic acid. Both groups showed similar survival rates and adverse event frequency.
### Multiple myeloma
Patients whom are diagnosed with multiple myeloma have approximately 80-100% chance of developing bone complications due to an increase in activity and/or formation of osteoclasts and a decrease activity of osteoblasts. In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway. Once this trial was completed, 1176 patients with either multiple myeloma or progressed cancers were entered into the stage III clinical trial (known as NCT00330759). The main objective of the NCT00330759 trial was to compare effects of patients who were given 120 mg of denosumab relative to patients give 4 mg of zoledronic acid. As a result of this trial, during a month period, patients who received denosumab had a decrease in pathological fractures and spinal cord compression; however, as time progressed it appear that denosumab had significantly delayed bone complications. In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.
## Medroxyprogesterone acetate
Women with menopause have often been given various types of postmenopausal hormone therapies to prevent osteoporosis and reduce menopausal symptoms. Medroxyprogesterone acetate (MPA) is a synthetic progestin and was commonly used as a contraceptive or used as a hormone therapy for endometriosis or osteoporosis. Recent studies suggest, using MPA increases patient risks of developing breast cancer due to an increase expression of RANKL. MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer. | RANKL
Receptor activator of nuclear factor kappa-.mw-parser-output .polytonic{font-family:"SBL BibLit","SBL Greek",Athena,"EB Garamond 12","Foulis Greek",Cardo,"Gentium Plus",Gentium,Garamond,"Palatino Linotype","DejaVu Sans","DejaVu Serif",FreeSerif,FreeSans,"Arial Unicode MS","Lucida Sans Unicode","Lucida Grande",Code2000,sans-serif}Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.[1][2]
RANKL is known as a type II membrane protein and is a member of the tumor necrosis factor (TNF) superfamily.[3] RANKL has been identified to affect the immune system and control bone regeneration and remodeling. RANKL is an apoptosis regulator gene, a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK and controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1.[4][5] RANKL is expressed in several tissues and organs including: skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoblast, mammary gland epithelial cells, prostate and pancreas.[5] Variation in concentration levels of RANKL throughout several organs reconfirms the importance of RANKL in tissue growth (particularly bone growth) and immune functions within the body.
# Tissue expression
The level of RANKL expression does not linearly correlate to the effect of this ligand. High protein expression of RANKL is commonly detected in the lungs, thymus and lymph nodes. Low protein expression is found in bone marrow, the stomach, peripheral blood, the spleen, the placenta, leukocytes, the heart, the thyroid, and skeletal muscle.[5] While bone marrow expresses low levels of RANKL, RANKL plays a critical role for adequate bone metabolism. This surface-bound molecule (also known as CD254), found on osteoblasts, serves to activate osteoclasts, which are critically involved in bone resorption. Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound receptor activator of nuclear factor kappa-B (RANK). Recent studies suggest that in postnatal bones, the osteocyte is the major source of RANKL regulating bone remodeling.[6][7][8] RANKL derived from other cell types contributes to bone loss in conditions involving inflammation such as rheumatoid arthritis, and in lytic lesions caused by cancer, such as in multiple myeloma.
# Gene and expression
RANKL can be expressed in three different molecular forms consisting of either a: (1) trimeric transmembrane protein, (2) primary secreted form, and (3) truncated ectodomain.[9] RANKL is identified as a part of the TNF family; RANKL is specifically categorized under the TNFSF11, the TNF ligand superfamily member. RANKL is composed of 314 amino acids and was originally described to have a gene sequence containing 5 exons.[10][11] Among the exons, Exon 1 encoded the intracellular and transmembrane protein domains and Exon 2-5 encoded the extracellular domains.[10] RANKL’s extracellular domains are similar to other TNF family members in regards to the structural homology and are able to cleave from the cell surface.[10] While the function and significance of A kinase anchor protein 11(AKAP11) is presently unknown, AKAP11 is immediately upstream from RANKL for all species that has a RANKL gene.[11] The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.
# Function
RANKL is a member of the tumor necrosis factor (TNF) cytokine family, it binds to RANK on cells of the myeloid lineage and functions as a key factor for osteoclast differentiation and activation. RANKL may also bind to osteoprotegerin, a protein secreted mainly by cells of the osteoblast lineage which is a potent inhibitor of osteoclast formation by preventing binding of RANKL to RANK. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor 6 (TRAF6), which indicated this protein may have a role in the regulation of cell apoptosis.[12]
# Animal models
Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. Deficient mice, with an inactivation of RANKL or its receptor RANK, exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy.[5][12]
It was observed that during pregnancy, RANK-RANKL signaling played a critical role in regulating skeletal calcium release; in which contributed to the hormone response that stimulated proliferation in the mammary cells.[5] Ultimately, impaired lobuloalveolar mammary structures resulted in death of the fetus.[5] Those who suffer from osteoporosis often have a cardiovascular defect, such as heart failure. Some studies suggest, since RANK-RANKL pathway regulates calcium release and homeostasis, RANK-RANKL signal could invertedly affect the cardiovascular system; thus, an explanation for the positive correlation between osteoporosis and cardiovascular deficiencies.[5]
# Role in cancer
Primary tumors will commonly metastasize into the bone. Breast and prostate cancers typically have a greater chance of inducing secondary cancers within bone.[13] Stephen Paget's seed and soil theory suggests, the microenvironment in bone creates a sufficient ‘soil’ for secondary tumors to grow in. Some studies suggest the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (i.e. chronic lymphocytic leukemia (CLL) and multiple myeloma).[14] Among patients with multiple myeloma, RANKL activity was greatly increased. In fact RANKL surface expression and secreted RANKL expression was reported to be increased, 80% and 50% respectively.[14] Therefore, RANKL is considered to be a key signal regulator for cancer-induced bone loss.
According to the vicious cycle hypothesis, after secondary tumors cells have migrated to bone, the tumor cell will secrete cytokines and growth factors that can act on osteoblast lineage cells. Since osteoblasts control the regulation of RANKL, the stimulation via cytokines and growth factors will then stimulate osteoblasts to increase the expression of RANKL, often while simultaneously reducing bone formation. The additional RANKL-mediated osteoclast frequency and activity will in turn increase secretion of growth factors, or matrix derived factors, which can ultimately increase tumor growth and bone destruction activity.
# Clinical significance
RANKL, through its ability to stimulate osteoclast formation and activity, is a critical mediator of bone resorption and overall bone density. Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis. In addition to degenerative bone diseases, bone metastases can also induce pain and other abnormal health complexities that can significantly reduce a cancer patient’s quality of life. Some examples of these complications that are a consequence of bone metastasis are: hypercalcemia, pathological fractures and spinal cord compression.[15] Some findings also suggest that some cancer cells, particularly prostate cancer cells, can activate an increase in bone remodeling and ultimately increase overall bone production.[15] This increase in bone remodeling and bone production increases the overall growth of bone metastasizes. The overall control of bone remodeling is regulated by the binding of RANKL with its receptor or its decoy receptor, respectively, RANK and OPG.[15]
## Denosumab
Denosumab is an FDA-approved fully human monoclonal antibody to RANKL and during pre-clinical trials was first used to treat postmenopausal patients suffering with osteoporosis (PMO).[15][16] In denosumab's third stage of the FDA's clinical trial, it was shown to: (1) decrease bone turnover, (2) reduce fractures in the PMO population, and (3) increase bone mineral density.[15] The anti-RANKL antibody, denosumab, is also approved for use in cancer settings, and in those indications, it is branded as Xgeva. In both prostate and breast cancer, denosumab has been shown to reduce cancer treatment–induced bone loss.[15]
### Prostate cancer
The HALT-prostate cancer trial (also known as NCT00089674) included 1468 non-metastatic prostate cancer patients who were currently receiving androgen deprivation therapy.[17] Randomly selected patients were given either 60 mg of denosumab or calcium and vitamin D supplements. This was done to measure the effectiveness of preventing treatment-induced bone loss.[15] The patients who received 60 mg of denosumab showed a +5.6% increased in bone mineral density and a 1.5% decrease in bone fracture rates.[15]
Another clinical trial (NCT00321620) was established to determine the safety and effectiveness of using denosumab compared to zoledronic acid.[18] In this trial, they used 1901 bone metastatic prostate patients whom were also suffering with other complication of bone diseases. Again, patients were randomized and some were given either 120 mg of denosumab or 4 mg of zoledronic acid.[15] Patients who were given 120 mg of denosumab (in comparison to those who were given 4 mg of zoledronic acid) showed a greater increase in hypocalcemia, a greater resistance to bone turnover markers uNTx, a delay response in both pathological fractures and spinal cord compression.[15] However, survival rates for both clinical groups were comparable.[15]
### Breast cancer
Hormone receptor positive breast cancer patients have a significant increased risk of complications such as osteopenia and osteoporosis. About two out of every three breast cancer patients are hormone receptor positive.[19] In the past several years, denosumab has been used in clinical trials, primarily because a large population is affected by bone complication among those who have breast cancer.
252 patients enlisted in the HALT-BC clinical trial (also known as NCT00089661). In addition to receiving vitamin D and calcium supplements, half of the patients were randomly given 60 mg of denosumab while the other half were given a placebo.[15][20] Patients given denosumab had an increase in lumbar spine bone mineral density, a decrease in bone turnover markers, with no significant change in survival rates.[15]
NCT00321464 was another phase III RCT.[21] Similar to NCT00321620 (prostate), this trial measured the safety and efficacy of denosumab versus zoledronic acid. Both groups showed similar survival rates and adverse event frequency.[15]
### Multiple myeloma
Patients whom are diagnosed with multiple myeloma have approximately 80-100% chance of developing bone complications due to an increase in activity and/or formation of osteoclasts and a decrease activity of osteoblasts.[14][15] In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway.[15] Once this trial was completed, 1176 patients with either multiple myeloma or progressed cancers were entered into the stage III clinical trial (known as NCT00330759).[22] The main objective of the NCT00330759 trial was to compare effects of patients who were given 120 mg of denosumab relative to patients give 4 mg of zoledronic acid. As a result of this trial, during a month period, patients who received denosumab had a decrease in pathological fractures and spinal cord compression; however, as time progressed it appear that denosumab had significantly delayed bone complications.[15] In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.[15]
## Medroxyprogesterone acetate
Women with menopause have often been given various types of postmenopausal hormone therapies to prevent osteoporosis and reduce menopausal symptoms.[23] Medroxyprogesterone acetate (MPA) is a synthetic progestin and was commonly used as a contraceptive or used as a hormone therapy for endometriosis or osteoporosis. Recent studies suggest, using MPA increases patient risks of developing breast cancer due to an increase expression of RANKL.[23] MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer.[24][25] | https://www.wikidoc.org/index.php/RANKL | |
9fd870dbf65c3c72ef0d1934caf5a258e23b65e2 | wikidoc | RAPSN | RAPSN
43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.
# Function
This protein belongs to a family of proteins that are receptor associated proteins of the synapse. It contains a conserved cAMP-dependent protein kinase phosphorylation site. It is believed to play some role in anchoring or stabilizing the nicotinic acetylcholine receptor at synaptic sites. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Two splice variants have been identified for this gene.
# Role in health and disease
In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of the acetylcholine receptor (AChR) on the postsynaptic folds. This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK protein), AChRs and the AChR-clustering protein rapsyn, encoded by RAPSN. Genetic mutations of the proteins in the neuromuscular junction are associated with Congenital myasthenic syndrome (CMS). Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor. The vast majority of mutations causing CMS are found in the AChR subunits and rapsyn genes.
The rapsyn protein interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created as the folds do not form properly. Patients with CMS-related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease.
Studies have shown that most patients with CMS that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene on both of their alleles. Two novel missense mutations that have been found are R164C and L283P and the result is a decrease in co-clustering of AChR with raspyn. A third mutation is the intronic base alteration IVS1-15C>A and it causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for CMS mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations
# Interactions
RAPSN has been shown to interact with KHDRBS1. | RAPSN
43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.[1][2]
# Function
This protein belongs to a family of proteins that are receptor associated proteins of the synapse. It contains a conserved cAMP-dependent protein kinase phosphorylation site. It is believed to play some role in anchoring or stabilizing the nicotinic acetylcholine receptor at synaptic sites. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Two splice variants have been identified for this gene.[2]
# Role in health and disease
In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of the acetylcholine receptor (AChR) on the postsynaptic folds. This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK protein), AChRs and the AChR-clustering protein rapsyn, encoded by RAPSN. Genetic mutations of the proteins in the neuromuscular junction are associated with Congenital myasthenic syndrome (CMS). Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor. The vast majority of mutations causing CMS are found in the AChR subunits and rapsyn genes.[3]
The rapsyn protein interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created as the folds do not form properly. Patients with CMS-related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease.[3]
Studies have shown that most patients with CMS that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene on both of their alleles. Two novel missense mutations that have been found are R164C and L283P and the result is a decrease in co-clustering of AChR with raspyn. A third mutation is the intronic base alteration IVS1-15C>A and it causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for CMS mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations[4]
# Interactions
RAPSN has been shown to interact with KHDRBS1.[5] | https://www.wikidoc.org/index.php/RAPSN | |
1c119f7da149765ec20ab0c09f4bb4cefec003e0 | wikidoc | RASD1 | RASD1
Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein that in humans is encoded by the RASD1 gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. As a member of the Ras superfamily of small G-proteins, RASD1 regulates signal transduction pathways through both G proteins and G protein-coupled receptors. RASD1 has been associated with several cancers. The RASD1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
## Gene
The RASD1 gene resides on chromosome 17 at the band 17p11.2 and contains 2 exons. This gene produces 2 isoforms through alternative splicing. A glucocorticoid response element (GRE) located in the 3'- flanking region of this gene allows glucocorticoids to induce expression of RASD1.
## Protein
This protein is a small GTPase belonging to the Ras superfamily. As a Ras superfamily member, RASD1 shares several motifs characteristic of Ras proteins, including four highly conserved GTP binding pocket domains: the phosphate/magnesium binding regions GXXXXGK(S/T) (domain Σ1), DXXG (domain Σ2), and the guanine base binding loops NKXD (domain Σ3) and EXSAK (domain Σ4). These four domains, along with an effector loop, are responsible for binding to other proteins and signaling molecules. Another common Ras motif, the CAAX motif, can be found in the C-terminal of RASD1 and promotes the subcellular localization of RASD1 to the plasma membrane. As a GTPase, RASD1 also shares motifs, such as in the regions G-1 to G-3, with other GTPases.
The full-length RASD1 cDNA produces a protein with a length of 280 amino acid residues and a molecular mass of 31.7 kDa.
# Function
RASD1 is expressed in many tissues including brain, heart, liver, and kidney. It is also present in bone marrow, but its expression is absent or at very low levels in spleen, lymph node, and peripheral blood leukocytes. RASD1 modulates multiple signaling cascades. RASD1 could activate G proteins in a receptor-independent manner and inhibit signal transduction through several different G protein-coupled receptors. Although RASD1 is a member of the Ras superfamily of small G-proteins, which often promotes cell growth and tumor expansion, it plays an active role in preventing aberrant cell growth. It can be induced by corticosteroids and may play a role in the negative feedback loop controlling adrenocorticotropic hormone (ACTH) secretion. In the hypothalamus, RASD1 expression is induced in two ways: one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. Based on its inhibitory actions on CREB phosphorylation, increased RASD1 in vasopressin-expressing neurons may be essential in controlling the transcriptional responses to stressors in both the supraoptic nucleus and paraventricular nucleus via modulation of the cAMP-PKA-CREB signaling pathway. RASD1 is also reported to function with leptin in the activation of TRPC4 transient receptor potential channels and, thus, plays a role in regulating electrical excitability in gastrointestinal myocytes, pancreatic β-cells, and neurons. In addition, the interaction between RASD1 and Ear2 is involved in renin transcriptional regulation.
# Clinical significance
In humans, upregulation of RASD1 leading to increased apoptosis has been observed in several human cancer cell lines such as DU-154 human prostate cancer cells and in human breast cancer cells MCF-7. In the latter, high concentrations of calycosin significantly suppressed the proliferation of MCF-7 cells, thereby promoting apoptosis of the cells. Moreover, compared with a control group, the expression of Bcl-2 decreased with calycosin while Bax increased, and these changes correlated with an elevated expression of RASD1. Together, it appears that, at relatively high concentrations, calycosin can trigger the mitochondrial apoptotic pathway by upregulating RASD1.
## Clinical marker
Additionally, in the cardiovascular field, a genome-wide analysis of common variants demonstrated a substantial overlap in the genetic risk of ischemic stroke and coronary artery disease, such as the link between RASD1 and other loci such as RAI1 and PEMT. A multi-locus genetic risk score study based on a combination of 27 loci, including the RASD1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
# Interactions
RASD1 has been shown to interact with NOS1AP. | RASD1
Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein that in humans is encoded by the RASD1 gene on chromosome 17.[1][2] It is ubiquitously expressed in many tissues and cell types.[3] As a member of the Ras superfamily of small G-proteins, RASD1 regulates signal transduction pathways through both G proteins and G protein-coupled receptors.[4] RASD1 has been associated with several cancers.[5] The RASD1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[6]
# Structure
## Gene
The RASD1 gene resides on chromosome 17 at the band 17p11.2 and contains 2 exons.[2] This gene produces 2 isoforms through alternative splicing.[7] A glucocorticoid response element (GRE) located in the 3'- flanking region of this gene allows glucocorticoids to induce expression of RASD1.[8]
## Protein
This protein is a small GTPase belonging to the Ras superfamily.[7] As a Ras superfamily member, RASD1 shares several motifs characteristic of Ras proteins, including four highly conserved GTP binding pocket domains: the phosphate/magnesium binding regions GXXXXGK(S/T) (domain Σ1), DXXG (domain Σ2), and the guanine base binding loops NKXD (domain Σ3) and EXSAK (domain Σ4). These four domains, along with an effector loop, are responsible for binding to other proteins and signaling molecules. Another common Ras motif, the CAAX motif, can be found in the C-terminal of RASD1 and promotes the subcellular localization of RASD1 to the plasma membrane. As a GTPase, RASD1 also shares motifs, such as in the regions G-1 to G-3, with other GTPases.
The full-length RASD1 cDNA produces a protein with a length of 280 amino acid residues and a molecular mass of 31.7 kDa.[8]
# Function
RASD1 is expressed in many tissues including brain, heart, liver, and kidney.[9][10][11] It is also present in bone marrow, but its expression is absent or at very low levels in spleen, lymph node, and peripheral blood leukocytes.[11][12] RASD1 modulates multiple signaling cascades. RASD1 could activate G proteins in a receptor-independent manner and inhibit signal transduction through several different G protein-coupled receptors.[13][4] Although RASD1 is a member of the Ras superfamily of small G-proteins, which often promotes cell growth and tumor expansion, it plays an active role in preventing aberrant cell growth.[12] It can be induced by corticosteroids and may play a role in the negative feedback loop controlling adrenocorticotropic hormone (ACTH) secretion.[14] In the hypothalamus, RASD1 expression is induced in two ways: one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. Based on its inhibitory actions on CREB phosphorylation, increased RASD1 in vasopressin-expressing neurons may be essential in controlling the transcriptional responses to stressors in both the supraoptic nucleus and paraventricular nucleus via modulation of the cAMP-PKA-CREB signaling pathway.[15] RASD1 is also reported to function with leptin in the activation of TRPC4 transient receptor potential channels and, thus, plays a role in regulating electrical excitability in gastrointestinal myocytes, pancreatic β-cells, and neurons.[16] In addition, the interaction between RASD1 and Ear2 is involved in renin transcriptional regulation.[17]
# Clinical significance
In humans, upregulation of RASD1 leading to increased apoptosis has been observed in several human cancer cell lines such as DU-154 human prostate cancer cells[18] and in human breast cancer cells MCF-7.[5] In the latter, high concentrations of calycosin significantly suppressed the proliferation of MCF-7 cells, thereby promoting apoptosis of the cells. Moreover, compared with a control group, the expression of Bcl-2 decreased with calycosin while Bax increased, and these changes correlated with an elevated expression of RASD1. Together, it appears that, at relatively high concentrations, calycosin can trigger the mitochondrial apoptotic pathway by upregulating RASD1.[5]
## Clinical marker
Additionally, in the cardiovascular field, a genome-wide analysis of common variants demonstrated a substantial overlap in the genetic risk of ischemic stroke and coronary artery disease, such as the link between RASD1 and other loci such as RAI1 and PEMT.[19] A multi-locus genetic risk score study based on a combination of 27 loci, including the RASD1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[6]
# Interactions
RASD1 has been shown to interact with NOS1AP.[11] | https://www.wikidoc.org/index.php/RASD1 | |
c9d4f7d1bcb6274459d5e890724596d2ed0ffb2e | wikidoc | RASEF | RASEF
Ras and EF-hand domain-containing protein also known as Ras-related protein Rab-45 is a protein that in humans is encoded by the RASEF gene.
The RASEF gene is located on chromosome 9 (9q21.32).
# Introduction
RASEF belongs to the small GTPase family, which means that it’s able to hydrolyse a molecule of GTP; known for its unusual conformation. In the small GTPase family it is classified in the RAS domain, a special group of oncogenes and oncoproteins that take part in the synthesis of molecules related to cell reproduction.
A feature of RASEF is its N-terminal EF-hand motif and C-terminal Rab-homology domain, that enables it to bind calcium.
Lately, RASEF has been studied for its role as an oncoprotein. Investigating which mutations affect it and how we could inhibit them could allow us to fight cancers that have an elevated mortality rate, such as lung cancer.
## Oncogenes
When studying cancer’s molecular biology we can identify two types of genes that intervene in its development:
- Tumor suppressor genes: Inhibit tumor formation.
- Oncogenes: Stimulate cell proliferation. It is in this group where members of the RAS family are found.
Oncogenes generally code for growth factors and their receptors, enzymes related to transduction signal or for DNA transcription factors. When those genes suffer some kind of mutation or translocation, they can change their conformation and cause a catalytic activity in cell reproduction that is normally inactivated, which causes abnormal cell proliferation. This could provoke a malignant tumor if combined with a separate mutation in a protein's RAS group.
Nowadays, there is important research in drugs that could eliminate these RAS group mutations but this has not been achieved yet.
We can find the RAS family in the oncogene category, to which the RASEF gene belongs.
# Ras / Rab family
RASEF or Rab 45 is classified in the Ras superfamily, which includes small (20kDa) guanosine triphosphatases (GTPases). The basic members of this group of proteins are Ras oncogens. It’s divided into five major families (Ras, Rho, Arf/Sar, Ran and Rab).
RASEF is included in the Rab family (the largest family), which is responsible for vesicular traffic of proteins between organelles via endocytotic and secretory pathways. Their function is to make budding from the donor compartment, transport, vesicle fusion and cargo release easier.
# Structure
RASEF is a 740 amino acids long protein which contains 3 distinct regions: 2 EF hand domains (which in turn contain 2 Calcium bindings and 3 nucleotide bindings -assumed by similarity with other proteins, without direct evidence-), a Coiled Coil region and a C-terminal Rab-homology domain.
## Domains
### N-terminal EF hand domain
Sequence found in RASEF protein that contains 35 amino acids (36 in the second one). The two EF hand domains are consecutively located at the “beginning” of the protein. Its name “N-terminal” indicates an amino group (characteristic of this group of biomolecules, as well as the C- terminal ending). The first one goes from the 8th amino acid to the 42nd, and the other to the 42nd to the 77th.
“EF hand” refers to the shape of this domain (similarity with the right hand’s morphology). Ca+2 ions are responsible for this structure, which by binding metals join two alpha helixes.
### Coiled coil region
Structural motif in proteins: from two to seven alpha helixes entwined. Each one of these helixes is a repeated 7 amino acid sequence (HPPHCPC), where H refers to hydrophobic amino acids. The position of hydrophobic remains (alpha helix exterior) causes their amphipathic behaviour.
The bond between different chains, produced in cytoplasm (aqueous region), is extremely tight, as Van der Waals forces appear between the hydrophobic radicals (H), surrounded by the hydrophilic amino acids (amphipathic molecule). This bond is known as the “Knobs into holes packing”.
Coiled coil motif, located in the intermediate region of the protein, is responsible for self-interaction.
### C-Terminal Rab-homology domain
Located at the end of the protein (opposite to N-terminal domain), it’s a carboxyl group (COOH).
In this region, there are guanine nucleotide bonds to tri-phosphates and di-phosphates. The variability of this domain is responsible for the high appearance of elements needed in the joints between proteins and their targets in the membrane.
Both the C-Terminal Rab-homology domain and the intermediate region of the protein are responsible for the intracellular location of the protein (perinuclear region).
# Function
RASEF intervenes in a direct manner in biological processes such as protein transport and small GTPase mediated signal transduction. Its molecular functions include GTP binding and calcium ion binding.
As mentioned previously, RASEF has 3 distinct structural regions: the C-terminus Rab domain, the N-terminus EF-hand domain and the self-interacting mid-region. Each of these has an individual function.
The guanine-nucleotide forms of the Rab domain regulate the protein's localization. RASEF is mainly found in the perinuclear region of the cell. In addition, the protein's mid-region also seems to be involved in the perinuclear localization. This could be due to its interaction with membrane compartments.
The EF-hand domain’s function still remains to be discovered. However, it is speculated that due to its conformational changes upon binding with Ca2+ ions, and these being responsible for interactions with target molecules; that in cooperation with the Rab-domain, the EF-hand domain's main function is regulating membrane traffic.
Over 60 Rab-family GTPase proteins have key roles in membrane traffic regulation. This isn’t surprising given the amount and variety of intracellular compartments, which require a high level of control to ensure a proper delivery and fusion of vesicles at the correct site.
This connects the RASEF protein directly to cell-growth mechanisms, making it susceptible to having a decisive role in the apparition of cancerous cells.
# Clinical significance
As we have seen, RASEF is involved in cell-growth mechanisms. When its active centre is stimulated by tyrosine kinase (GDP is exchanged by GTP), this part of the oncoprotein adopts a conformation which has much affinity with many effectors.
This induces a huge diversity of biochemical intracellular cascades which, in addition to some other reactions, influence cell behaviour. When these growth factors are altered, the signal cytoplasmatic circuits can not function properly, which could provoke serious pathologies like cancer. The constitutively active form of Ras oncoprotein is expressed in high levels in bladder carcinomas, leukemias, colon, breast, lung and skin cancers.
Some researchers have discovered that Ras and Ef-hand domain containing proteins are commonly overexpressed in primary lung cancers and its intervention is crucial for the proliferation and survival of cancerous cells. Apart from binding calcium ions in the N-terminus, RASEF plays a significant role in lung cancer cell-growth. This occurs because of its interaction with ERK (extracellular signal-regulated kinase) molecules involved in the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells, whose pathway can be activated by carcinogens or viral infections. .
There is ongoing research that is studying the possibility of using RASEF as a clinically promising prognostic biomarker and therapeutic target for lung cancer. Some recent studies have revealed the viability of using RASEF as a target for this disease.
Also, a segregation study in families with uveal and cutaneous melanoma identified a potential locus harboring a tumor-suppressor gene (TSG). One of the genes in this area (9q21), RASEF, was then analyzed as a candidate TSG, but the lack of point mutations and copy number changes could not confirm this. Nowadays, the RASEF gene has been investigated for potential mutations and gene silencing by promoting methylation in uveal melanoma. It appears to be the mechanism targeting RASEF in uveal melanoma, and allelic imbalance at this locus supports a TSG role for the Ras and Ef-hand domain containing. | RASEF
Ras and EF-hand domain-containing protein also known as Ras-related protein Rab-45 is a protein that in humans is encoded by the RASEF gene.[1]
The RASEF gene is located on chromosome 9 (9q21.32).[2]
# Introduction
RASEF belongs to the small GTPase family, which means that it’s able to hydrolyse a molecule of GTP; known for its unusual conformation. In the small GTPase family it is classified in the RAS domain, a special group of oncogenes and oncoproteins that take part in the synthesis of molecules related to cell reproduction.[3]
A feature of RASEF is its N-terminal EF-hand motif and C-terminal Rab-homology domain, that enables it to bind calcium.[3]
Lately, RASEF has been studied for its role as an oncoprotein. Investigating which mutations affect it and how we could inhibit them could allow us to fight cancers that have an elevated mortality rate, such as lung cancer.[3]
## Oncogenes
When studying cancer’s molecular biology we can identify two types of genes that intervene in its development:
- Tumor suppressor genes: Inhibit tumor formation.
- Oncogenes: Stimulate cell proliferation. It is in this group where members of the RAS family are found.
Oncogenes generally code for growth factors and their receptors, enzymes related to transduction signal or for DNA transcription factors. When those genes suffer some kind of mutation or translocation, they can change their conformation and cause a catalytic activity in cell reproduction that is normally inactivated, which causes abnormal cell proliferation. This could provoke a malignant tumor if combined with a separate mutation in a protein's RAS group.[4]
Nowadays, there is important research in drugs that could eliminate these RAS group mutations but this has not been achieved yet.[5]
We can find the RAS family in the oncogene category, to which the RASEF gene belongs.[6]
# Ras / Rab family
RASEF or Rab 45 is classified in the Ras superfamily, which includes small (20kDa) guanosine triphosphatases (GTPases). The basic members of this group of proteins are Ras oncogens. It’s divided into five major families (Ras, Rho, Arf/Sar, Ran and Rab).[7]
RASEF is included in the Rab family (the largest family), which is responsible for vesicular traffic of proteins between organelles via endocytotic and secretory pathways. Their function is to make budding from the donor compartment, transport, vesicle fusion and cargo release easier.[8]
# Structure
RASEF is a 740 amino acids[9] long protein which contains 3 distinct regions: 2 EF hand domains (which in turn contain 2 Calcium bindings and 3 nucleotide bindings -assumed by similarity with other proteins, without direct evidence-), a Coiled Coil region and a C-terminal Rab-homology domain.[3]
## Domains
### N-terminal EF hand domain
Sequence found in RASEF protein that contains 35 amino acids (36 in the second one). The two EF hand domains are consecutively located at the “beginning” of the protein. Its name “N-terminal” indicates an amino group (characteristic of this group of biomolecules, as well as the C- terminal ending). The first one goes from the 8th amino acid to the 42nd, and the other to the 42nd to the 77th.[7]
“EF hand” refers to the shape of this domain (similarity with the right hand’s morphology). Ca+2 ions are responsible for this structure, which by binding metals join two alpha helixes.[10]
### Coiled coil region
Structural motif in proteins: from two to seven alpha helixes entwined. Each one of these helixes is a repeated 7 amino acid sequence (HPPHCPC), where H refers to hydrophobic amino acids.[11] The position of hydrophobic remains (alpha helix exterior) causes their amphipathic behaviour.[citation needed]
The bond between different chains, produced in cytoplasm (aqueous region), is extremely tight, as Van der Waals forces appear between the hydrophobic radicals (H), surrounded by the hydrophilic amino acids (amphipathic molecule). This bond is known as the “Knobs into holes packing”.[12]
Coiled coil motif, located in the intermediate region of the protein, is responsible for self-interaction.[13]
### C-Terminal Rab-homology domain
Located at the end of the protein (opposite to N-terminal domain), it’s a carboxyl group (COOH).
In this region, there are guanine nucleotide bonds to tri-phosphates and di-phosphates. The variability of this domain is responsible for the high appearance of elements needed in the joints between proteins and their targets in the membrane.[14]
Both the C-Terminal Rab-homology domain and the intermediate region of the protein are responsible for the intracellular location of the protein (perinuclear region).[citation needed]
# Function
RASEF intervenes in a direct manner in biological processes such as protein transport and small GTPase mediated signal transduction. Its molecular functions include GTP binding and calcium ion binding.[15]
As mentioned previously, RASEF has 3 distinct structural regions: the C-terminus Rab domain, the N-terminus EF-hand domain and the self-interacting mid-region. Each of these has an individual function.[citation needed]
The guanine-nucleotide forms of the Rab domain regulate the protein's localization. RASEF is mainly found in the perinuclear region of the cell. In addition, the protein's mid-region also seems to be involved in the perinuclear localization. This could be due to its interaction with membrane compartments.[citation needed]
The EF-hand domain’s function still remains to be discovered. However, it is speculated that due to its conformational changes upon binding with Ca2+ ions, and these being responsible for interactions with target molecules; that in cooperation with the Rab-domain, the EF-hand domain's main function is regulating membrane traffic.[citation needed]
Over 60 Rab-family GTPase proteins have key roles in membrane traffic regulation. This isn’t surprising given the amount and variety of intracellular compartments, which require a high level of control to ensure a proper delivery and fusion of vesicles at the correct site.[3]
This connects the RASEF protein directly to cell-growth mechanisms, making it susceptible to having a decisive role in the apparition of cancerous cells.[citation needed]
# Clinical significance
As we have seen, RASEF is involved in cell-growth mechanisms. When its active centre is stimulated by tyrosine kinase (GDP is exchanged by GTP), this part of the oncoprotein adopts a conformation which has much affinity with many effectors.[16]
This induces a huge diversity of biochemical intracellular cascades which, in addition to some other reactions, influence cell behaviour. When these growth factors are altered, the signal cytoplasmatic circuits can not function properly, which could provoke serious pathologies like cancer. The constitutively active form of Ras oncoprotein is expressed in high levels in bladder carcinomas, leukemias, colon, breast, lung and skin cancers.[17]
Some researchers have discovered that Ras and Ef-hand domain containing proteins are commonly overexpressed in primary lung cancers and its intervention is crucial for the proliferation and survival of cancerous cells. Apart from binding calcium ions in the N-terminus, RASEF plays a significant role in lung cancer cell-growth. This occurs because of its interaction with ERK (extracellular signal-regulated kinase) molecules involved in the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells, whose pathway can be activated by carcinogens or viral infections. .[18]
There is ongoing research that is studying the possibility of using RASEF as a clinically promising prognostic biomarker and therapeutic target for lung cancer. Some recent studies have revealed the viability of using RASEF as a target for this disease.[18]
Also, a segregation study in families with uveal and cutaneous melanoma identified a potential locus harboring a tumor-suppressor gene (TSG). One of the genes in this area (9q21), RASEF, was then analyzed as a candidate TSG, but the lack of point mutations and copy number changes could not confirm this. Nowadays, the RASEF gene has been investigated for potential mutations and gene silencing by promoting methylation in uveal melanoma. It appears to be the mechanism targeting RASEF in uveal melanoma, and allelic imbalance at this locus supports a TSG role for the Ras and Ef-hand domain containing.[19] | https://www.wikidoc.org/index.php/RASEF | |
aae617170383d0f0d4cd501378ce343496d87a16 | wikidoc | RBBP4 | RBBP4
Histone-binding protein RBBP4 (also known as RbAp48, or NURF55) is a protein that in humans is encoded by the RBBP4 gene.
# Function
This gene encodes a ubiquitously expressed nuclear protein that belongs to a highly conserved subfamily of WD-repeat proteins. It is present in protein complexes involved in histone acetylation and chromatin assembly. It is part of the Mi-2/NuRD complex that has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation. This encoded protein is also part of corepressor complexes, which is an integral component of transcriptional silencing. It is found among several cellular proteins that bind directly to retinoblastoma protein to regulate cell proliferation. This protein also seems to be involved in transcriptional repression of E2F-responsive genes.
# Clinical significance
A decrease of RbAp48 in the dentate gyrus (DG) of the hippocampus in the brain is suspected to be a main cause of memory loss in normal aging. An age related decrease in RbAp48 is observed in the DG from human post-mortem tissue and also in mice. Furthermore, a gene knockin of a dominant negative form of RbAp48 of causes memory deficits in young mice similar to that observed in older mice. Finally lentiviral gene transfer to increase the expression of RbAp48 in the brain reverses memory deficits in older mice.
RBBP4 works at least in part through the PKA-CREB1-CPB pathway. Hence one possible therapeutic approach to restore age-related memory loss is the use of PKA-CREB1-CPB pathway stimulating drugs. It has previously been shown that dopamine D1/D5 agonists such as 6-Br-APB and SKF-38,393 that are positively coupled to adenylyl cyclase and the cAMP phosphodieserase inhibitor rolipram reduce memory defects in aged mice.
