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09f8d2625fb8a1fc746cf98a24cf8b35866474a2 | wikidoc | GSK3B | GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene. In mice, the enzyme is encoded by the GSK-3β gene. Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards bipolar disorder.
# Function
Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and an inactivating agent of glycogen synthase. Two isoforms, alpha (GSK3A) and beta, show a high degree of amino acid homology. GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation. It might be a new therapeutic target for ischemic stroke.
# Loss of function mutations
Homozygous disruption of the GSK-3β locus in mice results in embryonic lethality during mid-gestation. This lethality phenotype could be rescued by inhibition of tumor necrosis factor.
# Signaling pathways
Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.
# Interactions
GSK3B has been shown to interact with:
- KIAA1211L
- AKAP11,
- AXIN1,
- AXIN2,
- AR,
- CTNNB1,
- DNM1L,
- MACF1
- MUC1,
- SMAD3
- NOTCH1,
- NOTCH2,
- P53,
- PRKAR2A,
- SGK3, and
- TSC2. | GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.[1][2] In mice, the enzyme is encoded by the GSK-3β gene.[3] Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards bipolar disorder.[4]
# Function
Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and an inactivating agent of glycogen synthase. Two isoforms, alpha (GSK3A) and beta, show a high degree of amino acid homology.[1] GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.[5][6] It might be a new therapeutic target for ischemic stroke.
# Loss of function mutations
Homozygous disruption of the GSK-3β locus in mice results in embryonic lethality during mid-gestation.[3] This lethality phenotype could be rescued by inhibition of tumor necrosis factor.[3]
# Signaling pathways
Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.[7]
# Interactions
GSK3B has been shown to interact with:
- KIAA1211L[8]
- AKAP11,[9]
- AXIN1,[10][11]
- AXIN2,[12][13]
- AR,[14]
- CTNNB1,[15][16]
- DNM1L,[17]
- MACF1[18]
- MUC1,[19][20]
- SMAD3[21]
- NOTCH1,[22]
- NOTCH2,[23]
- P53,[24]
- PRKAR2A,[9]
- SGK3,[25] and
- TSC2.[10][26] | https://www.wikidoc.org/index.php/GSK3B | |
942043a3fa4a0a00fd105a39edef53617ace360c | wikidoc | GSTA4 | GSTA4
Glutathione S-transferase A4, also known as GSTA4, is an enzyme which in humans is encoded by the GSTA4 gene.
# Function
Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase belonging to the alpha class. The alpha class genes, which are located in a cluster on chromosome 6, are highly related and encode enzymes with glutathione peroxidase activity that function in the detoxification of lipid peroxidation products.
GSTA4 shows very high activity with reactive carbonyl compounds such as alk-2-enals. GSTA4 is highly effective in catalyzing the conjugate addition of reduced glutathione to 4-hydroxynonenal, an important product of peroxidative degradation of arachidonic acid and a commonly used biomarker for oxidative damage in tissue.
# Clinical significance
Reactive electrophiles produced by oxidative metabolism have been linked to a number of degenerative diseases including Parkinson's disease, Alzheimer's disease, cataract formation, and atherosclerosis hence reduced expression of the GSTA4 enzyme may have pathophysiological consequences. The expression of this gene is decreased drastically among burn and trauma victims. | GSTA4
Glutathione S-transferase A4, also known as GSTA4, is an enzyme which in humans is encoded by the GSTA4 gene.[1][2][3]
# Function
Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase belonging to the alpha class. The alpha class genes, which are located in a cluster on chromosome 6, are highly related and encode enzymes with glutathione peroxidase activity that function in the detoxification of lipid peroxidation products.[1]
GSTA4 shows very high activity with reactive carbonyl compounds such as alk-2-enals.[2] GSTA4 is highly effective in catalyzing the conjugate addition of reduced glutathione to 4-hydroxynonenal, an important product of peroxidative degradation of arachidonic acid and a commonly used biomarker for oxidative damage in tissue.[3]
# Clinical significance
Reactive electrophiles produced by oxidative metabolism have been linked to a number of degenerative diseases including Parkinson's disease, Alzheimer's disease, cataract formation, and atherosclerosis hence reduced expression of the GSTA4 enzyme may have pathophysiological consequences.[1] The expression of this gene is decreased drastically among burn and trauma victims.[citation needed] | https://www.wikidoc.org/index.php/GSTA4 | |
d913e454c22510b3f9ed708bcb2649d820a80b00 | wikidoc | GSTK1 | GSTK1
Glutathione S-transferase kappa 1 (GSTK1) is an enzyme that in humans is encoded by the GSTK1 gene which is located on chromosome seven. It belongs to the superfamily of enzymes known as glutathione S-transferase (GST), which are mainly known for cellular detoxification. The GSTK1 gene consists of eight exons and seven introns and although it is a member of the GST family, its structure has been found to be similar to bacterial HCCA (2-hydroxychromene-2-carboxylate) isomerases and bacterial disulphide-bond-forming DsbA oxidoreductase. This similarity has later allowed the enzyme GSTK1 to be renamed to DsbA-L. Research has also suggested that several variations of the GSTK1 gene can be responsible for metabolic diseases and certain types of cancer.
# Structure
The GSTK1 enzyme is a homodimer and, like all GSTs, it contains a TRX-like domain and a helical domain. However, the GSTK1 is substantially different in its secondary structure compared to the other GSTs. The helical domain has been observed to be placed between the βαβ and ββα motifs of the TRX-like domain, rather than the TRX-like domain and the C-terminal helical domain being connected together by a short linker of alpha-helixes as normally seen in GSTs. Also, the GSTK1 dimer employs a butterfly shape and not a V-shaped crevice like in the other classes. As for the GSTK1 gene, it is ~5 kb long, has eight exons, is located on chromosome 7q34, and includes an initiator element at the transcription start site instead of a TATA or a CCAAT box.
# Function
GSTK1 has been observed in promoting adiponectin multimerization in the endoplasmic reticulum (ER). How the GSTK1 is able to do this is still unknown. The enzyme can also prevent ER stress and ER stress induced adiponectin down-regulation, which implies that GSTK1 assists the ER’s functions. GSTK1 is not only located in the ER, but also in the mitochondria of hepatocytes. This indicates that GSTK1 could be vital to the ER, the mitochondria, and the interactions between the two organelles; however, there is still limited knowledge about this and more studies must be conducted to find out.
The discovery of GSTK1 in the peroxisome of a cell has further led to more studies based on its function. It has been suggested that, based on the GSTA enzyme, GSTK1 could play a role in the buffering system of acyl-CoA and xenobiotic-CoA and be involved in their binding activities. Also, it is hypothesized that GSTK1 is responsible for the detoxification of lipid peroxides, which are created in the peroxisome. This is based on the fact that there is peroxidase activity towards three substrates: tert-butyl hydroperoxide, cumene hydroperoxide, and 15-S-hydroperoxy-5,8,11,13-eicosatetraenoic acid.
# Clinical significance
The amount of expression of adiponectin has been observed to be related to diseases such as insulin resistance, obesity, and type 2 diabetes. Decreased amounts of the protein indicates that there is a higher probability of receiving said diseases. Because the GSTK1 is seen to play a role in the multimerization of adiponectin, this enzyme can regulate the concentration of adiponectin and thus enhance insulin sensitivity and protect against diabetes. Also, the GSTK1 gene is unregulated when it is inflicted with oxidative stress and are over expressed in many tumors leading to difficulties during cancer chemotherapy. Moreover, GSTK1 gene expression has been seen to increase significantly in correlation to drug resistance in tumor cells such as erythroleukemia and mammary adenocarcinoma suggesting that it, along with GSTP1 and GSTA4, could be responsible for the drug resistance.
GSTK1 can also be a potential tool to help investigate cancer. Tyrosine phosphorylated proteins are responsible for many of the cell functions such as the cell’s growth, division, adhesion, and motility. These activities are also very related to cancer and thus studying this protein could allow access to information which could classify tumors for prognosis and prediction. Due to GSTK1’s C-terminal SH2 domain, tyrosine phosphorylated proteins can bind to it and allow for easier detection to which the protein can be studied.