# Interactions
RBBP4 has been shown to interact with:
- BRCA1,
- CREBBP,
- GATAD2B,
- HDAC1,
- HDAC2,
- HDAC3,
- MTA2,
- RB,
- SAP30, and
- SIN3A. | RBBP4
Histone-binding protein RBBP4 (also known as RbAp48, or NURF55) is a protein that in humans is encoded by the RBBP4 gene.[1][2]
# Function
This gene encodes a ubiquitously expressed nuclear protein that belongs to a highly conserved subfamily of WD-repeat proteins. It is present in protein complexes involved in histone acetylation and chromatin assembly. It is part of the Mi-2/NuRD complex that has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation. This encoded protein is also part of corepressor complexes, which is an integral component of transcriptional silencing. It is found among several cellular proteins that bind directly to retinoblastoma protein to regulate cell proliferation. This protein also seems to be involved in transcriptional repression of E2F-responsive genes.[3]
# Clinical significance
A decrease of RbAp48 in the dentate gyrus (DG) of the hippocampus in the brain is suspected to be a main cause of memory loss in normal aging.[4] An age related decrease in RbAp48 is observed in the DG from human post-mortem tissue and also in mice. Furthermore, a gene knockin of a dominant negative form of RbAp48 of causes memory deficits in young mice similar to that observed in older mice. Finally lentiviral gene transfer to increase the expression of RbAp48 in the brain reverses memory deficits in older mice.[4]
RBBP4 works at least in part through the PKA-CREB1-CPB pathway.[4] Hence one possible therapeutic approach to restore age-related memory loss is the use of PKA-CREB1-CPB pathway stimulating drugs. It has previously been shown that dopamine D1/D5 agonists such as 6-Br-APB and SKF-38,393 that are positively coupled to adenylyl cyclase and the cAMP phosphodieserase inhibitor rolipram reduce memory defects in aged mice.[5]
# Interactions
RBBP4 has been shown to interact with:
- BRCA1,[6]
- CREBBP,[7]
- GATAD2B,[8]
- HDAC1,[9][10][11][12][13][14][15][16][17][18][19]
- HDAC2,[9][17][20][21]
- HDAC3,[11]
- MTA2,[10][16]
- RB,[11][22][23]
- SAP30,[16][24][25] and
- SIN3A.[14][24] | https://www.wikidoc.org/index.php/RBBP4 | |
fa2df9a33f1f15493cd3fcbadfee3a2766139002 | wikidoc | RBBP6 | RBBP6
Retinoblastoma-binding protein 6 is a protein that in humans is encoded by the RBBP6 gene.
# Function
The retinoblastoma tumor suppressor (pRB) protein binds with many other proteins. In various human cancers, pRB suppresses cellular proliferation and is inactivated. Cell cycle-dependent phosphorylation regulates the activity of pRB. This gene encodes a protein which binds to underphosphorylated but not phosphorylated pRB. Multiple alternatively spliced transcript variants that encode different isoforms have been found for this gene.
# Interactions
RBBP6 has been shown to interact with Y box binding protein 1. | RBBP6
Retinoblastoma-binding protein 6 is a protein that in humans is encoded by the RBBP6 gene.[1][2][3]
# Function
The retinoblastoma tumor suppressor (pRB) protein binds with many other proteins. In various human cancers, pRB suppresses cellular proliferation and is inactivated. Cell cycle-dependent phosphorylation regulates the activity of pRB. This gene encodes a protein which binds to underphosphorylated but not phosphorylated pRB. Multiple alternatively spliced transcript variants that encode different isoforms have been found for this gene.[3]
# Interactions
RBBP6 has been shown to interact with Y box binding protein 1.[4] | https://www.wikidoc.org/index.php/RBBP6 | |
9b7e822a56fb7371bea6d47f95bb01f33bcc3c8b | wikidoc | RBBP7 | RBBP7
Histone-binding protein RBBP7 is a protein that in humans is encoded by the RBBP7 gene.
# Function
This protein is a ubiquitously expressed nuclear protein and belongs to a highly conserved subfamily of WD-repeat proteins. It is found among several proteins that binds directly to retinoblastoma protein, which regulates cell proliferation. The encoded protein is found in many histone deacetylase complexes, including mSin3 co-repressor complex. It is also present in protein complexes involved in chromatin assembly. This protein can interact with BRCA1 tumor-suppressor gene and may have a role in the regulation of cell proliferation and differentiation.
# Model organisms
Model organisms have been used in the study of RBBP7 function. A conditional knockout mouse line, called Rbbp7tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on mutant mice and one significant abnormality was observed: hemizygous mutant males had decreased CD4-positive and CD8-positive T cell numbers.
# Interactions
RBBP7 has been shown to interact with:
- BRCA1,
- GATAD2B,
- HDAC1,
- MTA2,
- Retinoblastoma protein,
- SAP30, and
- SIN3A. | RBBP7
Histone-binding protein RBBP7 is a protein that in humans is encoded by the RBBP7 gene.[1]
# Function
This protein is a ubiquitously expressed nuclear protein and belongs to a highly conserved subfamily of WD-repeat proteins. It is found among several proteins that binds directly to retinoblastoma protein, which regulates cell proliferation. The encoded protein is found in many histone deacetylase complexes, including mSin3 co-repressor complex. It is also present in protein complexes involved in chromatin assembly. This protein can interact with BRCA1 tumor-suppressor gene and may have a role in the regulation of cell proliferation and differentiation.[2]
# Model organisms
Model organisms have been used in the study of RBBP7 function. A conditional knockout mouse line, called Rbbp7tm1a(EUCOMM)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty one tests were carried out on mutant mice and one significant abnormality was observed: hemizygous mutant males had decreased CD4-positive and CD8-positive T cell numbers.[4]
# Interactions
RBBP7 has been shown to interact with:
- BRCA1,[12][13][14]
- GATAD2B,[15]
- HDAC1,[16][17][18][19]
- MTA2,[16][18]
- Retinoblastoma protein,[1][12]
- SAP30,[18][20][21] and
- SIN3A.[20][21] | https://www.wikidoc.org/index.php/RBBP7 | |
e7727371ea0ec919bb6371056b5b1e58ec6d3a19 | wikidoc | RBCK1 | RBCK1
RanBP-type and C3HC4-type zinc finger-containing protein 1 is a protein that in humans is encoded by the RBCK1 gene.
The protein encoded by this gene is similar to mouse UIP28/UbcM4 interacting protein. Alternative splicing has been observed at this locus, resulting in distinct isoforms.
# Clinical significance
A family quartet was found with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet SNP genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products. Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified. | RBCK1
RanBP-type and C3HC4-type zinc finger-containing protein 1 is a protein that in humans is encoded by the RBCK1 gene.[1]
The protein encoded by this gene is similar to mouse UIP28/UbcM4 interacting protein. Alternative splicing has been observed at this locus, resulting in distinct isoforms.[1]
# Clinical significance
A family quartet was found with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, one additional unrelated patient was found with a comparable phenotype. From whole-genome sequence data, RBCK1, a gene encoding an E3 ubiquitin-protein ligase, was identified as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet SNP genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products.[2] Ten other individuals with mutations in RBCK1 and overlapping phenotypes have been identified.[3] | https://www.wikidoc.org/index.php/RBCK1 | |
eb6bc25b4277fe528c0639e07a921eb1441b7312 | wikidoc | RBM39 | RBM39
RNA-binding protein 39 is a protein that in humans is encoded by the RBM39 gene.
# Function
The protein encoded by this gene is an RNA binding protein and possible splicing factor. The encoded protein is found in the nucleus, where it colocalizes with core spliceosomal proteins. Studies of a mouse protein with high sequence similarity to this protein suggest that this protein may act as a transcriptional coactivator for JUN/AP-1 and estrogen receptors. Multiple transcript variants encoding different isoforms have been observed for this gene.
# Interactions
RBM39 has been shown to interact with Estrogen receptor alpha, Estrogen receptor beta and C-jun. | RBM39
RNA-binding protein 39 is a protein that in humans is encoded by the RBM39 gene.[1][2]
# Function
The protein encoded by this gene is an RNA binding protein and possible splicing factor. The encoded protein is found in the nucleus, where it colocalizes with core spliceosomal proteins. Studies of a mouse protein with high sequence similarity to this protein suggest that this protein may act as a transcriptional coactivator for JUN/AP-1 and estrogen receptors. Multiple transcript variants encoding different isoforms have been observed for this gene.[2]
# Interactions
RBM39 has been shown to interact with Estrogen receptor alpha,[3] Estrogen receptor beta[3] and C-jun.[3] | https://www.wikidoc.org/index.php/RBM39 | |
4cbde86791592dad056d82c190c3abf281014535 | wikidoc | RBM8A | RBM8A
RNA-binding protein 8A is a protein that in humans is encoded by the RBM8A gene.
This gene encodes a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. Previously, it was thought that two genes encode this protein, RBM8A and RBM8B; it is now thought that the RBM8B locus is a pseudogene. Two alternative start codons result in two forms of the protein, and this gene also uses multiple polyadenylation sites.
# Interactions
RBM8A has been shown to interact with IPO13, MAGOH and UPF3A.
# Related gene problems
- TAR syndrome
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | RBM8A
RNA-binding protein 8A is a protein that in humans is encoded by the RBM8A gene.[1][2]
This gene encodes a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. Previously, it was thought that two genes encode this protein, RBM8A and RBM8B; it is now thought that the RBM8B locus is a pseudogene. Two alternative start codons result in two forms of the protein, and this gene also uses multiple polyadenylation sites.[3]
# Interactions
RBM8A has been shown to interact with IPO13,[4] MAGOH[5][6] and UPF3A.[7]
# Related gene problems
- TAR syndrome[8]
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | https://www.wikidoc.org/index.php/RBM8A | |
d71384290ad14b2e21301f4fe8281e7b9ce32fe6 | wikidoc | RBMS1 | RBMS1
RNA-binding motif, single-stranded-interacting protein 1 is a protein that in humans is encoded by the RBMS1 gene.
# Function
This gene encodes a member of a small family of proteins which bind single stranded DNA/RNA. These proteins are characterized by the presence of two sets of ribonucleoprotein consensus sequence (RNP-CS) that contain conserved motifs, RNP1 and RNP2, originally described in RNA binding proteins, and required for DNA binding. These proteins have been implicated in such diverse functions as DNA replication, gene transcription, cell cycle progression and apoptosis. Multiple transcript variants, resulting from alternative splicing and encoding different isoforms, have been described. Several of these were isolated by virtue of their binding to either strand of an upstream element of c-myc (MSSPs), or by phenotypic complementation of cdc2 and cdc13 mutants of yeast (scr2), or as a potential human repressor of HIV-1 and ILR-2 alpha promoter transcription (YC1). A pseudogene for this locus is found on chromosome 12.
# Interactions
RBMS1 has been shown to interact with Polymerase (DNA directed), alpha 1. | RBMS1
RNA-binding motif, single-stranded-interacting protein 1 is a protein that in humans is encoded by the RBMS1 gene.[1][2][3][4]
# Function
This gene encodes a member of a small family of proteins which bind single stranded DNA/RNA. These proteins are characterized by the presence of two sets of ribonucleoprotein consensus sequence (RNP-CS) that contain conserved motifs, RNP1 and RNP2, originally described in RNA binding proteins, and required for DNA binding. These proteins have been implicated in such diverse functions as DNA replication, gene transcription, cell cycle progression and apoptosis. Multiple transcript variants, resulting from alternative splicing and encoding different isoforms, have been described. Several of these were isolated by virtue of their binding to either strand of an upstream element of c-myc (MSSPs), or by phenotypic complementation of cdc2 and cdc13 mutants of yeast (scr2), or as a potential human repressor of HIV-1 and ILR-2 alpha promoter transcription (YC1). A pseudogene for this locus is found on chromosome 12.[4]
# Interactions
RBMS1 has been shown to interact with Polymerase (DNA directed), alpha 1.[5] | https://www.wikidoc.org/index.php/RBMS1 | |
cad924ca67a80946aae67a1f45f566b77a3f5795 | wikidoc | RBPMS | RBPMS
RNA-binding protein with multiple splicing is a protein that in humans is encoded by the RBPMS gene.
# Function
This gene encodes a member of the RRM family of RNA-binding proteins. The RRM domain is between 80-100 amino acids in length and family members contain one to four copies of the domain. The RRM domain consists of two short stretches of conserved sequence called RNP1 and RNP2, as well as a few highly conserved hydrophobic residues. The protein encoded by this gene has a single, putative RRM domain in its N-terminus. Alternative splicing results in multiple transcript variants encoding different isoforms.
It is uniquely expressed in retinal ganglion cells in the mammalian retina, for reasons unknown.
# Interactions
RBPMS has been shown to interact with SMUG1. | RBPMS
RNA-binding protein with multiple splicing is a protein that in humans is encoded by the RBPMS gene.[1][2]
# Function
This gene encodes a member of the RRM family of RNA-binding proteins. The RRM domain is between 80-100 amino acids in length and family members contain one to four copies of the domain. The RRM domain consists of two short stretches of conserved sequence called RNP1 and RNP2, as well as a few highly conserved hydrophobic residues. The protein encoded by this gene has a single, putative RRM domain in its N-terminus. Alternative splicing results in multiple transcript variants encoding different isoforms.[2]
It is uniquely expressed in retinal ganglion cells in the mammalian retina,[3] for reasons unknown.
# Interactions
RBPMS has been shown to interact with SMUG1.[4] | https://www.wikidoc.org/index.php/RBPMS | |
1a37d04a216aaac63a5f25eded6feeb5f3a4635f | wikidoc | RCHY1 | RCHY1
RING finger and CHY zinc finger domain-containing protein 1 is a protein that in humans is encoded by the RCHY1 gene.
# Function
The protein encoded by this gene has ubiquitin-protein ligase activity. This protein binds with p53 and promotes the ubiquitin-mediated proteosomal degradation of p53. This gene is oncogenic because loss of p53 function contributes directly to malignant tumor development. Transcription of this gene is regulated by p53. Alternative splicing results in multiple transcript variants encoding different isoforms.
# Interactions
RCHY1 has been shown to interact with P53 and Androgen receptor. | RCHY1
RING finger and CHY zinc finger domain-containing protein 1 is a protein that in humans is encoded by the RCHY1 gene.[1]
# Function
The protein encoded by this gene has ubiquitin-protein ligase activity. This protein binds with p53 and promotes the ubiquitin-mediated proteosomal degradation of p53. This gene is oncogenic because loss of p53 function contributes directly to malignant tumor development. Transcription of this gene is regulated by p53. Alternative splicing results in multiple transcript variants encoding different isoforms.[1]
# Interactions
RCHY1 has been shown to interact with P53[2][3] and Androgen receptor.[4] | https://www.wikidoc.org/index.php/RCHY1 | |
0c96d2b46b2a6550f66b495c52e597330e050636 | wikidoc | RDH11 | RDH11
Retinol dehydrogenase 11 is an enzyme that in humans is encoded by the RDH11 gene.
RHD11, a member of the short-chain dehydrogenase/reductase (SDR) superfamily of oxidoreductases, is expressed at high levels in prostate epithelium, and its expression is regulated by androgens.
# Clinical significance
Mutations in RDH11 are associated to retinitis pigmentosa . | RDH11
Retinol dehydrogenase 11 is an enzyme that in humans is encoded by the RDH11 gene.[1][2][3][4]
RHD11, a member of the short-chain dehydrogenase/reductase (SDR) superfamily of oxidoreductases, is expressed at high levels in prostate epithelium, and its expression is regulated by androgens.[supplied by OMIM][4]
# Clinical significance
Mutations in RDH11 are associated to retinitis pigmentosa .[5] | https://www.wikidoc.org/index.php/RDH11 | |
026e939d68132915dc351b67eede0f9b94232786 | wikidoc | RDH13 | RDH13
Retinol dehydrogenase 13 (all-trans/9-cis) is a protein that in humans is encoded by the RDH13 gene. This gene encodes a mitochondrial short-chain dehydrogenase/reductase, which catalyzes the reduction and oxidation of retinoids. The encoded enzyme may function in retinoic acid production and may also protect the mitochondria against oxidative stress. Alternatively spliced transcript variants have been described.
# Gene
The human RDH13 gene is on the 19th chromosome, with its specific localization being 19q13.42. The gene contains 12 exons in total.
# Structure
The analysis of the submitochondrial localization of RDH13 indicates its association with the inner mitochondrial membrane. The primary structure of RDH13 contains two hydrophobic segments, 2–21 and 242–261, which are sufficiently long to serve as transmembrane segments; however, as shown in the present study, alkaline extraction completely removes the protein from the membrane, indicating that RDH13 is a peripheral membrane protein. The peripheral association of RDH13 with the membrane further distinguishes this protein from the microsomal retinaldehyde reductases, which are integral membrane proteins that appear to be anchored in the membrane via their N-terminal hydrophobic segments.
# Function
RDH13 is most closely related to the NADP+-dependent microsomal enzymes RDH11, RDH12 and RDH14. Purified RDH13 acts on retinoids in an oxidative reductive manner, and strongly prefers the cofactor NADPH over NADH. Moreover, RDH13 is much has much more efficient reductase activity than dehydrogenase activity. RDH13 as a retinaldehyde reductase is significantly less active than that of a related protein RDH11, primarily because of the much higher Km value for retinaldehyde. However, the kcat value of RDH13 for retinaldehyde reduction. arable with that of RDH11, and the Km values of the two enzymes for NADPH are also very similar. Thus, consistent with its sequence similarity to RDH11, RDH12 and RDH14, RDH13 acts as an NADP+-dependent retinaldehyde reductase.
RDH13 is localized in the mitochondria, which is different from the other members of this family, as they localize to the endoplasmic reticulum. The exact sequence targeting RDH13 to the mitochondria remains to be established.
# Clinical significance
RDH13 is part of a subfamily of four retinol dehydrogenases, RDH11, RDH12, RDH13, and RDH14, that display dual-substrate specificity, uniquely metabolizing all-trans- and cis-retinols with C(15) pro-R specificity. The metabolites involved in these reactions are known as retinoids, which are chromophores involved in vision, transcriptional regulation, and cellular differentiation. RDH11-14 could be involved in the first step of all-trans- and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor and retinal pigment epithelial cells. The dual-substrate specificity of this subfamily explains the minor phenotype associated with mutations in 11-cis-retinol dehydrogenase (RDH5) causing fundus albipunctatus in humans. | RDH13
Retinol dehydrogenase 13 (all-trans/9-cis) is a protein that in humans is encoded by the RDH13 gene. This gene encodes a mitochondrial short-chain dehydrogenase/reductase, which catalyzes the reduction and oxidation of retinoids. The encoded enzyme may function in retinoic acid production and may also protect the mitochondria against oxidative stress. Alternatively spliced transcript variants have been described.[1]
# Gene
The human RDH13 gene is on the 19th chromosome, with its specific localization being 19q13.42. The gene contains 12 exons in total.[1]
# Structure
The analysis of the submitochondrial localization of RDH13 indicates its association with the inner mitochondrial membrane. The primary structure of RDH13 contains two hydrophobic segments, 2–21 and 242–261, which are sufficiently long to serve as transmembrane segments; however, as shown in the present study, alkaline extraction completely removes the protein from the membrane, indicating that RDH13 is a peripheral membrane protein.[2] The peripheral association of RDH13 with the membrane further distinguishes this protein from the microsomal retinaldehyde reductases, which are integral membrane proteins that appear to be anchored in the membrane via their N-terminal hydrophobic segments.[3]
# Function
RDH13 is most closely related to the NADP+-dependent microsomal enzymes RDH11, RDH12 and RDH14.[4][5] Purified RDH13 acts on retinoids in an oxidative reductive manner, and strongly prefers the cofactor NADPH over NADH. Moreover, RDH13 is much has much more efficient reductase activity than dehydrogenase activity. RDH13 as a retinaldehyde reductase is significantly less active than that of a related protein RDH11, primarily because of the much higher Km value for retinaldehyde. However, the kcat value of RDH13 for retinaldehyde reduction. arable with that of RDH11, and the Km values of the two enzymes for NADPH are also very similar. Thus, consistent with its sequence similarity to RDH11, RDH12 and RDH14, RDH13 acts as an NADP+-dependent retinaldehyde reductase.[6]
RDH13 is localized in the mitochondria, which is different from the other members of this family, as they localize to the endoplasmic reticulum. The exact sequence targeting RDH13 to the mitochondria remains to be established.
# Clinical significance
RDH13 is part of a subfamily of four retinol dehydrogenases, RDH11, RDH12, RDH13, and RDH14, that display dual-substrate specificity, uniquely metabolizing all-trans- and cis-retinols with C(15) pro-R specificity. The metabolites involved in these reactions are known as retinoids, which are chromophores involved in vision, transcriptional regulation, and cellular differentiation. RDH11-14 could be involved in the first step of all-trans- and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor and retinal pigment epithelial cells. The dual-substrate specificity of this subfamily explains the minor phenotype associated with mutations in 11-cis-retinol dehydrogenase (RDH5) causing fundus albipunctatus in humans.[5] | https://www.wikidoc.org/index.php/RDH13 | |
951940e003651359bd25daa13910f7803cbcdbc7 | wikidoc | RECQL | RECQL
ATP-dependent DNA helicase Q1 is an enzyme that in humans is encoded by the RECQL gene.
The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. Some members of this family are associated with genetic disorders with predisposition to malignancy and chromosomal instability. The biological function of this helicase has not yet been determined. Two alternatively spliced transcripts, which encode the same isoform but differ in their 5' and 3' UTRs, have been described.
# Interactions
RECQL has been shown to interact with KPNA4 and Karyopherin alpha 2. | RECQL
ATP-dependent DNA helicase Q1 is an enzyme that in humans is encoded by the RECQL gene.[1][2][3]
The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. Some members of this family are associated with genetic disorders with predisposition to malignancy and chromosomal instability. The biological function of this helicase has not yet been determined. Two alternatively spliced transcripts, which encode the same isoform but differ in their 5' and 3' UTRs, have been described.[3]
# Interactions
RECQL has been shown to interact with KPNA4[4] and Karyopherin alpha 2.[4] | https://www.wikidoc.org/index.php/RECQL | |
e723186f40585bdea4447d97d10beef725963377 | wikidoc | REEP2 | REEP2
Receptor expression-enhancing protein 2 is a protein that in humans is encoded by the REEP2 gene.
# Function
The protein encoded by REEP2 belongs to a family of proteins with receptor enhancing expression capabilities, including possible enhancement of G protein-coupled receptors. The REEP2 protein shows a restricted mode of expression in human tissues .
# Clinical significance
REEP2 mutations have been reported in families with hereditary spastic paraplegia. | REEP2
Receptor expression-enhancing protein 2 is a protein that in humans is encoded by the REEP2 gene.[1][2]
# Function
The protein encoded by REEP2 belongs to a family of proteins with receptor enhancing expression capabilities, including possible enhancement of G protein-coupled receptors[3]. The REEP2 protein shows a restricted mode of expression in human tissues [4].
# Clinical significance
REEP2 mutations have been reported in families with hereditary spastic paraplegia[5]. | https://www.wikidoc.org/index.php/REEP2 | |
ce4f182e8975e9e04cf2688c059d3165d3deb362 | wikidoc | REG3A | REG3A
Regenerating islet-derived protein 3 alpha (or Regenerating islet-derived protein III-alpha) formerly known as HIP/PAP (Hepatocarcinoma-Intestine-Pancreas/Pancreatitis-Associated Protein) and peptide 23 is a protein that in humans is encoded by the REG3A gene.
This gene encodes a pancreatic secretory protein that may be involved in cell proliferation or differentiation. It has similarity to the C-type lectin superfamily. The enhanced expression of this gene is observed during pancreatic inflammation and liver carcinogenesis. Multiple alternatively spliced transcript variants encoding the same protein have been described for this gene but the full length nature of some transcripts is not yet known.
Reg3A (UniProt Q0614 1) is a bactericidal C-type lectin that is constitutively produced in the intestine that has antibacterial properties against Gram-positive bacteria. Bacterial killing is mediated by binding to surface-exposed carbohydrate moieties of bacterial peptidoglycan. | REG3A
Regenerating islet-derived protein 3 alpha (or Regenerating islet-derived protein III-alpha) formerly known as HIP/PAP (Hepatocarcinoma-Intestine-Pancreas/Pancreatitis-Associated Protein) and peptide 23[1] is a protein that in humans is encoded by the REG3A gene.[2][3]
This gene encodes a pancreatic secretory protein that may be involved in cell proliferation or differentiation. It has similarity to the C-type lectin superfamily. The enhanced expression of this gene is observed during pancreatic inflammation and liver carcinogenesis. Multiple alternatively spliced transcript variants encoding the same protein have been described for this gene but the full length nature of some transcripts is not yet known.[3]
Reg3A (UniProt Q0614 1) is a bactericidal C-type lectin that is constitutively produced in the intestine that has antibacterial properties against Gram-positive bacteria. Bacterial killing is mediated by binding to surface-exposed carbohydrate moieties of bacterial peptidoglycan.[4][5] | https://www.wikidoc.org/index.php/REG3A | |
824d079d0ab66db0709f74ac78eeea610709b04d | wikidoc | REG3G | REG3G
Regenerating islet-derived protein 3 gamma (also Regenerating islet-derived protein III-gamma) is a protein that in humans is encoded by the REG3G gene.
Intestinal paneth cells produce REG3G (or REG3 gamma) via stimulation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs). REG3 gamma specifically targets Gram-positive bacteria because it binds to their surface peptidoglycan layer. It is one of several antimicrobial peptides produced by paneth cells.
# Notes and references
- ↑ Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (Oct 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nata K, Liu Y, Xu L, Ikeda T, Akiyama T, Noguchi N, Kawaguchi S, Yamauchi A, Takahashi I, Shervani NJ, Onogawa T, Takasawa S, Okamoto H (September 2004). "Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III". Gene. 340 (1): 161–70. doi:10.1016/j.gene.2004.06.010. PMID 15556304.
- ↑ Laurine E, Manival X, Montgelard C, Bideau C, Bergé-Lefranc JL, Erard M, Verdier JM (March 2005). "PAP IB, a new member of the Reg gene family: cloning, expression, structural properties, and evolution by gene duplication". Biochim. Biophys. Acta. 1727 (3): 177–87. doi:10.1016/j.bbaexp.2005.01.011. PMID 15777617.
- ↑ "Entrez Gene: REG3G regenerating islet-derived 3 gamma".
- ↑ Abreu MT (February 2010). "Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function". Nat. Rev. Immunol. 10 (2): 131–44. doi:10.1038/nri2707. PMID 20098461.
# Bibliography
- Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. doi:10.1038/nature03466. PMID 15815621.
- Laurine E, Manival X, Montgelard C, et al. (2005). "PAP IB, a new member of the Reg gene family: cloning, expression, structural properties, and evolution by gene duplication". Biochim. Biophys. Acta. 1727 (3): 177–87. doi:10.1016/j.bbaexp.2005.01.011. PMID 15777617.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG (2007). "MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection". J. Exp. Med. 204 (8): 900–1891. doi:10.1084/jem.20070563. PMC 2118673. PMID 17635956. | REG3G
Regenerating islet-derived protein 3 gamma (also Regenerating islet-derived protein III-gamma) is a protein that in humans is encoded by the REG3G gene.[1][2][3][4]
Intestinal paneth cells produce REG3G (or REG3 gamma) via stimulation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs). REG3 gamma specifically targets Gram-positive bacteria because it binds to their surface peptidoglycan layer. It is one of several antimicrobial peptides produced by paneth cells.[5]
# Notes and references
- ↑ Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (Oct 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nata K, Liu Y, Xu L, Ikeda T, Akiyama T, Noguchi N, Kawaguchi S, Yamauchi A, Takahashi I, Shervani NJ, Onogawa T, Takasawa S, Okamoto H (September 2004). "Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III". Gene. 340 (1): 161–70. doi:10.1016/j.gene.2004.06.010. PMID 15556304.
- ↑ Laurine E, Manival X, Montgelard C, Bideau C, Bergé-Lefranc JL, Erard M, Verdier JM (March 2005). "PAP IB, a new member of the Reg gene family: cloning, expression, structural properties, and evolution by gene duplication". Biochim. Biophys. Acta. 1727 (3): 177–87. doi:10.1016/j.bbaexp.2005.01.011. PMID 15777617.
- ↑ "Entrez Gene: REG3G regenerating islet-derived 3 gamma".
- ↑ Abreu MT (February 2010). "Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function". Nat. Rev. Immunol. 10 (2): 131–44. doi:10.1038/nri2707. PMID 20098461.
# Bibliography
- Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. doi:10.1038/nature03466. PMID 15815621.
- Laurine E, Manival X, Montgelard C, et al. (2005). "PAP IB, a new member of the Reg gene family: cloning, expression, structural properties, and evolution by gene duplication". Biochim. Biophys. Acta. 1727 (3): 177–87. doi:10.1016/j.bbaexp.2005.01.011. PMID 15777617.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG (2007). "MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection". J. Exp. Med. 204 (8): 900–1891. doi:10.1084/jem.20070563. PMC 2118673. PMID 17635956. | https://www.wikidoc.org/index.php/REG3G | |
37ee991a1ce00a9ebf90423a1a0da18596397a98 | wikidoc | REPS2 | REPS2
RalBP1-associated Eps domain-containing protein 2 is a protein that in humans is encoded by the REPS2 gene.
# Function
The product of this gene is part of a protein complex that regulates the endocytosis of growth factor receptors. The encoded protein directly interacts with a GTPase activating protein that functions downstream of the small G protein Ral. Its expression can negatively affect receptor internalization and inhibit growth factor signaling. Multiple transcript variants encoding different isoforms have been found for this gene.
# Interactions
REPS2 has been shown to interact with EPN1, EPS15 and RALBP1. | REPS2
RalBP1-associated Eps domain-containing protein 2 is a protein that in humans is encoded by the REPS2 gene.[1][2][3]
# Function
The product of this gene is part of a protein complex that regulates the endocytosis of growth factor receptors. The encoded protein directly interacts with a GTPase activating protein that functions downstream of the small G protein Ral. Its expression can negatively affect receptor internalization and inhibit growth factor signaling. Multiple transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
REPS2 has been shown to interact with EPN1,[4] EPS15[5] and RALBP1.[1] | https://www.wikidoc.org/index.php/REPS2 | |
e2e209e745a3f0e5de344eddf31249a829d98a56 | wikidoc | RGS13 | RGS13
Regulator of G-protein signaling 13 is a protein that in humans is encoded by the RGS13 gene.
RGS 13 is a member of R4 subfamily of RGS (Regulators of G Protein Signaling) proteins which have only short peptide sequences flanking the RGS domain. RGS 13 suppresses the immunoglobulin E- mediated allergic responses.
The protein encoded by this gene is a member of the regulator of G protein signaling (RGS) family. RGS family members share similarity with S. cerevisiae SST2 and C. elegans egl-10 proteins, which contain a characteristic conserved RGS domain. RGS proteins accelerate GTPase activity of G protein alpha-subunits, thereby driving G protein into their inactive GDP-bound form, thus negatively regulating G protein signaling. RGS proteins have been implicated in the fine tuning of a variety of cellular events in response to G protein-coupled receptor activation. The biological function of this gene, however, is unknown. Two transcript variants encoding the same isoform exist. | RGS13
Regulator of G-protein signaling 13 is a protein that in humans is encoded by the RGS13 gene.[1][2]
RGS 13 is a member of R4 subfamily of RGS (Regulators of G Protein Signaling) proteins which have only short peptide sequences flanking the RGS domain. RGS 13 suppresses the immunoglobulin E- mediated allergic responses.[3]
The protein encoded by this gene is a member of the regulator of G protein signaling (RGS) family. RGS family members share similarity with S. cerevisiae SST2 and C. elegans egl-10 proteins, which contain a characteristic conserved RGS domain. RGS proteins accelerate GTPase activity of G protein alpha-subunits, thereby driving G protein into their inactive GDP-bound form, thus negatively regulating G protein signaling. RGS proteins have been implicated in the fine tuning of a variety of cellular events in response to G protein-coupled receptor activation. The biological function of this gene, however, is unknown. Two transcript variants encoding the same isoform exist.[2] | https://www.wikidoc.org/index.php/RGS13 | |
6a3190029a5eb5724f7dcef6fc4f1140b3c5d40e | wikidoc | RGS14 | RGS14
Regulator of G-protein signaling 14 (RGS14) is a protein that in humans is encoded by the RGS14 gene.
# Function
RGS14 is a member of the regulator of G protein signalling family. This protein contains one RGS domain, two Raf-like Ras-binding domains (RBDs), and one GoLoco motif. The protein attenuates the signaling activity of G-proteins by binding, through its GoLoco domain, to specific types of activated, GTP-bound G alpha subunits. Acting as a GTPase activating protein (GAP), the protein increases the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.
Increasing the expression of the RGS14 protein in the V2 secondary visual cortex of mice promotes the conversion of short-term to long-term object-recognition memory. Conversely RGS14 is enriched in CA2 pyramidal neurons and suppresses synaptic plasticity of these synapses and hippocampal-based learning and memory.
# Interactions
RGS14 has been shown to interact with:
- GNAI1 and
- GNAI3. | RGS14
Regulator of G-protein signaling 14 (RGS14) is a protein that in humans is encoded by the RGS14 gene.[1]
# Function
RGS14 is a member of the regulator of G protein signalling family. This protein contains one RGS domain, two Raf-like Ras-binding domains (RBDs), and one GoLoco motif. The protein attenuates the signaling activity of G-proteins by binding, through its GoLoco domain, to specific types of activated, GTP-bound G alpha subunits. Acting as a GTPase activating protein (GAP), the protein increases the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.[1]
Increasing the expression of the RGS14 protein in the V2 secondary visual cortex of mice promotes the conversion of short-term to long-term object-recognition memory.[2] Conversely RGS14 is enriched in CA2 pyramidal neurons and suppresses synaptic plasticity of these synapses and hippocampal-based learning and memory.[3]
# Interactions
RGS14 has been shown to interact with:
- GNAI1[4][5][6][7] and
- GNAI3.[4] | https://www.wikidoc.org/index.php/RGS14 | |
c24ef74f43c162b140f128d006ec493e50abfbcb | wikidoc | RGS17 | RGS17
Regulator of G-protein signaling 17 is a protein that in humans is encoded by the RGS17 gene.
# Function
This gene encodes a member of the regulator of G-protein signaling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region. The protein attenuates the signaling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal. Along with RGS4, RGS9 and RGS14, RGS17 plays an important role in termination of signalling by mu opioid receptors and development of tolerance to opioid analgesic drugs.
# Clinical significance
RGS17 is a putative lung cancer susceptibility gene in the lung cancer associated locus on chromosome 6q in humans. RGS17 is overexpressed in lung and prostate cancers, induces cAMP production, CREB phosphorylation and CREB responsive gene expression. Expression of RGS17 is required for maintenance of proliferation in lung tumor cell lines. | RGS17
Regulator of G-protein signaling 17 is a protein that in humans is encoded by the RGS17 gene.[1][2]
# Function
This gene encodes a member of the regulator of G-protein signaling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region. The protein attenuates the signaling activity of G-proteins by binding to activated, GTP-bound G alpha subunits and acting as a GTPase activating protein (GAP), increasing the rate of conversion of the GTP to GDP. This hydrolysis allows the G alpha subunits to bind G beta/gamma subunit heterodimers, forming inactive G-protein heterotrimers, thereby terminating the signal.[2] Along with RGS4, RGS9 and RGS14,[3][4] RGS17 plays an important role in termination of signalling by mu opioid receptors and development of tolerance to opioid analgesic drugs.[5][6]
# Clinical significance
RGS17 is a putative lung cancer susceptibility gene in the lung cancer associated locus on chromosome 6q in humans.[7] RGS17 is overexpressed in lung and prostate cancers, induces cAMP production, CREB phosphorylation and CREB responsive gene expression[2]. Expression of RGS17 is required for maintenance of proliferation in lung tumor cell lines.[8] | https://www.wikidoc.org/index.php/RGS17 | |
f06ba56bd5c30128be98759bdba2e25bef842485 | wikidoc | RGS19 | RGS19
Regulator of G-protein signaling 19 is a protein that in humans is encoded by the RGS19 gene.
G proteins mediate a number of cellular processes. The protein encoded by this gene belongs to the RGS (regulators of G-protein signaling) family and specifically interacts with G protein, GAI3. This protein is a guanosine triphosphatase-activating protein that functions to down-regulate Galpha i/Galpha q-linked signaling.
# Interactions
RGS19 has been shown to interact with GNAO1, GIPC1, OSTM1, GNAI1, GNAI3 and GNAZ. | RGS19
Regulator of G-protein signaling 19 is a protein that in humans is encoded by the RGS19 gene.[1][2]
G proteins mediate a number of cellular processes. The protein encoded by this gene belongs to the RGS (regulators of G-protein signaling) family and specifically interacts with G protein, GAI3. This protein is a guanosine triphosphatase-activating protein that functions to down-regulate Galpha i/Galpha q-linked signaling.[2][3]
# Interactions
RGS19 has been shown to interact with GNAO1,[4][5] GIPC1,[6] OSTM1,[7] GNAI1,[4][5] GNAI3[1][4][5] and GNAZ.[4][8] | https://www.wikidoc.org/index.php/RGS19 | |
be2023e3f4cdda7c7243c54dff2ca4083c48b3a7 | wikidoc | RGS20 | RGS20
Regulator of G-protein signaling 20 is a protein that in humans is encoded by the RGS20 gene.
Regulator of G protein signaling (RGS) proteins are regulatory and structural components of G protein-coupled receptor complexes. RGS proteins are GTPase-activating proteins for Gi (see GNAI1; MIM 139310) and Gq (see GNAQ; MIM 600998) class G-alpha proteins. They accelerate transit through the cycle of GTP binding and hydrolysis and thereby accelerate signaling kinetics and termination.
In melanocytic cells RGS20 gene expression may be regulated by MITF.
# Interactions
RGS20 has been shown to interact with GNAO1 and GNAZ. | RGS20
Regulator of G-protein signaling 20 is a protein that in humans is encoded by the RGS20 gene.[1][2][3]
Regulator of G protein signaling (RGS) proteins are regulatory and structural components of G protein-coupled receptor complexes. RGS proteins are GTPase-activating proteins for Gi (see GNAI1; MIM 139310) and Gq (see GNAQ; MIM 600998) class G-alpha proteins. They accelerate transit through the cycle of GTP binding and hydrolysis and thereby accelerate signaling kinetics and termination.[supplied by OMIM][3]
In melanocytic cells RGS20 gene expression may be regulated by MITF.[4]
# Interactions
RGS20 has been shown to interact with GNAO1[5] and GNAZ.[1][6] | https://www.wikidoc.org/index.php/RGS20 | |
e4b7b592b6dd39176251774c4401649d200b48fc | wikidoc | RHOT1 | RHOT1
Mitochondrial Rho GTPase 1 (MIRO1) is an enzyme that in humans is encoded by the RHOT1 gene on chromosome 17. As a Miro protein isoform, the protein facilitates mitochondrial transport by attaching the mitochondria to the motor/adaptor complex. Through its key role in mitochondrial transport, RHOT1 is involved in mitochondrial homeostasis and apoptosis, as well as Parkinson’s disease (PD) and cancer.
# Structure
In mammals, RHOT1 is one of two Miro isoforms. Both isoforms share a structure consisting of two EF-hand motifs linking two GTP-binding domains and a C-terminal transmembrane domain that attaches the protein to the outer mitochondrial membrane (OMM). The EF-hand motifs serve as binding sites for the adaptor protein Milton and the kinesin heavy chain. These domains can also bind calcium ions, and the binding results in a conformational change that dissociates the mitochondrial surface from kinesin.
# Function
RHOT1 is a member of the Rho GTPase family and one of two isoforms of the protein Miro: RHOT1 (Miro1) and RHOT2 (Miro2). Compared to the rest of the Rho GTPase family, the Miro isoforms are considered atypical due to their different regulation. Moreover, the Miro isoforms are only expressed in the mitochondria.
Miro associates with Milton (TRAK1/2) and the motor proteins kinesin and dynein to form the mitochondrial motor/adaptor complex. Miro functions to tether the complex to the mitochondrion while the complex transports the mitochondrion via microtubules within cells. Though Miro has been predominantly studied in neurons, the protein has also been observed to participate in the transport of mitochondria in lymphocytes toward inflamed endothelia.
The motor/adaptor complex is regulated by calcium ion levels. At high concentrations, calcium ions arrest mitochondrial transport by binding Miro, causing the complex to detach from the organelle. Considering that physiological factors such as activation of glutamate receptors in dendrites, action potentials in axons, and neuromodulators may elevate calcium ion levels, this regulatory mechanism likely serves to keep mitochondria in such areas to provide calcium ion buffering and active export and, thus, maintain homeostasis.
In addition, Miro regulates mitochondrial fusion and mitophagy in conjunction with mitofusin. According to one model, damaged mitochondria are sequestered from healthy mitochondria by the degradation of Miro and mitofusin. Miro degradation halts their movement while mitofusin degradation prevents them from fusing with healthy mitochondria, thus facilitating their clearance by autophagosomes.
Though the exact mechanisms remain to be elucidated, RHOT1 has been implicated in promoting caspase-dependent apoptosis.
# Clinical significance
Studies indicate that Miro may be involved in PD. In neurons, Miro interacts with two key proteins involved in PD, PINK1 and Parkin. Following depolarization of the mitochondria, PINK1 phosphorylates Miro at multiple sites, including S156, and Parkin ubiquitinates Miro, targeting it for proteasomal degradation. Degradation of Miro then halts mitochondrial transport.
Though the Rho GTPase family is closely associated with cancer progression, there are few studies demonstrating such association with the atypical Miro proteins. Nonetheless, RHOT1 has been implicated in pancreatic cancer as a tumor suppressor through its regulation of mitochondrial homeostasis and apoptosis. Thus, this protein could serve as a therapeutic target for cancer treatment.
# Model organisms
Model organisms have been used in the study of RHOT1 function. A conditional knockout mouse line, called Rhot1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and one significant abnormality was observed: no homozygous mutants survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.
# Interactions
RHOT1 has been shown to interact with:
- ALEX3,
- DISC1,
- Dynein,
- HUMMR,
- kinesin heavy chain (KHC),
- Mitofusin (MFN1/MFN2),
- Milton (TRAK1/TRAK2),
- Parkin,
- PINK1, and
- OGT. | RHOT1
Mitochondrial Rho GTPase 1 (MIRO1) is an enzyme that in humans is encoded by the RHOT1 gene on chromosome 17.[1][2] As a Miro protein isoform, the protein facilitates mitochondrial transport by attaching the mitochondria to the motor/adaptor complex.[3] Through its key role in mitochondrial transport, RHOT1 is involved in mitochondrial homeostasis and apoptosis, as well as Parkinson’s disease (PD) and cancer.[3][4][5]
# Structure
In mammals, RHOT1 is one of two Miro isoforms. Both isoforms share a structure consisting of two EF-hand motifs linking two GTP-binding domains and a C-terminal transmembrane domain that attaches the protein to the outer mitochondrial membrane (OMM).[3][6] The EF-hand motifs serve as binding sites for the adaptor protein Milton and the kinesin heavy chain.[7] These domains can also bind calcium ions, and the binding results in a conformational change that dissociates the mitochondrial surface from kinesin.[3][6]
# Function
RHOT1 is a member of the Rho GTPase family and one of two isoforms of the protein Miro: RHOT1 (Miro1) and RHOT2 (Miro2).[3][7] Compared to the rest of the Rho GTPase family, the Miro isoforms are considered atypical due to their different regulation.[5] Moreover, the Miro isoforms are only expressed in the mitochondria.[8]
Miro associates with Milton (TRAK1/2) and the motor proteins kinesin and dynein to form the mitochondrial motor/adaptor complex. Miro functions to tether the complex to the mitochondrion while the complex transports the mitochondrion via microtubules within cells.[3][4] Though Miro has been predominantly studied in neurons, the protein has also been observed to participate in the transport of mitochondria in lymphocytes toward inflamed endothelia.[7]
The motor/adaptor complex is regulated by calcium ion levels. At high concentrations, calcium ions arrest mitochondrial transport by binding Miro, causing the complex to detach from the organelle. Considering that physiological factors such as activation of glutamate receptors in dendrites, action potentials in axons, and neuromodulators may elevate calcium ion levels, this regulatory mechanism likely serves to keep mitochondria in such areas to provide calcium ion buffering and active export and, thus, maintain homeostasis.[3]
In addition, Miro regulates mitochondrial fusion and mitophagy in conjunction with mitofusin. According to one model, damaged mitochondria are sequestered from healthy mitochondria by the degradation of Miro and mitofusin. Miro degradation halts their movement while mitofusin degradation prevents them from fusing with healthy mitochondria, thus facilitating their clearance by autophagosomes.[3]
Though the exact mechanisms remain to be elucidated, RHOT1 has been implicated in promoting caspase-dependent apoptosis.[1]
# Clinical significance
Studies indicate that Miro may be involved in PD.[4] In neurons, Miro interacts with two key proteins involved in PD, PINK1 and Parkin.[3] Following depolarization of the mitochondria, PINK1 phosphorylates Miro at multiple sites, including S156, and Parkin ubiquitinates Miro, targeting it for proteasomal degradation.[3][4] Degradation of Miro then halts mitochondrial transport.[3]
Though the Rho GTPase family is closely associated with cancer progression, there are few studies demonstrating such association with the atypical Miro proteins. Nonetheless, RHOT1 has been implicated in pancreatic cancer as a tumor suppressor through its regulation of mitochondrial homeostasis and apoptosis. Thus, this protein could serve as a therapeutic target for cancer treatment.[5]
# Model organisms
Model organisms have been used in the study of RHOT1 function. A conditional knockout mouse line, called Rhot1tm1a(EUCOMM)Wtsi[13][14] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[15][16][17]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[11][18] Twenty six tests were carried out on mutant mice and one significant abnormality was observed: no homozygous mutants survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.[11]
# Interactions
RHOT1 has been shown to interact with:
- ALEX3,[3]
- DISC1,[8]
- Dynein,[3]
- HUMMR,[3]
- kinesin heavy chain (KHC),[3]
- Mitofusin (MFN1/MFN2),[3]
- Milton (TRAK1/TRAK2),[3]
- Parkin,[3]
- PINK1,[3] and
- OGT.[3] | https://www.wikidoc.org/index.php/RHOT1 | |
5cc46f76e17b6ce69c5ece12af574096064db7fc | wikidoc | RING1 | RING1
E3 ubiquitin-protein ligase RING1 is an enzyme that in humans is encoded by the RING1 gene.
# Function
This gene belongs to the RING finger family, members of which encode proteins characterized by a RING domain, a zinc-binding motif related to the zinc finger domain. The gene product can bind DNA and can act as a transcriptional repressor. It is associated with the multimeric polycomb group protein complex. The gene product interacts with the polycomb group proteins BMI1, EDR1, and CBX4, and colocalizes with these proteins in large nuclear domains. It interacts with the CBX4 protein via its glycine-rich C-terminal domain. The gene maps to the HLA class II region, where it is contiguous with the RING finger genes FABGL and HKE4.
# Interactions
RING1 has been shown to interact with CBX8, BMI1 and RYBP. | RING1
E3 ubiquitin-protein ligase RING1 is an enzyme that in humans is encoded by the RING1 gene.[1][2]
# Function
This gene belongs to the RING finger family, members of which encode proteins characterized by a RING domain, a zinc-binding motif related to the zinc finger domain. The gene product can bind DNA and can act as a transcriptional repressor. It is associated with the multimeric polycomb group protein complex. The gene product interacts with the polycomb group proteins BMI1, EDR1, and CBX4, and colocalizes with these proteins in large nuclear domains. It interacts with the CBX4 protein via its glycine-rich C-terminal domain. The gene maps to the HLA class II region, where it is contiguous with the RING finger genes FABGL and HKE4.[2]
# Interactions
RING1 has been shown to interact with CBX8,[3] BMI1[4][5] and RYBP.[6][7] | https://www.wikidoc.org/index.php/RING1 | |
78d863e861015c7652089a538fd0bbce2db9f2a2 | wikidoc | RIPK1 | RIPK1
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6. This protein belongs to the Receptor Interacting Protein (RIP) kinases family, which consists of 7 members, RIPK1 being the first member of the family.
RIPK1 is known to have function in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.
# Structure
RIPK1 protein is composed of 671 amino acids, and has a molecular weight of about 76 kDa. It contains a serine/threonine kinase domain (KD) in the 300 aa N-Terminus, a death domain (DD) in the 112 aa C-Terminus, and a central region between the KD and DD called intermediate domain (ID).
- The kinase domain plays different roles in cell survival and is important in necroptosis induction. RIP interacts with TRAF2 via the kinase domain. The KD can also interact with Necrostatin-1, which is an allosteric inhibitor of RIPK1 kinase activity. Overexpression of RIP lacking kinase activity can activate NF-kB.
- The death domain is homologous to the DD of other receptors such as Fas, TRAILR2 (DR5), TNFR1 and TRAILR1 (DR4), so it can bind to these receptors, as well as TRADD and FADD in the TNFR1 signalling complex. Overexpression of RIP can induce apoptosis and can activate NF-kB, but overexpression of the RIP death domain can block NF-kB activation by TNF-R1.
- The intermediate domain is important for NF-kB activation and (RHIM)-dependent signalling. Via the intermediate domain, RIP can interact with TRAF2, NEMO, RIPK3, ZBP1, OPTN and other small molecules and proteins, depending on cellular context.
# Function
Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPK1 is also activated in response to diverse stimuli.
The kinase domain, while important for necroptotic (programmed necrotic) functions, appears dispensable for pro-survival roles. Kinase activity of RIPK1 is also required for RIPK1-dependent apoptosis in conditions of IAP1/2 depletion, TAK1inhibition/depletion, RIPK3 depletion or MLKL depletion. Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is dependent on the generation of one or more specific C-terminal cleavage product(s) of RIPk1 upon stress.
## Role in cell survival
It has been shown that cell survival can be regulated through different RIPK1-mediated pathways that ultimately result in the expression of NF-kB, a protein complex known to regulate transcription of DNA and thus, related to survival processes.
### Receptor-mediated signalling
The best well-known pathway of NF-kB activation is that mediated by the death receptor TNFR1, which starts as in the necroptosis pathway with the assembly of TRADD, RIPK1, TRAF2 and clAP1 in the lipid rafts of the plasma membrane (complex I is formed). In survival signalling, RIPK1 is then polyubiquitinated, allowing NEMO (Necrosis Factor – kappa – B essential modulator) to bind to the IkB kinase or IKK complex. To activate IKK, TAB2 and TAB3 adaptor proteins recruit TAK1 or MEKK3, which phosphorylate the complex. This results in the phosphorylation of the NF-kB inhibitors by the activated IKK complex, which in turn triggers their polyubiquitination and posterior degradation in the 26S proteasome.
As a result, NF-kB can now migrate to the nucleus where it will control DNA transcription by binding itself to the promoters of specific genes. Some of those genes are thought to have anti-apoptotic properties as well as to promote proteasomal degradation of RIPK1, resulting in a self-regulatory cycle.
While being in complex I, RIPK1 has also been proved to play a role in the activation of MAP (mitogen-activated protein) kinases such as JNK, ERK and p38. In particular, JNK can be found in both cell death and survival pathways, with its role in the cell death process being suppressed by activated NF-kB.
Cell survival signalling can also be mediated by TLR-3 (toll-like receptors) and TLR-4. In here, RIPK1 is recruited to the receptors where it is phosphorylated and polyubiquitinated. This results in the recruit of the IKK complex activating proteins (TAK1, TAB1 and TAB2) so eventually NF-kB can now too migrate to the nucleus.
RIPK2 is involved in this TLR-mediated signalling, which suggests that there might be a regulation of cell survival or death (the two possible outcomes) through the mutual interaction between the two RIPK family members.
### Genotoxic stress-mediated activation
Upon DNA damage, RIPK1 mediates another NF-kB activation pathway where two simultaneous and exclusive processes occur. A pro-apoptotic complex is created while RIPK1 also mediates the interaction between PIDD, NEMO and IKK subunits that will eventually result in the IKK complex activation after interaction with ATM kinase (a DNA double-strand breaks stimulated protein). The interaction between RIPK1 and PIDD through their death domains is thought to promote cell survival to neutralize this pro-apoptotic complex.
### Others
It has been observed that RIPK1 may also interact with IGF-1R (insulin-like growth factor 1 receptor) to activate JNK (c-Jun N-terminal Kinases), it may be related to epidermal growth factor receptor signalling and it is largely expressed in glioblastoma cells, suggesting that RIPK1 is indeed involved in cell survival and proliferation processes.
## Role in cell death
### Necroptosis
Necroptosis is a programmed form of necrosis which starts with the assembly of the TNF (tumor necrosis factor) ligand to its membrane receptor, the TNFR (tumor necrosis factor receptor). Once activated, the intracellular domain of TNFR starts the recruitment of the adaptor TNFR-1-associated death domain protein TRADD, which recruits RIPK1 and two ubiquitin ligases: TRAF2 and clAP1. This complex is called the TNFR-1 complex I.
Complex-I is then modified by the IAPs (Inhibitor of Apoptosis Proteins) and the LUBAC (Linear Ubiquitination Assembly Complex), which generate linear ubiquitin linkages. The ubiquitination of complex-I leads to the activation of NF-κB , which in turn activates the expression of FLICE-like inhibitory protein FLIP. FLIP then binds to caspase-8, forming a caspase-8 FLIP heterodimer in the cytosol that disrupts the activity of caspase-8 and prevents caspase-8 mediated apoptosis from taking place.
The assembly of complex II-b then starts in the cytosol. This new complex contains the caspase-8 FLIP heterodimer as well as RIPK1 and RIPK3. Caspase inhibition within this complex allows RIPK1 and RIPK3 to autotransphosphorylate each other, forming another complex called the necrosome. The necrosome starts recruiting MLKL (Mixed Kinase Domain Like protein), which is phosphorylated by RIPK3 and immediately translocates to lipid rafts inside the plasma membrane. This leads to the formation of pores in the membrane, allowing the sodium influx to increase -and consequently the osmotic pressure-, which eventually causes cell membrane rupture.
### Apoptosis
The apoptotic extrinsic pathway starts with the formation of the TNFR-1 complex-I, which contains TRADD, RIPK1, and two ubiquitin ligases:TRAF2 and clAP1.
Unlike the necroptotic pathway, this pathway doesn’t include the inhibition of caspase-8. Thus, in absence of NF-κB function, FLIP is not produced, and therefore active caspase-8 assembles with FADD, RIPK1 and RIPK3 in the cytosol, forming what is known as complex IIa.
Caspase-8 activates Bid, a protein that binds to the mitochondrial membrane, allowing the release of intermembrane mitochondrial molecules such as cytocrome c. Cytocrome c then assembles with Apaf 1 and ATP molecules, forming a complex called apoptosome. The activation of caspase 3 and 9 by the apoptosome starts a proteolitic cascade that eventually leads to the degradation of organelles and proteins, and the fragmentation of the DNA, inducing apoptotic cell death.
# Neurodegenerative diseases
## Alzheimer's disease
Patients with Alzheimer's disease, a neurodegenerative disease characterized by a cognitive deterioration and a behavioural disorder, experience a chronic brain inflammation which leads to the atrophy of several brain regions.
A sign of this inflammation is an increased number of microglia, a type of glial cells located in the brain and the spinal cord. RIPK1 is known to appear in larger quantities in brains from those affected with AD. This enzyme regulates not only necroptosis, but cell inflammation as well, and as a result it is involved in the regulation of microglial functions, specially those associated with the appearance and development of neurodegenerative diseases such as AD.
## Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of motor neurons which leads to the progressive loss of mobility. Consequently, patients are unable to do any physical activity due to the atrophy of their muscles.
The optineurin gene (OPTN) and its mutation are known to be involved in ALS. When the organism loses OPTN, the dysmyelination of axons and its degeneration start. The degeneration of the axons is produced by several components from the Central Nervous System (CNS) including RIPK1 and another enzyme from the Receptor Interacting Protein kinases family, RIPK3, as well as other proteins such as MLKL.
Once RIPK1, RIPK3 and MLKL have contributed to the dysmyelination and the consequent degeneration of axons, the nerve impulse can't to go from one neuron to another due to the lack of myelin, which leads to the consequent mobility problems as the nerve impulse does not arrive to its final destination.
# Interactions
RIPK1 has been shown to interact with:
- BIRC2,
- BIRC3,
- CA11,
- CASP8,
- CFLAR,
- CRADD,
- RIPK2,
- RIPK3,
- RNF11,
- RNF216,
- SQSTM1,
- TNFRSF1A,
- TRADD,
- TRAF2,
- UBC.
- clAP1
- IAPs
- LUBAC
- IGF-1R
- FLIP
- MLKL | RIPK1
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6.[1][2][3] This protein belongs to the Receptor Interacting Protein (RIP) kinases family, which consists of 7 members, RIPK1 being the first member of the family.[4]
RIPK1 is known to have function in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.[5]
# Structure
RIPK1 protein is composed of 671 amino acids, and has a molecular weight of about 76 kDa. It contains a serine/threonine kinase domain (KD) in the 300 aa N-Terminus, a death domain (DD) in the 112 aa C-Terminus, and a central region between the KD and DD called intermediate domain (ID).
- The kinase domain plays different roles in cell survival and is important in necroptosis induction. RIP interacts with TRAF2 via the kinase domain. The KD can also interact with Necrostatin-1,[6] which is an allosteric inhibitor of RIPK1 kinase activity. Overexpression of RIP lacking kinase activity can activate NF-kB.
- The death domain is homologous to the DD of other receptors such as Fas, TRAILR2 (DR5), TNFR1 and TRAILR1 (DR4), so it can bind to these receptors, as well as TRADD and FADD in the TNFR1 signalling complex. Overexpression of RIP can induce apoptosis and can activate NF-kB, but overexpression of the RIP death domain can block NF-kB activation by TNF-R1.[7]
- The intermediate domain is important for NF-kB activation and (RHIM)-dependent signalling. Via the intermediate domain, RIP can interact with TRAF2, NEMO, RIPK3, ZBP1, OPTN[8] and other small molecules and proteins, depending on cellular context.
.
# Function
Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPK1 is also activated in response to diverse stimuli.[9]
The kinase domain, while important for necroptotic (programmed necrotic) functions, appears dispensable for pro-survival roles. Kinase activity of RIPK1 is also required for RIPK1-dependent apoptosis in conditions of IAP1/2 depletion, TAK1inhibition/depletion, RIPK3 depletion or MLKL depletion.[10][11] Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is dependent on the generation of one or more specific C-terminal cleavage product(s) of RIPk1 upon stress.
## Role in cell survival
It has been shown that cell survival can be regulated through different RIPK1-mediated pathways that ultimately result in the expression of NF-kB, a protein complex known to regulate transcription of DNA and thus, related to survival processes.[12]
### Receptor-mediated signalling
The best well-known pathway of NF-kB activation is that mediated by the death receptor TNFR1, which starts as in the necroptosis pathway with the assembly of TRADD, RIPK1, TRAF2 and clAP1 in the lipid rafts of the plasma membrane (complex I is formed). In survival signalling, RIPK1 is then polyubiquitinated, allowing NEMO (Necrosis Factor – kappa – B essential modulator) to bind to the IkB kinase or IKK complex.[13] To activate IKK, TAB2 and TAB3 adaptor proteins recruit TAK1 or MEKK3, which phosphorylate the complex. This results in the phosphorylation of the NF-kB inhibitors by the activated IKK complex, which in turn triggers their polyubiquitination and posterior degradation in the 26S proteasome.
As a result, NF-kB can now migrate to the nucleus where it will control DNA transcription by binding itself to the promoters of specific genes. Some of those genes are thought to have anti-apoptotic properties as well as to promote proteasomal degradation of RIPK1, resulting in a self-regulatory cycle.
While being in complex I, RIPK1 has also been proved to play a role in the activation of MAP (mitogen-activated protein) kinases such as JNK, ERK and p38. In particular, JNK can be found in both cell death and survival pathways, with its role in the cell death process being suppressed by activated NF-kB.[14]
Cell survival signalling can also be mediated by TLR-3 (toll-like receptors) and TLR-4. In here, RIPK1 is recruited to the receptors where it is phosphorylated and polyubiquitinated. This results in the recruit of the IKK complex activating proteins (TAK1, TAB1 and TAB2) so eventually NF-kB can now too migrate to the nucleus.
RIPK2 is involved in this TLR-mediated signalling, which suggests that there might be a regulation of cell survival or death (the two possible outcomes) through the mutual interaction between the two RIPK family members.[14][15]
### Genotoxic stress-mediated activation
Upon DNA damage, RIPK1 mediates another NF-kB activation pathway where two simultaneous and exclusive processes occur. A pro-apoptotic complex is created while RIPK1 also mediates the interaction between PIDD, NEMO and IKK subunits that will eventually result in the IKK complex activation after interaction with ATM kinase (a DNA double-strand breaks stimulated protein). The interaction between RIPK1 and PIDD through their death domains is thought to promote cell survival to neutralize this pro-apoptotic complex.[15]
### Others
It has been observed that RIPK1 may also interact with IGF-1R (insulin-like growth factor 1 receptor) to activate JNK (c-Jun N-terminal Kinases), it may be related to epidermal growth factor receptor signalling and it is largely expressed in glioblastoma cells, suggesting that RIPK1 is indeed involved in cell survival and proliferation processes.[14]
## Role in cell death
### Necroptosis
Necroptosis is a programmed form of necrosis which starts with the assembly of the TNF (tumor necrosis factor) ligand to its membrane receptor, the TNFR (tumor necrosis factor receptor). Once activated, the intracellular domain of TNFR starts the recruitment of the adaptor TNFR-1-associated death domain protein TRADD, which recruits RIPK1 and two ubiquitin ligases: TRAF2 and clAP1. This complex is called the TNFR-1 complex I.[16]
Complex-I is then modified by the IAPs (Inhibitor of Apoptosis Proteins) and the LUBAC (Linear Ubiquitination Assembly Complex), which generate linear ubiquitin linkages. The ubiquitination of complex-I leads to the activation of NF-κB , which in turn activates the expression of FLICE-like inhibitory protein FLIP. FLIP then binds to caspase-8, forming a caspase-8 FLIP heterodimer in the cytosol that disrupts the activity of caspase-8 and prevents caspase-8 mediated apoptosis from taking place.[17]
The assembly of complex II-b then starts in the cytosol. This new complex contains the caspase-8 FLIP heterodimer as well as RIPK1 and RIPK3. Caspase inhibition within this complex allows RIPK1 and RIPK3 to autotransphosphorylate each other, forming another complex called the necrosome.[18] The necrosome starts recruiting MLKL (Mixed Kinase Domain Like protein), which is phosphorylated by RIPK3 and immediately translocates to lipid rafts inside the plasma membrane. This leads to the formation of pores in the membrane, allowing the sodium influx to increase -and consequently the osmotic pressure-, which eventually causes cell membrane rupture.[18]
### Apoptosis
The apoptotic extrinsic pathway starts with the formation of the TNFR-1 complex-I, which contains TRADD, RIPK1, and two ubiquitin ligases:TRAF2 and clAP1.[19][16]
Unlike the necroptotic pathway, this pathway doesn’t include the inhibition of caspase-8. Thus, in absence of NF-κB function, FLIP is not produced, and therefore active caspase-8 assembles with FADD, RIPK1 and RIPK3 in the cytosol, forming what is known as complex IIa.[18]
Caspase-8 activates Bid, a protein that binds to the mitochondrial membrane, allowing the release of intermembrane mitochondrial molecules such as cytocrome c. Cytocrome c then assembles with Apaf 1 and ATP molecules, forming a complex called apoptosome. The activation of caspase 3 and 9 by the apoptosome starts a proteolitic cascade that eventually leads to the degradation of organelles and proteins, and the fragmentation of the DNA, inducing apoptotic cell death.
# Neurodegenerative diseases
## Alzheimer's disease
Patients with Alzheimer's disease, a neurodegenerative disease characterized by a cognitive deterioration and a behavioural disorder, experience a chronic brain inflammation which leads to the atrophy of several brain regions.[2]
A sign of this inflammation is an increased number of microglia, a type of glial cells located in the brain and the spinal cord. RIPK1 is known to appear in larger quantities in brains from those affected with AD.[20] This enzyme regulates not only necroptosis, but cell inflammation as well, and as a result it is involved in the regulation of microglial functions, specially those associated with the appearance and development of neurodegenerative diseases such as AD.[20]
## Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of motor neurons which leads to the progressive loss of mobility. Consequently, patients are unable to do any physical activity due to the atrophy of their muscles.[21]
The optineurin gene (OPTN) and its mutation are known to be involved in ALS. When the organism loses OPTN, the dysmyelination of axons and its degeneration start. The degeneration of the axons is produced by several components from the Central Nervous System (CNS) including RIPK1 and another enzyme from the Receptor Interacting Protein kinases family, RIPK3, as well as other proteins such as MLKL.[22]
Once RIPK1, RIPK3 and MLKL have contributed to the dysmyelination and the consequent degeneration of axons, the nerve impulse can't to go from one neuron to another due to the lack of myelin, which leads to the consequent mobility problems as the nerve impulse does not arrive to its final destination.[23]
# Interactions
RIPK1 has been shown to interact with:
- BIRC2,[24]
- BIRC3,[24]
- CA11,[25]
- CASP8,[24][26][27]
- CFLAR,[26][28]
- CRADD,[29][30]
- RIPK2,[14][15]
- RIPK3,[31][32]
- RNF11,[33]
- RNF216,[34]
- SQSTM1,[35]
- TNFRSF1A,[2][29][36][37][38][39]
- TRADD,[2]
- TRAF2,[2][40][41][42]
- UBC.[24][25][38][39][43]
- clAP1[19]
- IAPs[19]
- LUBAC[19]
- IGF-1R[14]
- FLIP[17]
- MLKL[44] | https://www.wikidoc.org/index.php/RIPK1 | |
5cfb63971e58039b7bfdc4d569fec3a450b058de | wikidoc | RIPK3 | RIPK3
Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the RIPK3 gene.
The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor.
# Interactions
RIPK3 has been shown to interact with RIPK1 to form an amyloid spine | RIPK3
Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the RIPK3 gene.[1][2][3][4]
The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor.[3]
# Interactions
RIPK3 has been shown to interact with RIPK1 to form an amyloid spine [1][4] | https://www.wikidoc.org/index.php/RIPK3 | |
1ae2c1e868f2b314a5b5aa45a61c54195aecb368 | wikidoc | RIPK5 | RIPK5
Dual serine/threonine and tyrosine protein kinase is an enzyme that in humans is encoded by the DSTYK gene.
This protein is also known as the Dusty protein kinase and the Receptor interacting protein 5 (RIP5).
This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. Multiple alternatively spliced transcript variants have been found, but the biological validity of some variants has not been determined.
In melanocytic cells RIPK5 gene expression may be regulated by MITF.
Mutations in this gene have been associated with hereditary spastic paraplegia type 23. | RIPK5
Dual serine/threonine and tyrosine protein kinase is an enzyme that in humans is encoded by the DSTYK gene.[1][2]
This protein is also known as the Dusty protein kinase and the Receptor interacting protein 5 (RIP5).
This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. Multiple alternatively spliced transcript variants have been found, but the biological validity of some variants has not been determined.[2]
In melanocytic cells RIPK5 gene expression may be regulated by MITF.[3]
Mutations in this gene have been associated with hereditary spastic paraplegia type 23.[4] | https://www.wikidoc.org/index.php/RIPK5 | |
72b659ab5f18ea980c7c46df429b14e6e31d6a36 | wikidoc | RMDN3 | RMDN3
Regulator of microtubule dynamics protein 3 (RMDN3), more commonly known as Protein tyrosine phosphatase interacting protein 51 (PTPIP51), is a protein that in humans is encoded by the RMDN3 gene on chromosome 15. This protein contributes to multiple biological functions, including cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis, and has been associated with numerous cancers.
# Structure
PTPIP51 contains two conserved domains, called conserved region 1 (CR1) and conserved region 2 (CR2), which serve as binding sites for 14-3-3 proteins. Close to these conserved domains are two tyrosine residues, tyrosine 53 and 158, which serve as phosphorylation sites for various kinases. In addition, PTPIP51 has a mitochondrial targeting sequence at its N-terminal which is responsible for inducing apoptosis, though some splicing variants lack this sequence. It also contains a 33-residue coiled coil domain at positions 92 – 124.
# Function
PTPIP51 is a member of the RMDN protein family and localizes to the outer mitochondrial membrane, cytoplasm, and nucleus. This protein is involved in cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis. These biological functions thus serve to facilitate mammalian development through processes such as placental villi formation and angiogenesis. In particular, it is expressed in differentiated cells and tissues, such as follicular and inter-follicular epidermis, epithelia, skeletal muscle, testis, and nervous tissue. PTPIP51 is also expressed differentially in neutrophils, but not other immune cells, and thus may partake in immune cell signaling and myeloid development by interacting with TCPTP and PTP1B. Its interactions with PTP1B, along with the proteins 14-3-3β, Raf-1, c-Src, PKA, and DAGKα, determine the mechanisms by which it influences the mitogen-activated protein kinase (MAPK) pathway. PTPIP51 has been observed to induce apoptosis by disrupting the mitochondrial membrane potential, resulting in the release of cytochrome c.
# Clinical significance
There is currently little known about the RMDN3 protein with respect to its clinical significance other than an apparent role in oncology. The main mechanism for the RMDN3 protein is its role as an apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Both the protein and mRNA of PTPIP51 have been implicated in various carcinomas, including prostate carcinoma (PCa), keratinocyte carcinoma, basal cell carcinomas, and squamous cell carcinomas. It is hypothesized that overexpression of PTPIP51 in PCa results from retrotransposon elements activated by CpG island hypomethylation, which has been observed in late prostate carcinogenesis. Moreover, the protein has been observed to interact with PTP1B to influence the MAPK pathway in acute myeloid leukemia. In addition to cancers, PTPIP51 has been associated with benign prostate hyperplasia (BPH) and, by extension, with BPH-related conditions, including aging and lower urinary tract dysfunction.
# Interactions
RMDN3 has been shown to interact with:
- PTP1B,
- TCPTP,
- c-Src,
- Raf-1,
- PKA,
- DAGKα, and
- VAPB. | RMDN3
Regulator of microtubule dynamics protein 3 (RMDN3), more commonly known as Protein tyrosine phosphatase interacting protein 51 (PTPIP51), is a protein that in humans is encoded by the RMDN3 gene on chromosome 15.[1][2] This protein contributes to multiple biological functions, including cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis, and has been associated with numerous cancers.[3][4][5]
# Structure
PTPIP51 contains two conserved domains, called conserved region 1 (CR1) and conserved region 2 (CR2), which serve as binding sites for 14-3-3 proteins. Close to these conserved domains are two tyrosine residues, tyrosine 53 and 158, which serve as phosphorylation sites for various kinases.[4] In addition, PTPIP51 has a mitochondrial targeting sequence at its N-terminal which is responsible for inducing apoptosis, though some splicing variants lack this sequence.[1][6] It also contains a 33-residue coiled coil domain at positions 92 – 124.[1]
# Function
PTPIP51 is a member of the RMDN protein family and localizes to the outer mitochondrial membrane, cytoplasm, and nucleus.[1] This protein is involved in cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis.[3][4] These biological functions thus serve to facilitate mammalian development through processes such as placental villi formation and angiogenesis.[3][6] In particular, it is expressed in differentiated cells and tissues, such as follicular and inter-follicular epidermis, epithelia, skeletal muscle, testis, and nervous tissue.[3][6] PTPIP51 is also expressed differentially in neutrophils, but not other immune cells, and thus may partake in immune cell signaling and myeloid development by interacting with TCPTP and PTP1B.[6] Its interactions with PTP1B, along with the proteins 14-3-3β, Raf-1, c-Src, PKA, and DAGKα, determine the mechanisms by which it influences the mitogen-activated protein kinase (MAPK) pathway.[4] PTPIP51 has been observed to induce apoptosis by disrupting the mitochondrial membrane potential, resulting in the release of cytochrome c.[7]
# Clinical significance
There is currently little known about the RMDN3 protein with respect to its clinical significance other than an apparent role in oncology. The main mechanism for the RMDN3 protein is its role as an apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[8] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Both the protein and mRNA of PTPIP51 have been implicated in various carcinomas, including prostate carcinoma (PCa), keratinocyte carcinoma, basal cell carcinomas, and squamous cell carcinomas.[3][5][6] It is hypothesized that overexpression of PTPIP51 in PCa results from retrotransposon elements activated by CpG island hypomethylation, which has been observed in late prostate carcinogenesis.[3] Moreover, the protein has been observed to interact with PTP1B to influence the MAPK pathway in acute myeloid leukemia.[4] In addition to cancers, PTPIP51 has been associated with benign prostate hyperplasia (BPH) and, by extension, with BPH-related conditions, including aging and lower urinary tract dysfunction.[3]
# Interactions
RMDN3 has been shown to interact with:
- PTP1B,[3][4]
- TCPTP,[3][4]
- c-Src,[3][4]
- 14-3-3β,[4]
- 14-3-3γ,[4]
- Raf-1,[4]
- PKA,[4]
- DAGKα,[4] and
- VAPB.[9] | https://www.wikidoc.org/index.php/RMDN3 | |
94a64673a70514e0df4a5306856ae528106e3542 | wikidoc | RNF10 | RNF10
RING finger protein 10 is a protein that in humans is encoded by the RNF10 gene.
# Function
The protein encoded by this gene contains a ring finger motif, which is known to be involved in protein-protein interactions. The specific function of this protein has not yet been determined. EST data suggests the existence of multiple alternatively spliced transcript variants, however, their full length nature is not known.