# Interactions
GSTK1 has been seen to interact with:
- adiponectin
- Erol-Lα | GSTK1
Glutathione S-transferase kappa 1 (GSTK1) is an enzyme that in humans is encoded by the GSTK1 gene which is located on chromosome seven.[1] It belongs to the superfamily of enzymes known as glutathione S-transferase (GST), which are mainly known for cellular detoxification.[2] The GSTK1 gene consists of eight exons and seven introns and although it is a member of the GST family, its structure has been found to be similar to bacterial HCCA (2-hydroxychromene-2-carboxylate) isomerases and bacterial disulphide-bond-forming DsbA oxidoreductase. This similarity has later allowed the enzyme GSTK1 to be renamed to DsbA-L.[3] Research has also suggested that several variations of the GSTK1 gene can be responsible for metabolic diseases and certain types of cancer.[3]
# Structure
The GSTK1 enzyme is a homodimer and, like all GSTs, it contains a TRX-like domain and a helical domain. However, the GSTK1 is substantially different in its secondary structure compared to the other GSTs. The helical domain has been observed to be placed between the βαβ and ββα motifs of the TRX-like domain, rather than the TRX-like domain and the C-terminal helical domain being connected together by a short linker of alpha-helixes as normally seen in GSTs.[2] Also, the GSTK1 dimer employs a butterfly shape and not a V-shaped crevice like in the other classes.[2] As for the GSTK1 gene, it is ~5 kb long, has eight exons, is located on chromosome 7q34, and includes an initiator element at the transcription start site instead of a TATA or a CCAAT box.[1]
# Function
GSTK1 has been observed in promoting adiponectin multimerization in the endoplasmic reticulum (ER). How the GSTK1 is able to do this is still unknown.[4] The enzyme can also prevent ER stress and ER stress induced adiponectin down-regulation, which implies that GSTK1 assists the ER’s functions. GSTK1 is not only located in the ER, but also in the mitochondria of hepatocytes. This indicates that GSTK1 could be vital to the ER, the mitochondria, and the interactions between the two organelles; however, there is still limited knowledge about this and more studies must be conducted to find out.[4]
The discovery of GSTK1 in the peroxisome of a cell has further led to more studies based on its function. It has been suggested that, based on the GSTA enzyme, GSTK1 could play a role in the buffering system of acyl-CoA and xenobiotic-CoA and be involved in their binding activities. Also, it is hypothesized that GSTK1 is responsible for the detoxification of lipid peroxides, which are created in the peroxisome. This is based on the fact that there is peroxidase activity towards three substrates: tert-butyl hydroperoxide, cumene hydroperoxide, and 15-S-hydroperoxy-5,8,11,13-eicosatetraenoic acid.[1]
# Clinical significance
The amount of expression of adiponectin has been observed to be related to diseases such as insulin resistance, obesity, and type 2 diabetes. Decreased amounts of the protein indicates that there is a higher probability of receiving said diseases. Because the GSTK1 is seen to play a role in the multimerization of adiponectin, this enzyme can regulate the concentration of adiponectin and thus enhance insulin sensitivity and protect against diabetes.[3] Also, the GSTK1 gene is unregulated when it is inflicted with oxidative stress and are over expressed in many tumors leading to difficulties during cancer chemotherapy.[5] Moreover, GSTK1 gene expression has been seen to increase significantly in correlation to drug resistance in tumor cells such as erythroleukemia and mammary adenocarcinoma suggesting that it, along with GSTP1 and GSTA4, could be responsible for the drug resistance.[6]
GSTK1 can also be a potential tool to help investigate cancer. Tyrosine phosphorylated proteins are responsible for many of the cell functions such as the cell’s growth, division, adhesion, and motility. These activities are also very related to cancer and thus studying this protein could allow access to information which could classify tumors for prognosis and prediction.[7] Due to GSTK1’s C-terminal SH2 domain, tyrosine phosphorylated proteins can bind to it and allow for easier detection to which the protein can be studied.[7]
# Interactions
GSTK1 has been seen to interact with:
- adiponectin[4]
- Erol-Lα[4] | https://www.wikidoc.org/index.php/GSTK1 | |
12857c893c7a7a38edff704531434b764374e674 | wikidoc | GSTM4 | GSTM4
Glutathione S-transferase Mu 4 is an enzyme that in humans is encoded by the GSTM4 gene.
Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. Multiple transcript variants, each encoding a distinct protein isoform, have been identified.
In the August 2009 issue of Oncogene journal, researchers at Huntsman Cancer Institute (HCI) at the University of Utah demonstrated that expression levels of GSTM4 could predict response to chemotherapy in patients with Ewing's Sarcoma. The study found that patients who did not respond to chemotherapy had high levels of GSTM4. | GSTM4
Glutathione S-transferase Mu 4 is an enzyme that in humans is encoded by the GSTM4 gene.[1][2]
Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. Multiple transcript variants, each encoding a distinct protein isoform, have been identified.[2]
In the August 2009 issue of Oncogene journal, researchers at Huntsman Cancer Institute (HCI) at the University of Utah demonstrated that expression levels of GSTM4 could predict response to chemotherapy in patients with Ewing's Sarcoma. The study found that patients who did not respond to chemotherapy had high levels of GSTM4.[3] | https://www.wikidoc.org/index.php/GSTM4 | |
d1b0399cd6447c8f3dbfd66af9e7e7ff495f7408 | wikidoc | GSTP1 | GSTP1
Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.
# Function
Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the soluble GSTs are categorized into four main classes: alpha, mu, pi, and theta. The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and play a role in susceptibility to cancer, and other diseases.
# Interactions
GSTP1 has been shown to interact with Fanconi anemia, complementation group C and MAPK8.
GST-Pi is expressed in many human tissues, particularly in the biliary tree and renal distal convoluted tubules.It the most common gene alteration in ca prostate (hyper methylation)
# Possible drug target
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and inhibitors are being studied. Piperlongumine has been found to silence the gene. | GSTP1
Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.[1][2]
# Function
Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the soluble GSTs are categorized into four main classes: alpha, mu, pi, and theta. The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and play a role in susceptibility to cancer, and other diseases.[3]
# Interactions
GSTP1 has been shown to interact with Fanconi anemia, complementation group C[4][5] and MAPK8.[6]
GST-Pi is expressed in many human tissues, particularly in the biliary tree and renal distal convoluted tubules.It the most common gene alteration in ca prostate (hyper methylation)[7]
# Possible drug target
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and inhibitors are being studied.[8] Piperlongumine has been found to silence the gene.[9] | https://www.wikidoc.org/index.php/GSTP1 | |
d01fab25d2b0c99e5550a749c5d6fe39857db1d2 | wikidoc | GSTZ1 | GSTZ1
Glutathione S-transferase Zeta 1 (also known as maleylacetoacetate isomerase) is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.
This gene is a member of the glutathione S-transferase (GSTs) super-family, which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme also plays a significant role in the catabolism of phenylalanine and tyrosine. Thus, defects in this enzyme may lead to severe metabolic disorders, including alkaptonuria, phenylketonuria and tyrosinaemia, and new discoveries may allow the enzyme to protect against certain diseases related to oxidative stress.
# Structure
Glutathione S-transferase Zeta 1 (GSTZ1) has a predominantly hydrophobic dimer, just like many other GST members. It is composed of 24.2 kDa subunits and it consists of an N-terminal thioredoxin-like domain and a C-terminal all alpha-helical domain. Both of these domains are intertwined by a linker region between amino acids 85 and 91. The active site of this enzyme is much smaller and more polar than that of other family members of GST, which allows for GSTZ1 to be more selective in terms of substrates. Also, the C-terminus is truncated and the GSTZ1 enzyme lacks the normal V-shaped dimer interface which are usually common in other GSTs. As for the GSTZ1 gene, it is located on chromosome 14q24.3, has 12 exons, and is approximately 10 kb long. GSTZ1 also contains a distinct motif (Ser14–Ser15–Cys16) which is seen as the active center in catalysis.
# Function
GSTZ1 is predominantly found in liver cells; more specifically, it is localized in both the cytosol and the mitochondria. GSTZ1 is essentially known for catalyzing glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, which is the second-to-last step in the vital phenylalanine and tyrosine degradation pathway. It is the only enzyme in the GST family that catalyses a significant process in intermediary metabolism and it ensures that this enzyme can be found in a variety of species from humans to bacteria. Another function of the GSTZ1 is that it is in control of the biotransformation of alpha-haloacids, like dichloroacetic acid (DCA), to glyoxylic acid. This prevents the buildup of DCA, which can lead to asymptomatic hepatotoxicity and a reversible peripheral neuropathy. Both functions for this enzyme requires the presence of glutathione (GSH) in order to work.
# Clinical Significance
Deficiencies in any of the enzymes in the catabolism of phenylalanine and tyrosine, like GSTZ1, has led to diseases such as alkaptonuria, phenylketonuria, and several forms of tyrosinemia. A lack of GSTZ1, specifically, leads to the amalgamation of maleylacetoacetate and succinylacetone which has been observed to cause oxidative stress. Also, scarcities have been seen to alter the metabolism of certain drugs and xenobiotics in mice.
Most importantly, researchers have successfully genetically engineered GSTZ1 to mimic one of the most significant antioxidant enzymes, glutathione peroxidase (GPX). GPX is most known for its role to protect cells and tissues against oxidative damage by catalyzing the reduction of hydroperoxides using GSH as a reducing substrate and blocking the radical reaction caused by lipid peroxides. By protecting against this oxidative damage, GPX essentially prevents against degenerative diseases such as atherosclerosis, myocardial ischemia, heart failure, diabetes, pulmonary fibrosis, neurodegenerative disorders, and Alzheimer’s disease. However, because of GPX’s poor stability and paucity, it cannot be used in clinical studies and other methods must be considered. The newfound seleno-hGSTZ1–1 (or the engineered GSTZ1 enzyme) has a high GPX activity and a very similar reaction mechanism to that of GPX.