# Model organisms
Model organisms have been used in the study of RNF10 function. A conditional knockout mouse line, called Rnf10tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice and five significant abnormalities were observed. Homozygous mutant animals displayed increased chromosomal stability in a micronucleus test. Females also had increased body weight, an increased amount of total body fat and an abnormal complete blood count. Males additionally displayed an increase in eating behavior. | RNF10
RING finger protein 10 is a protein that in humans is encoded by the RNF10 gene.[1]
# Function
The protein encoded by this gene contains a ring finger motif, which is known to be involved in protein-protein interactions. The specific function of this protein has not yet been determined. EST data suggests the existence of multiple alternatively spliced transcript variants, however, their full length nature is not known.[1]
# Model organisms
Model organisms have been used in the study of RNF10 function. A conditional knockout mouse line, called Rnf10tm1a(KOMP)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty two tests were carried out on mutant mice and five significant abnormalities were observed.[8] Homozygous mutant animals displayed increased chromosomal stability in a micronucleus test. Females also had increased body weight, an increased amount of total body fat and an abnormal complete blood count. Males additionally displayed an increase in eating behavior.[8] | https://www.wikidoc.org/index.php/RNF10 | |
1387485b1ea46636550961c7a7b1df38231bb424 | wikidoc | ROBO1 | ROBO1
Roundabout homolog 1 is a protein that in humans is encoded by the ROBO1 gene.
# Function
Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline]. In Drosophila, the roundabout gene, a member of the immunoglobulin gene superfamily, encodes an integral membrane protein that is both an axon guidance receptor and a cell adhesion receptor. This receptor is involved in the decision by axons to cross the central nervous system midline. The protein encoded by this gene is structurally similar to the Drosophila roundabout protein. Two transcript variants encoding different isoforms have been found for this gene.
# Clinical significance
ROBO1 was implicated in communication disorder based on a Finnish pedigree with severe dyslexia. Analyses revealed a translocation had occurred disrupting ROBO1. Study of the phonological memory component of the language acquisition system suggests that ROBO1 polymorphisms are associated with functioning in this system. | ROBO1
Roundabout homolog 1 is a protein that in humans is encoded by the ROBO1 gene.[1][2][3]
# Function
Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline]. In Drosophila, the roundabout gene, a member of the immunoglobulin gene superfamily, encodes an integral membrane protein that is both an axon guidance receptor and a cell adhesion receptor. This receptor is involved in the decision by axons to cross the central nervous system midline. The protein encoded by this gene is structurally similar to the Drosophila roundabout protein. Two transcript variants encoding different isoforms have been found for this gene.[3]
# Clinical significance
ROBO1 was implicated in communication disorder based on a Finnish pedigree with severe dyslexia. Analyses revealed a translocation had occurred disrupting ROBO1.[4] Study of the phonological memory component of the language acquisition system suggests that ROBO1 polymorphisms are associated with functioning in this system.[5] | https://www.wikidoc.org/index.php/ROBO1 | |
b3601dba5fa4425eefdc4ea1f5455b15e885c41c | wikidoc | ROCK1 | ROCK1
ROCK1 is a protein serine/threonine kinase also known as rho-associated, coiled-coil-containing protein kinase 1. Other common names are ROKβ and P160ROCK. ROCK1 is a major downstream effecter of the small GTPase RhoA and is a regulator of the actomyosin cytoskeleton which promotes contractile force generation. ROCK1 plays a role in cancer and in particular cell motility, metastasis, and angiogenesis.
# Gene and expression
ROCK1 is also the name of the gene that encodes the protein ROCK1, a serine/threonine kinase. ROCK1 is activated when bound to the GTP-bound form of RhoA. The human ROCK1 gene is located on human chromosome 18 with specific location of 18q11.1. The location of the base pair starts at 18,529,703 and ends at 18,691,812 bp and translates into 1354 amino acids.
ROCK1 has a ubiquitous tissue distribution, but subcellularly it is thought to colocalize with the centrosomes. This is consistent with its function as a key modulator of cell motility, tumor cell invasion, and actin cytoskeleton organization. In rats, ROCK1 is expressed in the lung, liver, spleen, kidney, and testis.
# Structure and regulation
The ROCK1 structure is a serine/threonine kinase with molecular weight of 158 kDa. It is a homodimer composed of a catalytic kinase domain (residues76-338) located at the amino or N-terminus of the protein, a coiled-coil region (residues 425-1100) containing the Rho-binding domain, and a pleckstrin-homology domain (residues 1118-1317) with a cysteine-rich domain. When a substrate is absent, ROCK1 is an autoinhibited loop structure. Enzyme activity of ROCK1 is inhibited when the pleckstrin-homology and Rho-binding domains in the C-terminus independently bind to the N-terminus kinase domain. When a substrate such as GTP-bound RhoA binds to the Rho-binding region of the coiled-coil domain, the interactions between the N-terminus and the C-terminus are disrupted, thus activating the protein. Cleavage of the C-terminal inhibitory domain by caspase-3 during apoptosis can also activate the kinase.
This view of autoinhibition released by RhoA binding has been challenged by low resolution electron microscopy data showing ROCK to be a constitutive linear dimer 120 nm in length. According to this new data ROCK does not need to be activated by RhoA or phosphorylation because it is always active, and whether ROCK will phosphorylate its substrates (e.g. myosin regulatory light chain) depends only on their subcellular localization.
There is one other isoform of ROCK known as ROCK2. ROCK2 is located at 2p24 and is highly homologous with ROCK1 with an overall amino acid sequence identity of 65%. The identity in the Rho-binding domain is 58% and approximately 92% in the kinase domain. The ROCK isoforms are encoded by two different identified genes and are ubiquitously expressed.
GTPase-RhoA binding can increase the activity of ROCK1 by 1.5-2-fold. Without RhoA binding, lipids such as arachidonic acid or sphingosine phosphorylcholine can increase ROCK1 activity 5- to 6-fold. These two lipids interact with the pleckstrin-homology domain, thus disrupting its ability to inhibit ROCK1. G-protein RhoE binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. Small G-proteins, Gem and Rad, have been shown to bind and inhibit ROCK1 function, but their mechanism of action is unclear.
# Substrates and interactions
ROCK1 phosphorylation sites are at RXXS/T or RXS/T. More than 15 ROCK1 substrates have been identified and activation from these substrates most often leads to actin filament formation and cytoskeleton rearrangements.
MYPT-1 is involved in a pathway for smooth muscle contraction. When ROCK1 is activated by binding of GTPase RhoA it produces multiple signaling cascades. For example, RhoA is one of the downstream signaling cascades activated by vascular endothelial growth factor (VEGF). ROCK1 acts as a negative regulator of VEGF endothelial cell activation and angiogensis. ROCK1 activation by RhoA also promotes stabilization of F-actin, phosphorylation of regulatory myosin light chain (MLC) and an increase in contractility, which plays a crucial role in tumor cell migration and metastasis. This activated ROCK1 also activates LIM kinase, which, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. This depolymerization results in stabilization of actin filaments and decreased branching which promotes contraction.
Cardiac troponin is another ROCK1 substrate that upon phosphrylation causes reduction in tension in cardiac myocytes. ROCK1 also acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability.
# Function
ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and cell polarity. These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility. These functions are activated by phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A.
Additionally, ROCK1 phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. It is also required for centrosome positioning and centrosome-dependent exit from mitosis.
# Interactions
ROCK1 has been shown to interact with:
- LIMK1,
- MLC,
- MYPT1,
- PFN2, and
- RHOA.
# Clinical significance
In humans, the main function of ROCK1 is actomyosin contractility. As mentioned before, this contributes to many proximal progresses such as regulation of morphology, motility, and cell–cell and cell–matrix adhesion. In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation. Given this diverse range of functions is not surprising that ROCK1 has been implicated in numerous aspects of cancer.
## Role in cancer
Recent studies have explored the role of ROCK1 in cancer with particular attention focused on cell motility, metastasis, and angiogenesis. Rho GTPases such as RhoA are highly involved in morphologic changes in cells. When a tumor progresses from invasive to metastatic form it requires that they undergo these dramatic morphologic changes. Therefore, increased expression of RhoA and its downstream effector ROCK1 is often observed in human cancers. These cancers are typically more invasive and metastatic phenotypes.
## Angiogenesis
Increased expression of RhoA and ROCK1 in endothelial cell migration pathways can cause an increase in angiogenesis and metastatic behavior in tumor cells. It has been suggested that ROCK1 either regulates the expression of angiogenic factors or ROCK1 activation facilitates angiogenesis by increasing the plasticity of the tumor. By reducing the strength of cell-cell interactions and aiding the movement of tumor cells, ROCK1 may enable endothelial cells to penetrate the tumor mass more easily.
## Breast cancer
Overexpression of ROCK1 and RhoA is often seen in breast cancer. Activated ROCK1 phosphorylates MLC involved in actin-myosin contractility. RhoA also activates focal adhesion kinase activity. Together, these two pathways create the motile and invasive phenotype of cancer cells. Breast cancers often contain regions of reduced O2 which increases the activity of hypoxia-inducible factors (HIFs). HIFs have been shown to activate transcription of RhoA and ROCK1 leading to cytoskeletoal changes that underlie the invasive cancer cell phenotype.
## ROCK1 inhibitors in cancer therapy
ROCK1 inhibitors might be used in cancer therapy for:
- targeting of stromal rather than tumor cells
- concomitant blocking of ROCK and proteasome activity in K‐Ras‐driven lung cancers
- treating haematological malignancies such as chronic myelogenous leukemia (CML)
ROCK1 inhibition for cancer treatment has not been approved for standard therapy use. Y27632 and Fasudil are examples of ROCK1 inhibitors. Both inhibit ROCK1 by competing with ATP for the kinase activation site. Experiments with Y27632 show it is a promising candidate as a therapeutic antihypertensive agent. Fasudil has been used to characterize the role of ROCK1 in vascular function in clinical studies and has been approved for use in Japan for treatment of cerebral vasospasm following subarachnoid hemorrhage.
## Other diseases
The ROCK1 signaling plays an important role in many diseases including diabetes, neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), and pulmonary hypertension. | ROCK1
ROCK1 is a protein serine/threonine kinase also known as rho-associated, coiled-coil-containing protein kinase 1. Other common names are ROKβ and P160ROCK. ROCK1 is a major downstream effecter of the small GTPase RhoA and is a regulator of the actomyosin cytoskeleton which promotes contractile force generation.[1] ROCK1 plays a role in cancer and in particular cell motility, metastasis, and angiogenesis.[1]
# Gene and expression
ROCK1 is also the name of the gene that encodes the protein ROCK1, a serine/threonine kinase. ROCK1 is activated when bound to the GTP-bound form of RhoA. The human ROCK1 gene is located on human chromosome 18 with specific location of 18q11.1.[2] The location of the base pair starts at 18,529,703 and ends at 18,691,812 bp and translates into 1354 amino acids.[3]
ROCK1 has a ubiquitous tissue distribution, but subcellularly it is thought to colocalize with the centrosomes. This is consistent with its function as a key modulator of cell motility, tumor cell invasion, and actin cytoskeleton organization.[3] In rats, ROCK1 is expressed in the lung, liver, spleen, kidney, and testis.[4][5][6]
# Structure and regulation
The ROCK1 structure is a serine/threonine kinase with molecular weight of 158 kDa.[3] It is a homodimer composed of a catalytic kinase domain (residues76-338)[7] located at the amino or N-terminus of the protein, a coiled-coil region (residues 425-1100)[7] containing the Rho-binding domain, and a pleckstrin-homology domain (residues 1118-1317)[7] with a cysteine-rich domain. When a substrate is absent, ROCK1 is an autoinhibited loop structure. Enzyme activity of ROCK1 is inhibited when the pleckstrin-homology and Rho-binding domains in the C-terminus independently bind to the N-terminus kinase domain. When a substrate such as GTP-bound RhoA binds to the Rho-binding region of the coiled-coil domain, the interactions between the N-terminus and the C-terminus are disrupted, thus activating the protein. Cleavage of the C-terminal inhibitory domain by caspase-3 during apoptosis can also activate the kinase.[8]
This view of autoinhibition released by RhoA binding has been challenged by low resolution electron microscopy data showing ROCK to be a constitutive linear dimer 120 nm in length.[9] According to this new data ROCK does not need to be activated by RhoA or phosphorylation because it is always active, and whether ROCK will phosphorylate its substrates (e.g. myosin regulatory light chain) depends only on their subcellular localization.[9]
There is one other isoform of ROCK known as ROCK2. ROCK2 is located at 2p24 and is highly homologous with ROCK1 with an overall amino acid sequence identity of 65%.[7] The identity in the Rho-binding domain is 58%[7] and approximately 92%[7] in the kinase domain. The ROCK isoforms are encoded by two different identified genes and are ubiquitously expressed.[7]
GTPase-RhoA binding can increase the activity of ROCK1 by 1.5-2-fold.[10] Without RhoA binding, lipids such as arachidonic acid or sphingosine phosphorylcholine can increase ROCK1 activity 5- to 6-fold.[10][11] These two lipids interact with the pleckstrin-homology domain, thus disrupting its ability to inhibit ROCK1.[12] G-protein RhoE binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. Small G-proteins, Gem and Rad, have been shown to bind and inhibit ROCK1 function, but their mechanism of action is unclear.[7]
# Substrates and interactions
ROCK1 phosphorylation sites are at RXXS/T or RXS/T.[7] More than 15 ROCK1 substrates have been identified and activation from these substrates most often leads to actin filament formation and cytoskeleton rearrangements.[7]
MYPT-1 is involved in a pathway for smooth muscle contraction. When ROCK1 is activated by binding of GTPase RhoA it produces multiple signaling cascades. For example, RhoA is one of the downstream signaling cascades activated by vascular endothelial growth factor (VEGF). ROCK1 acts as a negative regulator of VEGF endothelial cell activation and angiogensis.[13] ROCK1 activation by RhoA also promotes stabilization of F-actin, phosphorylation of regulatory myosin light chain (MLC) and an increase in contractility, which plays a crucial role in tumor cell migration and metastasis.[14] This activated ROCK1 also activates LIM kinase, which, phosphorylates cofilin, inhibiting its actin-depolymerizing activity.[15] This depolymerization results in stabilization of actin filaments and decreased branching which promotes contraction.
Cardiac troponin is another ROCK1 substrate that upon phosphrylation causes reduction in tension in cardiac myocytes.[7] ROCK1 also acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability.
# Function
ROCK1 has a diverse range of functions in the body. It is a key regulator of actin-myosin contraction, stability, and cell polarity.[13] These contribute to many progresses such as regulation of morphology, gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation.[1] Other functions involve smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility. These functions are activated by phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A.[13]
Additionally, ROCK1 phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing.[13] It is also required for centrosome positioning and centrosome-dependent exit from mitosis.[13]
# Interactions
ROCK1 has been shown to interact with:
- LIMK1,[1]
- MLC,[1]
- MYPT1,[1]
- PFN2,[16] and
- RHOA.[17][18][19]
# Clinical significance
In humans, the main function of ROCK1 is actomyosin contractility. As mentioned before, this contributes to many proximal progresses such as regulation of morphology, motility, and cell–cell and cell–matrix adhesion.[1] In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation.[1] Given this diverse range of functions is not surprising that ROCK1 has been implicated in numerous aspects of cancer.[1]
## Role in cancer
Recent studies have explored the role of ROCK1 in cancer with particular attention focused on cell motility, metastasis, and angiogenesis.[1] Rho GTPases such as RhoA are highly involved in morphologic changes in cells. When a tumor progresses from invasive to metastatic form it requires that they undergo these dramatic morphologic changes. Therefore, increased expression of RhoA and its downstream effector ROCK1 is often observed in human cancers. These cancers are typically more invasive and metastatic phenotypes.[20]
## Angiogenesis
Increased expression of RhoA and ROCK1 in endothelial cell migration pathways can cause an increase in angiogenesis and metastatic behavior in tumor cells.[20] It has been suggested that ROCK1 either regulates the expression of angiogenic factors or ROCK1 activation facilitates angiogenesis by increasing the plasticity of the tumor. By reducing the strength of cell-cell interactions and aiding the movement of tumor cells, ROCK1 may enable endothelial cells to penetrate the tumor mass more easily.[20]
## Breast cancer
Overexpression of ROCK1 and RhoA is often seen in breast cancer.[21] Activated ROCK1 phosphorylates MLC involved in actin-myosin contractility.[21] RhoA also activates focal adhesion kinase activity. Together, these two pathways create the motile and invasive phenotype of cancer cells. Breast cancers often contain regions of reduced O2 which increases the activity of hypoxia-inducible factors (HIFs). HIFs have been shown to activate transcription of RhoA and ROCK1 leading to cytoskeletoal changes that underlie the invasive cancer cell phenotype.[21]
## ROCK1 inhibitors in cancer therapy
ROCK1 inhibitors might be used in cancer therapy for:
- targeting of stromal rather than tumor cells[7]
- concomitant blocking of ROCK and proteasome activity in K‐Ras‐driven lung cancers [7]
- treating haematological malignancies such as chronic myelogenous leukemia (CML)[7]
ROCK1 inhibition for cancer treatment has not been approved for standard therapy use. Y27632 and Fasudil are examples of ROCK1 inhibitors. Both inhibit ROCK1 by competing with ATP for the kinase activation site. Experiments with Y27632 show it is a promising candidate as a therapeutic antihypertensive agent.[7] Fasudil has been used to characterize the role of ROCK1 in vascular function in clinical studies and has been approved for use in Japan for treatment of cerebral vasospasm following subarachnoid hemorrhage.[7]
## Other diseases
The ROCK1 signaling plays an important role in many diseases including diabetes, neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis (ALS),[22] and pulmonary hypertension.[23] | https://www.wikidoc.org/index.php/ROCK1 | |
99529f55938da20bd247a979163549fbc6c48d53 | wikidoc | RPAP2 | RPAP2
RNA polymerase II associated protein 2, also known as RPAP2, is a human gene.
# Model organisms
Model organisms have been used in the study of RPAP2 function. A conditional knockout mouse line, called Rpap2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals. | RPAP2
RNA polymerase II associated protein 2, also known as RPAP2, is a human gene.[1]
# Model organisms
Model organisms have been used in the study of RPAP2 function. A conditional knockout mouse line, called Rpap2tm1a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[4] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[4] | https://www.wikidoc.org/index.php/RPAP2 | |
359e7e5a74f143dbc8152852fe50c3ed5fca45ca | wikidoc | RPE65 | RPE65
Retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase, is an enzyme of the vertebrate visual cycle that is encoded in humans by the RPE65 gene. RPE65 is expressed in the retinal pigment epithelium (RPE, a layer of epithelial cells that nourish the photoreceptor cells) and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction. 11-cis-retinol is then used in visual pigment regeneration in photoreceptor cells. RPE65 belongs to the carotenoid oxygenase family of enzymes.
# Function
RPE65 is a critical enzyme in the vertebrate visual cycle found in both rods and cones. The photoisomerization of 11-cis-retinal to all-trans-retinal initiates the phototransduction pathway through which the brain detects light. All-trans-retinol is not photoactive and therefore must be reconverted to 11-cis-retinal before it can recombine with opsin to form an active visual pigment. RPE65 reverses the photoisomerization by converting an all-trans-retinyl ester to 11-cis-retinol. Most commonly, the ester substrate is retinyl palmitate. The other enzymes of the visual cycle complete the reactions necessary to oxidize and esterify all-trans-retinol to a retinyl ester (RPE65's substrate) and to oxidize 11-cis-retinol to 11-cis-retinal (the required photoactive visual pigment component).
RPE65 is also referred to as retinol isomerase or retinoid isomerase, owing to past debates about the enzyme's substrate and whether it was involved in ester hydrolysis.
# Structure
RPE65 is a dimer of two identical, enzymatically independent subunits. The active site of each subunit has a seven-bladed beta-propeller structure with four histidines that hold an iron(II) cofactor. This structural motif is common across the studied members of the carotenoid oxygenase family of enzymes. RPE65 is strongly associated with the membrane of the smooth endoplasmic reticulum in RPE cells.
## Active site structure
The active site of each RPE65 active site contains an Fe(II) cofactor bound by four histidines (His180, His241, His313, and His527), each contributed by a separate blade on the beta-propeller structure. Three of the four histidines are coordinated to nearby glutamic acid residues (Glu148, Glu417, and Glu469), which are thought to help position the histidines to bind the iron cofactor in an octahedral geometry. Phe103, Thr147, and Glu148 surround the active site where they help stabilize the carbocation intermediate and increase the stereoselectivity of RPE65 for 11-cis-retinol over 13-cis-retinol.
Reactants and products likely enter and leave the active site through a hydrophobic tunnel which is thought to open into the lipid membrane for direct lipid substrate absorption. A second, smaller tunnel also reaches the active site and may serve as a pathway for water, but is too narrow to transport the retinoid reactants and products.
## Membrane interactions
RPE65 is strongly associated with the membrane of the sER. sER is abnormally abundant in RPE cells due to their role in processing lipidic retinoids. Structural studies indicate that RPE65 is partially imbedded in the sER membrane via interactions between its hydrophobic face and the interior of the lipid membrane. This is supported by the need for detergent to solubilize RPE65. A major portion of RPE65’s hydrophobic face, residues 109-126, forms an amphipathic alpha helix that likely contributes to the protein’s membrane affinity. Additionally, Cys112 is palmitoylated in native RPE65, further supporting the theory that the hydrophobic face of RPE65 is imbedded in the membrane.
The hydrophobic face contains the entrance to the large tunnel that leads to the enzyme’s active site. The presence of this channel on the hydrophobic face combined with RPE65’s demonstrated ability to absorb substrate direction from the lipid bilayer is consistent with RPE65 being partially embedded in the membrane.
## Conservation
RPE65 has been isolated from a wide range of vertebrates including zebra fish, chicken, mice, frogs, and humans. Its structure is highly conserved between species, particularly in the beta-propeller and likely membrane bound regions. The amino acid sequences of human and bovine RPE65 differ by less than 1%. The histidine residues of the beta-propeller structure and the bound iron(II) cofactor are 100% conserved across studied RPE65 orthologs and other members of the carotenoid oxygenase family.
## Soluble RPE65 (sRPE65)
Previously, it was proposed that RPE65 exists in two, interconverted forms: membrane bound mRPE65 and soluble sRPE65. This theory suggested that the reversible conversion of sRPE65 to mRPE65 by palmitoylation at Cys231, Cys329, and Cys330 played a role in regulating the retinoid cycle and endowing mRPE65 with its membrane affinity. However, crystallographic studies of RPE65 have demonstrated that these residues are neither palmitoylated nor surface facing. New studies have also failed to confirm the presence of abundant soluble RPE65. Thus, this theory has been largely abandoned.
# Mechanism
RPE65 catalyzes the conversion of all-trans-retinyl ester to 11-cis-retinol through a proposed SN1 O-alkyl bond cleavage. RPE65’s combination of an O-alkyl ester cleavage, geometric isomerization, and water addition is currently thought to be unique in biology. However, O-alkyl ester cleavage reactions with similarly stabilized carbocation intermediates are used by organic chemists.
## O-Alkyl cleavage
The O-alkyl cleavage of the ester bond, assisted by an Fe(II) cofactor, creates a carbocation intermediate that is stabilized by the conjugated polyene chain. The delocalization of the carbocation reduces the bond order of the polyene chain, thereby reducing the activation energy of the trans-to-cis isomerization. Phe103 and Thr178 additionally stabilize the isomerized carbocation and are thought to be responsible for the stereoselectivity of the enzyme. After isomerization, a nucleophilic attack by water at C15 restores the conjugation of the polyene chain and completes the ester bond cleavage.
## Alternate SN2 mechanism
Nearly all other biochemical ester hydrolysis reactions occur through SN2 reaction at the acyl carbon. However, isotope labeling studies have demonstrated that the oxygen on the final 11-cis-retinol product of RPE65 originates from the solvent rather than the reacting ester, supporting the O-alkyl cleavage mechanism. Additionally, an SN2 ester hydrolysis reaction mechanism would rely on a separate, unfavorable SN2 attack at electron rich C11 by some nucleophile - most likely a cystine residue - to complete the isomerization portion of the reaction. Not only is nucleophilic attack of an alkene energetically unfavorable, but the active site region is lacking cystine residues to act as the nucleophile.
# Clinical significance
Mutations in this gene have been associated with Leber's congenital amaurosis type 2 (LCA2) and retinitis pigmentosa (RP). RPE65 mutations are the most commonly detected mutations in LCA patients in Denmark. The vast majority of RPE65 mutations in patients with LCA2 and RP occur in the beta-propeller regime and are believed to inhibit proper protein folding and iron cofactor binding. Particularly common propeller mutation sites are Tyr368 and His182. Substitution at Arg91 is also common and have been shown to impact RPE65 membrane interactions and substrate uptake.
Though complete loss of function is associated with diseases such as LCA and RP, partial inhibition of RPE65 has been proposed as a treatment for age-related macular degeneration (AMD). All-trans-retinylamine (Ret-NH2) and emixustat have both been shown to competitively inhibit RPE65. Emixustat is currently undergoing FDA phase 3 clinical trials as a therapy for AMD.
Jean Bennett and Katherine A. High's work with the RPE65 mutation has reversed an inherited form of blindness. They received the first FDA approval of a gene therapy for a genetic disease. For this, in 2018, they were named as one of three finalists for Sanford Health's $1 million Lorraine Cross Award for innovation in science and medicine. | RPE65
Retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase, is an enzyme of the vertebrate visual cycle that is encoded in humans by the RPE65 gene.[1][2] RPE65 is expressed in the retinal pigment epithelium (RPE, a layer of epithelial cells that nourish the photoreceptor cells) and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction.[3] 11-cis-retinol is then used in visual pigment regeneration in photoreceptor cells.[4][5] RPE65 belongs to the carotenoid oxygenase family of enzymes.[4]
# Function
RPE65 is a critical enzyme in the vertebrate visual cycle found in both rods and cones.[6] The photoisomerization of 11-cis-retinal to all-trans-retinal initiates the phototransduction pathway through which the brain detects light. All-trans-retinol is not photoactive and therefore must be reconverted to 11-cis-retinal before it can recombine with opsin to form an active visual pigment.[4][7] RPE65 reverses the photoisomerization by converting an all-trans-retinyl ester to 11-cis-retinol. Most commonly, the ester substrate is retinyl palmitate. The other enzymes of the visual cycle complete the reactions necessary to oxidize and esterify all-trans-retinol to a retinyl ester (RPE65's substrate) and to oxidize 11-cis-retinol to 11-cis-retinal (the required photoactive visual pigment component).[4][5]
RPE65 is also referred to as retinol isomerase or retinoid isomerase, owing to past debates about the enzyme's substrate and whether it was involved in ester hydrolysis.[5]
# Structure
RPE65 is a dimer of two identical, enzymatically independent subunits. The active site of each subunit has a seven-bladed beta-propeller structure with four histidines that hold an iron(II) cofactor.[5][8] This structural motif is common across the studied members of the carotenoid oxygenase family of enzymes. RPE65 is strongly associated with the membrane of the smooth endoplasmic reticulum in RPE cells.[4]
## Active site structure
The active site of each RPE65 active site contains an Fe(II) cofactor bound by four histidines (His180, His241, His313, and His527), each contributed by a separate blade on the beta-propeller structure. Three of the four histidines are coordinated to nearby glutamic acid residues (Glu148, Glu417, and Glu469), which are thought to help position the histidines to bind the iron cofactor in an octahedral geometry.[9] Phe103, Thr147, and Glu148 surround the active site where they help stabilize the carbocation intermediate and increase the stereoselectivity of RPE65 for 11-cis-retinol over 13-cis-retinol.[5]
Reactants and products likely enter and leave the active site through a hydrophobic tunnel which is thought to open into the lipid membrane for direct lipid substrate absorption. A second, smaller tunnel also reaches the active site and may serve as a pathway for water, but is too narrow to transport the retinoid reactants and products.[5][9]
## Membrane interactions
RPE65 is strongly associated with the membrane of the sER. sER is abnormally abundant in RPE cells due to their role in processing lipidic retinoids. Structural studies indicate that RPE65 is partially imbedded in the sER membrane via interactions between its hydrophobic face and the interior of the lipid membrane. This is supported by the need for detergent to solubilize RPE65. A major portion of RPE65’s hydrophobic face, residues 109-126, forms an amphipathic alpha helix that likely contributes to the protein’s membrane affinity. Additionally, Cys112 is palmitoylated in native RPE65, further supporting the theory that the hydrophobic face of RPE65 is imbedded in the membrane.[9]
The hydrophobic face contains the entrance to the large tunnel that leads to the enzyme’s active site. The presence of this channel on the hydrophobic face combined with RPE65’s demonstrated ability to absorb substrate direction from the lipid bilayer is consistent with RPE65 being partially embedded in the membrane.[4]
## Conservation
RPE65 has been isolated from a wide range of vertebrates including zebra fish, chicken, mice, frogs, and humans.[4][10][11] Its structure is highly conserved between species, particularly in the beta-propeller and likely membrane bound regions. The amino acid sequences of human and bovine RPE65 differ by less than 1%.[9] The histidine residues of the beta-propeller structure and the bound iron(II) cofactor are 100% conserved across studied RPE65 orthologs and other members of the carotenoid oxygenase family.[5]
## Soluble RPE65 (sRPE65)
Previously, it was proposed that RPE65 exists in two, interconverted forms: membrane bound mRPE65 and soluble sRPE65. This theory suggested that the reversible conversion of sRPE65 to mRPE65 by palmitoylation at Cys231, Cys329, and Cys330 played a role in regulating the retinoid cycle and endowing mRPE65 with its membrane affinity.[12] However, crystallographic studies of RPE65 have demonstrated that these residues are neither palmitoylated nor surface facing. New studies have also failed to confirm the presence of abundant soluble RPE65. Thus, this theory has been largely abandoned.[4][9]
# Mechanism
RPE65 catalyzes the conversion of all-trans-retinyl ester to 11-cis-retinol through a proposed SN1 O-alkyl bond cleavage. RPE65’s combination of an O-alkyl ester cleavage, geometric isomerization, and water addition is currently thought to be unique in biology. However, O-alkyl ester cleavage reactions with similarly stabilized carbocation intermediates are used by organic chemists.[5][13]
## O-Alkyl cleavage
The O-alkyl cleavage of the ester bond, assisted by an Fe(II) cofactor, creates a carbocation intermediate that is stabilized by the conjugated polyene chain. The delocalization of the carbocation reduces the bond order of the polyene chain, thereby reducing the activation energy of the trans-to-cis isomerization. Phe103 and Thr178 additionally stabilize the isomerized carbocation and are thought to be responsible for the stereoselectivity of the enzyme. After isomerization, a nucleophilic attack by water at C15 restores the conjugation of the polyene chain and completes the ester bond cleavage.[5][9]
## Alternate SN2 mechanism
Nearly all other biochemical ester hydrolysis reactions occur through SN2 reaction at the acyl carbon. However, isotope labeling studies have demonstrated that the oxygen on the final 11-cis-retinol product of RPE65 originates from the solvent rather than the reacting ester, supporting the O-alkyl cleavage mechanism.[9] Additionally, an SN2 ester hydrolysis reaction mechanism would rely on a separate, unfavorable SN2 attack at electron rich C11 by some nucleophile - most likely a cystine residue - to complete the isomerization portion of the reaction. Not only is nucleophilic attack of an alkene energetically unfavorable, but the active site region is lacking cystine residues to act as the nucleophile.[4][5]
# Clinical significance
Mutations in this gene have been associated with Leber's congenital amaurosis type 2 (LCA2) and retinitis pigmentosa (RP).[2][14] RPE65 mutations are the most commonly detected mutations in LCA patients in Denmark.[15] The vast majority of RPE65 mutations in patients with LCA2 and RP occur in the beta-propeller regime and are believed to inhibit proper protein folding and iron cofactor binding. Particularly common propeller mutation sites are Tyr368 and His182. Substitution at Arg91 is also common and have been shown to impact RPE65 membrane interactions and substrate uptake.[9]
Though complete loss of function is associated with diseases such as LCA and RP, partial inhibition of RPE65 has been proposed as a treatment for age-related macular degeneration (AMD). All-trans-retinylamine (Ret-NH2) and emixustat have both been shown to competitively inhibit RPE65.[5] Emixustat is currently undergoing FDA phase 3 clinical trials as a therapy for AMD.[5][16]
Jean Bennett and Katherine A. High's work with the RPE65 mutation has reversed an inherited form of blindness. They received the first FDA approval of a gene therapy for a genetic disease. For this, in 2018, they were named as one of three finalists for Sanford Health's $1 million Lorraine Cross Award for innovation in science and medicine. | https://www.wikidoc.org/index.php/RPE65 | |
e9f68055cdac85cd88498922beb0e7bd7556eab5 | wikidoc | RPL36 | RPL36
60S ribosomal protein L36 is a protein that in humans is encoded by the RPL36 gene.
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.
# Further reading
- Wool IG, Chan YL, Glück A (1996). "Structure and evolution of mammalian ribosomal proteins". Biochem. Cell Biol. 73 (11–12): 933–47. doi:10.1139/o95-101. PMID 8722009..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Zhang QH, Ye M, Wu XY, et al. (2001). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Res. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Uechi T, Tanaka T, Kenmochi N (2001). "A complete map of the human ribosomal protein genes: assignment of 80 genes to the cytogenetic map and implications for human disorders". Genomics. 72 (3): 223–30. doi:10.1006/geno.2000.6470. PMID 11401437.
- Yoshihama M, Uechi T, Asakawa S, et al. (2002). "The human ribosomal protein genes: sequencing and comparative analysis of 73 genes". Genome Res. 12 (3): 379–90. doi:10.1101/gr.214202. PMC 155282. PMID 11875025.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Odintsova TI, Müller EC, Ivanov AV, et al. (2004). "Characterization and analysis of posttranslational modifications of the human large cytoplasmic ribosomal subunit proteins by mass spectrometry and Edman sequencing". J. Protein Chem. 22 (3): 249–58. doi:10.1023/A:1025068419698. PMID 12962325.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Andersen JS, Lam YW, Leung AK, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. doi:10.1038/nature03207. PMID 15635413.
- Stelzl U, Worm U, Lalowski M, et al. (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070.
- Oh JH, Yang JO, Hahn Y, et al. (2006). "Transcriptome analysis of human gastric cancer". Mamm. Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
- Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Ewing RM, Chu P, Elisma F, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. | RPL36
60S ribosomal protein L36 is a protein that in humans is encoded by the RPL36 gene.[1]
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.[1]
# Further reading
- Wool IG, Chan YL, Glück A (1996). "Structure and evolution of mammalian ribosomal proteins". Biochem. Cell Biol. 73 (11–12): 933–47. doi:10.1139/o95-101. PMID 8722009..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Zhang QH, Ye M, Wu XY, et al. (2001). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Res. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Uechi T, Tanaka T, Kenmochi N (2001). "A complete map of the human ribosomal protein genes: assignment of 80 genes to the cytogenetic map and implications for human disorders". Genomics. 72 (3): 223–30. doi:10.1006/geno.2000.6470. PMID 11401437.
- Yoshihama M, Uechi T, Asakawa S, et al. (2002). "The human ribosomal protein genes: sequencing and comparative analysis of 73 genes". Genome Res. 12 (3): 379–90. doi:10.1101/gr.214202. PMC 155282. PMID 11875025.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Odintsova TI, Müller EC, Ivanov AV, et al. (2004). "Characterization and analysis of posttranslational modifications of the human large cytoplasmic ribosomal subunit proteins by mass spectrometry and Edman sequencing". J. Protein Chem. 22 (3): 249–58. doi:10.1023/A:1025068419698. PMID 12962325.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Andersen JS, Lam YW, Leung AK, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. doi:10.1038/nature03207. PMID 15635413.
- Stelzl U, Worm U, Lalowski M, et al. (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070.
- Oh JH, Yang JO, Hahn Y, et al. (2006). "Transcriptome analysis of human gastric cancer". Mamm. Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
- Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Ewing RM, Chu P, Elisma F, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. | https://www.wikidoc.org/index.php/RPL36 | |
239be09f4271c3720bd77f8ed65254287ef5b3c3 | wikidoc | RPTOR | RPTOR
Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 (isoform 1) and 1177 (isoform 2) amino acids long.
# Gene and expression
The human gene is located on human chromosome 17 with location of the cytogenic band at 17q25.3.
# Location
RPTOR is highly expressed in skeletal muscle and is somewhat less present in brain, lung, small intestine, kidney, and placenta tissue. Isoform 3 is widely expressed and most highly expressed in the nasal mucosa and pituitary. The lowest levels occur in the spleen. In the cell, RPTOR is present in cytoplasm, lysosomes, and cytoplasmic granules. Amino acid availability determines RPTOR targeting to lysosomes. In stressed cells, RPTOR associates with SPAG5 and accumulates in stress granules, which significantly reduces its presence in lysosomes...
# Function
RPTOR encodes part of a signaling pathway regulating cell growth which responds to nutrient and insulin levels. RPTOR is an evolutionarily conserved protein with multiple roles in the mTOR pathway. The adapter protein and mTOR kinase form a stoichiometric complex. The encoded protein also associates with eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. It upregulates S6 kinase, the downstream effector ribosomal protein, and it downregulates the mTOR kinase. RPTOR also has a positive role in maintaining cell size and mTOR protein expression. The association of mTOR and RPTOR is stabilized by nutrient deprivation and other conditions which suppress the mTOR pathway. Multiple transcript variants exist for this gene which encode different isoforms.