# Interactions
GSTZ1 has been seen to interact with:
- α-haloacids
- GSH
- Maleylacetoacetate | GSTZ1
Glutathione S-transferase Zeta 1 (also known as maleylacetoacetate isomerase) is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.[1][2][3]
This gene is a member of the glutathione S-transferase (GSTs) super-family, which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme also plays a significant role in the catabolism of phenylalanine and tyrosine. Thus, defects in this enzyme may lead to severe metabolic disorders, including alkaptonuria, phenylketonuria and tyrosinaemia, and new discoveries may allow the enzyme to protect against certain diseases related to oxidative stress.[3]
# Structure
Glutathione S-transferase Zeta 1 (GSTZ1) has a predominantly hydrophobic dimer, just like many other GST members. It is composed of 24.2 kDa subunits and it consists of an N-terminal thioredoxin-like domain and a C-terminal all alpha-helical domain. Both of these domains are intertwined by a linker region between amino acids 85 and 91. The active site of this enzyme is much smaller and more polar than that of other family members of GST, which allows for GSTZ1 to be more selective in terms of substrates. Also, the C-terminus is truncated and the GSTZ1 enzyme lacks the normal V-shaped dimer interface which are usually common in other GSTs.[4] As for the GSTZ1 gene, it is located on chromosome 14q24.3, has 12 exons, and is approximately 10 kb long.[3] GSTZ1 also contains a distinct motif (Ser14–Ser15–Cys16) which is seen as the active center in catalysis.[5]
# Function
GSTZ1 is predominantly found in liver cells; more specifically, it is localized in both the cytosol and the mitochondria.[6] GSTZ1 is essentially known for catalyzing glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, which is the second-to-last step in the vital phenylalanine and tyrosine degradation pathway. It is the only enzyme in the GST family that catalyses a significant process in intermediary metabolism and it ensures that this enzyme can be found in a variety of species from humans to bacteria.[7] Another function of the GSTZ1 is that it is in control of the biotransformation of alpha-haloacids, like dichloroacetic acid (DCA), to glyoxylic acid. This prevents the buildup of DCA, which can lead to asymptomatic hepatotoxicity and a reversible peripheral neuropathy.[6] Both functions for this enzyme requires the presence of glutathione (GSH) in order to work.[5]
# Clinical Significance
Deficiencies in any of the enzymes in the catabolism of phenylalanine and tyrosine, like GSTZ1, has led to diseases such as alkaptonuria, phenylketonuria, and several forms of tyrosinemia.[4] A lack of GSTZ1, specifically, leads to the amalgamation of maleylacetoacetate and succinylacetone which has been observed to cause oxidative stress. Also, scarcities have been seen to alter the metabolism of certain drugs and xenobiotics in mice.[8]
Most importantly, researchers have successfully genetically engineered GSTZ1 to mimic one of the most significant antioxidant enzymes, glutathione peroxidase (GPX). GPX is most known for its role to protect cells and tissues against oxidative damage by catalyzing the reduction of hydroperoxides using GSH as a reducing substrate and blocking the radical reaction caused by lipid peroxides. By protecting against this oxidative damage, GPX essentially prevents against degenerative diseases such as atherosclerosis, myocardial ischemia, heart failure, diabetes, pulmonary fibrosis, neurodegenerative disorders, and Alzheimer’s disease. However, because of GPX’s poor stability and paucity, it cannot be used in clinical studies and other methods must be considered. The newfound seleno-hGSTZ1–1 (or the engineered GSTZ1 enzyme) has a high GPX activity and a very similar reaction mechanism to that of GPX.[9]
# Interactions
GSTZ1 has been seen to interact with:
- α-haloacids[5]
- GSH[6]
- Maleylacetoacetate[7] | https://www.wikidoc.org/index.php/GSTZ1 | |
8e4fbbfc2ccece1f7d604cf8b827dd4de6473715 | wikidoc | Gamma | Gamma
Gamma (uppercase Γ, lowercase γ; Template:Lang-el) is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. It was derived from the Phoenician letter Gimel Gimel. Letters that arose from Gamma include the Roman C and G and the Cyrillic letters Ge Г and Ghe Ґ.
In Modern Greek, it represents either a voiced velar fricative Template:IPA or a voiced palatal fricative Template:IPA. In Ancient Greek, it represented a voiced velar stop Template:IPA. Before velars, it represents a velar nasal Template:IPA in Modern as well as Ancient Greek, and a double gamma represents a prenasalized voiced velar stop (Template:IPA).
# Gamma combinations
The gamma can be combined with other letters or itself.
- A double gamma (γγ) is pronounced like the ng in "jumping"
- A gamma with xi (γξ) is pronounced roughly like the nx in "Sphinx"
- A gamma with chi (γχ) is pronounced like the nkh in "ankh"
- A gamma combined with kappa (γκ) is pronounced like the nk in "banker"
# Use as a symbol or a term
Gamma is often used to denote a variable in mathematics and physics.
In certain areas it has a specific meaning, such as representing gamma radiation in nuclear physics and the Lorentz factor in theory of relativity. In mathematics, there is a gamma function (usually written as Γ-function.)
als:Γ
ar:غاما (حرف إغريقي)
arc:Γ
ast:Gamma
br:Gamma (lizherenn)
bg:Гама (буква)
ca:Gamma
cy:Gamma
da:Gamma (bogstav)
de:Gamma
el:Γάμμα
eo:Gamo (litero)
eu:Gamma (greko)
ga:Gáma
gd:Gamma
gl:Gamma
ko:Γ
hr:Gama
id:Gamma (huruf Yunani)
is:Gamma
it:Gamma (lettera)
he:גמא (אות)
ka:გამა (ასო)
sw:Gamma
ht:Γ
ku:Gamma
la:Gamma
lt:Gama (raidė)
hu:Gamma
ms:Gama
nah:Γ
nl:Gamma (letter)
no:Gamma
nn:Gamma
nds:Gamma
simple:Gamma
sk:Gama (grécke písmeno)
sl:Gama
sr:Гама
sh:Gama
fi:Gamma
sv:Gamma
th:แกมมา
uk:Гамма (літера) | Gamma
Template:Two other uses
Template:Wiktionarypar2
Template:Table Greekletters
Gamma (uppercase Γ, lowercase γ; Template:Lang-el) is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. It was derived from the Phoenician letter Gimel Gimel. Letters that arose from Gamma include the Roman C and G and the Cyrillic letters Ge Г and Ghe Ґ.
In Modern Greek, it represents either a voiced velar fricative Template:IPA or a voiced palatal fricative Template:IPA. In Ancient Greek, it represented a voiced velar stop Template:IPA. Before velars, it represents a velar nasal Template:IPA in Modern as well as Ancient Greek, and a double gamma represents a prenasalized voiced velar stop (Template:IPA).
# Gamma combinations
The gamma can be combined with other letters or itself.
- A double gamma (γγ) is pronounced like the ng in "jumping"
- A gamma with xi (γξ) is pronounced roughly like the nx in "Sphinx"
- A gamma with chi (γχ) is pronounced like the nkh in "ankh"
- A gamma combined with kappa (γκ) is pronounced like the nk in "banker"
# Use as a symbol or a term
Gamma is often used to denote a variable in mathematics and physics.
In certain areas it has a specific meaning, such as representing gamma radiation in nuclear physics and the Lorentz factor in theory of relativity. In mathematics, there is a gamma function (usually written as Γ-function.)
als:Γ
ar:غاما (حرف إغريقي)
arc:Γ
ast:Gamma
br:Gamma (lizherenn)
bg:Гама (буква)
ca:Gamma
cy:Gamma
da:Gamma (bogstav)
de:Gamma
el:Γάμμα
eo:Gamo (litero)
eu:Gamma (greko)
ga:Gáma
gd:Gamma
gl:Gamma
ko:Γ
hr:Gama
id:Gamma (huruf Yunani)
is:Gamma
it:Gamma (lettera)
he:גמא (אות)
ka:გამა (ასო)
sw:Gamma
ht:Γ
ku:Gamma
la:Gamma
lt:Gama (raidė)
hu:Gamma
ms:Gama
nah:Γ
nl:Gamma (letter)
no:Gamma
nn:Gamma
nds:Gamma
simple:Gamma
sk:Gama (grécke písmeno)
sl:Gama
sr:Гама
sh:Gama
fi:Gamma
sv:Gamma
th:แกมมา
uk:Гамма (літера)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Gamma | |
120aa460c6cdcc5fcea4c903a69965c300711796 | wikidoc | Genes | Genes
A gene is a distinct sequence of nucleotides forming part of a chromosome, the order of which determines the order of monomers in a polypeptide or nucleic acid molecule which a cell (or virus) may synthesize.
# Theoretical genes
Def. a "theoretical unit of heredity of living organisms ; a gene may take several values and in principle predetermines a precise trait of an organism's form (phenotype), such as hair color" or a "segment of DNA or RNA from a cell's or an organism's genome, that may take several forms and thus parameterizes a phenomenon, in general the structure of a protein; locus" is called a gene.
Here's a theoretical definition:
Def. a specific nucleotide sequence within a gene locus with its own transcription start site(s), introns, exons, and UTRs, that transcribes a specific RNA product is called an isoform, or gene isoform.
Def. any "of several different forms of the same protein, arising from either single nucleotide polymorphisms, differential splicing of mRNA, or post-translational modifications (e.g. sulfation, glycosylation, etc.)" is called an isoform.
Def. a "region of a transcribed gene present in the final functional RNA molecule" is called an exon.
Def. a "portion of a split gene that is included in pre-RNA transcripts but is removed during RNA processing and rapidly degraded" is called an intron.
# Gene clusters
GeneID: 348 APOE apolipoprotein E description contains this: "This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes."
# Gene expressions
Gene expressions is a suite of genes, and their isoforms, that appear to be biochemically involved in the appearance of a trait.
Although it is harder to regulate the transcription of genes with multiple transcription start sites, "variations in the expression of a constitutive gene would be minimized by the use of multiple start sites."
Earlier "studies led to the design of a super core promoter (SCP) that contains a TATA, Inr, MTE, and DPE in a single promoter (Juven-Gershon et al., 2006b). The SCP is the strongest core promoter observed in vitro and in cultured cells and yields high levels of transcription in conjunction with transcriptional enhancers. These findings indicate that gene expression levels can be modulated via the core promoter."
# Gene regulations
Each gene, or its isoforms, is likely to have upregulation and downregulation transcription factors. As each gene is investigated, these enhancers and inhibitors are noted as discovered.
For example, submitting "gene regulation" APOE human to the NCBI gene database returns 28 genes and 21 mouse analogs. The first on the list is GeneID: 2099 ESR1 estrogen receptor 1. "This gene encodes an estrogen receptor, a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription. Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone. Estrogen receptors are also involved in pathological processes including breast cancer, endometrial cancer, and osteoporosis." from the page url=. The database also maintains the DNA sequence upstream, downstream, and through the entire gene locus so that analysis of "Alternative promoter usage and alternative splicing result in dozens of transcript variants, but the full-length nature of many of these variants has not been determined. " can be attempted. The site lists gene interactions and six variants for three isoforms (1, 2, and 3) and ten experimental transcriptions.
# Gene similarities
There are genes on other chromosomes that are similar to each gene being considered. For example, GeneID: 338, Apolipoprotein B, is on chromosome 2.
# Eukaryote genes
Def. any "of the single-celled or multicellular organisms, of the taxonomic domain Eukaryota, whose cells contain at least one distinct nucleus" is called a eukaryote.
Those specific genes that cause cells to contain at least one distinct nucleus are eukaryote genes.
# Genetics
There are "more than 4 million sites where proteins bind to DNA to regulate genetic function, sort of like a switch."
"Humans belong to the biological group known as Primates, and are classified with the great apes, one of the major groups of the primate evolutionary tree. Besides similarities in anatomy and behavior, our close biological kinship with other primate species is indicated by DNA evidence. It confirms that our closest living biological relatives are chimpanzees and bonobos, with whom we share many traits. But we did not evolve directly from any primates living today."
"DNA also shows that our species and chimpanzees diverged from a common ancestor species that lived between 8 and 6 million years ago. The last common ancestor of monkeys and apes lived about 25 million years ago."
# Human DNA
"uman DNA has millions of on-off switches and complex networks that control the genes' activities. ... t least 80% of the human genome is active, which opposed the previously held idea that most of the DNA are useless."
"DNA contains genes, which hold the instructions for take up only about 2 percent of the genome ... The human genome is made up of about 3 billion “letters” along strands that make up the familiar double helix structure of DNA. Particular sequences of these letters form genes, which tell cells how to make proteins. People have about 20,000 genes, but the vast majority of DNA lies outside of genes. ... t least three-quarters of the genome is involved in making RNA it appears to help regulate gene activity."
# Human genes
"Nine elements were tested, representing a sampling of elements present in the two gene deserts and DACH introns, spread over a 1530-kb region surrounding the human DACH's TATA box."
Gene ID: 1602 is the human gene DACH1 dachshund homolog 1 also known as DACH. DACH1 has three isoforms: a, b, and c.
"he human ... prostaglandin-endoperoxide-synthase-2 a canonical TATA box (nucleotide residues at positions -31 to -25 for the human gene)." This is Gene ID: 5743.
The Drosophila hsp70 has a TATA box containing promoter. This suggests that GeneID: 3308 HSPA4 heat shock 70kDa protein 4 , also known as hsp70, has a TATA box in its core promoter.
# Genotypes
The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame.
Only about 1.5% of the human genome consists of protein-coding exons.
# Pseudogenes
"An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.
About 2700 formerly active genes are now pseudogenes.
# Deaminations
The CpG deficiency is due to an increased vulnerability of methylcytosines to spontaneously deaminate to thymine in genomes with CpG cytosine methylation.
# Methylations
Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can turn the gene off, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Enzymes that add a methyl group are called DNA methyltransferases.
In mammals, 70% to 80% of CpG cytosines are methylated.
CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% GC content, a pair of nucleotides consisting of cytosine followed by guanine would be expected to occur 0.21 - 0.21 = 4.41% of the time. The frequency of CpG dinucleotides in human genomes is 1% — less than one-quarter of the expected frequency.
Unmethylated CpG sites can be detected by Toll-Like Receptor 9 (TLR 9) on plasmacytoid dendritic cells and B cells in humans. This is used to detect intracellular viral, fungal, and bacterial pathogen DNA.
Methylation is central to imprinting, along with histone modifications. Most of the methylation occurs a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves.
Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumor suppressor genes). In contrast, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells.
# Mutations
Alu elements are a common source of mutation in humans, but such mutations are often confined to non-coding regions where they have little discernible impact on the bearer.
The mutagenic effect of Alu and retrotransposons in general has played a major role in the recent evolution of the human genome.
The first report of Alu-mediated recombination causing a prevalent inherited predisposition to cancer was a 1995 report about hereditary nonpolyposis colorectal cancer.
"The human diseases caused by Alu insertions include":
- Breast cancer
- Ewing's sarcoma
- Familial hypercholesterolemia
- Hemophilia
- Neurofibromatosis
- Diabetes mellitus type II.
The following diseases have been associated with single-nucleotide DNA variations in Alu elements impacting transcription levels:
- Alzheimer's disease
- Lung cancer
- Gastric cancer.
"The ACE gene, encoding angiotensin-converting enzyme, has 2 common variants, one with an Alu insertion (ACE-I) and one with the Alu deleted (ACE-D). This variation has been linked to changes in sporting ability: the presence of the Alu element is associated with better performance in endurance-oriented events (e.g. triathlons), whereas its absence is associated with strength- and power-oriented performance
The opsin gene duplication which resulted in the re-gaining of trichromacy in Old World primates (including humans) is flanked by an Alu element, implicating the role of Alu in the evolution of three colour vision.
# Hypotheses
- Each gene may be expressed by one of more isoforms usually subject to cell type. | Genes
Editor-In-Chief: Henry A. Hoff
A gene is a distinct sequence of nucleotides forming part of a chromosome, the order of which determines the order of monomers in a polypeptide or nucleic acid molecule which a cell (or virus) may synthesize.
# Theoretical genes
Def. a "theoretical unit of heredity of living organisms ; a gene may take several values and in principle predetermines a precise trait of an organism's form (phenotype), such as hair color"[1] or a "segment of DNA or RNA from a cell's or an organism's genome, that may take several forms and thus parameterizes a phenomenon, in general the structure of a protein; locus"[1] is called a gene.
Here's a theoretical definition:
Def. a specific nucleotide sequence within a gene locus with its own transcription start site(s), introns, exons, and UTRs, that transcribes a specific RNA product is called an isoform, or gene isoform.
Def. any "of several different forms of the same protein, arising from either single nucleotide polymorphisms,[2] differential splicing of mRNA, or post-translational modifications (e.g. sulfation, glycosylation, etc.)"[3] is called an isoform.
Def. a "region of a transcribed gene present in the final functional RNA molecule"[4] is called an exon.
Def. a "portion of a split gene that is included in pre-RNA transcripts but is removed during RNA processing and rapidly degraded"[5] is called an intron.
# Gene clusters
GeneID: 348 APOE apolipoprotein E description contains this: "This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes."
# Gene expressions
Gene expressions is a suite of genes, and their isoforms, that appear to be biochemically involved in the appearance of a trait.
Although it is harder to regulate the transcription of genes with multiple transcription start sites, "variations in the expression of a constitutive gene would be minimized by the use of multiple start sites."[6]
Earlier "studies led to the design of a super core promoter (SCP) that contains a TATA, Inr, MTE, and DPE in a single promoter (Juven-Gershon et al., 2006b). The SCP is the strongest core promoter observed in vitro and in cultured cells and yields high levels of transcription in conjunction with transcriptional enhancers. These findings indicate that gene expression levels can be modulated via the core promoter."[6]
# Gene regulations
Each gene, or its isoforms, is likely to have upregulation and downregulation transcription factors. As each gene is investigated, these enhancers and inhibitors are noted as discovered.
For example, submitting "gene regulation" APOE human to the NCBI gene database returns 28 genes and 21 mouse analogs. The first on the list is GeneID: 2099 ESR1 estrogen receptor 1. "This gene encodes an estrogen receptor, a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription. [...] Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone. Estrogen receptors are also involved in pathological processes including breast cancer, endometrial cancer, and osteoporosis." from the page url=http://www.ncbi.nlm.nih.gov/gene/2099. The database also maintains the DNA sequence upstream, downstream, and through the entire gene locus so that analysis of "Alternative promoter usage and alternative splicing result in dozens of transcript variants, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Mar 2014]" can be attempted. The site lists gene interactions and six variants for three isoforms (1, 2, and 3) and ten experimental transcriptions.
# Gene similarities
There are genes on other chromosomes that are similar to each gene being considered. For example, GeneID: 338, Apolipoprotein B, is on chromosome 2.
# Eukaryote genes
Def. any "of the single-celled or multicellular organisms, of the taxonomic domain Eukaryota, whose cells contain at least one distinct nucleus"[7] is called a eukaryote.
Those specific genes that cause cells to contain at least one distinct nucleus are eukaryote genes.
# Genetics
There are "more than 4 million sites where proteins bind to DNA to regulate genetic function, sort of like a switch."[8]
"Humans belong to the biological group known as Primates, and are classified with the great apes, one of the major groups of the primate evolutionary tree. Besides similarities in anatomy and behavior, our close biological kinship with other primate species is indicated by DNA evidence. It confirms that our closest living biological relatives are chimpanzees and bonobos, with whom we share many traits. But we did not evolve directly from any primates living today."[9]
"DNA also shows that our species and chimpanzees diverged from a common ancestor species that lived between 8 and 6 million years ago. The last common ancestor of monkeys and apes lived about 25 million years ago."[9]
# Human DNA
"[H]uman DNA has millions of on-off switches and complex networks that control the genes' activities. ... [A]t least 80% of the human genome is active, which opposed the previously held idea that most of the DNA are useless."[10]
"DNA contains genes, which hold the instructions for [life. But, these] take up only about 2 percent of the genome ... The human genome is made up of about 3 billion “letters” along strands that make up the familiar double helix structure of DNA. Particular sequences of these letters form genes, which tell cells how to make proteins. People have about 20,000 genes, but the vast majority of DNA lies outside of genes. ... [A]t least three-quarters of the genome is involved in making RNA [...] it appears to help regulate gene activity."[8]
# Human genes
"Nine elements were tested, representing a sampling of elements present in the two gene deserts and DACH introns, spread over a 1530-kb region surrounding the human DACH's TATA box."[11]
Gene ID: 1602 is the human gene DACH1 dachshund homolog 1 also known as DACH.[12] DACH1 has three isoforms: a, b, and c.
"[T]he human ... prostaglandin-endoperoxide-synthase-2 [gene contains] a canonical TATA box (nucleotide residues at positions -31 to -25 for the human gene)."[13] This is Gene ID: 5743.