# Structure
RPTOR is a 150 kDa mTOR binding protein that is part of the mammalian target of rapamycin complex 1 (mTORC1). This complex contains mTOR, MLST8, RPTOR, AKT1S1/PRAS40, and DEPTOR. mTORC1 both binds to and is inhibited by FKBP12-rapamycin. mTORC1 activity is upregulated by mTOR and MPAK8 by insulin-stimulated phosphorylation at Ser-863. MAPK8 also causes phosphorylation at Ser-696, Thr-706, and Ser-863 as a result of osmotic stress. AMPK causes phosphorylation in the event of nutrient starvation and promotes 14-3-3 binding to raptor, which downregulates the mTORC1 complex. RPS6KA1 stimulates mTORC1 activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.
# Interactions
- mTORC1 binds to and is inhibited by FKBP12-rapamycin
- RPTOR binds to 4EBP1 and RPS6KB1 directly whether or not it is associated with mTOR
- RPTOR binds to poorly phosphorylated or non-phosphorylated EIF4EBP1 preferentially, which is important for mTOR to be able to catalyze phosphorylation.
- RPTOR interacts with ULK1. This interaction depends on nutrients and is reduced in the case of starvation.
- When RPTOR is phosphorylated by AMPK, it interacts with 14-3-3 protein and inhibits its activity.
- RPTOR interacts with SPAG5, which competes with mTOR for binding RPTOR and causes decreased mTORC1 formation.
- RPTOR interacts with G3BP1. Oxidative stress increases the formation of the complex formed with RPTOR, G3BP1, and SPAG5
RPTOR has also been shown to interact with:
- FKBP1A,
- P70-S6 Kinase 1
- RHEB,
- RICTOR, and
- mammalian target of rapamycin (mTOR),
# Clinical significance
## Signaling in cancer
The clinical significance of RPTOR is primarily due to its involvement in the mTOR pathway, which plays roles in mRNA translation, autophagy, and cell growth. Mutations in the PTEN tumor suppressor gene are the best known genetic deficiencies in cancer which affect mTOR signaling. These mutations are frequently found in a very large variety of cancers, including prostate, breast, lung, bladder, melanoma, endometrial, thyroid, brain, and renal carcinomas. PTEN inhibits the lipid-kinase activity of class I PtdIns3Ks, which phosphorylate PtdIns(4,5)P2 to create PtdIns(3,4,5)P3 (PIP3). PIP3 is a membrane-docking site for AKT and PDK1. In turn, active PDK1, along with mTORC1, phosphorylates S6K in the part of the mTOR pathway which promotes protein synthesis and cell growth.
The mTOR pathway has also been found to be involved in aging. Studies with C. elegans, fruitflies, and mice have shown that the lifespan of the organism is significantly increased by inhibiting mTORC1. mTORC1 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells. Because mTORC1 inhibits autophagy and stimulates cell growth, it can cause damaged proteins and cell structures to accumulate. For this reason, dysfunction in the process of autophagy can contribute to several diseases, including cancer.
The mTOR pathway is important in many cancers. In cancer cells, astrin is required to suppress apoptosis during stress. Astrin recruits RPTOR to stress granules, inhibiting mTORC1 association and preventing apoptosis induced by mTORC1 hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to apoptosis through the mTORC1 pathway.
RPTOR is overexpressed in pituitary adenoma, and its expression increases with tumor staging. RPTOR could be valuable in the prediction and prognosis of pituitary adenoma due to this correlation between protein expression and the growth and invasion of the tumor.
## As a drug target
mTOR is found in two different complexes. When it associates with rapamycin-insensitive companion of mTOR (rictor), the complex is known as mTORC2 and it is insensitive to rapamycin. However, the complex mTORC1 formed by association with accessory protein RPTOR is sensitive to rapamycin. Rapamycin is a macrolide which is an immunosuppressant in humans that inhibits mTOR by binding to its intracellular receptor FKBP12. In many cancers, hyperactive AKT signaling leads to increased mTOR signaling, so rapamycin has been considered as an anti-cancer therapeutic for cancers with PTEN inactivation. Numerous clinical trials involving rapamycin analogs, such as CCI-779, RAD001, and AP23573, are ongoing. Early reports have been promising for renal-cell carcinoma, breast carcinomas, and non-small-cell lung carcinomas. | RPTOR
Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene.[1][2][3] Two mRNAs from the gene have been identified that encode proteins of 1335 (isoform 1) and 1177 (isoform 2) amino acids long.
# Gene and expression
The human gene is located on human chromosome 17 with location of the cytogenic band at 17q25.3.[3]
# Location
RPTOR is highly expressed in skeletal muscle and is somewhat less present in brain, lung, small intestine, kidney, and placenta tissue. Isoform 3 is widely expressed and most highly expressed in the nasal mucosa and pituitary. The lowest levels occur in the spleen.[4] In the cell, RPTOR is present in cytoplasm, lysosomes, and cytoplasmic granules. Amino acid availability determines RPTOR targeting to lysosomes. In stressed cells, RPTOR associates with SPAG5 and accumulates in stress granules, which significantly reduces its presence in lysosomes...[5][6]
# Function
RPTOR encodes part of a signaling pathway regulating cell growth which responds to nutrient and insulin levels. RPTOR is an evolutionarily conserved protein with multiple roles in the mTOR pathway. The adapter protein and mTOR kinase form a stoichiometric complex. The encoded protein also associates with eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. It upregulates S6 kinase, the downstream effector ribosomal protein, and it downregulates the mTOR kinase. RPTOR also has a positive role in maintaining cell size and mTOR protein expression. The association of mTOR and RPTOR is stabilized by nutrient deprivation and other conditions which suppress the mTOR pathway.[4] Multiple transcript variants exist for this gene which encode different isoforms.[3]
# Structure
RPTOR is a 150 kDa mTOR binding protein that is part of the mammalian target of rapamycin complex 1 (mTORC1). This complex contains mTOR, MLST8, RPTOR, AKT1S1/PRAS40, and DEPTOR. mTORC1 both binds to and is inhibited by FKBP12-rapamycin. mTORC1 activity is upregulated by mTOR and MPAK8 by insulin-stimulated phosphorylation at Ser-863.[7][8] MAPK8 also causes phosphorylation at Ser-696, Thr-706, and Ser-863 as a result of osmotic stress.[9] AMPK causes phosphorylation in the event of nutrient starvation and promotes 14-3-3 binding to raptor, which downregulates the mTORC1 complex.[10] RPS6KA1 stimulates mTORC1 activity by phosphorylating at Ser-719, Ser-721, and Ser-722 as a response to growth factors.
# Interactions
- mTORC1 binds to and is inhibited by FKBP12-rapamycin
- RPTOR binds to 4EBP1 and RPS6KB1 directly whether or not it is associated with mTOR[11]
- RPTOR binds to poorly phosphorylated or non-phosphorylated EIF4EBP1 preferentially, which is important for mTOR to be able to catalyze phosphorylation.[2][11][12][13][14][15][16][17]
- RPTOR interacts with ULK1. This interaction depends on nutrients and is reduced in the case of starvation.[18]
- When RPTOR is phosphorylated by AMPK, it interacts with 14-3-3 protein and inhibits its activity.[10]
- RPTOR interacts with SPAG5, which competes with mTOR for binding RPTOR and causes decreased mTORC1 formation.
- RPTOR interacts with G3BP1. Oxidative stress increases the formation of the complex formed with RPTOR, G3BP1, and SPAG5[6]
RPTOR has also been shown to interact with:
- FKBP1A,[19][20]
- P70-S6 Kinase 1[2][13][14][21]
- RHEB,[22]
- RICTOR,[23] and
- mammalian target of rapamycin (mTOR),[2][4][11][12][13][14][19][20][23][24][25][26][27][28][29][30][31][32][33][34]
# Clinical significance
## Signaling in cancer
The clinical significance of RPTOR is primarily due to its involvement in the mTOR pathway, which plays roles in mRNA translation, autophagy, and cell growth. Mutations in the PTEN tumor suppressor gene are the best known genetic deficiencies in cancer which affect mTOR signaling. These mutations are frequently found in a very large variety of cancers, including prostate, breast, lung, bladder, melanoma, endometrial, thyroid, brain, and renal carcinomas. PTEN inhibits the lipid-kinase activity of class I PtdIns3Ks, which phosphorylate PtdIns(4,5)P2 to create PtdIns(3,4,5)P3 (PIP3). PIP3 is a membrane-docking site for AKT and PDK1. In turn, active PDK1, along with mTORC1, phosphorylates S6K in the part of the mTOR pathway which promotes protein synthesis and cell growth.[35]
The mTOR pathway has also been found to be involved in aging. Studies with C. elegans, fruitflies, and mice have shown that the lifespan of the organism is significantly increased by inhibiting mTORC1.[36][37] mTORC1 phosphorylates Atg13 and stops it from forming the ULK1 kinase complex. This inhibits autophagy, the major degradation pathway in eukaryotic cells.[38] Because mTORC1 inhibits autophagy and stimulates cell growth, it can cause damaged proteins and cell structures to accumulate. For this reason, dysfunction in the process of autophagy can contribute to several diseases, including cancer.[39]
The mTOR pathway is important in many cancers. In cancer cells, astrin is required to suppress apoptosis during stress. Astrin recruits RPTOR to stress granules, inhibiting mTORC1 association and preventing apoptosis induced by mTORC1 hyperactivation. Because astrin is frequently upregulated in tumors, it is a potential target to sensitize tumors to apoptosis through the mTORC1 pathway.[6]
RPTOR is overexpressed in pituitary adenoma, and its expression increases with tumor staging. RPTOR could be valuable in the prediction and prognosis of pituitary adenoma due to this correlation between protein expression and the growth and invasion of the tumor.[40]
## As a drug target
mTOR is found in two different complexes. When it associates with rapamycin-insensitive companion of mTOR (rictor), the complex is known as mTORC2 and it is insensitive to rapamycin. However, the complex mTORC1 formed by association with accessory protein RPTOR is sensitive to rapamycin. Rapamycin is a macrolide which is an immunosuppressant in humans that inhibits mTOR by binding to its intracellular receptor FKBP12. In many cancers, hyperactive AKT signaling leads to increased mTOR signaling, so rapamycin has been considered as an anti-cancer therapeutic for cancers with PTEN inactivation. Numerous clinical trials involving rapamycin analogs, such as CCI-779, RAD001, and AP23573, are ongoing. Early reports have been promising for renal-cell carcinoma, breast carcinomas, and non-small-cell lung carcinomas.[35] | https://www.wikidoc.org/index.php/RPTOR | |
fbaaf00322e13621808fb63789459ea0950e88ba | wikidoc | RRBP1 | RRBP1
Ribosome-binding protein 1, also referred to as p180, is a protein that in humans is encoded by the RRBP1 gene.
RRBP1 is a membrane-bound protein found in the endoplasmic reticulum (ER). It was originally identified as the ribosome receptor for the ER, however several groups later demonstrated that this activity did not co-fractionate with RRBP1
but rather with Sec61 (i.e. the translocon). RRBP1 can enhance the association of certain mRNAs to the endoplasmic reticulum in a manner that does not require ribosome activity, likely by directly associating the mRNA's phosphate backbone. In addition, RRBP1 may promote the association of polysomes with the translocon and play a role in ER morphology. RRBP1 may also bind to microtubules. Although the p180 isoform is the most abundant, it may exist in different forms due to removal of tandem repeats by partial intraexonic splicing. RRBP1 has been excluded as a candidate gene in the cause of Alagille syndrome. | RRBP1
Ribosome-binding protein 1, also referred to as p180, is a protein that in humans is encoded by the RRBP1 gene.[1][2]
RRBP1 is a membrane-bound protein found in the endoplasmic reticulum (ER). It was originally identified as the ribosome receptor for the ER,[3] however several groups later demonstrated that this activity did not co-fractionate with RRBP1 [4]
[5] but rather with Sec61 (i.e. the translocon).[6][7] RRBP1 can enhance the association of certain mRNAs to the endoplasmic reticulum in a manner that does not require ribosome activity, likely by directly associating the mRNA's phosphate backbone[8]. In addition, RRBP1 may promote the association of polysomes with the translocon [9][10] and play a role in ER morphology.[11] RRBP1 may also bind to microtubules.[12] Although the p180 isoform is the most abundant, it may exist in different forms due to removal of tandem repeats by partial intraexonic splicing. RRBP1 has been excluded as a candidate gene in the cause of Alagille syndrome.[2] | https://www.wikidoc.org/index.php/RRBP1 | |
9bd1bf7a704c0fa62614efb3f3e12db3f0cce82b | wikidoc | RRM2B | RRM2B
Ribonucleoside-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the RRM2B gene. The gene encoding the RRM2B protein is located on chromosome 8, at position 8q23.1. The gene and its products are also known by designations MTDPS8A, MTDPS8B, and p53R2.
# Function
RRM2B codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for DNA replication by reducing ribonucleoside diphosphates to deoxyribonucloside diphosphates. The version of R2 encoded by RRM2B is induced by p53, and is required for normal DNA repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells.
# Interactions
RRM2B has been shown to interact with Mdm2 and Ataxia telangiectasia mutated.
# Clinical relevance
Abnormalities in this gene are one of the causes of mitochondrial DNA depletion syndrome (MDDS). Neonatal hypotonia, developmental delay, encephalopathy, with seizures, deafness and lactic acidosis have been associated with mutations in this gene. MDDS is fatal, with death occurring from respiratory failure in early childhood.
It has been associated with some cases of pediatric acute liver failure.
Mutations in this gene have been shown to cause progressive external ophthalmoplegia.
Increased expression of RRM2B has been correlated with gemcitabine resistance in human cholangiocarcinoma cells and may be predictive of lack of clinical benefit from gemcitabine for human cancers. | RRM2B
Ribonucleoside-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the RRM2B gene.[1][2][3][4] The gene encoding the RRM2B protein is located on chromosome 8, at position 8q23.1. The gene and its products are also known by designations MTDPS8A, MTDPS8B, and p53R2.
# Function
RRM2B codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for DNA replication by reducing ribonucleoside diphosphates to deoxyribonucloside diphosphates. The version of R2 encoded by RRM2B is induced by p53, and is required for normal DNA repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells.[5]
# Interactions
RRM2B has been shown to interact with Mdm2[6] and Ataxia telangiectasia mutated.[6]
# Clinical relevance
Abnormalities in this gene are one of the causes of mitochondrial DNA depletion syndrome (MDDS).[7][8] Neonatal hypotonia, developmental delay, encephalopathy, with seizures, deafness and lactic acidosis have been associated with mutations in this gene. MDDS is fatal, with death occurring from respiratory failure in early childhood.[9][10]
It has been associated with some cases of pediatric acute liver failure.[11]
Mutations in this gene have been shown to cause progressive external ophthalmoplegia.[12]
Increased expression of RRM2B has been correlated with gemcitabine resistance in human cholangiocarcinoma cells[13] and may be predictive of lack of clinical benefit from gemcitabine for human cancers. | https://www.wikidoc.org/index.php/RRM2B | |
96e2e21fd20cfea48d84f82ecb0814127739c9fc | wikidoc | RSPO1 | RSPO1
R-spondin-1 is a secreted protein that in humans is encoded by the Rspo1 gene, found on chromosome 1. In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal. Furthermore, it promotes canonical WNT/β catenin signaling.
# Structure
The protein has two cysteine-rich, furin-like domains and one thrombospondin type 1 domain.
# Function
## Sex Development
### Early Gonads
RSPO1 is required for the early development of gonads, regardless of sex. It has been found in mice only eleven days after fertilization. To induce cell proliferation, it acts synergistically with WNT4. They help stabilize β-catenin, which activates downstream targets. If both are deficient in XY mice, there is less expression of SRY and a reduction in the amount of SOX9. Moreover, defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.
### Ovaries
RSPO1 is necessary in female sex development. It augments the WNT/β catenin pathway to oppose male sex development. In critical gonadal stages, between six and nine weeks after fertilization, the ovaries upregulate it while the testes downregulate it.
## Mucositis
Oral mucosa has been identified as a target tissue for RSPO1. When administered to normal mice, it causes nuclear translocation of β-catenin to this region. Modulation of the WNT/β catenin pathway occurs through the relief of Dkk1 inhibition. This occurrence results in increased basal cellularity, thickened mucosa, and elevated epithelial cell proliferation in the tongue. RSPO1 can therefore potentially aid in the treatment of mucositis, which is characterized by inflammation of the oral cavity. This unfortunate condition often accompanies chemotherapy and radiation in cancer patients with head and neck tumors. RSPO1 has also been shown to promote gastrointestinal epithelial cell proliferation in mice. | RSPO1
R-spondin-1 is a secreted protein that in humans is encoded by the Rspo1 gene, found on chromosome 1.[1] In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal.[2] Furthermore, it promotes canonical WNT/β catenin signaling.[3]
# Structure
The protein has two cysteine-rich, furin-like domains and one thrombospondin type 1 domain.[1]
# Function
## Sex Development
### Early Gonads
RSPO1 is required for the early development of gonads, regardless of sex. It has been found in mice only eleven days after fertilization.[2] To induce cell proliferation, it acts synergistically with WNT4.[2] They help stabilize β-catenin, which activates downstream targets. If both are deficient in XY mice, there is less expression of SRY and a reduction in the amount of SOX9. Moreover, defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.[2]
### Ovaries
RSPO1 is necessary in female sex development. It augments the WNT/β catenin pathway to oppose male sex development. In critical gonadal stages, between six and nine weeks after fertilization, the ovaries upregulate it while the testes downregulate it.[4]
## Mucositis
Oral mucosa has been identified as a target tissue for RSPO1. When administered to normal mice, it causes nuclear translocation of β-catenin to this region.[3] Modulation of the WNT/β catenin pathway occurs through the relief of Dkk1 inhibition. This occurrence results in increased basal cellularity, thickened mucosa, and elevated epithelial cell proliferation in the tongue. RSPO1 can therefore potentially aid in the treatment of mucositis, which is characterized by inflammation of the oral cavity. This unfortunate condition often accompanies chemotherapy and radiation in cancer patients with head and neck tumors.[3] RSPO1 has also been shown to promote gastrointestinal epithelial cell proliferation in mice.[1] | https://www.wikidoc.org/index.php/RSPO1 | |
491f162e26ed90b59d536516433767e69ae694f2 | wikidoc | RSPO3 | RSPO3
R-spondin-3 is a protein that in humans is encoded by the RSPO3 gene.
# Function
This gene encodes a member of the thrombospondin type 1 repeat supergene family. In addition, the protein contains a furin-like cysteine-rich region. Furin-like repeat domains have been found in a variety of eukaryotic proteins involved in the mechanism of signal transduction by receptor tyrosine kinases.
During embryonic development, RSPO3 is expressed in the tail bud and the posterior presomitic mesoderm of the embryo. In tissue engineering, R-spondin 3 has been used to differentiate pluripotent stem cells into paraxial mesoderm progenitors | RSPO3
R-spondin-3 is a protein that in humans is encoded by the RSPO3 gene.[1][2][3]
# Function
This gene encodes a member of the thrombospondin type 1 repeat supergene family. In addition, the protein contains a furin-like cysteine-rich region. Furin-like repeat domains have been found in a variety of eukaryotic proteins involved in the mechanism of signal transduction by receptor tyrosine kinases.[3]
During embryonic development, RSPO3 is expressed in the tail bud and the posterior presomitic mesoderm of the embryo. In tissue engineering, R-spondin 3 has been used to differentiate pluripotent stem cells into paraxial mesoderm progenitors[4] | https://www.wikidoc.org/index.php/RSPO3 | |
63489a9dfe448c3179e46bcb202e7f90febbe4dd | wikidoc | RUFY2 | RUFY2
RUN and FYVE domain containing 2 (RUFY2) is a protein that in humans is encoded by the RUFY2 gene. The RUFY2 gene is named for two of its domains, the RUN domain and FYVE domains. RUFY2 is a member of the RUFY family of proteins that include RUFY1, RUFY2, RUFY3, and RUFY4. RUFY2 protein has a dynamic role in endosomal membrane trafficking.
# Gene
The human RUFY2 gene is located on the long (q) arm of chromosome 10 at region 21 band 3, from base pair 70,100,864 to base pair 70,167,051 on the reverse strand (Build GRCh37/hg19) (map). The gene produces a 2,080 base pair mRNA. There are 18 predicted exons in the human gene with 13 alternative transcripts.
## Gene neighborhood
8,180 base pairs upstream of RUFY2 is the protein-coding gene for phenazine biosynthesis-like protein domain containing (PBLD). While 6,770 base pairs downstream from RUFY2 is a DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability.
# Protein
The protein of RUFY2 consists of 655 amino acid residues. RUFY2 protein contains a N-terminal RUN domain and a C-terminal FYVE domain with 2 coiled coil domains in between. The molecular weight of the mature protein is 70.0 kdal with an isoelectric point of 5.494. PHYRE2 protein tertiary structure tool suggests that RUFY2 has 15 alpha helices and the longest helix spanning amino acids 199...512 as seen in the figure to the right. RUFY2 is a soluble protein that localizes to the nucleus and to membranes of early endosomes. RUFY2 protein contains no signal peptide, no DNA/RNA binding sites, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus. There is no transmembrane domain in RUFY2.
## Domains
## RUN domain
The RUN domain is between amino acids 45...168 and consists of the RPIP8, UNC-14, and NESCA proteins. The RUN domain has been shown to have interacting functions with GTPases in the Rap and Rab signal transduction pathways and endosomal membrane trafficking.
## DUF972
Domain of unknown function that is part of a family of hypothetical bacterial sequences pfam06156. It make be linked to the YabA initiation control protein which functions as the chromosomal replication initiation control in bacteria.
## PspA/IM30
The PspA/IM30 family is a negative regulator of sigma54 transcription initiation factor in bacteria.
## FYVE domain
FYVE domain consists of Fab-1, YGL023, Vps27, and EEA1 proteins. Within the FYVE domain there are Zinc finger binding sites that interact with phosphatidylinositol-3-phosphate, to bring target proteins to membrane lipids.
## Protein interactions
The proline rich motif in the FYVE domain of RUFY2 has been shown to have binding activity with the SH3 domain of EPHA3 (Etk) in signal transduction pathways.
## Post-translational modifications
RUFY2 possibly has 6 phosphorylation sites and are located mainly in the DUF972 region.
RUFY2 also has 6 protein kinase C phosphorylation sites that are located mainly within the FYVE domain.
### Other notable modification sites within the protein
- 4 Lysine acetylation sites
- 4 N-myristolation sites
- 3 N-glycosylation sites
# Homology and evolution
RUFY2 has 4 paralogs: RUFY3, RUFY1, RUNDC3A, RUNDC3B.
There are 60 orthologs of RUFY2 that have been identified including mammals, some birds, reptiles and fish. RUFY2 is highly conserved among its orthologs but is not present in plants, bacteria, archea or protist.
## Species distribution
The following table lists the homologs of RUFY2.
# Clinical significance
Certain neurodegenerative diseases such as Alzheimer's have been found to have defective endosomal trafficking. Therefore, the involvement of RUFY2 protein domains, RUN and FYVE, may possibly play a role in neurodegenerative diseases such as Alzheimer's.
# Expression
RUFY2 protein has been shown to mainly be expressed in the brain, lung, and testes while microarray expression shows RUFY2 ubiquitous expression. | RUFY2
RUN and FYVE domain containing 2 (RUFY2) is a protein that in humans is encoded by the RUFY2 gene.[1] The RUFY2 gene is named for two of its domains, the RUN domain and FYVE domains. RUFY2 is a member of the RUFY family of proteins that include RUFY1, RUFY2, RUFY3, and RUFY4. RUFY2 protein has a dynamic role in endosomal membrane trafficking.[2]
# Gene
The human RUFY2 gene is located on the long (q) arm of chromosome 10 at region 21 band 3, from base pair 70,100,864 to base pair 70,167,051 on the reverse strand (Build GRCh37/hg19) (map).[3] The gene produces a 2,080 base pair mRNA. There are 18 predicted exons in the human gene [4] with 13 alternative transcripts.[5]
## Gene neighborhood
8,180 base pairs upstream of RUFY2 is the protein-coding gene for phenazine biosynthesis-like protein domain containing (PBLD).[6] While 6,770 base pairs downstream from RUFY2 is a DNA2 conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability.[7]
# Protein
The protein of RUFY2 consists of 655[8] amino acid residues. RUFY2 protein contains a N-terminal RUN domain and a C-terminal FYVE domain with 2 coiled coil domains in between.[9] The molecular weight of the mature protein is 70.0 kdal[10] with an isoelectric point of 5.494.[11] PHYRE2 protein tertiary structure tool suggests that RUFY2 has 15 alpha helices and the longest helix spanning amino acids 199...512 as seen in the figure to the right. RUFY2 is a soluble[12] protein that localizes to the nucleus[13] and to membranes of early endosomes.[14] RUFY2 protein contains no signal peptide, no DNA/RNA binding sites, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus.[13] There is no transmembrane domain in RUFY2.[15]
## Domains
## RUN domain
The RUN domain is between amino acids 45...168 and consists of the RPIP8, UNC-14, and NESCA proteins.[2] The RUN domain has been shown to have interacting functions with GTPases in the Rap and Rab signal transduction pathways[16] and endosomal membrane trafficking.[2]
## DUF972
Domain of unknown function that is part of a family of hypothetical bacterial sequences pfam06156.[17] It make be linked to the YabA initiation control protein which functions as the chromosomal replication initiation control in bacteria.[18]
## PspA/IM30
The PspA/IM30 family is a negative regulator of sigma54 transcription initiation factor in bacteria.[19]
## FYVE domain
FYVE domain consists of Fab-1, YGL023, Vps27, and EEA1 proteins. Within the FYVE domain there are Zinc finger binding sites that interact with phosphatidylinositol-3-phosphate, to bring target proteins to membrane lipids.[20]
## Protein interactions
The proline rich motif in the FYVE domain of RUFY2 has been shown to have binding activity with the SH3 domain of EPHA3 (Etk) in signal transduction pathways.[14]
## Post-translational modifications
RUFY2 possibly has 6 phosphorylation sites and are located mainly in the DUF972 region.
RUFY2 also has 6 protein kinase C phosphorylation sites that are located mainly within the FYVE domain.[21]
### Other notable modification sites within the protein
- 4 Lysine acetylation sites
- 4 N-myristolation sites
- 3 N-glycosylation sites
# Homology and evolution
RUFY2 has 4 paralogs: RUFY3, RUFY1, RUNDC3A, RUNDC3B.[22]
There are 60[23] orthologs of RUFY2 that have been identified including mammals, some birds, reptiles and fish.[24] RUFY2 is highly conserved among its orthologs but is not present in plants, bacteria, archea or protist.
## Species distribution
The following table lists the homologs of RUFY2.
# Clinical significance
Certain neurodegenerative diseases such as Alzheimer's have been found to have defective endosomal trafficking. Therefore, the involvement of RUFY2 protein domains, RUN and FYVE, may possibly play a role in neurodegenerative diseases such as Alzheimer's.[2]
# Expression
RUFY2 protein has been shown to mainly be expressed in the brain, lung, and testes while microarray expression shows RUFY2 ubiquitous expression.[2][39][40] | https://www.wikidoc.org/index.php/RUFY2 | |
ef9983b247225e59dab113fca99d1410e4a8cee2 | wikidoc | RUNX1 | RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.
RUNX1 is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells. In addition it plays a major role in the development of the neurons that transmit pain. It belongs to the Runt-related transcription factor (RUNX) family of genes which are also called core binding factor-α (CBFα). RUNX proteins form a heterodimeric complex with CBFβ which confers increased DNA binding and stability to the complex.
Chromosomal translocations involving the RUNX1 gene are associated with several types of leukemia including M2 AML. Mutations in RUNX1 are implicated in cases of breast cancer.
# Gene and protein
In humans, the gene RUNX1 is 260 kilobases (kb) in length, and is located on chromosome 21 (21q22.12). The gene can be transcribed from 2 alternative promoters, promoter 1 (distal) or promoter 2 (proximal). As a result, various isoforms of RUNX1 can be synthesized, facilitated by alternative splicing. The full-length RUNX1 protein is encoded by 12 exons. Among the exons are two defined domains, namely the runt homology domain (RHD) or the runt domain (exons 2, 3 and 4), and the transactivation domain (TAD) (exon 6). These domains are necessary for RUNX1 to mediate DNA binding and protein-protein interactions respectively. The transcription of RUNX1 is regulated by 2 enhancers (regulatory element 1 and regulatory element 2), and these tissue specific enhancers enable the binding of lymphoid or erythroid regulatory proteins, therefore the gene activity of RUNX1 is highly active in the haematopoietic system.
The protein RUNX1 is composed of 453 amino acids. As a transcription factor (TF), its DNA binding ability is encoded by the runt domain (residues 50 – 177), which is homologous to the p53 family. The runt domain of RUNX1 binds to the core consensus sequence TGTGGNNN (where NNN can represent either TTT or TCA). DNA recognition is achieved by loops of the 12-stranded β-barrel and the C-terminus “tail” (residues 170 – 177), which clamp around the sugar phosphate backbone and fits into the major and minor grooves of DNA. Specificity is achieved by making direct or water-mediated contacts with the bases. RUNX1 can bind DNA as a monomer, but its DNA binding affinity is enhanced by 10 fold if it heterodimerises with the core binding factor β (CBFβ), also via the runt domain. In fact, the RUNX family is often referred to as α-subunits, together with binding of a common β-subunit CBFβ, RUNX can behave as heterodimeric transcription factors collectively called the core binding factors (CBFs).
The consensus binding site for CBF has been identified to be a 7 bp sequence PyGPyGGTPy. Py denotes pyrimidine which can be either cytosine or thymine.
# Discovery and characterization of RUNX1
Nusslein-Volhard and Wieschaus discovered the transcription factor RUNX in a screen that was conducted to identify mutations that affect segment number and polarity in Drosophila. The mutation that led to presegmentation patterning defects and runted embryos was named runt. Following this discovery, the Drosophila segmentation gene runt was cloned by Gergen et al. Although the protein encoded by runt was demonstrated to exhibit nuclear translocation, it was not yet established that this protein is a transcription factor. Subsequently, in 1991, Ohki et al. cloned the human RUNX1 gene; RUNX1 was found to be rearranged in the leukemic cell DNAs from t(8;21)(q22;q22) AML patients. However, the function of human RUNX1 was not established. Soon after the discovery of the drosophila runt protein and the human RUNX1 protein, other teams discovered RUNX1’s function. Nancy Speck purified Runx1 as a sequence-specific DNA-binding protein that regulated the disease specificity of the Moloney murine Leukemia virus. Furthermore, Ito et al purified Runx2, the homolog of Runx1. Both these teams diligently demonstrated that the purified transcription factors consisted of two subunits, a DNA binding CBFα chain (RUNX1 or RUNX2) and a non-DNA-binding subunit called core binding factor β (CBFβ); the binding affinity of RUNX1 and RUNX2 was significantly increased by association with CBFβ.,, During her 35-year career, Nancy A. Speck, PhD, a global leader in the field of blood-cell development, has made seminal contributions to our understanding of development hematopoiesis and how this process is disrupted in certain leukemias. Particularly, Dr. Speck’s contributions to the field of hematopoiesis include identification and characterization of the proteins Runx1 and CBFβ. Dr. Speck’s research focused on the CBF (RUNX1-CBFβ) has helped identify the roles of RUNX1-CBFβ in hematopoietic stem cell (HSC) formation, HSC function and malignant hematopoiesis.,
# Mouse knockout
Mice embryos with homozygous mutations on RUNX1 died at about 12.5 days. The embryos displayed lack of fetal liver hematopoiesis.
Similar experiments from a different research group demonstrated that the knockout embryos die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS).
# Participation in haematopoiesis
RUNX1 plays a crucial role in adult (definitive) haematopoiesis during embryonic development. It is expressed in all haematopoietic sites that contribute to the formation of haematopoietic stem and progenitor cells (HSPCs), including the yolk sac, allantois, placenta, para-aortic splanchnopleura (P-Sp; (the visceral mesodermal layer), aorta-gonad-mesonephros (AGM) and the umbilical and vitelline arteries. HSPCs are generated via the hemogenic endothelium, a special subset of endothelial cells scattered within blood vessels that can differentiate into haematopoietic cells. The emergence of HSPCs is often studied in mouse and zebrafish animal models, in which HSPCs appear as “intra-aortic” clusters that adhere to the ventral wall of the dorsal aorta. RUNX1 or CBF takes part in this process by mediating the transition of an endothelial cell to become a haematopoietic cell. There is increasing evidence that RUNX1 may also be important during primitive haematopoiesis. This is because in RUNX1 knockout mice, primitive erythrocytes displayed a defective morphology and the size of blast cell population was substantially reduced, apart from the absence of HSPCs which would result in embryonic lethality by Embryonic day (E) 11.5 – 12.5.
At a molecular level, expression of the gene RUNX1 is upregulated by the RUNX1 intronic cis-regulatory element (+23 RUNX1 enhancer). This +23 RUNX1 enhancer contains conserved motifs that encourage binding of various haematopoiesis related regulators such as Gata2, ETS factors (Fli-1, Elf-1, PU.1) and the SCL / Lmo2 / Ldb1 complex, as well as RUNX1 itself acting in an auto-regulatory loop. As mentioned before, the main role of RUNX1 is to modulate the fate of haematopoietic cells. This can be achieved by binding to the thrombopoietin (TPO) receptor/ c-Mpl promoter, followed by the recruitment of transcription activators or repressors in order to promote transition of the hemogenic endothelium to HSCs, or differentiation into lineages of lower haematopoietic hierarchies. RUNX1 can also modulate its own level by upregulating the expression of Smad6 to target itself for proteolysis.
# Mutations and acute myeloid leukemia
At least 39 forms of RUNX1 mutation are implicated in various myeloid malignancies. Examples range from RUNX1 point mutations acquired from low-dose radiation leading to myelodysplastic neoplasms or therapy-related myeloid neoplasms, to chromosomal translocation of the RUNX1 gene with the ETO / MTG8 / RUNX1T1 gene located on chromosome 8q22, t(8; 21), generating a fusion protein AML-ETO, categorized as acute myeloid leukemia (AML) M2.
In t(8; 21), breakpoints frequently occur at intron 5 – 6 of RUNX1 and intron 1b – 2 of ETO, creating chimeric transcripts that inherit the runt domain from RUNX1, and all Nervy homology regions (NHR) 1-4 from ETO. As a consequence, AML-ETO retains the ability to bind at RUNX1 target genes whilst acting as a transcription repressor via the recruitment of corepressors and histone deacetylases, which is an intrinsic function of ETO. Oncogenic potential of AML-ETO is exerted because it blocks differentiation and promote self-renewal in blast cells, resulting in massive accumulation of blasts (>20%) in the bone marrow. This is further characterized histologically by the presence of Auer rods and epigenetically by lysine acetylation on residues 24 and 43. Other actions of AML-ETO that could induce leukemogenesis include downregulation of the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) and increase in the level of intracellular reactive oxygen species, making cells that express AML-ETO more susceptible to additional genetic mutations.
# Participation in hair follicle development
Runx1 was first discovered to be expressed in mouse embryonic skin. It is expressed in the epithelial compartment to control hair follicle activation from telogen to anagen through activating Wnt singaling and Lef1 levels At the same time it is expressed in the dermis where it suppresses the same targets to allow for embryogenic development of hair shaft and follicles. In the human hair follicle the expression patterns are similar to the mouse - indicating that it plays a similar role. In addition to hair follicle development, Runx1 is also implicated in skin and epithelial cancer development. Thus there are similarities across tissue in Runx1 behavior.
# Interactions
RUNX1 has been shown to interact with:
- C-Fos,
- C-jun,
- SUV39H1
- TLE1, and
- VDR.
- Stat3 | RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.[1][2]
RUNX1 is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells.[3] In addition it plays a major role in the development of the neurons that transmit pain.[4] It belongs to the Runt-related transcription factor (RUNX) family of genes which are also called core binding factor-α (CBFα). RUNX proteins form a heterodimeric complex with CBFβ which confers increased DNA binding and stability to the complex.
Chromosomal translocations involving the RUNX1 gene are associated with several types of leukemia including M2 AML.[5] Mutations in RUNX1 are implicated in cases of breast cancer.[6]
# Gene and protein
In humans, the gene RUNX1 is 260 kilobases (kb) in length, and is located on chromosome 21 (21q22.12). The gene can be transcribed from 2 alternative promoters, promoter 1 (distal) or promoter 2 (proximal). As a result, various isoforms of RUNX1 can be synthesized, facilitated by alternative splicing. The full-length RUNX1 protein is encoded by 12 exons. Among the exons are two defined domains, namely the runt homology domain (RHD) or the runt domain (exons 2, 3 and 4), and the transactivation domain (TAD) (exon 6). These domains are necessary for RUNX1 to mediate DNA binding and protein-protein interactions respectively. The transcription of RUNX1 is regulated by 2 enhancers (regulatory element 1 and regulatory element 2), and these tissue specific enhancers enable the binding of lymphoid or erythroid regulatory proteins, therefore the gene activity of RUNX1 is highly active in the haematopoietic system.