The Drosophila hsp70 has a TATA box containing promoter.[14] This suggests that GeneID: 3308 HSPA4 heat shock 70kDa protein 4 [Homo sapiens], also known as hsp70,[15] has a TATA box in its core promoter.
# Genotypes
The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the transcription of the open reading frame.
Only about 1.5% of the human genome consists of protein-coding exons.
# Pseudogenes
"An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.[16] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.[17]
About 2700 formerly active genes are now pseudogenes.
# Deaminations
The CpG deficiency is due to an increased vulnerability of methylcytosines to spontaneously deaminate to thymine in genomes with CpG cytosine methylation.[18]
# Methylations
Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can turn the gene off, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Enzymes that add a methyl group are called DNA methyltransferases.
In mammals, 70% to 80% of CpG cytosines are methylated.[19]
CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% GC content, a pair of nucleotides consisting of cytosine followed by guanine would be expected to occur 0.21 * 0.21 = 4.41% of the time. The frequency of CpG dinucleotides in human genomes is 1% — less than one-quarter of the expected frequency.
Unmethylated CpG sites can be detected by Toll-Like Receptor 9[20] (TLR 9) on plasmacytoid dendritic cells and B cells in humans. This is used to detect intracellular viral, fungal, and bacterial pathogen DNA.
Methylation is central to imprinting, along with histone modifications.[21] Most of the methylation occurs a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves.[22]
Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumor suppressor genes). In contrast, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells.[23]
# Mutations
Alu elements are a common source of mutation in humans, but such mutations are often confined to non-coding regions where they have little discernible impact on the bearer.[24]
The mutagenic effect of Alu[25] and retrotransposons in general[26] has played a major role in the recent evolution of the human genome.
The first report of Alu-mediated recombination causing a prevalent inherited predisposition to cancer was a 1995 report about hereditary nonpolyposis colorectal cancer.[27]
"The human diseases caused by Alu insertions include":[28]
- Breast cancer
- Ewing's sarcoma
- Familial hypercholesterolemia
- Hemophilia
- Neurofibromatosis
- Diabetes mellitus type II.
The following diseases have been associated with single-nucleotide DNA variations in Alu elements impacting transcription levels:[29]
- Alzheimer's disease
- Lung cancer
- Gastric cancer.
"The ACE gene, encoding angiotensin-converting enzyme, has 2 common variants, one with an Alu insertion (ACE-I) and one with the Alu deleted (ACE-D). This variation has been linked to changes in sporting ability: the presence of the Alu element is associated with better performance in endurance-oriented events (e.g. triathlons), whereas its absence is associated with strength- and power-oriented performance[30]
The opsin gene duplication which resulted in the re-gaining of trichromacy in Old World primates (including humans) is flanked by an Alu element,[31] implicating the role of Alu in the evolution of three colour vision.
# Hypotheses
- Each gene may be expressed by one of more isoforms usually subject to cell type. | https://www.wikidoc.org/index.php/Genes | |
7fe5cef8dedf4259d2de8d71296fa13e6c111928 | wikidoc | Gonad | Gonad
# Overview
The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, sperm and egg cells are gametes. Although medically the gonad term can refer to either male gonads (testicles) or female gonads (ovaries), the vernacular, or slang use of "gonads" (or "nads") usually only refers to the testicles.
# Function
In addition to producting gametes, the gonads are a combined glands providing both exocrine and endocrine functions. The male and female gonads produce steroid sex hormones, identical to those producted by adrenal cortical cells. The major distinction is the source and relative amounts produced.
# Testes
The male gonads, known as the testes or testicles, secrete a class of hormones called androgens, and produce spermatozoa. The predominant androgen in males is testosterone.
# Ovaries
In females, the female gonads, known as the ovaries, secrete a hormone estrogen and progesterone, as well as ova. The dominant estrogen is known as estradiol, which is derived from testosterone.
# Regulation
The gonads are controlled hormonally by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secreted by the anterior pituitary gland. The anterior pituitary gland's excretion of LH and FSH are, in turn, controlled by the hypothalamus' gonadotropin-releasing hormone.
# Development
Gonads start developing as a common anlage, in the form of gonadal ridges, and only later are differentiated to male or female sex organs. The SRY gene, located on the Y chromosome and encoding the testis determining factor, decides the direction of this differentiation.
In 1943, Matthew Browne started a development of gonads in a part of the development of the urinary and reproductive organs.
ca:Gònada
da:Gonade
de:Gonade
et:Sugunääre
io:Gonado
it:Gonadi
lt:Lytinė liauka
mk:Гонада
nl:Gonade
simple:Gonad
fi:Sukupuolirauhaset
sv:Könskörtel
th:อวัยวะเพศ | Gonad
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, sperm and egg cells are gametes. Although medically the gonad term can refer to either male gonads (testicles) or female gonads (ovaries), the vernacular, or slang use of "gonads" (or "nads") usually only refers to the testicles.
# Function
In addition to producting gametes, the gonads are a combined glands providing both exocrine and endocrine functions. The male and female gonads produce steroid sex hormones, identical to those producted by adrenal cortical cells. The major distinction is the source and relative amounts produced.
# Testes
The male gonads, known as the testes or testicles, secrete a class of hormones called androgens, and produce spermatozoa. The predominant androgen in males is testosterone.
# Ovaries
In females, the female gonads, known as the ovaries, secrete a hormone estrogen and progesterone, as well as ova. The dominant estrogen is known as estradiol, which is derived from testosterone.
# Regulation
The gonads are controlled hormonally by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secreted by the anterior pituitary gland. The anterior pituitary gland's excretion of LH and FSH are, in turn, controlled by the hypothalamus' gonadotropin-releasing hormone.
# Development
Gonads start developing as a common anlage, in the form of gonadal ridges, and only later are differentiated to male or female sex organs. The SRY gene, located on the Y chromosome and encoding the testis determining factor, decides the direction of this differentiation.
In 1943, Matthew Browne started a development of gonads in a part of the development of the urinary and reproductive organs.
ca:Gònada
da:Gonade
de:Gonade
et:Sugunääre
io:Gonado
it:Gonadi
lt:Lytinė liauka
mk:Гонада
nl:Gonade
simple:Gonad
fi:Sukupuolirauhaset
sv:Könskörtel
th:อวัยวะเพศ
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Genital_glands | |
80f9c07f5567a260369d6a0b3f43b65614e7ba40 | wikidoc | Genus | Genus
A genus (from Ancient Greek γένος genos, "offspring, family, race, gender" - plural: genera) is a low-level taxonomic rank used in the classification of living and fossil organisms.
Like almost all other taxonomic units, genera may sometimes be divided into subgenera, singular: subgenus. The largest main taxonomic unit below the genus is the species.
How to more precisely define a genus is a matter of continuing debate, as outlined a few paragraphs below this.
# Generic name
Generic name is a part of the Latinized name for an organism. It is a name which reflects the classification of the organism by grouping it with other closely similar organisms.
A generic name is a category name that is given to every species in a group of species which are closely related to one another. Ideally the same generic name is given to species which are all descended from a common ancestor.
The generic name is the first part of the two-part Latin name of an organism. To take one example, for our human species, the Latin name is Homo sapiens, (Homo means man, and sapiens means rational.) In this name, the generic name is Homo. There are no longer any other non-extinct species in the genus Homo (although it seems that several Homo species existed in the geologically recent past).
# Taxonomy: the traditional significance of the genus
Ever since the flowering of evolutionary theory with Charles Darwin's writings, a genus is intended to be a name for a group of species that are very closely related to one another, by descent from a common ancestor.
Before the age of DNA analysis, a presumed close relationship within a group of species was largely a matter of informed guesswork, based primarily on external observation, and studies of the anatomy of the organism.
# Taxonomy: the new phylogenetic approach to the genus
Thus historically-speaking, the boundaries between genera have been rather subjective, but with the advent of phylogenetics, and because of much subsequent research, it is now increasingly common for taxonomic ranks below the class level to be restricted to confirmed monophyletic groupings. Indeed, in the better-researched groups like birds and mammals, most genera represent clades already.
# Types and genera
Because of the rules of scientific naming, or "nomenclature", each genus must have a designated type species (see Type (zoology)) which defines the genus; the generic name is permanently associated with the type specimen of its type species. Should this specimen turn out to be assignable to another genus, the genus name linked to it becomes a junior synonym, and the remaining taxa in the now-invalid genus need to be reassessed. See scientific classification and Nomenclature Codes for more details of this system. Also see type genus.
# One attempt to define a genus
The rules-of-thumb for delimiting a genus are outlined e.g. in Gill et al. (2005). According to these, a genus should fulfill 3 criteria to be descriptively useful:
- monophyly - all descendants of an ancestral taxon are grouped together;
- reasonable compactness - a genus should not be expanded needlessly; and
- distinctness - in regards of evolutionarily relevant criteria, i.e. ecology, morphology, or biogeography; note that DNA sequences are a consequence rather than a condition of diverging evolutionarily lineages except in cases where they directly inhibit gene flow (e.g. postzygotic barriers).
# The transition to modern phylogenetic classification
Neither the ICZN nor the ICBN require such criteria for establishment of a genus, and this is because they are concerned with the rules of nomenclature rather than the rules of taxonomy. The ICZN and ICBN rule books cover the formalities of what makes a description valid.
Because there is no equivalent rule book for taxonomy (classification), there is an on-going vigorous debate about what criteria to consider relevant for generic distinctness. At present, most of the classifications based on the old-fashioned idea of phenetics - overall similarity - are being gradually replaced by new ones based on cladistics. For example, the use of Reptilia and Amphibia in taxonomy is now discouraged. The formal attempt to use overall similarity or phenetics was only of major relevance for a comparatively short time around the 1960s before it turned out to be unworkable.
The three criteria given above are almost always fulfillable for a given clade. However, an example of a situation where at least one criterion is crassly violated no matter what the generic arrangement is the case of the dabbling ducks in the genus Anas. This group is is paraphyletic in regard to the extremely distinct fossil species, moa-nalo. Considering these to be distinct genera (as is usually done) violates criterion 1, including them all in the genus Anas violates criterion 2 and 3, and splitting up the genus Anas so that the mallard and the American black duck are in distinct genera violates criterion 3.
# The problem of identical names used for different genera
A genus in one kingdom is allowed to bear a name that is in use as a genus name or other taxon name in another kingdom. Although this is discouraged by both the International Code of Zoological Nomenclature and the International Code of Botanical Nomenclature there are some five thousand such names that are in use in more than one kingdom. For instance, Anura is the name of the order of frogs but also is the name of a genus of plants (although not current: it is a synonym); and Aotus is the genus of golden peas and night monkeys; Oenanthe is the genus of wheatears and water dropworts, and Prunella is the genus of accentors and self-heal.
Obviously, within the same kingdom one generic name can apply to only one genus. This explains why the platypus genus is named Ornithorhynchus — George Shaw named it Platypus in 1799, but the name Platypus had already been given to the pinhole borer beetle by Johann Friedrich Wilhelm Herbst in 1793. Names with the same form but applying to different taxa are called homonyms. Since beetles and platypuses are both members of the kingdom Animalia, the name Platypus could not be used for both. Johann Friedrich Blumenbach published the replacement name Ornithorhynchus in 1800. | Genus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Biological classification
A genus (from Ancient Greek γένος genos, "offspring, family, race, gender" - plural: genera) is a low-level taxonomic rank used in the classification of living and fossil organisms.
Like almost all other taxonomic units, genera may sometimes be divided into subgenera, singular: subgenus. The largest main taxonomic unit below the genus is the species.
How to more precisely define a genus is a matter of continuing debate, as outlined a few paragraphs below this.
# Generic name
Generic name is a part of the Latinized name for an organism. It is a name which reflects the classification of the organism by grouping it with other closely similar organisms.
A generic name is a category name that is given to every species in a group of species which are closely related to one another. Ideally the same generic name is given to species which are all descended from a common ancestor.
The generic name is the first part of the two-part Latin name of an organism. To take one example, for our human species, the Latin name is Homo sapiens, (Homo means man, and sapiens means rational.) In this name, the generic name is Homo. There are no longer any other non-extinct species in the genus Homo (although it seems that several Homo species existed in the geologically recent past).
# Taxonomy: the traditional significance of the genus
Ever since the flowering of evolutionary theory with Charles Darwin's writings, a genus is intended to be a name for a group of species that are very closely related to one another, by descent from a common ancestor.
Before the age of DNA analysis, a presumed close relationship within a group of species was largely a matter of informed guesswork, based primarily on external observation, and studies of the anatomy of the organism.
# Taxonomy: the new phylogenetic approach to the genus
Thus historically-speaking, the boundaries between genera have been rather subjective, but with the advent of phylogenetics, and because of much subsequent research, it is now increasingly common for taxonomic ranks below the class level to be restricted to confirmed monophyletic groupings. Indeed, in the better-researched groups like birds and mammals, most genera represent clades already.
# Types and genera
Because of the rules of scientific naming, or "nomenclature", each genus must have a designated type species (see Type (zoology)) which defines the genus; the generic name is permanently associated with the type specimen of its type species. Should this specimen turn out to be assignable to another genus, the genus name linked to it becomes a junior synonym, and the remaining taxa in the now-invalid genus need to be reassessed. See scientific classification and Nomenclature Codes for more details of this system. Also see type genus.
# One attempt to define a genus
The rules-of-thumb for delimiting a genus are outlined e.g. in Gill et al. (2005). According to these, a genus should fulfill 3 criteria to be descriptively useful:
- monophyly - all descendants of an ancestral taxon are grouped together;
- reasonable compactness - a genus should not be expanded needlessly; and
- distinctness - in regards of evolutionarily relevant criteria, i.e. ecology, morphology, or biogeography; note that DNA sequences are a consequence rather than a condition of diverging evolutionarily lineages except in cases where they directly inhibit gene flow (e.g. postzygotic barriers).
# The transition to modern phylogenetic classification
Neither the ICZN nor the ICBN require such criteria for establishment of a genus, and this is because they are concerned with the rules of nomenclature rather than the rules of taxonomy. The ICZN and ICBN rule books cover the formalities of what makes a description valid.
Because there is no equivalent rule book for taxonomy (classification), there is an on-going vigorous debate about what criteria to consider relevant for generic distinctness. At present, most of the classifications based on the old-fashioned idea of phenetics - overall similarity - are being gradually replaced by new ones based on cladistics. For example, the use of Reptilia and Amphibia in taxonomy is now discouraged. The formal attempt to use overall similarity or phenetics was only of major relevance for a comparatively short time around the 1960s before it turned out to be unworkable.
The three criteria given above are almost always fulfillable for a given clade. However, an example of a situation where at least one criterion is crassly violated no matter what the generic arrangement is the case of the dabbling ducks in the genus Anas. This group is is paraphyletic in regard to the extremely distinct fossil species, moa-nalo. Considering these to be distinct genera (as is usually done) violates criterion 1, including them all in the genus Anas violates criterion 2 and 3, and splitting up the genus Anas so that the mallard and the American black duck are in distinct genera violates criterion 3.
# The problem of identical names used for different genera
A genus in one kingdom is allowed to bear a name that is in use as a genus name or other taxon name in another kingdom. Although this is discouraged by both the International Code of Zoological Nomenclature and the International Code of Botanical Nomenclature there are some five thousand such names that are in use in more than one kingdom. For instance, Anura is the name of the order of frogs but also is the name of a genus of plants (although not current: it is a synonym); and Aotus is the genus of golden peas and night monkeys; Oenanthe is the genus of wheatears and water dropworts, and Prunella is the genus of accentors and self-heal.
Obviously, within the same kingdom one generic name can apply to only one genus. This explains why the platypus genus is named Ornithorhynchus — George Shaw named it Platypus in 1799, but the name Platypus had already been given to the pinhole borer beetle by Johann Friedrich Wilhelm Herbst in 1793. Names with the same form but applying to different taxa are called homonyms. Since beetles and platypuses are both members of the kingdom Animalia, the name Platypus could not be used for both. Johann Friedrich Blumenbach published the replacement name Ornithorhynchus in 1800. | https://www.wikidoc.org/index.php/Genus | |
f3f87dc15c4d29ebc761aa9eb0484432b6e6f5af | wikidoc | Gland | Gland
A gland is an organ in an animal's body that synthesizes a substance for release such as hormones or breast milk, often into the bloodstream (endocrine gland) or into cavities inside the body or its outer surface (exocrine gland).
# Types
Glands can be divided into two groups:
- Endocrine glands- are glands that secrete their product directly onto a surface rather than through a duct.
- Exocrine glands- secrete their products via a duct, the glands in this group can be divided into three groups:
Apocrine glands - a portion of the secreting cell's body is lost during secretion. Apocrine gland is often used to refer to the apocrine sweat glands, however it is thought that apocrine sweat glands may not be true apocrine glands as they may not use the apocrine method of secretion.
Holocrine glands - the entire cell disintegrates to secrete its substances (e.g., sebaceous glands)
Merocrine glands - cells secrete their substances by exocytosis (e.g., mucous and serous glands). Also called "eccrine."
- Apocrine glands - a portion of the secreting cell's body is lost during secretion. Apocrine gland is often used to refer to the apocrine sweat glands, however it is thought that apocrine sweat glands may not be true apocrine glands as they may not use the apocrine method of secretion.
- Holocrine glands - the entire cell disintegrates to secrete its substances (e.g., sebaceous glands)
- Merocrine glands - cells secrete their substances by exocytosis (e.g., mucous and serous glands). Also called "eccrine."
The type of secretory product of an Exocrine gland may also be one of three categories:
- Serous glands- secrete a watery, often protein-rich product.
- Mucous glands- secrete a viscous product, rich in carbohydrates (e.g., glycoproteins).
- Sebaceous glands- secrete a lipid product.
# Formation
Every gland is formed by an ingrowth from an epithelial surface. This ingrowth may from the beginning possess a tubular structure, but in other instances glands may start as a solid column of cells which subsequently becomes tubulated.
As growth proceeds, the column of cells may divide or give off offshoots, in which case a compound gland is formed. In many glands the number of branches is limited, in others (salivary, pancreas) a very large structure is finally formed by repeated growth and sub-division. As a rule, the branches do not unite with one another, but in one instance, the liver, this does occur when a reticulated compound gland is produced. In compound glands the more typical or secretory epithelium is found forming the terminal portion of each branch, and the uniting portions form ducts and are lined with a less modified type of epithelial cell.
Glands are classified according to their shape.
- If the gland retains its shape as a tube throughout it is termed a tubular gland.
- In the second main variety of gland the secretory portion is enlarged and the lumen variously increased in size. These are termed alveolar or saccular glands.
# Specific glands
A list of human exocrine glands is available here.
A list of human endocrine glands is available here.
# Additional images
- Section of submaxillary gland of kitten. Duct semidiagrammatic.
- Section of pancreas of dog. X 250.
- Dissection of a lactating breast.
- Section of portion of mamma.
- Apocrine
- Methods of secretion | Gland
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
A gland is an organ in an animal's body that synthesizes a substance for release such as hormones or breast milk, often into the bloodstream (endocrine gland) or into cavities inside the body or its outer surface (exocrine gland).
# Types
Glands can be divided into two groups:
- Endocrine glands- are glands that secrete their product directly onto a surface rather than through a duct.