The protein RUNX1 is composed of 453 amino acids. As a transcription factor (TF), its DNA binding ability is encoded by the runt domain (residues 50 – 177), which is homologous to the p53 family. The runt domain of RUNX1 binds to the core consensus sequence TGTGGNNN (where NNN can represent either TTT or TCA).[7] DNA recognition is achieved by loops of the 12-stranded β-barrel and the C-terminus “tail” (residues 170 – 177), which clamp around the sugar phosphate backbone and fits into the major and minor grooves of DNA. Specificity is achieved by making direct or water-mediated contacts with the bases. RUNX1 can bind DNA as a monomer, but its DNA binding affinity is enhanced by 10 fold if it heterodimerises with the core binding factor β (CBFβ), also via the runt domain. In fact, the RUNX family is often referred to as α-subunits, together with binding of a common β-subunit CBFβ, RUNX can behave as heterodimeric transcription factors collectively called the core binding factors (CBFs).
The consensus binding site for CBF has been identified to be a 7 bp sequence PyGPyGGTPy. Py denotes pyrimidine which can be either cytosine or thymine.[8]
# Discovery and characterization of RUNX1
Nusslein-Volhard and Wieschaus discovered the transcription factor RUNX in a screen that was conducted to identify mutations that affect segment number and polarity in Drosophila.[9] The mutation that led to presegmentation patterning defects and runted embryos was named runt. Following this discovery, the Drosophila segmentation gene runt was cloned by Gergen et al. Although the protein encoded by runt was demonstrated to exhibit nuclear translocation, it was not yet established that this protein is a transcription factor.[10] Subsequently, in 1991, Ohki et al. cloned the human RUNX1 gene; RUNX1 was found to be rearranged in the leukemic cell DNAs from t(8;21)(q22;q22) AML patients.[11] However, the function of human RUNX1 was not established. Soon after the discovery of the drosophila runt protein and the human RUNX1 protein, other teams discovered RUNX1’s function. Nancy Speck purified Runx1 as a sequence-specific DNA-binding protein that regulated the disease specificity of the Moloney murine Leukemia virus.[12] Furthermore, Ito et al purified Runx2, the homolog of Runx1.[13] Both these teams diligently demonstrated that the purified transcription factors consisted of two subunits, a DNA binding CBFα chain (RUNX1 or RUNX2) and a non-DNA-binding subunit called core binding factor β (CBFβ); the binding affinity of RUNX1 and RUNX2 was significantly increased by association with CBFβ.[13],[14],[15] During her 35-year career, Nancy A. Speck, PhD,[16] a global leader in the field of blood-cell development, has made seminal contributions to our understanding of development hematopoiesis and how this process is disrupted in certain leukemias. Particularly, Dr. Speck’s contributions to the field of hematopoiesis include identification and characterization of the proteins Runx1 and CBFβ. Dr. Speck’s research focused on the CBF (RUNX1-CBFβ) has helped identify the roles of RUNX1-CBFβ in hematopoietic stem cell (HSC) formation, HSC function and malignant hematopoiesis.[17],[18]
# Mouse knockout
Mice embryos with homozygous mutations on RUNX1 died at about 12.5 days. The embryos displayed lack of fetal liver hematopoiesis.[19]
Similar experiments from a different research group demonstrated that the knockout embryos die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS).[20]
# Participation in haematopoiesis
RUNX1 plays a crucial role in adult (definitive) haematopoiesis during embryonic development. It is expressed in all haematopoietic sites that contribute to the formation of haematopoietic stem and progenitor cells (HSPCs), including the yolk sac, allantois, placenta, para-aortic splanchnopleura (P-Sp; (the visceral mesodermal layer), aorta-gonad-mesonephros (AGM) and the umbilical and vitelline arteries. HSPCs are generated via the hemogenic endothelium, a special subset of endothelial cells scattered within blood vessels that can differentiate into haematopoietic cells. The emergence of HSPCs is often studied in mouse and zebrafish animal models, in which HSPCs appear as “intra-aortic” clusters that adhere to the ventral wall of the dorsal aorta. RUNX1 or CBF takes part in this process by mediating the transition of an endothelial cell to become a haematopoietic cell. There is increasing evidence that RUNX1 may also be important during primitive haematopoiesis. This is because in RUNX1 knockout mice, primitive erythrocytes displayed a defective morphology and the size of blast cell population was substantially reduced, apart from the absence of HSPCs which would result in embryonic lethality by Embryonic day (E) 11.5 – 12.5.
At a molecular level, expression of the gene RUNX1 is upregulated by the RUNX1 intronic cis-regulatory element (+23 RUNX1 enhancer). This +23 RUNX1 enhancer contains conserved motifs that encourage binding of various haematopoiesis related regulators such as Gata2, ETS factors (Fli-1, Elf-1, PU.1) and the SCL / Lmo2 / Ldb1 complex, as well as RUNX1 itself acting in an auto-regulatory loop. As mentioned before, the main role of RUNX1 is to modulate the fate of haematopoietic cells. This can be achieved by binding to the thrombopoietin (TPO) receptor/ c-Mpl promoter, followed by the recruitment of transcription activators or repressors in order to promote transition of the hemogenic endothelium to HSCs, or differentiation into lineages of lower haematopoietic hierarchies. RUNX1 can also modulate its own level by upregulating the expression of Smad6 to target itself for proteolysis.[21]
# Mutations and acute myeloid leukemia
At least 39 forms of RUNX1 mutation are implicated in various myeloid malignancies. Examples range from RUNX1 point mutations acquired from low-dose radiation leading to myelodysplastic neoplasms or therapy-related myeloid neoplasms, to chromosomal translocation of the RUNX1 gene with the ETO / MTG8 / RUNX1T1 gene located on chromosome 8q22, t(8; 21), generating a fusion protein AML-ETO, categorized as acute myeloid leukemia (AML) M2.
In t(8; 21), breakpoints frequently occur at intron 5 – 6 of RUNX1 and intron 1b – 2 of ETO, creating chimeric transcripts that inherit the runt domain from RUNX1, and all Nervy homology regions (NHR) 1-4 from ETO. As a consequence, AML-ETO retains the ability to bind at RUNX1 target genes whilst acting as a transcription repressor via the recruitment of corepressors and histone deacetylases, which is an intrinsic function of ETO. Oncogenic potential of AML-ETO is exerted because it blocks differentiation and promote self-renewal in blast cells, resulting in massive accumulation of blasts (>20%) in the bone marrow. This is further characterized histologically by the presence of Auer rods and epigenetically by lysine acetylation on residues 24 and 43. Other actions of AML-ETO that could induce leukemogenesis include downregulation of the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) and increase in the level of intracellular reactive oxygen species, making cells that express AML-ETO more susceptible to additional genetic mutations.
# Participation in hair follicle development
Runx1 was first discovered to be expressed in mouse embryonic skin.[22] It is expressed in the epithelial compartment to control hair follicle activation from telogen to anagen through activating Wnt singaling and Lef1 levels [23] At the same time it is expressed in the dermis where it suppresses the same targets to allow for embryogenic development of hair shaft and follicles.[24] In the human hair follicle the expression patterns are similar to the mouse - indicating that it plays a similar role.[25] In addition to hair follicle development, Runx1 is also implicated in skin and epithelial cancer development.[25][26] Thus there are similarities across tissue in Runx1 behavior.
# Interactions
RUNX1 has been shown to interact with:
- C-Fos,[27][28]
- C-jun,[27][28]
- SUV39H1[29]
- TLE1,[30] and
- VDR.[31]
- Stat3 [25] | https://www.wikidoc.org/index.php/RUNX1 | |
4c4aa635b35062a8fdaf181efaaac4c4d6804699 | wikidoc | RUNX2 | RUNX2
Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the RUNX2 gene. RUNX2 is a key transcription factor associated with osteoblast differentiation.
It has also been suggested that Runx2 plays a cell proliferation regulatory role in cell cycle entry and exit in osteoblasts, as well as endothelial cells. Runx2 suppresses pre-osteoblast proliferation by affecting cell cycle progression in the G1 phase. In osteoblasts, the levels of Runx2 is highest in G1 phase and is lowest in S, G2, and M. The comprehensive cell cycle regulatory mechanisms that Runx2 may play are still unknown, although it is generally accepted that the varying activity and levels of Runx2 throughout the cell cycle contribute to cell cycle entry and exit, as well as cell cycle progression. These functions are especially important when discussing bone cancer, particularly osteosarcoma development, that can be attributed to aberrant cell proliferation control.
# Function
## Osteoblast differentiation
This protein is a member of the RUNX family of transcription factors and has a Runt DNA-binding domain. It is essential for osteoblastic differentiation and skeletal morphogenesis. It acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing.
The cellular dynamics of Runx2 protein are also important for proper osteoblast differentiation. Runx2 protein is detected in preosteoblasts and the expression is upregulated in immature osteoblasts and downregulated in mature osteoblasts. It is the first transcription factor required for determination of osteoblast commitment, followed by Sp7 and Wnt-signaling. Runx2 is responsible for inducing the differentiation of multipotent mesenchymal cells into immature osteoblasts, as well as activating expression of several key downstream proteins that maintain osteoblast differentiation and bone matrix genes.
Knock-out of the DNA-binding activity results in inhibition of osteoblastic differentiation. Because of this, Runx2 is often referred to as the master regulator of bone.
## Cell cycle regulation
In addition to being the master regulator of osteoblast differentiation, Runx2 has also been shown to play several roles in cell cycle regulation. This is due, in part, to the fact that Runx2 interacts with many cellular proliferation genes on a transcription level, such as c-Myb and C/EBP, as well as p53/ These functions are critical for osteoblast proliferation and maintenance. This is often controlled via oscillating levels of Runx2 within throughout cell cycle due to regulated degradation and transcriptional activity.
Oscillating levels of Runx2 within the cell contribute to cell cycle dynamics. In the MC3T3-E1 osteoblast cell line, Runx2 levels are a maximum during G1 and a minimum during G2, S, and mitosis. In addition, the oscillations in Runx2 contribute to G1-related anti-proliferative function. It has also been proposed that decreasing levels of Runx2 leads to cell cycle exit for proliferating and differentiating osteoblasts, and that Runx2 plays a role in mediating the final stages of osteoblast via this mechanism. Current research posits that the levels of Runx2 serve various functions.
In addition, Runx2 has been shown to interact with several kinases that contribute to facilitate cell-cycle dependent dynamics via direct protein phosphorylation. Furthermore, Runx2 controls the gene expression of cyclin D2, D3, and the CDK inhibitor p21(cip1) in hematopoietic cells. It has been shown that on a molecular level, Runx associates with the cdc2 partner cyclin B1 during mitosis. The phosphorylation state of Runx2 also mediates it’s DNA-binding activity. The Runx2 DNA-binding activity is correlated with cellular proliferation, which suggests Runx2 phosphorylation may also be related to Runx2-mediated cellular proliferation and cell cycle control. To support this, it has been noted that Runx is phosphorylated at Ser451 by cdc2 kinase, which facilitates cell cycle progression through the regulation of G2 and M phases.
# Pathology
## Cleidocranial dysplasia
Mutations in Runx2 are associated with the disease Cleidocranial dysostosis. One study proposes that this phenotype arises partly due to the Runx2 dosage insufficiencies. Because Runx2 promotes exit from the cell cycle, insufficient amounts of Runx2 are related to increased proliferation of osteoblasts observed in patients with cleodocranial disostosis.
## Osteosarcoma
Variants of Runx2 have been associated with the osteosarcoma phenotype. Current research suggests that this is partly due to the role of Runx2 in mitigating the cell cycle. Runx2 plays a role as a tumor suppressor of osteoblasts by halting cell cycle progression at G1. Compared to normal osteoblast cell line MC3T3-E1, the oscillations of Runx2 in osteosarcoma ROS and SaOS cell lines are aberrant when compared to the oscillations of Runx2 levels in normal osteoblasts, suggesting that deregulation of Runx2 levels may contribute to abnormal cell proliferation by an inability to escape the cell cycle. Molecularly, It has been proposed that proteasome inhibition by MG132 can stabilize Runx2 protein levels in late G1 and S in MC3T3 cells, but not in osteosarcoma cells which consequently leads to a cancerous phenotype.
# Regulation and co-factors
Due to its role as a master transcription factor of osteoblast differentiation, the regulation of Runx2 is intricately connected to other processes within the cell.
Twist, Msh homeobox 2 (Msx2), and promyeloctic leukemia zinc-finger protein (PLZF) act upstream of Runx2. Osterix (Osx) acts downstream of Runx2 and serves as a marker for normal osteoblast differentiation. Zinc finger protein 521 (ZFP521) and activating transcription factor 4 (ATF4) are cofactors of Runx2.
Furthermore, in proliferating chondrocytes, Runx2 is inhibited by CyclinD1/CDK4 as part of the cell cycle.
# Interactions
RUNX2 has been shown to interact with:
- AR
- ER-α
- C-Fos,
- C-jun,
- HDAC3,
- MYST4,
- SMAD1
- SMAD3, and
- STUB1.
miR-133 and CyclinD1/CDK4 directly inhibits Runx2. | RUNX2
Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the RUNX2 gene. RUNX2 is a key transcription factor associated with osteoblast differentiation.
It has also been suggested that Runx2 plays a cell proliferation regulatory role in cell cycle entry and exit in osteoblasts, as well as endothelial cells. Runx2 suppresses pre-osteoblast proliferation by affecting cell cycle progression in the G1 phase.[2] In osteoblasts, the levels of Runx2 is highest in G1 phase and is lowest in S, G2, and M.[1] The comprehensive cell cycle regulatory mechanisms that Runx2 may play are still unknown, although it is generally accepted that the varying activity and levels of Runx2 throughout the cell cycle contribute to cell cycle entry and exit, as well as cell cycle progression. These functions are especially important when discussing bone cancer, particularly osteosarcoma development, that can be attributed to aberrant cell proliferation control.
# Function
## Osteoblast differentiation
This protein is a member of the RUNX family of transcription factors and has a Runt DNA-binding domain. It is essential for osteoblastic differentiation and skeletal morphogenesis. It acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing.
The cellular dynamics of Runx2 protein are also important for proper osteoblast differentiation. Runx2 protein is detected in preosteoblasts and the expression is upregulated in immature osteoblasts and downregulated in mature osteoblasts. It is the first transcription factor required for determination of osteoblast commitment, followed by Sp7 and Wnt-signaling. Runx2 is responsible for inducing the differentiation of multipotent mesenchymal cells into immature osteoblasts, as well as activating expression of several key downstream proteins that maintain osteoblast differentiation and bone matrix genes.
Knock-out of the DNA-binding activity results in inhibition of osteoblastic differentiation. Because of this, Runx2 is often referred to as the master regulator of bone.[3]
## Cell cycle regulation
In addition to being the master regulator of osteoblast differentiation, Runx2 has also been shown to play several roles in cell cycle regulation. This is due, in part, to the fact that Runx2 interacts with many cellular proliferation genes on a transcription level, such as c-Myb and C/EBP,[1] as well as p53/[3] These functions are critical for osteoblast proliferation and maintenance. This is often controlled via oscillating levels of Runx2 within throughout cell cycle due to regulated degradation and transcriptional activity.
Oscillating levels of Runx2 within the cell contribute to cell cycle dynamics. In the MC3T3-E1 osteoblast cell line, Runx2 levels are a maximum during G1 and a minimum during G2, S, and mitosis.[1] In addition, the oscillations in Runx2 contribute to G1-related anti-proliferative function.[4] It has also been proposed that decreasing levels of Runx2 leads to cell cycle exit for proliferating and differentiating osteoblasts, and that Runx2 plays a role in mediating the final stages of osteoblast via this mechanism.[5] Current research posits that the levels of Runx2 serve various functions.
In addition, Runx2 has been shown to interact with several kinases that contribute to facilitate cell-cycle dependent dynamics via direct protein phosphorylation. Furthermore, Runx2 controls the gene expression of cyclin D2, D3, and the CDK inhibitor p21(cip1) in hematopoietic cells. It has been shown that on a molecular level, Runx associates with the cdc2 partner cyclin B1 during mitosis.[6] The phosphorylation state of Runx2 also mediates it’s DNA-binding activity. The Runx2 DNA-binding activity is correlated with cellular proliferation, which suggests Runx2 phosphorylation may also be related to Runx2-mediated cellular proliferation and cell cycle control. To support this, it has been noted that Runx is phosphorylated at Ser451 by cdc2 kinase, which facilitates cell cycle progression through the regulation of G2 and M phases.[6]
# Pathology
## Cleidocranial dysplasia
Mutations in Runx2 are associated with the disease Cleidocranial dysostosis. One study proposes that this phenotype arises partly due to the Runx2 dosage insufficiencies. Because Runx2 promotes exit from the cell cycle, insufficient amounts of Runx2 are related to increased proliferation of osteoblasts observed in patients with cleodocranial disostosis.[7]
## Osteosarcoma
Variants of Runx2 have been associated with the osteosarcoma phenotype.[1] Current research suggests that this is partly due to the role of Runx2 in mitigating the cell cycle.[2] Runx2 plays a role as a tumor suppressor of osteoblasts by halting cell cycle progression at G1.[1] Compared to normal osteoblast cell line MC3T3-E1, the oscillations of Runx2 in osteosarcoma ROS and SaOS cell lines are aberrant when compared to the oscillations of Runx2 levels in normal osteoblasts, suggesting that deregulation of Runx2 levels may contribute to abnormal cell proliferation by an inability to escape the cell cycle. Molecularly, It has been proposed that proteasome inhibition by MG132 can stabilize Runx2 protein levels in late G1 and S in MC3T3 cells, but not in osteosarcoma cells which consequently leads to a cancerous phenotype.[2][1]
# Regulation and co-factors
Due to its role as a master transcription factor of osteoblast differentiation, the regulation of Runx2 is intricately connected to other processes within the cell.
Twist, Msh homeobox 2 (Msx2), and promyeloctic leukemia zinc-finger protein (PLZF) act upstream of Runx2. Osterix (Osx) acts downstream of Runx2 and serves as a marker for normal osteoblast differentiation. Zinc finger protein 521 (ZFP521) and activating transcription factor 4 (ATF4) are cofactors of Runx2.[8]
Furthermore, in proliferating chondrocytes, Runx2 is inhibited by CyclinD1/CDK4 as part of the cell cycle.[9]
# Interactions
RUNX2 has been shown to interact with:
- AR[10]
- ER-α[11]
- C-Fos,[12][13]
- C-jun,[12][13]
- HDAC3,[14]
- MYST4,[15]
- SMAD1[16][17]
- SMAD3,[16][17] and
- STUB1.[18]
miR-133 and CyclinD1/CDK4 directly inhibits Runx2.[19][9] | https://www.wikidoc.org/index.php/RUNX2 | |
ed74efd499181701a9db581aa4b36046afd0064d | wikidoc | RUNX3 | RUNX3
Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.
# Function
This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-YGYGGT-3' found in a number of enhancers and promoters, and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Multiple transcript variants encoding different isoforms have been found for this gene.
In melanocytic cells RUNX3 gene expression may be regulated by MITF.
# Knockout mouse
Runx3 null mouse gastric mucosa exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to TGF-beta stimulation.
# The RUNX3 controversy
In 2011 serious doubt was cast over the tumor suppressor function of Runx3 originated from the earlier publication by Li and co-workers.
On the basis of the original study by Li and co-workers (2002), the majority of later literature citing Li and co-workers (2002) assumed that RUNX3 was expressed in the normal gut epithelium and that it is therefore likely to act as a tumor suppressor in the particular epithelial cancer investigated. Most of this literature used RUNX3 promoter methylation status in various cancers as a proxy for its expression. However, quite many genes are known to be methylated in tumor cell genomes, and the majority of these genes are not expressed in the normal tissue of origin of these cancers. Others used poorly characterized (or fully invalidated) antibodies to detect the RUNX3 protein, or used RT-PCR or validated antibodies and failed to detect RUNX3 in the gut epithelium but still did not question the original finding by Li and co-workers (2002). This facts have recently been discussed in a novel by Ülo Maiväli.
# Interactions
RUNX3 has been shown to interact with TLE1. | RUNX3
Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.[1]
# Function
This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-YGYGGT-3' found in a number of enhancers and promoters,[2] and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[3]
In melanocytic cells RUNX3 gene expression may be regulated by MITF.[4]
# Knockout mouse
Runx3 null mouse gastric mucosa exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to TGF-beta stimulation.[5]
# The RUNX3 controversy
In 2011 serious doubt was cast over the tumor suppressor function of Runx3 originated from the earlier publication by Li and co-workers.[6]
On the basis of the original study by Li and co-workers (2002), the majority of later literature citing Li and co-workers (2002) assumed that RUNX3 was expressed in the normal gut epithelium and that it is therefore likely to act as a tumor suppressor in the particular epithelial cancer investigated. Most of this literature used RUNX3 promoter methylation status in various cancers as a proxy for its expression. However, quite many genes are known to be methylated in tumor cell genomes, and the majority of these genes are not expressed in the normal tissue of origin of these cancers. Others used poorly characterized (or fully invalidated) antibodies to detect the RUNX3 protein, or used RT-PCR or validated antibodies and failed to detect RUNX3 in the gut epithelium but still did not question the original finding by Li and co-workers (2002). This facts have recently been discussed in a novel by Ülo Maiväli.[7]
# Interactions
RUNX3 has been shown to interact with TLE1.[8] | https://www.wikidoc.org/index.php/RUNX3 | |
b18933961d215818fe3fc17ebc628a8315d5413f | wikidoc | Rad50 | Rad50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.
# Function
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1 (also known as Xrs2 in yeast). This MRN complex (MRX complex in yeast) binds to broken DNA ends and displays numerous enzymatic activities that are required for double-strand break repair by nonhomologous end-joining or homologous recombination. Gene knockout studies of the mouse homolog of Rad50 suggest it is essential for cell growth and viability. Two alternatively spliced transcript variants of Rad50, which encode distinct proteins, have been reported.
# Structure
Rad50 is a member of the structural maintenance of chromosomes (SMC) family of proteins. Like other SMC proteins, Rad50 contains a long internal coiled-coil domain that folds back on itself, bringing the N- and C-termini together to form a globular ABC ATPase head domain. Rad50 can dimerize both through its head domain and through a zinc-binding dimerization motif at the opposite end of the coiled-coil known as the “zinc-hook”. Results from atomic force microscopy suggest that in free Mre11-Rad50-Nbs1 complexes, the zinc-hooks of a single Rad50 dimer associate to form a closed loop, while the zinc-hooks snap apart upon binding DNA, adopting a conformation that is thought to enable zinc-hook-mediated tethering of broken DNA ends.
# Interactions
Rad50 has been shown to interact with:
- BRCA1,
- MRE11A,
- NBN,
- RINT1,
- TERF2IP, and
- TERF2.
# Evolutionary ancestry
Rad50 protein has been mainly studied in eukaryotes. However, recent work has shown that orthologs of the Rad50 protein are also conserved in extant prokaryotic archaea where they likely function in homologous recombinational repair. In the hyperthermophilic archeon Sulfolobus acidocaldarius, the Rad50 and Mre11 proteins interact and appear to have an active role in repair of DNA damages introduced by gamma radiation. These findings suggest that eukaryotic Rad50 may be descended from an ancestral archaeal Rad50 protein that served a role in homologous recombinational repair of DNA damage. | Rad50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.[1]
# Function
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1 (also known as Xrs2 in yeast). This MRN complex (MRX complex in yeast) binds to broken DNA ends and displays numerous enzymatic activities that are required for double-strand break repair by nonhomologous end-joining or homologous recombination. Gene knockout studies of the mouse homolog of Rad50 suggest it is essential for cell growth and viability. Two alternatively spliced transcript variants of Rad50, which encode distinct proteins, have been reported.[1]
# Structure
Rad50 is a member of the structural maintenance of chromosomes (SMC) family of proteins.[2] Like other SMC proteins, Rad50 contains a long internal coiled-coil domain that folds back on itself, bringing the N- and C-termini together to form a globular ABC ATPase head domain. Rad50 can dimerize both through its head domain and through a zinc-binding dimerization motif at the opposite end of the coiled-coil known as the “zinc-hook”.[3] Results from atomic force microscopy suggest that in free Mre11-Rad50-Nbs1 complexes, the zinc-hooks of a single Rad50 dimer associate to form a closed loop, while the zinc-hooks snap apart upon binding DNA, adopting a conformation that is thought to enable zinc-hook-mediated tethering of broken DNA ends.[4]
# Interactions
Rad50 has been shown to interact with:
- BRCA1,[5][6][7]
- MRE11A,[5][6][8][9][10]
- NBN,[5][9][11][12]
- RINT1,[13]
- TERF2IP,[14] and
- TERF2.[14][15]
# Evolutionary ancestry
Rad50 protein has been mainly studied in eukaryotes. However, recent work has shown that orthologs of the Rad50 protein are also conserved in extant prokaryotic archaea where they likely function in homologous recombinational repair.[16] In the hyperthermophilic archeon Sulfolobus acidocaldarius, the Rad50 and Mre11 proteins interact and appear to have an active role in repair of DNA damages introduced by gamma radiation.[17] These findings suggest that eukaryotic Rad50 may be descended from an ancestral archaeal Rad50 protein that served a role in homologous recombinational repair of DNA damage. | https://www.wikidoc.org/index.php/Rad50 | |
d07a16015f520087c2ca9d630cd73f078526e1f4 | wikidoc | Ramus | Ramus
Ramus can refer to:
- A portion of a bone (from Latin ramus, "branch"), as in the Ramus mandibulæ or Superior pubic ramus
- A nerve ramus such as the Dorsal ramus of spinal nerve
- An arterial branch such as the ramus intermedius in the heart | Ramus
Ramus can refer to:
- A portion of a bone (from Latin ramus, "branch"), as in the Ramus mandibulæ or Superior pubic ramus
- A nerve ramus such as the Dorsal ramus of spinal nerve
- An arterial branch such as the ramus intermedius in the heart | https://www.wikidoc.org/index.php/Ramus | |
fd0bb2655ad04a03ef8a77980849ada5eb5b5376 | wikidoc | Raphe | Raphe
A raphe has different uses:
# In science
Pronounced "RAY-fee" Template:IPA), it is most commonly used when describing diatoms, seeds, and human anatomy.
In the field of anatomy, the term refers to a continuous ridge of tissue. There are several different significant raphes:
- The perineal raphe extends from the anus, through the mid-line of the scrotum (scrotal raphe) and upwards through the posterior mid-line aspect of the penis (penile raphe).
- The buccal raphe which is on the cheek and evidence of the fusion of the maxillary and mandibular processes.
- The lingual raphe on the tongue. Obvious physical evidence of the lingual raphe includes the frenulum (also called the frenum), or band of mucous membrane that is visible under the tongue attaching it to the floor of the mouth. If this raphe is too tight at birth, movement of the tongue is restricted and the child is said to be "tongue tied".
- The palatine raphe on the roof of the mouth (or palate). Incomplete fusion of the palatine raphe results in a congenital defect known as cleft palate.
- The pharyngeal raphe is near the pharyngeal constrictors.
- The raphe nucleus is a moderate-size cluster of nuclei found in the brain stem which releases serotonin to the rest of the brain. Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act at these nuclei.
- The anococcygeal raphe
- The pterygomandibular raphe
- The lateral palpebral raphe | Raphe
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A raphe has different uses:
# In science
Pronounced "RAY-fee" Template:IPA), it is most commonly used when describing diatoms, seeds, and human anatomy.
In the field of anatomy, the term refers to a continuous ridge of tissue. There are several different significant raphes:
- The perineal raphe extends from the anus, through the mid-line of the scrotum (scrotal raphe) and upwards through the posterior mid-line aspect of the penis (penile raphe).
- The buccal raphe which is on the cheek and evidence of the fusion of the maxillary and mandibular processes.
- The lingual raphe on the tongue. Obvious physical evidence of the lingual raphe includes the frenulum (also called the frenum), or band of mucous membrane that is visible under the tongue attaching it to the floor of the mouth. If this raphe is too tight at birth, movement of the tongue is restricted and the child is said to be "tongue tied".
- The palatine raphe on the roof of the mouth (or palate). Incomplete fusion of the palatine raphe results in a congenital defect known as cleft palate.
- The pharyngeal raphe is near the pharyngeal constrictors.
- The raphe nucleus is a moderate-size cluster of nuclei found in the brain stem which releases serotonin to the rest of the brain. Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act at these nuclei.
- The anococcygeal raphe
- The pterygomandibular raphe
- The lateral palpebral raphe
# External links
- Template:GPnotebook
de:Raphe
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Raphe | |
c5436b9f8116f50c3fe36d180eae9647321f45d5 | wikidoc | Rayon | Rayon
# Overview
Rayon is a manufactured regenerated cellulosic fiber. Rayon is produced from naturally occurring polymers and therefore it is not a truly synthetic fiber, nor is it a natural fiber.
# History
## Nitrocellulose
The fact that Nitrocellulose is soluble in organic solvents such as ether and acetone, made it possible for Georges Audemars to develop the first "artificial silk" about 1855, but his method was impractical for commercial use. Hilaire de Charbonnet, Comte de Chardonnay, patented "Chardonnay silk" in 1884. The commercial production started 1891, but it was flammable, and more expensive than acetate or cuprammonium rayon. Because of this, production was stopped before World War I, for example 1912 in Germany.
## Acetate Method
Paul Schützenberger discovered that cellulose can be reacted with acetic acid anhydride to form cellulose acetate. The triacetate is only soluble in chloroform making the method expensive. The discovery that hydrolyzed cellulose acetate is soluble in less polar solvents, like acetone, made production of cellulose acetate fibers cheap and efficient.
## Cuprammonium Method
The German chemist Eduard Schweizer discovered that tetraamminecopper dihydroxide could dissolve cellulose. Max Fremery and Johann Urban developed a method to produce carbon fibers for use in light bulbs in 1892. Production of rayon for textiles started in 1899 in the Vereinigte Glanzstofffabriken AG in Oberbruch. Improvement by the J.P. Bemberger AG in 1901 made the artificial silk a product comparable to real silk.
## Viscose Method
Viscose finally, in 1894, Charles Frederick Cross, Edward John Bevan, and Clayton Beadle patented their artificial silk, which they named "viscose", because the reaction product of carbon disulfide and cellulose in basic conditions gave a highly viscous solution of xanthate. Avtex Fibers Incorporated began selling their formulation in 1910 in the United States.
The name "rayon" was adopted in 1924, with "viscose" being used for the viscous organic liquid used to make both rayon and cellophane. In Europe, though, the fabric itself became known as "viscose," which has been ruled an acceptable alternative term for rayon by the Federal Trade Commission.
The method is able to use wood (cellulose and lignin) as a source of cellulose while the other methods need lignin-free cellulose as starting material. This makes it cheaper and therefore it was used on a larger scale than the other methods.
Contamination of the waste water by carbon disulfide, lignin and the xanthates made this process detrimental to the environment. Rayon was only produced as a filament fiber until the 1930s when it was discovered that broken waste rayon could be used in staple fiber.
The physical properties of rayon were unchanged until the development of high-tenacity rayon in the 1940s. Further research and development led to the creation of high-wet-modulus rayon (HWM rayon) in the 1950s .
# Major fiber properties
Rayon is a very versatile fiber and has the same comfort properties as natural fibers. It can imitate the feel and texture of silk, wool, cotton and linen. The fibers are easily dyed in a wide range of colors. Rayon fabrics are soft, smooth, cool, comfortable, and highly absorbent, but they do not insulate body heat, making them ideal for use in hot and humid climates .
The durability and appearance retention of regular rayon are low, especially when wet; also, rayon has the lowest elastic recovery of any fiber. However, HWM rayon is much stronger and exhibits higher durability and appearance retention. Recommended care for regular rayon is dry-cleaning only; HWM rayon can also be machine washed .
# Physical structure of rayon
Regular rayon has lengthwise lines called striations and its cross-section is an indented circular shape. The cross-sections of HWM and cupra rayon are rounder. Filament rayon yarns vary from 80 to 980 filaments per yarn and vary in size from 40 to 5000 denier. Staple fibers range from 1.5 to 15 denier and are mechanically or chemically crimped. Rayon fibers are naturally very bright, but the addition of delustering pigments cuts down on this natural brightness .
# Production method
Regular rayon (or viscose) is the most widely produced form of rayon. This method of rayon production has been utilized since the early 1900s and it has the ability to produce either filament or staple fibers. The process is as follows:
- Cellulose: Production begins with processed cellulose
- Immersion: The cellulose is dissolved in caustic soda
- Pressing: The solution is then pressed between rollers to remove excess liquid
- White Crumb: The pressed sheets are crumbled or shredded to produce what is known as "white crumb"
- Aging: The "white crumb" aged through exposure to oxygen
- Xanthation: The aged "white crumb" is mixed with carbon disulfide in a process known as Xanthation
- Yellow Crumb: Xanthation changes the chemical makeup of the cellulose mixture and the resulting product is now called "yellow crumb"
- Viscose: The "yellow crumb" is dissolved in a caustic solution to form viscose
- Ripening: The viscose is set to stand for a period of time, allowing it to ripen
- Filtering: After ripening, the viscose is filtered to remove any undissolved particles
- Degassing: Any bubbles of air are pressed from the viscose in a degassing process
- Extruding: The viscose solution is extruded through a spinneret, which resembles a shower head with many small holes
- Acid Bath: As the viscose exits the spinneret, it lands in a bath of sulfuric acid resulting in the formation of rayon filaments
- Drawing: The rayon filaments are stretched, known as drawing, to straighten out the fibers
- Washing: The fibers are then washed to remove any residual chemicals
- Cutting: If filament fibers are desired the process ends here. The filaments are cut down when producing staple fibers .
High Wet Modulus rayon (HWM) is a modified version of viscose that has a greater strength when wet. It also has the ability to be mercerized like cotton. HWM rayons are also known as "polynosic" or can be identified by the trade name MODAL .
High Tenacity rayon is another modified version of viscose that has almost twice the strength of HWM. This type of rayon is typically used for industrial purposes such as tire cord .
Cupramonium rayon has properties similar to viscose but during production, the cellulose is combined with copper and ammonia (Schweizer's reagent). Due to the environmental effects of this production method, cupramonium rayon is no longer produced in the United States .
# Producers
Trade names are used within the rayon industry to determine the type of rayon used.
Bemberg, for example, is a trade name for cupramonium rayon that is only produced in Italy due to EPA regulations in the US .
Modal and Tencel are widely used forms of rayon produced by Lenzing Fibers Corp. which is based in northern Austria .
Galaxy, Danufil, and Viloft are rayon brands produced by Kelheim Fibres, a German manufacturer.
Acordis is a major manufacturer of cellulose based fibers and yarns. Production facilities can be found throughout Europe, the U.S. and Brazil .
Visil rayon is a flame retardant form of viscose which has silica embedded in the fiber during manufacturing. .
North American Rayon Corp of Tennessee produced viscose rayon until its closure in the year 2000. .
Grasim of India is the largest producer of rayon in the world (claiming 24% market share). It has plants in Nagda, Kharach and Harihar - all in India. .
# Uses of rayon
Some major rayon fiber uses include apparel (e.g. blouses, dresses, jackets, lingerie, linings, suits, ties), furnishings (e.g. bedspreads, blankets, window treatments, upholstery, slipcovers), industrial uses (e.g. medical surgery products, non-woven products, tire cord), and other uses (e.g. yarn, feminine hygiene products) . | Rayon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rayon is a manufactured regenerated cellulosic fiber. Rayon is produced from naturally occurring polymers and therefore it is not a truly synthetic fiber, nor is it a natural fiber.
# History
## Nitrocellulose
The fact that Nitrocellulose is soluble in organic solvents such as ether and acetone, made it possible for Georges Audemars to develop the first "artificial silk" about 1855, but his method was impractical for commercial use. Hilaire de Charbonnet, Comte de Chardonnay, patented "Chardonnay silk" in 1884. The commercial production started 1891, but it was flammable, and more expensive than acetate or cuprammonium rayon. Because of this, production was stopped before World War I, for example 1912 in Germany.
## Acetate Method
Paul Schützenberger discovered that cellulose can be reacted with acetic acid anhydride to form cellulose acetate. The triacetate is only soluble in chloroform making the method expensive. The discovery that hydrolyzed cellulose acetate is soluble in less polar solvents, like acetone, made production of cellulose acetate fibers cheap and efficient.