- Exocrine glands- secrete their products via a duct, the glands in this group can be divided into three groups:
Apocrine glands - a portion of the secreting cell's body is lost during secretion. Apocrine gland is often used to refer to the apocrine sweat glands, however it is thought that apocrine sweat glands may not be true apocrine glands as they may not use the apocrine method of secretion.
Holocrine glands - the entire cell disintegrates to secrete its substances (e.g., sebaceous glands)
Merocrine glands - cells secrete their substances by exocytosis (e.g., mucous and serous glands). Also called "eccrine."
- Apocrine glands - a portion of the secreting cell's body is lost during secretion. Apocrine gland is often used to refer to the apocrine sweat glands, however it is thought that apocrine sweat glands may not be true apocrine glands as they may not use the apocrine method of secretion.
- Holocrine glands - the entire cell disintegrates to secrete its substances (e.g., sebaceous glands)
- Merocrine glands - cells secrete their substances by exocytosis (e.g., mucous and serous glands). Also called "eccrine."
The type of secretory product of an Exocrine gland may also be one of three categories:
- Serous glands- secrete a watery, often protein-rich product.
- Mucous glands- secrete a viscous product, rich in carbohydrates (e.g., glycoproteins).
- Sebaceous glands- secrete a lipid product.
# Formation
Every gland is formed by an ingrowth from an epithelial surface. This ingrowth may from the beginning possess a tubular structure, but in other instances glands may start as a solid column of cells which subsequently becomes tubulated.
As growth proceeds, the column of cells may divide or give off offshoots, in which case a compound gland is formed. In many glands the number of branches is limited, in others (salivary, pancreas) a very large structure is finally formed by repeated growth and sub-division. As a rule, the branches do not unite with one another, but in one instance, the liver, this does occur when a reticulated compound gland is produced. In compound glands the more typical or secretory epithelium is found forming the terminal portion of each branch, and the uniting portions form ducts and are lined with a less modified type of epithelial cell.
Glands are classified according to their shape.
- If the gland retains its shape as a tube throughout it is termed a tubular gland.
- In the second main variety of gland the secretory portion is enlarged and the lumen variously increased in size. These are termed alveolar or saccular glands.
# Specific glands
A list of human exocrine glands is available here.
A list of human endocrine glands is available here.
# Additional images
- Section of submaxillary gland of kitten. Duct semidiagrammatic.
- Section of pancreas of dog. X 250.
- Dissection of a lactating breast.
- Section of portion of mamma.
- Apocrine
- Methods of secretion | https://www.wikidoc.org/index.php/Gland | |
ca27cd815f3c7f6dcb0600d810d64301d9e5e225 | wikidoc | Gluma | Gluma
Gluma Desensitizer is the most widely used product in the United States for the treatment of dental sensitivity. Its formula of 5% glutaraldehyde and 35% HEMA (hydroxyethyl methacrylate) in water is used to help control both hypersensitive dentin and reduce the incidence of post-operative sensitivity in restorative dentistry procedures.
It’s also useful as a cavity disinfectant, a rewetting agent and an adhesion promoter (when combined with most dentin bonding systems).
The Gluma formula is under patent protection. Therefore, no other desensitizing agents on the market can have the same formula or work exactly like it.
Gluma is manufactured and produced by the Heraeus Kulzer, a German dental supply company. | Gluma
Gluma Desensitizer is the most widely used product in the United States for the treatment of dental sensitivity. Its formula of 5% glutaraldehyde and 35% HEMA (hydroxyethyl methacrylate) in water is used to help control both hypersensitive dentin and reduce the incidence of post-operative sensitivity in restorative dentistry procedures.
It’s also useful as a cavity disinfectant, a rewetting agent and an adhesion promoter (when combined with most dentin bonding systems).
The Gluma formula is under patent protection. Therefore, no other desensitizing agents on the market can have the same formula or work exactly like it.
Gluma is manufactured and produced by the Heraeus Kulzer, a German dental supply company.
# External links
- Heraeus Kulzer
- Heraeus Kulzer South America
- Gluma Desensitizer
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Gluma | |
0048f9b4d972f55dee02dd5df0f21cc5c038aeba | wikidoc | GnRH2 | GnRH2
GnRH2, also known as gonadotropin-releasing hormone II or LHRH-II. Its gene is located on human chromosome 20.
Most vertebrate species possess two or three forms of gonadotropin-releasing hormone (GnRH) expressed in three distinct brain regions. Although the function of the hypothalamic form (GnRH1; common to many vertebrates), in controlling the reproductive axis has been defined, the functions of the other two isoforms (GnRH2 and GnRH3) remain largely unknown. The presence and conservation of GnRH2 across vertebrate species indicate important biological roles, but the absence of GnRH2 in rodents has greatly hampered the use of these vertebrate models and modern molecular tools to pursue its functions.
A relatively well-documented function of GnRH2 is that the administration of GnRH2 has anorexigenic effects in female musk shrew, mouse, goldfish and zebrafish, but the mechanisms are still unclear. | GnRH2
GnRH2, also known as gonadotropin-releasing hormone II or LHRH-II. Its gene is located on human chromosome 20.[1]
Most vertebrate species possess two or three forms of gonadotropin-releasing hormone (GnRH) expressed in three distinct brain regions. Although the function of the hypothalamic form (GnRH1; common to many vertebrates), in controlling the reproductive axis has been defined, the functions of the other two isoforms (GnRH2 and GnRH3) remain largely unknown.[2] The presence and conservation of GnRH2 across vertebrate species indicate important biological roles, but the absence of GnRH2 in rodents has greatly hampered the use of these vertebrate models and modern molecular tools to pursue its functions.[3]
A relatively well-documented function of GnRH2 is that the administration of GnRH2 has anorexigenic effects in female musk shrew,[4] mouse,[5] goldfish [6] and zebrafish,[7] but the mechanisms are still unclear. | https://www.wikidoc.org/index.php/GnRH2 | |
79f5931ff1bb0cf6d4376c2bd7bfe7d05fc514c7 | wikidoc | Gorse | Gorse
Gorse (Ulex) comprises a genus of about 20 species of evergreen shrubs in the subfamily Faboideae of the pea family Fabaceae, native to western Europe and northwest Africa, with the majority of species in Iberia. Other common names for gorse include furse, whin and furze.
Gorse is closely related to the brooms, and like them, has green stems and very small leaves and adapts to dry growing conditions, but differs in its extreme spininess, with the leaves being modified into 1-4 cm long spines. All the species have yellow flowers, some with a very long flowering season.
The most widely familiar species is the Common Gorse (Ulex europaeus), the only species native in most of western Europe, where it grows in sunny sites, usually on dry, sandy soils. It is also the largest species, reaching 2-3 m height; this compares with typically 0.2-0.4 m for Western gorse (U. gallii). This latter species is characteristic of highly exposed Atlantic coastal heathland and montane habitats.
Common gorse flowers most strongly in spring, though it bears some flowers year round, hence the old country phrase: "When gorse is out of blossom, kissing's out of fashion". The flowers have a very distinctive strong coconut scent. Western gorse or Dwarf Furze differs in being almost entirely late summer flowering (August-September in Ireland and Britain), and also have somewhat darker yellow flowers than Common gorse.
Gorse is a fire-climax plant, very well adapted to stand-replacing fires, being highly inflammable, and having seed pods that are to a large extent opened by fire, thus allowing rapid regeneration after fire. The burnt stumps also readily sprout new growth from the roots. Where fire is excluded, gorse soon tends to be shaded out by taller-growing trees, unless other factors like exposure also apply. Typical fire recurrence periods in gorse stands are 5-20 years.
Gorse thrives best in poor growing areas and conditions; it has been widely used for land reclamation (e.g., mine tailings), where its nitrogen-fixing capacity helps other plants establish better.
It is a valuable plant for wildlife, providing dense thorny cover ideal for protecting bird nests; in Britain, France and Ireland, it is particularly noted for supporting European Stonechats and Dartford Warblers. The flowers are sometimes eaten by the larva of the Double-striped Pug moth and another moth, Coleophora albicosta feeds exclusively on Ulex.
In many areas of North America, southern South America, Australia and New Zealand, the Common Gorse, introduced as an ornamental plant, has become naturalised and an invasive weed due to its aggressive seed dispersal; it has proved very difficult to eradicate. However, in New Zealand, it has been found to form a useful nursery species for native bush regeneration. If gorse stands are left for several years, native seedlings generate in their shelter and grow up through the gorse, cutting out its light and eventually replacing it.
Gorse flowers are edible and can be used in salads, tea and to make a non-grape based 'wine'.
The furse is the badge of the MacLennan clan from Kintail, Scotland.
Furse is also a Devon surname. | Gorse
Gorse (Ulex) comprises a genus of about 20 species of evergreen shrubs in the subfamily Faboideae of the pea family Fabaceae, native to western Europe and northwest Africa, with the majority of species in Iberia. Other common names for gorse include furse, whin and furze.
Gorse is closely related to the brooms, and like them, has green stems and very small leaves and adapts to dry growing conditions, but differs in its extreme spininess, with the leaves being modified into 1-4 cm long spines. All the species have yellow flowers, some with a very long flowering season.
The most widely familiar species is the Common Gorse (Ulex europaeus), the only species native in most of western Europe, where it grows in sunny sites, usually on dry, sandy soils. It is also the largest species, reaching 2-3 m height; this compares with typically 0.2-0.4 m for Western gorse (U. gallii). This latter species is characteristic of highly exposed Atlantic coastal heathland and montane habitats.
Common gorse flowers most strongly in spring, though it bears some flowers year round, hence the old country phrase: "When gorse is out of blossom, kissing's out of fashion". The flowers have a very distinctive strong coconut scent. Western gorse or Dwarf Furze differs in being almost entirely late summer flowering (August-September in Ireland and Britain), and also have somewhat darker yellow flowers than Common gorse.