## Cuprammonium Method
The German chemist Eduard Schweizer discovered that tetraamminecopper dihydroxide could dissolve cellulose. Max Fremery and Johann Urban developed a method to produce carbon fibers for use in light bulbs in 1892. Production of rayon for textiles started in 1899 in the Vereinigte Glanzstofffabriken AG in Oberbruch. Improvement by the J.P. Bemberger AG in 1901 made the artificial silk a product comparable to real silk.
## Viscose Method
Viscose finally, in 1894, Charles Frederick Cross, Edward John Bevan, and Clayton Beadle patented their artificial silk, which they named "viscose", because the reaction product of carbon disulfide and cellulose in basic conditions gave a highly viscous solution of xanthate. Avtex Fibers Incorporated began selling their formulation in 1910 in the United States.
The name "rayon" was adopted in 1924, with "viscose" being used for the viscous organic liquid used to make both rayon and cellophane. In Europe, though, the fabric itself became known as "viscose," which has been ruled an acceptable alternative term for rayon by the Federal Trade Commission.
The method is able to use wood (cellulose and lignin) as a source of cellulose while the other methods need lignin-free cellulose as starting material. This makes it cheaper and therefore it was used on a larger scale than the other methods.
Contamination of the waste water by carbon disulfide, lignin and the xanthates made this process detrimental to the environment. Rayon was only produced as a filament fiber until the 1930s when it was discovered that broken waste rayon could be used in staple fiber.
The physical properties of rayon were unchanged until the development of high-tenacity rayon in the 1940s. Further research and development led to the creation of high-wet-modulus rayon (HWM rayon) in the 1950s [1].
# Major fiber properties
Rayon is a very versatile fiber and has the same comfort properties as natural fibers. It can imitate the feel and texture of silk, wool, cotton and linen. The fibers are easily dyed in a wide range of colors. Rayon fabrics are soft, smooth, cool, comfortable, and highly absorbent, but they do not insulate body heat, making them ideal for use in hot and humid climates [2].
The durability and appearance retention of regular rayon are low, especially when wet; also, rayon has the lowest elastic recovery of any fiber. However, HWM rayon is much stronger and exhibits higher durability and appearance retention. Recommended care for regular rayon is dry-cleaning only; HWM rayon can also be machine washed [1].
# Physical structure of rayon
Regular rayon has lengthwise lines called striations and its cross-section is an indented circular shape. The cross-sections of HWM and cupra rayon are rounder. Filament rayon yarns vary from 80 to 980 filaments per yarn and vary in size from 40 to 5000 denier. Staple fibers range from 1.5 to 15 denier and are mechanically or chemically crimped. Rayon fibers are naturally very bright, but the addition of delustering pigments cuts down on this natural brightness [1].
# Production method
Regular rayon (or viscose) is the most widely produced form of rayon. This method of rayon production has been utilized since the early 1900s and it has the ability to produce either filament or staple fibers. The process is as follows:
- Cellulose: Production begins with processed cellulose
- Immersion: The cellulose is dissolved in caustic soda
- Pressing: The solution is then pressed between rollers to remove excess liquid
- White Crumb: The pressed sheets are crumbled or shredded to produce what is known as "white crumb"
- Aging: The "white crumb" aged through exposure to oxygen
- Xanthation: The aged "white crumb" is mixed with carbon disulfide in a process known as Xanthation
- Yellow Crumb: Xanthation changes the chemical makeup of the cellulose mixture and the resulting product is now called "yellow crumb"
- Viscose: The "yellow crumb" is dissolved in a caustic solution to form viscose
- Ripening: The viscose is set to stand for a period of time, allowing it to ripen
- Filtering: After ripening, the viscose is filtered to remove any undissolved particles
- Degassing: Any bubbles of air are pressed from the viscose in a degassing process
- Extruding: The viscose solution is extruded through a spinneret, which resembles a shower head with many small holes
- Acid Bath: As the viscose exits the spinneret, it lands in a bath of sulfuric acid resulting in the formation of rayon filaments
- Drawing: The rayon filaments are stretched, known as drawing, to straighten out the fibers
- Washing: The fibers are then washed to remove any residual chemicals
- Cutting: If filament fibers are desired the process ends here. The filaments are cut down when producing staple fibers [3].
High Wet Modulus rayon (HWM) is a modified version of viscose that has a greater strength when wet. It also has the ability to be mercerized like cotton. HWM rayons are also known as "polynosic" or can be identified by the trade name MODAL [4].
High Tenacity rayon is another modified version of viscose that has almost twice the strength of HWM. This type of rayon is typically used for industrial purposes such as tire cord [4].
Cupramonium rayon has properties similar to viscose but during production, the cellulose is combined with copper and ammonia (Schweizer's reagent). Due to the environmental effects of this production method, cupramonium rayon is no longer produced in the United States [4].
# Producers
Trade names are used within the rayon industry to determine the type of rayon used.
Bemberg, for example, is a trade name for cupramonium rayon that is only produced in Italy due to EPA regulations in the US [5].
Modal and Tencel are widely used forms of rayon produced by Lenzing Fibers Corp. which is based in northern Austria [6].
Galaxy, Danufil, and Viloft are rayon brands produced by Kelheim Fibres, a German manufacturer. [7]
Acordis is a major manufacturer of cellulose based fibers and yarns. Production facilities can be found throughout Europe, the U.S. and Brazil [8].
Visil rayon is a flame retardant form of viscose which has silica embedded in the fiber during manufacturing. [9].
North American Rayon Corp of Tennessee produced viscose rayon until its closure in the year 2000. [10].
Grasim of India is the largest producer of rayon in the world (claiming 24% market share). It has plants in Nagda, Kharach and Harihar - all in India. [11].
# Uses of rayon
Some major rayon fiber uses include apparel (e.g. blouses, dresses, jackets, lingerie, linings, suits, ties), furnishings (e.g. bedspreads, blankets, window treatments, upholstery, slipcovers), industrial uses (e.g. medical surgery products, non-woven products, tire cord), and other uses (e.g. yarn, feminine hygiene products) [3]. | https://www.wikidoc.org/index.php/Rayon | |
77089b8f00ccb8a32d39050574f01013bbf95caf | wikidoc | Relay | Relay
A relay is an electrical switch that opens and closes under the control of another electrical circuit. In the original form, the switch is operated by an electromagnet to open or close one or many sets of contacts. It was invented by Joseph Henry in 1835. Because a relay is able to control an output circuit
-f higher power than the input circuit, it can be considered to be, in a broad sense, a form of an electrical amplifier.
# Operation
When a current flows through the coil, the resulting magnetic field attracts an armature that is mechanically linked to a moving contact. The movement either makes or breaks a connection with a fixed contact. When the current to the coil is switched off, the armature is returned by a force approximately half as strong as the magnetic force to its relaxed position. Usually this is a spring, but gravity is also used commonly in industrial motor starters. Most relays are manufactured to operate quickly. In a low voltage application, this is to reduce noise. In a high voltage or high current application, this is to reduce arcing.
If the coil is energized with DC, a diode is frequently installed across the coil, to dissipate the energy from the collapsing magnetic field at deactivation, which would otherwise generate a spike of voltage and might cause damage to circuit components. Some automotive relays already include that diode inside the relay case. Alternatively a contact protection network, consisting of a capacitor and resistor in series, may absorb the surge. If the coil is designed to be energized with AC, a small copper ring can be crimped to the end of the solenoid. This "shading ring" creates a small out-of-phase current, which increases the minimum pull on the armature during the AC cycle.
By analogy with the functions of the original electromagnetic device, a solid-state relay is made with a thyristor or other solid-state switching device. To achieve electrical isolation an optocoupler can be used which is a light-emitting diode (LED) coupled with a photo transistor.
# Types of relay
## Latching relay
A latching relay has two relaxed states (bistable). These are also called 'keep' or 'stay' relays. When the current is switched off, the relay remains in its last state. This is achieved with a solenoid operating a ratchet and cam mechanism, or by having two opposing coils with an over-center spring or permanent magnet to hold the armature and contacts in position while the coil is relaxed, or with a remnant core. In the ratchet and cam example, the first pulse to the coil turns the relay on and the second pulse turns it off. In the two coil example, a pulse to one coil turns the relay on and a pulse to the opposite coil turns the relay off. This type of relay has the advantage that it consumes power only for an instant, while it is being switched, and it retains its last setting across a power outage.
## Reed relay
A reed relay has a set of contacts inside a vacuum or inert gas filled glass tube, which protects the contacts against atmospheric corrosion. The contacts are closed by a magnetic field generated when current passes through a coil around the glass tube. Reed relays are capable of faster switching speeds than larger types of relays, but have low switch current and voltage ratings. See also reed switch.
## Mercury-wetted relay
A mercury-wetted reed relay is a form of reed relay in which the contacts are wetted with mercury. Such relays are used to switch low-voltage signals (one volt or less) because of its low contact resistance, or for high-speed counting and timing applications where the mercury eliminates contact bounce. Mercury wetted relays are position-sensitive and must be mounted vertically to work properly. Because of the toxicity and expense of liquid mercury, these relays are rarely specified for new equipment. See also mercury switch.
## Polarized relay
A Polarized Relay placed the armature between the poles of a permanent magnet to increase sensitivity. Polarized relays were used in middle 20th Century telephone exchanges to detect faint pulses and correct telegraphic distortion. The poles were on screws, so a technician could first adjust them for maximum sensitivity and then apply a bias spring to set the critical current that would operate the relay.
## Machine tool relay
A machine tool relay is a type standardized for industrial control of machine tools, transfer machines, and other sequential control. They are characterized by a large number of contacts (sometimes extendable in the field) which are easily converted from normally-open to normally-closed status, easily replaceable coils, and a form factor that allows compactly installing many relays in a control panel. Although such relays once were the backbone of automation in such industries as automobile assembly, the programmable logic controller (PLC) mostly displaced the machine tool relay from sequential control applications.
## Contactor relay
A contactor is a very heavy-duty relay used for switching electric motors and lighting loads. With high current, the contacts are made with pure silver. The unavoidable arcing causes the contacts to oxidize and silver oxide is still a good conductor. Such devices are often used for motor starters. A motor starter is a contactor with overload protection devices attached. The overload sensing devices are a form of heat operated relay where a coil heats a bi-metal strip, or where a solder pot melts, releasing a spring to operate auxiliary contacts. These auxiliary contacts are in series with the coil. If the overload senses excess current in the load, the coil is de-energized. Contactor relays can be extremely loud to operate, making them unfit for use where noise is a chief concern.
## Solid state contactor relay
A solid state contactor is a very heavy-duty solid state relay, including the necessary heat sink, used for switching electric heaters, small electric motors and lighting loads; where frequent on/off cycles are required. There are no moving parts to wear out and there is no contact bounce due to vibration. They are activated by AC control signals or DC control signals from Programmable logic controller (PLCs), PCs, Transistor-transistor logic (TTL) sources, or other microprocessor controls.
## Buchholz relay
A Buchholz relay is a safety device sensing the accumulation of gas in large oil-filled transformers, which will alarm on slow accumulation of gas or shut down the transformer if gas is produced rapidly in the transformer oil.
## Forced-guided contacts relay
A forced-guided contacts relay has relay contacts that are mechanically linked together, so that when the relay coil is energized or de-energized, all of the linked contacts move together. If one set of contacts in the relay becomes immobilized, no other contact of the same relay will be able to move. The function of forced-guided contacts is to enable the safety circuit to check the status of the relay. Forced-guided contacts are also known as "positive-guided contacts", "captive contacts", "locked contacts", or "safety relays".
## Solid-state relay
A solid state relay (SSR) is a solid state electronic component that provides a similar function to an electromechanical relay but does not have any moving components, increasing long-term reliability. With early SSR's, the tradeoff came from the fact that every transistor has a small voltage drop across it. This collective voltage drop limited the amount of current a given SSR could handle. As transistors improved, higher current SSR's, able to handle 100 to 1,200 amps, have become commercially available.
Compared to electromagnetic relays, they may be falsely triggered by transients.
## Overload protection relay
One type of electric motor overload protection relay is operated by a heating element in series with the electric motor . The heat generated by the motor current operates a bi-metal strip or melts solder, releasing a spring to operate contacts. Where the overload relay is exposed to the same environment as the motor, a useful though crude compensation for motor ambient temperature is provided.
# Pole & Throw
Since relays are switches, the terminology applied to switches is also applied to relays. A relay will switch one or more poles, each of whose contacts can be thrown by energizing the coil in one of three ways:
- Normally-open (NO) contacts connect the circuit when the relay is activated; the circuit is disconnected when the relay is inactive. It is also called a Form A contact or "make" contact.
- Normally-closed (NC) contacts disconnect the circuit when the relay is activated; the circuit is connected when the relay is inactive. It is also called a Form B contact or "break" contact.
- Change-over, or double-throw, contacts control two circuits: one normally-open contact and one normally-closed contact with a common terminal. It is also called a Form C contact or "transfer" contact. If this type of contact utilizes a "make before break" functionality, then it is called a Form D contact.
The following designations are commonly encountered:
- SPST - Single Pole Single Throw. These have two terminals which can be connected or disconnected. Including two for the coil, such a relay has four terminals in total. It is ambiguous whether the pole is normally open or normally closed. The terminology "SPNO" and "SPNC" is sometimes used to resolve the ambiguity.
- SPDT - Single Pole Double Throw. A common terminal connects to either of two others. Including two for the coil, such a relay has five terminals in total.
- DPST - Double Pole Single Throw. These have two pairs of terminals. Equivalent to two SPST switches or relays actuated by a single coil. Including two for the coil, such a relay has six terminals in total. The poles may be Form A or Form B (or one of each).
- DPDT - Double Pole Double Throw. These have two rows of change-over terminals. Equivalent to two SPDT switches or relays actuated by a single coil. Such a relay has eight terminals, including the coil.
The "S" or "D" may be replaced with a number, indicating multiple switches connected to a single actuator. For example 4PDT indicates a four pole double throw relay (with 14 terminals).
# Applications
Relays are used:
- to control a high-voltage circuit with a low-voltage signal, as in some types of modems or audio amplifiers,
- to control a high-current circuit with a low-current signal, as in the starter solenoid of an automobile,
- to detect and isolate faults on transmission and distribution lines by opening and closing circuit breakers (protection relays),
- to isolate the controlling circuit from the controlled circuit when the two are at different potentials, for example when controlling a mains-powered device from a low-voltage switch. The latter is often applied to control office lighting as the low voltage wires are easily installed in partitions, which may be often moved as needs change. They may also be controlled by room occupancy detectors in an effort to conserve energy,
- to perform logic functions. For example, the boolean AND function is realised by connecting NO relay contacts in series, the OR function by connecting NO contacts in parallel. The change-over or Form C contacts perform the XOR (exclusive or) function. Similar functions for NAND and NOR are accomplished using NC contacts. The Ladder programming language is often used for designing relay logic networks.
Early computing. Before vacuum tubes and transistors, relays were used as logical elements in digital computers. See ARRA (computer), Harvard Mark II, Zuse Z2, and Zuse Z3.
Safety-critical logic. Because relays are much more resistant than semiconductors to nuclear radiation, they are widely used in safety-critical logic, such as the control panels of radioactive waste-handling machinery.
- Early computing. Before vacuum tubes and transistors, relays were used as logical elements in digital computers. See ARRA (computer), Harvard Mark II, Zuse Z2, and Zuse Z3.
- Safety-critical logic. Because relays are much more resistant than semiconductors to nuclear radiation, they are widely used in safety-critical logic, such as the control panels of radioactive waste-handling machinery.
- to perform time delay functions. Relays can be modified to delay opening or delay closing a set of contacts. A very short (a fraction of a second) delay would use a copper disk between the armature and moving blade assembly. Current flowing in the disk maintains magnetic field for a short time, lengthening release time. For a slightly longer (up to a minute) delay, a dashpot is used. A dashpot is a piston filled with fluid that is allowed to escape slowly. The time period can be varied by increasing or decreasing the flow rate. For longer time periods, a mechanical clockwork timer is installed.
# Relay application considerations
Selection of an appropriate relay for a particular application requires evaluation of many different factors:
- Number and type of contacts - normally open, normally closed, (double-throw)
- There are two types. This style of relay can be manufactured two different ways. "Make before Break" and "Break before Make". The old style telephone switch required Make-before-break so that the connection didn't get dropped while dialing the number. The railroad still uses them to control railroad crossings.
- Rating of contacts - small relays switch a few amperes, large contactors are rated for up to 3000 amperes, alternating or direct current
- Voltage rating of contacts - typical control relays rated 300 VAC or 600 VAC, automotive types to 50 VDC, special high-voltage relays to about 15,000 V
- Coil voltage - machine-tool relays usually 24 VAC or 120 VAC, relays for switchgear may have 125 V or 250 VDC coils, "sensitive" relays operate on a few milliamperes
- Package/enclosure - open, touch-safe, double-voltage for isolation between circuits, explosion proof, outdoor, oil-splashresistant
- Mounting - sockets, plug board, rail mount, panel mount, through-panel mount, enclosure for mounting on walls or equipment
- Switching time - where high speed is required
- "Dry" contacts - when switching very low level signals, special contact materials may be needed such as gold-plated contacts
- Contact protection - suppress arcing in very inductive circuits
- Coil protection - suppress the surge voltage produced when switching the coil current
- Isolation between coil circuit and contacts
- Aerospace or radiation-resistant testing, special quality assurance
- Expected mechanical loads due to acceleration - some relays used in aerospace applications are designed to function in shock loads of 50 g or more
- Accessories such as timers, auxiliary contacts, pilot lamps, test buttons
- Regulatory approvals
- Stray magnetic linkage between coils of adjacent relays on a printed circuit board.
# Protective relay
A protective relay is a complex electromechanical apparatus, often with more than one coil, designed to calculate operating conditions on an electrical circuit and trip circuit breakers when a fault was found. Unlike switching type relays with fixed and usually ill-defined operating voltage thresholds and operating times, protective relays had well-established, selectable, time/current (or other operating parameter) curves. Such relays were very elaborate, using arrays of induction disks, shaded-pole magnets, operating and restraint coils, solenoid-type operators, telephone-relay style contacts, and phase-shifting networks to allow the relay to respond to such conditions as over-current, over-voltage, reverse power flow, over- and under- frequency, and even distance relays that would trip for faults up to a certain distance away from a substation but not beyond that point. An important transmission line or generator unit would have had cubicles dedicated to protection, with a score of individual electromechanical devices. The various protective functions available on a given relay are denoted by standard ANSI Device Numbers. For example, a relay including function 51 would be a timed overcurrent protective relay.
These protective relays provide various types of electrical protection by detecting abnormal conditions and isolating them from the rest of the electrical system by circuit breaker operation. Such relays may be located at the service entrance or at major load centers.
Design and theory of these protective devices is an important part of the education of an electrical engineer who specializes in power systems. Today these devices are nearly entirely replaced (in new designs) with microprocessor-based instruments (numerical relays) that emulate their electromechanical ancestors with great precision and convenience in application. By combining several functions in one case, numerical relays also save capital cost and maintenance cost over electromechanical relays. However, due to their very long life span, tens of thousands of these "silent sentinels" are still protecting transmission lines and electrical apparatus all over the world.
## Overcurrent relay
An "Overcurrent Relay" is a type of protective relay which operates when the load current exceeds a preset value. The ANSI Device Designation Number is 50 for an Instantaneous OverCurrent (IOC), 51 for a Time OverCurrent (TOC). In a typical application the overcurrent relay is used for overcurrent protection, connected to a current transformer and calibrated to operate at or above a specific current level. When the relay operates, one or more contacts will operate and energize a trip coil in a Circuit Breaker and trip (open) the Circuit Breaker.
## Induction disc overcurrent relay
The robust and reliable electromagnetic relays use the induction principle first discovered by Ferraris in the late 19th century. The magnetic system in the induction disc overcurrent relays is designed to simulate overcurrents in a power system and operate with a pre determined time delay when certain overcurrent limits have been reached. In order to operate the magnetic system in the relays produce rotational torque that acts on a metal disc to make contacts, according to the following basic current/torque equation:
T = K x φ1 x φ2 Sinθ
Where
K – is a constant
φ1 and φ2 are the two fluxes
θ is the phase angle between the fluxes
The relays primary winding is supplied from the power systems current transformer via a plug bridge, which is also commonly known as the plug setting multiplier (psm). The variations in the current setting are usually seven equally spaced tappings or operating bands that determine the relays sensitivity. The primary winding is located on the upper electromagnet. The secondary winding has connections on the upper electromagnet that are energised from the primary winding and connected to the lower electromagnet. Once the upper and lower electromagnets are energised they produce eddy currents that are induced onto the metal disc and flow through the flux paths. This relationship of eddy currents and fluxes creates rotational torque proportional to the input current of the primary winding, due to the two flux paths been out of phase by 90º.
Therefore in an overcurrent condition a value of current will be reached that overcomes the control spring pressure on the spindle and the breaking magnet causing the metal disc to rotate moving towards the fixed contact. This initial movement of the disc is also held off to a critical positive value of current by small slots that are often cut into the side of the disc. The time taken for rotation to make the contacts is not only dependent on current but also the spindle backstop position, known as the time multiplier (tm). The time multiplier is divided into 10 linear divisions of the full rotation time.
Providing the relay is free from dirt the metal disc and the spindle with its contact will reach the fixed contact. Sending a signal to trip and isolate the circuit, within its designed time and current specifications. Drop off current of the relay is much lower than its operating value, and once reached the relay will be reset in a reverse motion by the pressure of the control spring governed by the braking magnet.
# Distance relay
The most common form of feeder protection on high voltage transmission systems is distance relay protection. Power lines have set impedance per kilometre and using this value and comparing voltage and current the distance to a fault can be determined. The main types of distance relay protection schemes are
- Three step distance protection
- Switched distance protection
- Accelerated or permissive intertrip protection
- Blocked distance protection
In three step distance protection, the relays are separated into three separate zones of impedance measurement to accommodate for over reach and under reach conditions. Zone 1 is instantaneous in operation and has a purposely set under reach of 80% of the total line length to avoid operation for the next line. This is due to measurements of impedance of lines not being entirely accurate, errors in voltage and current transformers and relay tolerances. These errors can be up to ±20% of the line impedance, hence the zones 80% reach. Zone 2 covers the last 20% of the feeder line length and provides backup to the next line by having a slight over reach. To prevent mal-operation the zone has a 0.5 second time delay. Zone 3 provides backup for the next line and has a time delay of 1 second to grade with zone 2 protection of the next line.
# Double switching
In railway signalling, relays energise to give a green light, so that if the power fails or a wire breaks, the signal goes to red. This is fail safe. To protect against false feeds relay circuits are often cut on both the positive and negative side, so that two false feeds are needed to cause a false green. | Relay
Template:Otheruses1
A relay is an electrical switch that opens and closes under the control of another electrical circuit. In the original form, the switch is operated by an electromagnet to open or close one or many sets of contacts. It was invented by Joseph Henry in 1835. Because a relay is able to control an output circuit
of higher power than the input circuit, it can be considered to be, in a broad sense, a form of an electrical amplifier.
# Operation
When a current flows through the coil, the resulting magnetic field attracts an armature that is mechanically linked to a moving contact. The movement either makes or breaks a connection with a fixed contact. When the current to the coil is switched off, the armature is returned by a force approximately half as strong as the magnetic force to its relaxed position. Usually this is a spring, but gravity is also used commonly in industrial motor starters. Most relays are manufactured to operate quickly. In a low voltage application, this is to reduce noise. In a high voltage or high current application, this is to reduce arcing.
If the coil is energized with DC, a diode is frequently installed across the coil, to dissipate the energy from the collapsing magnetic field at deactivation, which would otherwise generate a spike of voltage and might cause damage to circuit components. Some automotive relays already include that diode inside the relay case. Alternatively a contact protection network, consisting of a capacitor and resistor in series, may absorb the surge. If the coil is designed to be energized with AC, a small copper ring can be crimped to the end of the solenoid. This "shading ring" creates a small out-of-phase current, which increases the minimum pull on the armature during the AC cycle.[1]
By analogy with the functions of the original electromagnetic device, a solid-state relay is made with a thyristor or other solid-state switching device. To achieve electrical isolation an optocoupler can be used which is a light-emitting diode (LED) coupled with a photo transistor.
# Types of relay
## Latching relay
A latching relay has two relaxed states (bistable). These are also called 'keep' or 'stay' relays. When the current is switched off, the relay remains in its last state. This is achieved with a solenoid operating a ratchet and cam mechanism, or by having two opposing coils with an over-center spring or permanent magnet to hold the armature and contacts in position while the coil is relaxed, or with a remnant core. In the ratchet and cam example, the first pulse to the coil turns the relay on and the second pulse turns it off. In the two coil example, a pulse to one coil turns the relay on and a pulse to the opposite coil turns the relay off. This type of relay has the advantage that it consumes power only for an instant, while it is being switched, and it retains its last setting across a power outage.
## Reed relay
A reed relay has a set of contacts inside a vacuum or inert gas filled glass tube, which protects the contacts against atmospheric corrosion. The contacts are closed by a magnetic field generated when current passes through a coil around the glass tube. Reed relays are capable of faster switching speeds than larger types of relays, but have low switch current and voltage ratings. See also reed switch.
## Mercury-wetted relay
A mercury-wetted reed relay is a form of reed relay in which the contacts are wetted with mercury. Such relays are used to switch low-voltage signals (one volt or less) because of its low contact resistance, or for high-speed counting and timing applications where the mercury eliminates contact bounce. Mercury wetted relays are position-sensitive and must be mounted vertically to work properly. Because of the toxicity and expense of liquid mercury, these relays are rarely specified for new equipment. See also mercury switch.
## Polarized relay
A Polarized Relay placed the armature between the poles of a permanent magnet to increase sensitivity. Polarized relays were used in middle 20th Century telephone exchanges to detect faint pulses and correct telegraphic distortion. The poles were on screws, so a technician could first adjust them for maximum sensitivity and then apply a bias spring to set the critical current that would operate the relay.
## Machine tool relay
A machine tool relay is a type standardized for industrial control of machine tools, transfer machines, and other sequential control. They are characterized by a large number of contacts (sometimes extendable in the field) which are easily converted from normally-open to normally-closed status, easily replaceable coils, and a form factor that allows compactly installing many relays in a control panel. Although such relays once were the backbone of automation in such industries as automobile assembly, the programmable logic controller (PLC) mostly displaced the machine tool relay from sequential control applications.
## Contactor relay
A contactor is a very heavy-duty relay used for switching electric motors and lighting loads. With high current, the contacts are made with pure silver. The unavoidable arcing causes the contacts to oxidize and silver oxide is still a good conductor. Such devices are often used for motor starters. A motor starter is a contactor with overload protection devices attached. The overload sensing devices are a form of heat operated relay where a coil heats a bi-metal strip, or where a solder pot melts, releasing a spring to operate auxiliary contacts. These auxiliary contacts are in series with the coil. If the overload senses excess current in the load, the coil is de-energized. Contactor relays can be extremely loud to operate, making them unfit for use where noise is a chief concern.
## Solid state contactor relay
A solid state contactor is a very heavy-duty solid state relay, including the necessary heat sink, used for switching electric heaters, small electric motors and lighting loads; where frequent on/off cycles are required. There are no moving parts to wear out and there is no contact bounce due to vibration. They are activated by AC control signals or DC control signals from Programmable logic controller (PLCs), PCs, Transistor-transistor logic (TTL) sources, or other microprocessor controls.
## Buchholz relay
A Buchholz relay is a safety device sensing the accumulation of gas in large oil-filled transformers, which will alarm on slow accumulation of gas or shut down the transformer if gas is produced rapidly in the transformer oil.
## Forced-guided contacts relay
A forced-guided contacts relay has relay contacts that are mechanically linked together, so that when the relay coil is energized or de-energized, all of the linked contacts move together. If one set of contacts in the relay becomes immobilized, no other contact of the same relay will be able to move. The function of forced-guided contacts is to enable the safety circuit to check the status of the relay. Forced-guided contacts are also known as "positive-guided contacts", "captive contacts", "locked contacts", or "safety relays".
## Solid-state relay
A solid state relay (SSR) is a solid state electronic component that provides a similar function to an electromechanical relay but does not have any moving components, increasing long-term reliability. With early SSR's, the tradeoff came from the fact that every transistor has a small voltage drop across it. This collective voltage drop limited the amount of current a given SSR could handle. As transistors improved, higher current SSR's, able to handle 100 to 1,200 amps, have become commercially available.
Compared to electromagnetic relays, they may be falsely triggered by transients.
## Overload protection relay
One type of electric motor overload protection relay is operated by a heating element in series with the electric motor . The heat generated by the motor current operates a bi-metal strip or melts solder, releasing a spring to operate contacts. Where the overload relay is exposed to the same environment as the motor, a useful though crude compensation for motor ambient temperature is provided.
# Pole & Throw
Since relays are switches, the terminology applied to switches is also applied to relays. A relay will switch one or more poles, each of whose contacts can be thrown by energizing the coil in one of three ways:
- Normally-open (NO) contacts connect the circuit when the relay is activated; the circuit is disconnected when the relay is inactive. It is also called a Form A contact or "make" contact.
- Normally-closed (NC) contacts disconnect the circuit when the relay is activated; the circuit is connected when the relay is inactive. It is also called a Form B contact or "break" contact.
- Change-over, or double-throw, contacts control two circuits: one normally-open contact and one normally-closed contact with a common terminal. It is also called a Form C contact or "transfer" contact. If this type of contact utilizes a "make before break" functionality, then it is called a Form D contact.
The following designations are commonly encountered:
- SPST - Single Pole Single Throw. These have two terminals which can be connected or disconnected. Including two for the coil, such a relay has four terminals in total. It is ambiguous whether the pole is normally open or normally closed. The terminology "SPNO" and "SPNC" is sometimes used to resolve the ambiguity.
- SPDT - Single Pole Double Throw. A common terminal connects to either of two others. Including two for the coil, such a relay has five terminals in total.
- DPST - Double Pole Single Throw. These have two pairs of terminals. Equivalent to two SPST switches or relays actuated by a single coil. Including two for the coil, such a relay has six terminals in total. The poles may be Form A or Form B (or one of each).
- DPDT - Double Pole Double Throw. These have two rows of change-over terminals. Equivalent to two SPDT switches or relays actuated by a single coil. Such a relay has eight terminals, including the coil.
The "S" or "D" may be replaced with a number, indicating multiple switches connected to a single actuator. For example 4PDT indicates a four pole double throw relay (with 14 terminals).
# Applications
Relays are used:
- to control a high-voltage circuit with a low-voltage signal, as in some types of modems or audio amplifiers,
- to control a high-current circuit with a low-current signal, as in the starter solenoid of an automobile,
- to detect and isolate faults on transmission and distribution lines by opening and closing circuit breakers (protection relays),
- to isolate the controlling circuit from the controlled circuit when the two are at different potentials, for example when controlling a mains-powered device from a low-voltage switch. The latter is often applied to control office lighting as the low voltage wires are easily installed in partitions, which may be often moved as needs change. They may also be controlled by room occupancy detectors in an effort to conserve energy,
- to perform logic functions. For example, the boolean AND function is realised by connecting NO relay contacts in series, the OR function by connecting NO contacts in parallel. The change-over or Form C contacts perform the XOR (exclusive or) function. Similar functions for NAND and NOR are accomplished using NC contacts. The Ladder programming language is often used for designing relay logic networks.
Early computing. Before vacuum tubes and transistors, relays were used as logical elements in digital computers. See ARRA (computer), Harvard Mark II, Zuse Z2, and Zuse Z3.
Safety-critical logic. Because relays are much more resistant than semiconductors to nuclear radiation, they are widely used in safety-critical logic, such as the control panels of radioactive waste-handling machinery.
- Early computing. Before vacuum tubes and transistors, relays were used as logical elements in digital computers. See ARRA (computer), Harvard Mark II, Zuse Z2, and Zuse Z3.
- Safety-critical logic. Because relays are much more resistant than semiconductors to nuclear radiation, they are widely used in safety-critical logic, such as the control panels of radioactive waste-handling machinery.
- to perform time delay functions. Relays can be modified to delay opening or delay closing a set of contacts. A very short (a fraction of a second) delay would use a copper disk between the armature and moving blade assembly. Current flowing in the disk maintains magnetic field for a short time, lengthening release time. For a slightly longer (up to a minute) delay, a dashpot is used. A dashpot is a piston filled with fluid that is allowed to escape slowly. The time period can be varied by increasing or decreasing the flow rate. For longer time periods, a mechanical clockwork timer is installed.
# Relay application considerations
Selection of an appropriate relay for a particular application requires evaluation of many different factors:
- Number and type of contacts - normally open, normally closed, (double-throw)
- There are two types. This style of relay can be manufactured two different ways. "Make before Break" and "Break before Make". The old style telephone switch required Make-before-break so that the connection didn't get dropped while dialing the number. The railroad still uses them to control railroad crossings.
- Rating of contacts - small relays switch a few amperes, large contactors are rated for up to 3000 amperes, alternating or direct current
- Voltage rating of contacts - typical control relays rated 300 VAC or 600 VAC, automotive types to 50 VDC, special high-voltage relays to about 15,000 V
- Coil voltage - machine-tool relays usually 24 VAC or 120 VAC, relays for switchgear may have 125 V or 250 VDC coils, "sensitive" relays operate on a few milliamperes
- Package/enclosure - open, touch-safe, double-voltage for isolation between circuits, explosion proof, outdoor, oil-splashresistant
- Mounting - sockets, plug board, rail mount, panel mount, through-panel mount, enclosure for mounting on walls or equipment
- Switching time - where high speed is required
- "Dry" contacts - when switching very low level signals, special contact materials may be needed such as gold-plated contacts
- Contact protection - suppress arcing in very inductive circuits
- Coil protection - suppress the surge voltage produced when switching the coil current
- Isolation between coil circuit and contacts
- Aerospace or radiation-resistant testing, special quality assurance
- Expected mechanical loads due to acceleration - some relays used in aerospace applications are designed to function in shock loads of 50 g or more
- Accessories such as timers, auxiliary contacts, pilot lamps, test buttons
- Regulatory approvals
- Stray magnetic linkage between coils of adjacent relays on a printed circuit board.
# Protective relay
A protective relay is a complex electromechanical apparatus, often with more than one coil, designed to calculate operating conditions on an electrical circuit and trip circuit breakers when a fault was found. Unlike switching type relays with fixed and usually ill-defined operating voltage thresholds and operating times, protective relays had well-established, selectable, time/current (or other operating parameter) curves. Such relays were very elaborate, using arrays of induction disks, shaded-pole magnets, operating and restraint coils, solenoid-type operators, telephone-relay style contacts, and phase-shifting networks to allow the relay to respond to such conditions as over-current, over-voltage, reverse power flow, over- and under- frequency, and even distance relays that would trip for faults up to a certain distance away from a substation but not beyond that point. An important transmission line or generator unit would have had cubicles dedicated to protection, with a score of individual electromechanical devices. The various protective functions available on a given relay are denoted by standard ANSI Device Numbers. For example, a relay including function 51 would be a timed overcurrent protective relay.
These protective relays provide various types of electrical protection by detecting abnormal conditions and isolating them from the rest of the electrical system by circuit breaker operation. Such relays may be located at the service entrance or at major load centers.
Design and theory of these protective devices is an important part of the education of an electrical engineer who specializes in power systems. Today these devices are nearly entirely replaced (in new designs) with microprocessor-based instruments (numerical relays) that emulate their electromechanical ancestors with great precision and convenience in application. By combining several functions in one case, numerical relays also save capital cost and maintenance cost over electromechanical relays. However, due to their very long life span, tens of thousands of these "silent sentinels" are still protecting transmission lines and electrical apparatus all over the world.
## Overcurrent relay
An "Overcurrent Relay" is a type of protective relay which operates when the load current exceeds a preset value. The ANSI Device Designation Number is 50 for an Instantaneous OverCurrent (IOC), 51 for a Time OverCurrent (TOC). In a typical application the overcurrent relay is used for overcurrent protection, connected to a current transformer and calibrated to operate at or above a specific current level. When the relay operates, one or more contacts will operate and energize a trip coil in a Circuit Breaker and trip (open) the Circuit Breaker.
## Induction disc overcurrent relay
The robust and reliable electromagnetic relays use the induction principle first discovered by Ferraris in the late 19th century. The magnetic system in the induction disc overcurrent relays is designed to simulate overcurrents in a power system and operate with a pre determined time delay when certain overcurrent limits have been reached. In order to operate the magnetic system in the relays produce rotational torque that acts on a metal disc to make contacts, according to the following basic current/torque equation:
T = K x φ1 x φ2 Sinθ
Where
K – is a constant
φ1 and φ2 are the two fluxes
θ is the phase angle between the fluxes
The relays primary winding is supplied from the power systems current transformer via a plug bridge, which is also commonly known as the plug setting multiplier (psm). The variations in the current setting are usually seven equally spaced tappings or operating bands that determine the relays sensitivity. The primary winding is located on the upper electromagnet. The secondary winding has connections on the upper electromagnet that are energised from the primary winding and connected to the lower electromagnet. Once the upper and lower electromagnets are energised they produce eddy currents that are induced onto the metal disc and flow through the flux paths. This relationship of eddy currents and fluxes creates rotational torque proportional to the input current of the primary winding, due to the two flux paths been out of phase by 90º.
Therefore in an overcurrent condition a value of current will be reached that overcomes the control spring pressure on the spindle and the breaking magnet causing the metal disc to rotate moving towards the fixed contact. This initial movement of the disc is also held off to a critical positive value of current by small slots that are often cut into the side of the disc. The time taken for rotation to make the contacts is not only dependent on current but also the spindle backstop position, known as the time multiplier (tm). The time multiplier is divided into 10 linear divisions of the full rotation time.
Providing the relay is free from dirt the metal disc and the spindle with its contact will reach the fixed contact. Sending a signal to trip and isolate the circuit, within its designed time and current specifications. Drop off current of the relay is much lower than its operating value, and once reached the relay will be reset in a reverse motion by the pressure of the control spring governed by the braking magnet.
# Distance relay
The most common form of feeder protection on high voltage transmission systems is distance relay protection. Power lines have set impedance per kilometre and using this value and comparing voltage and current the distance to a fault can be determined. The main types of distance relay protection schemes are
- Three step distance protection
- Switched distance protection
- Accelerated or permissive intertrip protection
- Blocked distance protection
In three step distance protection, the relays are separated into three separate zones of impedance measurement to accommodate for over reach and under reach conditions. Zone 1 is instantaneous in operation and has a purposely set under reach of 80% of the total line length to avoid operation for the next line. This is due to measurements of impedance of lines not being entirely accurate, errors in voltage and current transformers and relay tolerances. These errors can be up to ±20% of the line impedance, hence the zones 80% reach. Zone 2 covers the last 20% of the feeder line length and provides backup to the next line by having a slight over reach. To prevent mal-operation the zone has a 0.5 second time delay. Zone 3 provides backup for the next line and has a time delay of 1 second to grade with zone 2 protection of the next line.
# Double switching
In railway signalling, relays energise to give a green light, so that if the power fails or a wire breaks, the signal goes to red. This is fail safe. To protect against false feeds relay circuits are often cut on both the positive and negative side, so that two false feeds are needed to cause a false green. | https://www.wikidoc.org/index.php/Relay | |
a63e72dce6550051074dca884172b3ed3d6407f2 | wikidoc | Ricin | Ricin
The protein ricin (pronounced Template:IPA) is a toxin extracted from the castor bean (Ricinus communis).
Ricin has an average lethal dose in humans of 0.2 milligrams (1/5,000th of a gram), though some sources give higher figures.
# Toxicity
Ricin is poisonous if inhaled, injected, or ingested, acting as a toxin by the inhibition of protein synthesis. While there is no known antidote, the US military has developed a vaccine. Symptomatic and supportive treatment is available. Long term organ damage is likely in survivors. Ricin causes severe diarrhea and victims can die of shock. (See abrin).
Deaths caused by ingestion of seeds are rare. Eight beans are considered toxic for an adult. A solution of saline and glucose has been used to treat ricin overdose. The case experience is not as negative as popular perception would indicate.
# Structure
Ricin consists of two distinct protein chains (almost 30 kDa each) that are linked to each other by a disulfide bond:
- Ricin A is an N-glycoside hydrolase that specifically removes an adenine base from ribosomal RNA, resulting in an inhibition of protein synthesis.
- Ricin B is a lectin that binds galactosyl residues and is important in assisting ricin A's entry into a cell by binding with a cell surface component.
Many plants such as barley have the A chain but not the B chain. Since people do not get sick from eating large amounts of such products, ricin A is of extremely low toxicity as long as the B chain is not present.
# Manufacture
Ricin is easily purified from castor-oil manufacturing waste. The seed-pulp left over from pressing for castor oil contains on average about 5% by weight of ricin. Since 0.2 mg of purified Ricin constitutes a fatal dose, this is a considerable amount of ricin.
In the United States, a person caught manufacturing or possessing ricin may be sentenced to up to 30 years in prison.
# Potential medicinal use
Ricins may have therapeutic use in the treatment of cancer. Ricin could be linked to a monoclonal antibody to target malignant cells recognized by the antibody. Genetic modification of ricin is believed to be possible to lessen its toxicity to humans, but not to the cancer cells. A promising approach is also to use the non-toxic B subunit as a vehicle for delivering antigens into cells thus greatly increasing their immunogenicity. Use of ricin as an adjuvant has potential implications for developing mucosal vaccines.
Therapeutically, ricin is used in magic bullets to specifically target and destroy cancer cells.
# Use as a chemical/biological warfare agent
The United States investigated ricin for its military potential during the First World War. At that time it was being considered for use either as a toxic dust or as a coating for bullets and shrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the Hague Convention of 1899. The War ended before it was weaponized.
During the Second World War the United States and Canada undertook studying ricin in cluster bombs. Though there were plans for mass production and several field trials with different bomblet concepts, the end conclusion was that it was no more economical than using phosgene. This conclusion was based on comparison of the final weapons rather than ricin's toxicity (LD50 <30 mg.min.m–3). Ricin was given the military symbol W.
The best-known documented use of ricin as an agent of biological warfare was by the Soviet Union's KGB during the Cold War. In 1978, the Bulgarian dissident Georgi Markov was assassinated by Bulgarian secret police who surreptitiously 'shot' him on a London street with a modified umbrella using compressed gas to fire a tiny pellet contaminated with ricin into his leg. He died in a hospital a few days later; the body of Georgi Markov was passed to a special poison branch of the British MOD who discovered the pellet during an autopsy. The main suspect was the Bulgarian secret police; this was because Georgi Markov had defected from Bulgaria several years prior to the incident and was wanted for writing many controversial books on the communist government at the time, however, it was believed at the time that Bulgaria would not have been able to produce the poison, and it was also believed that the KGB had supplied it. The KGB denied any involvement although high-profile KGB defectors Oleg Kalugin and Oleg Gordievsky have since confirmed the KGB's involvement. Earlier, Soviet dissident Aleksandr Solzhenitsyn also suffered (but survived) ricin-like symptoms after a 1971 encounter with KGB agents.
Despite ricin's extreme toxicity and utility as an agent of chemical/biological warfare, it is extremely difficult to limit the production of the toxin. Under both the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, ricin is listed as a schedule 1 controlled substance. Despite this, more than 1 million metric tonnes of castor beans are processed each year, and approximately 5% of the total is rendered into a waste containing high concentrations of ricin toxin.
In August of 2002, US officials asserted that the Islamic militant group Ansar al-Islam tested ricin, along with other chemical and biological agents, in northern Iraq.
To put ricin used as weapon into perspective, it is worth noting that as a biological weapon or chemical weapon, ricin may be considered as not very powerful, if only in comparison with other poisons such as botulinum or anthrax. Hence, a military willing to use biological weapons and having advanced resources would rather use either of the latter instead. Ricin is easy to produce, but is not as practical nor likely to cause as high casualties as other agents. Ricin denatures (ie, the protein changes structure and becomes less dangerous) much more readily than anthrax spores, which may remain lethal for decades. (Jan van Aken, an expert on biological weapons explained in an interview with the German magazine Der Spiegel that he judges it rather reassuring that Al Qaeda experimented with ricin as it suggests their inability to produce botulin or anthrax.)
Pure ricin could be dispersed through the air, but ozone, nitrogen oxides, and other pollutants would oxidize it within a few hours, rendering it harmless. Since it acts as an enzyme, catalyzing destruction of ribosomes, even a single oxidation is likely to render the ricin molecule harmless. Presumably it could be sealed inside some sort of dust particle that would dissolve in water, but this would be difficult.
The major reason it is dangerous is that there is no specific antidote, and that it is very easy to obtain (the castor bean plant is a common ornamental, and can be grown at home without any special care). Ricin is actually several orders of magnitude less toxic than botulinum or tetanus toxin, but those are more difficult to obtain.
# Patented extraction process
The process for creating ricin is well-known, and for example described in a patent. The described extraction method is very similar to the preparation of soy protein isolates.
The patent was removed from the United States Patent and Trademark Office (USPTO) database sometime in 2004, but is still available online through international patent databases. Modern theories of protein chemistry cast doubt on the effectiveness of the methods disclosed in the patent.
# Detected ricin incidents
## Assassination of Bulgarian Dissident Georgi Markov, London 1978
On September 7, 1978 the Bulgarian dissident Georgi Markov was shot in the leg in public on Waterloo Bridge in the middle of London by a man using a weapon built into an umbrella. The weapon embedded a small pellet in Markov's leg which contained ricin. Markov died three days later.
## Related arrests in Britain in 2003
On 5 January, 2003 the Metropolitan Police raided a flat in north London and arrested six Algerian men whom they claimed were manufacturing ricin as part of a plot for a poison attack on the London Underground. No ricin was recovered as a result of this raid.
## In South Carolina
In 2003, a package and letter sealed in a ricin-contaminated envelope was intercepted in Greenville, South Carolina, at a United States Postal Service processing center.
## In Washington, D.C. in 2003
Ricin was detected in the mail at the White House in Washington, D.C. in November of 2003. The letter containing it was intercepted at a mail handling facility off the grounds of the White House, and it never reached its intended destination. The letter contained a fine powdery substance that later tested positive for ricin. Investigators said it was low potency and was not considered a health risk. This information was not made public until February 3, 2004, when preliminary tests showed the presence of ricin in an office mailroom of U.S. Senate Majority Leader Bill Frist's office. There were no signs that anyone who was near the contaminated area developed any medical problems. Several Senate office buildings were closed as a precaution.
## In Richmond, VA
In January 2006, ricin was found in a home in the suburbs of Richmond, VA. It was in the form of mashed castor beans. Although the suspect, Chetanand Sewraz, was allegedly isolating the toxin to kill his estranged wife, and not for some form of bioterrorism, it nonetheless highlighted the ease with which ricin toxin can be made.
## In Austin, Texas
On 23 February 2006, a student in the Moore-Hill dormitory at the University of Texas at Austin found a strange powder in a roll of quarters she was using to do laundry. The University Environmental Health and Safety department immediately sanitized the affected rooms. Lab results (returned the following Friday) indicated ricin. The source of the powder remains unknown, with both the university and Joint Terrorism Task Force investigating. The student and her roommate were being treated for potential exposure to the poison, although neither has exhibited symptoms. After cleansing and reinspection of the affected rooms (completed at 2:30am), the dorm reopened. News reports on 25 February report that further testing has indicated that the substance found is not, in fact, ricin. The identity of the powder has yet to be determined.
# Cultural references
- (1929) Ricin was the poison used in the Agatha Christie "Tommy and Tuppence" whodunnit, The House of Lurking Death in a 1929 collection of short stories called Partners in Crime.
- (1962) Ricin was used as the poison of choice of the murderer in the comedy film Kill or Cure.
- (1979) A killer used ricin to murder Travis McGee's girlfriend in The Green Ripper
- (1992) The Penn and Teller book How To Play With Your Food (ISBN 0-679-74311-1) includes a "gimmicks envelope" of small objects related to the tricks inside the book. One of these is a sticker reading "Contains all-natural ricin," intended to be placed on food as a joke. The book explains that ricin is a poison.
- (c. 1993) In Walker, Texas Ranger, CD Parker is killed by Ricin poisoning. His death was originally covered up by his murderers as a heart attack (they had a vendetta against Walker and the rangers that put them away, including CD) until the rangers realized something was going on and an autopsy was performed.
- (1999) Ricin was the poison used in Agatha Raisin and the Wizard of Evesham by M.C. Beaton.
- (2001) Ricin appears in CSI: Crime Scene Investigation Season 2 Episode 7 Caged .
- (c. 2003) The Umbrella-gun pellet assassination incident was featured in Mythbusters.
- (2004) Ricin was one of the poisons used to exact terrorism in the book, "3rd Degree" by James Patterson
- (2004) It is mentioned in the song 'Paracetamoxyfrusebendroneomycin' by the British duo, the Amateur Transplants
- (2006) In Hour 1 of 24: The Game, terrorists plan to release ricin into Los Angeles Harbor.
- (2007) In Episode 15 of Season 2 in The Unit, Ricin is used in a bomb inside the United Nations building.
- (2007) Ricin-laced hot chocolate was the weapon used to kill a private school history professor in J. D. Robb's novel, "Innocent in Death".
- (2007) Ricin is mentioned as being dispersed in Dirty Bombs across LA in the alternate-reality game "Year Zero," based on the new Nine Inch Nails album of the same name.
- (2007) In the episode Past Imperfect (Season 3 episode 21) of CSI:NY, one murder was committed when a man was shot in the leg with a pellet laced with ricin shot from an air gun.
- (2007) Ricin poisoning plays a role in the Law & Order show 'Fallout,' Season 17, episode 19.
- In the song "Master Thesis" by rap artist Canibus, he states, "Words concocted by the lyrical locksmith, as deadly as 10 droplets of Ricin toxin." Song on YouTube
- In the Season two opener of Dexter (TV Series), entitled "It's Alive!" Dexters victim is a Voodoo high priest who causes his "death curses" to come true by poisoning his victims with ricin. | Ricin
The protein ricin (pronounced Template:IPA) is a toxin extracted from the castor bean (Ricinus communis).
Ricin has an average lethal dose in humans of 0.2 milligrams (1/5,000th of a gram), though some sources give higher figures.[1]
# Toxicity
Ricin is poisonous if inhaled, injected, or ingested, acting as a toxin by the inhibition of protein synthesis. While there is no known antidote, the US military has developed a vaccine.[2] Symptomatic and supportive treatment is available. Long term organ damage is likely in survivors. Ricin causes severe diarrhea and victims can die of shock. (See abrin).
Deaths caused by ingestion of seeds are rare.[3] Eight beans are considered toxic for an adult.[4] A solution of saline and glucose has been used to treat ricin overdose. [5] The case experience is not as negative as popular perception would indicate.[6]
# Structure
Ricin consists of two distinct protein chains (almost 30 kDa each) that are linked to each other by a disulfide bond:
- Ricin A is an N-glycoside hydrolase that specifically removes an adenine base from ribosomal RNA, resulting in an inhibition of protein synthesis.
- Ricin B is a lectin that binds galactosyl residues and is important in assisting ricin A's entry into a cell by binding with a cell surface component.
Many plants such as barley have the A chain but not the B chain. Since people do not get sick from eating large amounts of such products, ricin A is of extremely low toxicity as long as the B chain is not present.
# Manufacture
Ricin is easily purified from castor-oil manufacturing waste. The seed-pulp left over from pressing for castor oil contains on average about 5% by weight of ricin. Since 0.2 mg of purified Ricin constitutes a fatal dose, this is a considerable amount of ricin.
In the United States, a person caught manufacturing or possessing ricin may be sentenced to up to 30 years in prison.
# Potential medicinal use
Ricins may have therapeutic use in the treatment of cancer. Ricin could be linked to a monoclonal antibody to target malignant cells recognized by the antibody. Genetic modification of ricin is believed to be possible to lessen its toxicity to humans, but not to the cancer cells. A promising approach is also to use the non-toxic B subunit as a vehicle for delivering antigens into cells thus greatly increasing their immunogenicity. Use of ricin as an adjuvant has potential implications for developing mucosal vaccines.
Therapeutically, ricin is used in magic bullets to specifically target and destroy cancer cells.[7]
# Use as a chemical/biological warfare agent
The United States investigated ricin for its military potential during the First World War. At that time it was being considered for use either as a toxic dust or as a coating for bullets and shrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the Hague Convention of 1899. The War ended before it was weaponized.
During the Second World War the United States and Canada undertook studying ricin in cluster bombs. Though there were plans for mass production and several field trials with different bomblet concepts, the end conclusion was that it was no more economical than using phosgene. This conclusion was based on comparison of the final weapons rather than ricin's toxicity (LD50 <30 mg.min.m–3). Ricin was given the military symbol W.
The best-known documented use of ricin as an agent of biological warfare was by the Soviet Union's KGB during the Cold War. In 1978, the Bulgarian dissident Georgi Markov was assassinated by Bulgarian secret police who surreptitiously 'shot' him on a London street with a modified umbrella using compressed gas to fire a tiny pellet contaminated with ricin into his leg. He died in a hospital a few days later; the body of Georgi Markov was passed to a special poison branch of the British MOD who discovered the pellet during an autopsy. The main suspect was the Bulgarian secret police; this was because Georgi Markov had defected from Bulgaria several years prior to the incident and was wanted for writing many controversial books on the communist government at the time, however, it was believed at the time that Bulgaria would not have been able to produce the poison, and it was also believed that the KGB had supplied it. The KGB denied any involvement although high-profile KGB defectors Oleg Kalugin and Oleg Gordievsky have since confirmed the KGB's involvement. Earlier, Soviet dissident Aleksandr Solzhenitsyn also suffered (but survived) ricin-like symptoms after a 1971 encounter with KGB agents.[8]
Despite ricin's extreme toxicity and utility as an agent of chemical/biological warfare, it is extremely difficult to limit the production of the toxin. Under both the 1972 Biological Weapons Convention and the 1997 Chemical Weapons Convention, ricin is listed as a schedule 1 controlled substance. Despite this, more than 1 million metric tonnes of castor beans are processed each year, and approximately 5% of the total is rendered into a waste containing high concentrations of ricin toxin.[9]
In August of 2002, US officials asserted that the Islamic militant group Ansar al-Islam tested ricin, along with other chemical and biological agents, in northern Iraq.
To put ricin used as weapon into perspective, it is worth noting that as a biological weapon or chemical weapon, ricin may be considered as not very powerful, if only in comparison with other poisons such as botulinum or anthrax. Hence, a military willing to use biological weapons and having advanced resources would rather use either of the latter instead. Ricin is easy to produce, but is not as practical nor likely to cause as high casualties as other agents. Ricin denatures (ie, the protein changes structure and becomes less dangerous) much more readily than anthrax spores, which may remain lethal for decades. (Jan van Aken, an expert on biological weapons explained in an interview with the German magazine Der Spiegel that he judges it rather reassuring that Al Qaeda experimented with ricin as it suggests their inability to produce botulin or anthrax.)
Pure ricin could be dispersed through the air, but ozone, nitrogen oxides, and other pollutants would oxidize it within a few hours, rendering it harmless. Since it acts as an enzyme, catalyzing destruction of ribosomes, even a single oxidation is likely to render the ricin molecule harmless. Presumably it could be sealed inside some sort of dust particle that would dissolve in water, but this would be difficult.
The major reason it is dangerous is that there is no specific antidote, and that it is very easy to obtain (the castor bean plant is a common ornamental, and can be grown at home without any special care). Ricin is actually several orders of magnitude less toxic than botulinum or tetanus toxin, but those are more difficult to obtain.
# Patented extraction process
The process for creating ricin is well-known, and for example described in a patent.[10] The described extraction method is very similar to the preparation of soy protein isolates.
The patent was removed from the United States Patent and Trademark Office (USPTO) database sometime in 2004, but is still available online through international patent databases.[11] Modern theories of protein chemistry cast doubt on the effectiveness of the methods disclosed in the patent.[12]
# Detected ricin incidents
## Assassination of Bulgarian Dissident Georgi Markov, London 1978
On September 7, 1978 the Bulgarian dissident Georgi Markov was shot in the leg in public on Waterloo Bridge in the middle of London by a man using a weapon built into an umbrella. The weapon embedded a small pellet in Markov's leg which contained ricin. Markov died three days later.
## Related arrests in Britain in 2003
On 5 January, 2003 the Metropolitan Police raided a flat in north London and arrested six Algerian men whom they claimed were manufacturing ricin as part of a plot for a poison attack on the London Underground. No ricin was recovered as a result of this raid.
## In South Carolina
In 2003, a package and letter sealed in a ricin-contaminated envelope was intercepted in Greenville, South Carolina, at a United States Postal Service processing center.[13]
## In Washington, D.C. in 2003
Ricin was detected in the mail at the White House in Washington, D.C. in November of 2003. The letter containing it was intercepted at a mail handling facility off the grounds of the White House, and it never reached its intended destination. The letter contained a fine powdery substance that later tested positive for ricin. Investigators said it was low potency and was not considered a health risk. This information was not made public until February 3, 2004, when preliminary tests showed the presence of ricin in an office mailroom of U.S. Senate Majority Leader Bill Frist's office. There were no signs that anyone who was near the contaminated area developed any medical problems. Several Senate office buildings were closed as a precaution.
## In Richmond, VA
In January 2006, ricin was found in a home in the suburbs of Richmond, VA. It was in the form of mashed castor beans. Although the suspect, Chetanand Sewraz, was allegedly isolating the toxin to kill his estranged wife, and not for some form of bioterrorism, it nonetheless highlighted the ease with which ricin toxin can be made.[14][15]
## In Austin, Texas
On 23 February 2006, a student in the Moore-Hill dormitory at the University of Texas at Austin found a strange powder in a roll of quarters she was using to do laundry. The University Environmental Health and Safety department immediately sanitized the affected rooms. Lab results (returned the following Friday) indicated ricin. The source of the powder remains unknown, with both the university and Joint Terrorism Task Force investigating. The student and her roommate were being treated for potential exposure to the poison, although neither has exhibited symptoms. After cleansing and reinspection of the affected rooms (completed at 2:30am), the dorm reopened.[16][17] News reports on 25 February report that further testing has indicated that the substance found is not, in fact, ricin.[18] The identity of the powder has yet to be determined.
# Cultural references
- (1929) Ricin was the poison used in the Agatha Christie "Tommy and Tuppence" whodunnit, The House of Lurking Death in a 1929 collection of short stories called Partners in Crime.
- (1962) Ricin was used as the poison of choice of the murderer in the comedy film Kill or Cure.
- (1979) A killer used ricin to murder Travis McGee's girlfriend in The Green Ripper
- (1992) The Penn and Teller book How To Play With Your Food (ISBN 0-679-74311-1) includes a "gimmicks envelope" of small objects related to the tricks inside the book. One of these is a sticker reading "Contains all-natural ricin," intended to be placed on food as a joke. The book explains that ricin is a poison.
- (c. 1993) In Walker, Texas Ranger, CD Parker is killed by Ricin poisoning. His death was originally covered up by his murderers as a heart attack (they had a vendetta against Walker and the rangers that put them away, including CD) until the rangers realized something was going on and an autopsy was performed.
- (1999) Ricin was the poison used in Agatha Raisin and the Wizard of Evesham by M.C. Beaton.
- (2001) Ricin appears in CSI: Crime Scene Investigation Season 2 Episode 7 Caged .[19]
- (c. 2003) The Umbrella-gun pellet assassination incident was featured in Mythbusters.
- (2004) Ricin was one of the poisons used to exact terrorism in the book, "3rd Degree" by James Patterson
- (2004) It is mentioned in the song 'Paracetamoxyfrusebendroneomycin' by the British duo, the Amateur Transplants
- (2006) In Hour 1 of 24: The Game, terrorists plan to release ricin into Los Angeles Harbor.
- (2007) In Episode 15 of Season 2 in The Unit, Ricin is used in a bomb inside the United Nations building.
- (2007) Ricin-laced hot chocolate was the weapon used to kill a private school history professor in J. D. Robb's novel, "Innocent in Death".
- (2007) Ricin is mentioned as being dispersed in Dirty Bombs across LA in the alternate-reality game "Year Zero," based on the new Nine Inch Nails album of the same name.[20]
- (2007) In the episode Past Imperfect (Season 3 episode 21) of CSI:NY, one murder was committed when a man was shot in the leg with a pellet laced with ricin shot from an air gun.
- (2007) Ricin poisoning plays a role in the Law & Order show 'Fallout,' Season 17, episode 19.
- In the song "Master Thesis" by rap artist Canibus, he states, "Words concocted by the lyrical locksmith, as deadly as 10 droplets of Ricin toxin." Song on YouTube
- In the Season two opener of Dexter (TV Series), entitled "It's Alive!" Dexters victim is a Voodoo high priest who causes his "death curses" to come true by poisoning his victims with ricin. | https://www.wikidoc.org/index.php/Ricin | |
1e8deb4e15e9ca2c3911b29cc09184a98d582de5 | wikidoc | Rosin | Rosin
Rosin, formerly called colophony or Greek pitch (Pix græca), is a solid form of resin obtained from pines and some other plants, mostly conifers, produced by heating fresh liquid resin to vaporize the volatile liquid terpene components. It is semi-transparent and varies in color from yellow to black. At room temperature rosin is brittle, but it melts at stove-top temperatures. It chiefly consists of different resin acids, especially abietic acid.
Rosin is also known as colophony or colophonia resina from its origin in Colophon, an ancient Ionic city.
# Uses
Rosin is an ingredient in printing inks, varnishes, adhesives (glues), soap, paper sizing, soda, soldering fluxes, and sealing wax.
Rosin can be used as a glazing agent in medicines and chewing gum. It is denoted by E number E915. A related glycerol ester (E445) can be used as an emulsifier in soft drinks. In pharmaceuticals, rosin forms an ingredient in several plasters and ointments.
In industry, rosin is the precursor to the flux used in soldering. The lead-tin solder commonly used in electronics has about 1% rosin as a flux core helping the molten metal flow and making a better connection by reducing the refractory solid oxide layer formed at the surface back to metal. It's frequently seen as the burnt or clear residue around new soldering.
A mixture of pitch and rosin is used to make a surface against which glass is polished when making optical components such as lenses.
Rosin is added in small quantities to traditional linseed oil/sand gap fillers, used in building work.
When mixed with waxes and oils, rosin is the main ingredient of mystic smoke, a gum which, when rubbed and suddenly stretched, appears to produce puffs of smoke from the finger tips.
Rosin is extensively used for its friction-increasing capacity:
- Bowed string players rub cakes or blocks of rosin on their bow hair so it can grip the strings and make them speak. Extra substances such as beeswax, gold, silver, tin, or meteoric iron are sometimes added to the rosin to modify its stiction/friction properties, and (disputably) the tone it produces. Powdered rosin is often applied to new hair, for example with a felt pad or cloth, to reduce the time taken in getting sufficient rosin onto the hair.
- Violin rosin can be applied to bridges in other musical instruments, such as the Banjo and Banjolele, in order to stop the bridge moving during vigorous playing.
- Ballet dancers sometimes rub their shoes in powdered rosin to reduce slipping before going on stage - it was at one time used in the same way in fencing.
- Bull riders rub rosin on their rope and glove for additional grip.
- Baseball pitchers and ten-pin bowlers may have a small bag of powdered rosin nearby, to use on their throwing hand, for better control of the ball.
# Production
Rosin is the resinous constituent of the oleo-resin exuded by various species of pine, known in commerce as crude turpentine. The separation of the oleo-resin into the essential oil-spirit of turpentine and common rosin is effected by distillation in large copper stills. The essential oil is carried off at a temperature of between 100° and 160°C, leaving fluid rosin, which is run off through a tap at the bottom of the still, and purified by passing through straining wadding. Rosin varies in color, according to the age of the tree from which the turpentine is drawn and the degree of heat applied in distillation, from an opaque, almost pitch-black substance through grades of brown and yellow to an almost perfectly transparent colorless glassy mass. The commercial grades are numerous, ranging by letters from A, the darkest, to N, extra pale, superior to which are W, window glass, and WW, water white varieties, the latter having about three times the value of the common qualities.
Other sources of rosin includes rosin (called tall oil rosin) obtained from the distillation of Crude Tall Oil (CTO). Crude Tall Oil is a byproduct obtained from the kraft paper making process. Additionally rosin may be obtained from aged pine stumps. This type of rosin is typically called wood rosin. In this process, aged wood stumps are chipped and soaked in a solvent solution. The solvents are recovered along with the rosin, fatty acids, turpentine, and other constituents through distillation.
On a large scale, rosin is treated by destructive distillation for the production of rosin spirit, pinoline and rosin oil. The last enters into the composition of some of the solid lubricating greases, and is also used as an adulterant of other oils.
# Properties
Rosin is brittle and friable, with a faint piny odor. It is typically a glassy solid, though some rosins will form crystals, especially when brought into solution. The practical melting point varies with different specimens, some being semi-fluid at the temperature of boiling water, others melting at 100°C to 120°C. It is very flammable, burning with a smoky flame, so care should be taken when melting it. It is soluble in alcohol, ether, benzene and chloroform. Rosin consists mainly of abietic acid, and combines with caustic alkalis to form salts (rosinates or pinates) that are known as rosin soaps. In addition to its extensive use in soap making, rosin is largely employed in making varnishes (including fine violin varnishes), sealing-wax and various adhesives. It is also used for preparing shoemakers' wax, as a flux for soldering metals, for pitching lager beer casks, for rosining the bows of musical instruments and numerous minor purposes.
Prolonged exposure to rosin fumes released during soldering can cause occupational asthma (formerly called colophony disease in this context) in sensitive individuals, although it is not known which component of the fumes causes the problem.
The type of rosin used for instruments is determined by the diameter of the strings. Generally this means that the larger the instrument is, the softer the rosin should be. For instance, double bass rosin is generally soft enough to be pliable with slow movements. A cake of bass rosin left in a single position for several months will show evidence of flow, especially in warmer weather.
# Sources
The chief region of rosin production is Indonesia, southern China, such as Guangdong, Guangxi, Fujian, Yunnan and Jiangxi, and Northern part of Vietnam. Chinese rosin is obtained mainly from the turpentine of Masson's Pine Pinus massoniana and Slash Pine P. elliottii.
The South Atlantic and Eastern Gulf states of the United States is also a chief region of production. American rosin is obtained from the turpentine of Longleaf Pine Pinus palustris and Loblolly Pine P. taeda. In Mexico, most of the rosin is derived from live tapping (gum rosin) of several species of pine trees, but mostly Pinus oocarpa, Pinus leiophylla, Pinus michoacana and Pinus montezumae. Most production is concentrated in the west-central state of Michoacán.
The main source of supply in Europe is the French district of Les Landes in the departments of Gironde and Landes, where the Maritime Pine P. pinaster is extensively cultivated. In the north of Europe rosin is obtained from the Scots Pine P. sylvestris, and throughout European countries local supplies are obtained from other species of pine, with Aleppo Pine P. halepensis being particularly important in the Mediterranean region.
# Gallery
- Colophony/rosin
Colophony/rosin
- Tartini violin rosin
Tartini violin rosin
- Light violin rosin
Light violin rosin
- Various types of violin/viola/cello rosin
Various types of violin/viola/cello rosin
# Also see
- Resin | Rosin
Rosin, formerly called colophony or Greek pitch (Pix græca), is a solid form of resin obtained from pines and some other plants, mostly conifers, produced by heating fresh liquid resin to vaporize the volatile liquid terpene components. It is semi-transparent and varies in color from yellow to black. At room temperature rosin is brittle, but it melts at stove-top temperatures. It chiefly consists of different resin acids, especially abietic acid.
Rosin is also known as colophony or colophonia resina from its origin in Colophon, an ancient Ionic city.
# Uses
Rosin is an ingredient in printing inks, varnishes, adhesives (glues), soap, paper sizing, soda, soldering fluxes, and sealing wax.
Rosin can be used as a glazing agent in medicines and chewing gum. It is denoted by E number E915. A related glycerol ester (E445) can be used as an emulsifier in soft drinks. In pharmaceuticals, rosin forms an ingredient in several plasters and ointments.
In industry, rosin is the precursor to the flux used in soldering. The lead-tin solder commonly used in electronics has about 1% rosin as a flux core helping the molten metal flow and making a better connection by reducing the refractory solid oxide layer formed at the surface back to metal. It's frequently seen as the burnt or clear residue around new soldering.
A mixture of pitch and rosin is used to make a surface against which glass is polished when making optical components such as lenses.
Rosin is added in small quantities to traditional linseed oil/sand gap fillers, used in building work.
When mixed with waxes and oils, rosin is the main ingredient of mystic smoke, a gum which, when rubbed and suddenly stretched, appears to produce puffs of smoke from the finger tips.[1]
Rosin is extensively used for its friction-increasing capacity:
- Bowed string players rub cakes or blocks of rosin on their bow hair so it can grip the strings and make them speak. Extra substances such as beeswax, gold, silver, tin, or meteoric iron are sometimes added to the rosin to modify its stiction/friction properties, and (disputably) the tone it produces. Powdered rosin is often applied to new hair, for example with a felt pad or cloth, to reduce the time taken in getting sufficient rosin onto the hair.
- Violin rosin can be applied to bridges in other musical instruments, such as the Banjo and Banjolele, in order to stop the bridge moving during vigorous playing.
- Ballet dancers sometimes rub their shoes in powdered rosin to reduce slipping before going on stage - it was at one time used in the same way in fencing.
- Bull riders rub rosin on their rope and glove for additional grip.
- Baseball pitchers and ten-pin bowlers may have a small bag of powdered rosin nearby, to use on their throwing hand, for better control of the ball.
# Production
Rosin is the resinous constituent of the oleo-resin exuded by various species of pine, known in commerce as crude turpentine. The separation of the oleo-resin into the essential oil-spirit of turpentine and common rosin is effected by distillation in large copper stills. The essential oil is carried off at a temperature of between 100° and 160°C, leaving fluid rosin, which is run off through a tap at the bottom of the still, and purified by passing through straining wadding. Rosin varies in color, according to the age of the tree from which the turpentine is drawn and the degree of heat applied in distillation, from an opaque, almost pitch-black substance through grades of brown and yellow to an almost perfectly transparent colorless glassy mass. The commercial grades are numerous, ranging by letters from A, the darkest, to N, extra pale, superior to which are W, window glass, and WW, water white varieties, the latter having about three times the value of the common qualities.
Other sources of rosin includes rosin (called tall oil rosin) obtained from the distillation of Crude Tall Oil (CTO). Crude Tall Oil is a byproduct obtained from the kraft paper making process. Additionally rosin may be obtained from aged pine stumps. This type of rosin is typically called wood rosin. In this process, aged wood stumps are chipped and soaked in a solvent solution. The solvents are recovered along with the rosin, fatty acids, turpentine, and other constituents through distillation.
On a large scale, rosin is treated by destructive distillation for the production of rosin spirit, pinoline and rosin oil. The last enters into the composition of some of the solid lubricating greases, and is also used as an adulterant of other oils.
# Properties
Rosin is brittle and friable, with a faint piny odor. It is typically a glassy solid, though some rosins will form crystals, especially when brought into solution.[2] The practical melting point varies with different specimens, some being semi-fluid at the temperature of boiling water, others melting at 100°C to 120°C. It is very flammable, burning with a smoky flame, so care should be taken when melting it. It is soluble in alcohol, ether, benzene and chloroform. Rosin consists mainly of abietic acid, and combines with caustic alkalis to form salts (rosinates or pinates) that are known as rosin soaps. In addition to its extensive use in soap making, rosin is largely employed in making varnishes (including fine violin varnishes), sealing-wax and various adhesives. It is also used for preparing shoemakers' wax, as a flux for soldering metals, for pitching lager beer casks, for rosining the bows of musical instruments and numerous minor purposes.
Prolonged exposure to rosin fumes released during soldering can cause occupational asthma (formerly called colophony disease[3] in this context) in sensitive individuals, although it is not known which component of the fumes causes the problem.[4]
The type of rosin used for instruments is determined by the diameter of the strings. Generally this means that the larger the instrument is, the softer the rosin should be. For instance, double bass rosin is generally soft enough to be pliable with slow movements. A cake of bass rosin left in a single position for several months will show evidence of flow, especially in warmer weather.
# Sources
The chief region of rosin production is Indonesia, southern China, such as Guangdong, Guangxi, Fujian, Yunnan and Jiangxi, and Northern part of Vietnam. Chinese rosin is obtained mainly from the turpentine of Masson's Pine Pinus massoniana and Slash Pine P. elliottii.
The South Atlantic and Eastern Gulf states of the United States is also a chief region of production. American rosin is obtained from the turpentine of Longleaf Pine Pinus palustris and Loblolly Pine P. taeda. In Mexico, most of the rosin is derived from live tapping (gum rosin) of several species of pine trees, but mostly Pinus oocarpa, Pinus leiophylla, Pinus michoacana and Pinus montezumae. Most production is concentrated in the west-central state of Michoacán.
The main source of supply in Europe is the French district of Les Landes in the departments of Gironde and Landes, where the Maritime Pine P. pinaster is extensively cultivated. In the north of Europe rosin is obtained from the Scots Pine P. sylvestris, and throughout European countries local supplies are obtained from other species of pine, with Aleppo Pine P. halepensis being particularly important in the Mediterranean region.
# Gallery
- Colophony/rosin
Colophony/rosin
- Tartini violin rosin
Tartini violin rosin
- Light violin rosin
Light violin rosin
- Various types of violin/viola/cello rosin
Various types of violin/viola/cello rosin
# Also see
- Resin | https://www.wikidoc.org/index.php/Rosin |
Subsets and Splits