Gorse is a fire-climax plant, very well adapted to stand-replacing fires, being highly inflammable, and having seed pods that are to a large extent opened by fire, thus allowing rapid regeneration after fire. The burnt stumps also readily sprout new growth from the roots. Where fire is excluded, gorse soon tends to be shaded out by taller-growing trees, unless other factors like exposure also apply. Typical fire recurrence periods in gorse stands are 5-20 years.
Gorse thrives best in poor growing areas and conditions; it has been widely used for land reclamation (e.g., mine tailings), where its nitrogen-fixing capacity helps other plants establish better.
It is a valuable plant for wildlife, providing dense thorny cover ideal for protecting bird nests; in Britain, France and Ireland, it is particularly noted for supporting European Stonechats and Dartford Warblers. The flowers are sometimes eaten by the larva of the Double-striped Pug moth and another moth, Coleophora albicosta feeds exclusively on Ulex.
In many areas of North America, southern South America, Australia and New Zealand, the Common Gorse, introduced as an ornamental plant, has become naturalised and an invasive weed due to its aggressive seed dispersal; it has proved very difficult to eradicate. However, in New Zealand, it has been found to form a useful nursery species for native bush regeneration. If gorse stands are left for several years, native seedlings generate in their shelter and grow up through the gorse, cutting out its light and eventually replacing it.
Gorse flowers are edible and can be used in salads, tea and to make a non-grape based 'wine'.
The furse is the badge of the MacLennan clan from Kintail, Scotland.
Furse is also a Devon surname.
# External Links
- Plants for a Future, database entry on uses
- Gorse on www.the-tree.org.uk
- 'A Modern Herbal' (Grieves 1931)
eo:Ulekso
it:Ulex
lt:Dygliakrūmis
no:Gulltorner
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Gorse | |
c633d624fcc2c9edde215e10898e6a33397eea76 | wikidoc | Gp120 | Gp120
# Gp120
gp120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons.
The crystal structure of gp120 complexed to D1D2 CD4 and a neutralizing antibody Fab was solved by Peter Kwong in 1998. It is organized with an outer domain, an inner domain with respect to its termini and a bridging sheet. The gp120 gene is around 1.5Kb long and codes for around 500 amino acids. Three copies of gp120 form into a trimer that caps the end of gp41.
The Human Immunodeficiency Virus (HIV) can mutate frequently to stay ahead of the immune system. There is however a highly conserved region in the virus genome near its receptor binding site.
The glycoprotein gp120 is anchored to the viral membrane through non-covalent bonds along with gp41, both coming from a cleaved protein, gp160. It infects any target cell with a CD4 receptor, particularly the helper T-cell, by binding to that receptor. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.
The exact mechanism of virus entry into a cell is unknown. However, gp120 plays a vital role in seeking out receptors on host cells for entry.
# gp120 vaccines
Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. These efforts have been hampered by the chemical and structural properties of gp120, which make it difficult for antibodies to bind to it; also, it can easily be shed from the virus' surface and captured by T-cells due to its loose binding with gp41. This has traditionally been a hindrance in developing gp120 based HIV vaccines. However, a study published in the February 15, 2007 edition of Nature provides new promise in the field .
The researchers have identified a region of susceptibilty in the gp120 glycoprotein that corresponds to a functional requirement for efficient association with CD4. This conserved region is involved in the metastable attachment of gp120 to CD4, and can potentially be targeted by the broadly neutralizing antibody b12. This study is promising in its prospects for developing a vaccine targeted at the invariant surface.
# Competition
The protein gp120 is necessary during the initial binding of HIV to its target cell. Consequently, anything which binds to gp120's target can block gp120 from binding to a cell by being physically in the way. Many of these are toxic to the immune system, such as the anti-CD4 monoclonal antibody OKT4.
EGCG, a flavonoid found in green tea, binds to the same CD4 receptor that gp120 binds to, effectively competing for this receptor. Test tube studies suggested that EGCG concentrations as low as 0.2 mmols/L – the amount of the molecule found in a cup or two of green tea – temporarily reduced HIV-CD4 cell binding by 40%. Substantial further research is needed both to confirm that this one-time laboratory experiment can be repeated successfully, and also to see whether it has any practical effect. For example, by binding to CD4, the flavonoid might slow HIV disease progression in a patient, but it might also attract an immune system-destroying antibody response against the non-human flavonoid. | Gp120
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Gp120
gp120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons.
The crystal structure of gp120 complexed to D1D2 CD4 and a neutralizing antibody Fab was solved by Peter Kwong in 1998. It is organized with an outer domain, an inner domain with respect to its termini and a bridging sheet. The gp120 gene is around 1.5Kb long and codes for around 500 amino acids. Three copies of gp120 form into a trimer that caps the end of gp41.
The Human Immunodeficiency Virus (HIV) can mutate frequently to stay ahead of the immune system. There is however a highly conserved region in the virus genome near its receptor binding site.
The glycoprotein gp120 is anchored to the viral membrane through non-covalent bonds along with gp41, both coming from a cleaved protein, gp160. It infects any target cell with a CD4 receptor, particularly the helper T-cell, by binding to that receptor. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.
The exact mechanism of virus entry into a cell is unknown. However, gp120 plays a vital role in seeking out receptors on host cells for entry.
# gp120 vaccines
Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. These efforts have been hampered by the chemical and structural properties of gp120, which make it difficult for antibodies to bind to it; also, it can easily be shed from the virus' surface and captured by T-cells due to its loose binding with gp41. This has traditionally been a hindrance in developing gp120 based HIV vaccines. However, a study published in the February 15, 2007 edition of Nature provides new promise in the field <4>.
The researchers have identified a region of susceptibilty in the gp120 glycoprotein that corresponds to a functional requirement for efficient association with CD4. This conserved region is involved in the metastable attachment of gp120 to CD4, and can potentially be targeted by the broadly neutralizing antibody b12. This study is promising in its prospects for developing a vaccine targeted at the invariant surface.
# Competition
The protein gp120 is necessary during the initial binding of HIV to its target cell. Consequently, anything which binds to gp120's target can block gp120 from binding to a cell by being physically in the way. Many of these are toxic to the immune system, such as the anti-CD4 monoclonal antibody OKT4.
EGCG, a flavonoid found in green tea, binds to the same CD4 receptor that gp120 binds to, effectively competing for this receptor. Test tube studies suggested that EGCG concentrations as low as 0.2 mmols/L – the amount of the molecule found in a cup or two of green tea – temporarily reduced HIV-CD4 cell binding by 40%. Substantial further research is needed both to confirm that this one-time laboratory experiment can be repeated successfully, and also to see whether it has any practical effect. For example, by binding to CD4, the flavonoid might slow HIV disease progression in a patient, but it might also attract an immune system-destroying antibody response against the non-human flavonoid. | https://www.wikidoc.org/index.php/Gp120 | |
86a92073c315d1ee7dbb7798dd8c0af51e061b73 | wikidoc | Graft | Graft
Graft or grafting may refer to:
- Vein grafting, which is used in coronary artery bypass operations
- Medical grafting, a surgical procedure to transplant tissue without a blood supply
- Skin grafting, a type of organ transplant procedure involving skin
- Grafting, where the tissues of one plant are affixed to the tissues of another | Graft
Graft or grafting may refer to:
- Vein grafting, which is used in coronary artery bypass operations
- Medical grafting, a surgical procedure to transplant tissue without a blood supply
- Skin grafting, a type of organ transplant procedure involving skin
- Grafting, where the tissues of one plant are affixed to the tissues of another
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Graft | |
e6f16cc37a35d717042a407722a2d94b260d47b2 | wikidoc | GroEL | GroEL
GroEL belongs to the chaperonin family of molecular chaperones, and is found in a large number of bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively.
# Mechanism
Within the cell, the process of GroEL/ES mediated protein folding involves multiple rounds of binding, encapsulation, and release of substrate protein. Unfolded substrate proteins bind to a hydrophobic binding patch on the interior rim of the open cavity of GroEL, forming a binary complex with the chaperonin. Binding of substrate protein in this manner, in addition to binding of ATP, induces a conformational change that allows association of the binary complex with a separate lid structure, GroES. Binding of GroES to the open cavity of the chaperonin induces the individual subunits of the chaperonin to rotate such that the hydrophobic substrate binding site is removed from the interior of the cavity, causing the substrate protein to be ejected from the rim into the now largely hydrophilic chamber. The hydrophilic environment of the chamber favors the burying of hydrophobic residues of the substrate, inducing substrate folding. Hydrolysis of ATP and binding of a new substrate protein to the opposite cavity sends an allosteric signal causing GroES and the encapsulated protein to be released into the cytosol. A given protein will undergo multiple rounds of folding, returning each time to its original unfolded state, until the native conformation or an intermediate structure committed to reaching the native state is achieved. Alternatively, the substrate may succumb to a competing reaction, such as misfolding and aggregation with other misfolded proteins.
## Thermodynamics
The constricted nature of the interior of the molecular complex strongly favors compact molecular conformations of the substrate protein. Free in solution, long-range, non-polar interactions can only occur at a high cost in entropy. In the close quarters of the GroEL complex, the relative loss of entropy is much smaller. The method of capture also tends to concentrate the non-polar binding sites separately from the polar sites. When the GroEL non-polar surfaces are removed, the chance that any given non-polar group will encounter a non-polar intramolecular site are much greater than in bulk solution. The hydrophobic sites which were on the outside are gathered together at the top of the cis domain and bind each other. The geometry of GroEL requires that the polar structures lead, and they envelop the non-polar core as it emerges from the trans side.
# Structure
Structurally, GroEL is a dual-ringed tetradecamer, with both the cis and trans rings consisting of seven subunits each. The conformational changes that occur within the central cavity of GroEL cause for the inside of GroEL to become hydrophilic, rather than hydrophobic, and is likely what facilitates protein folding.
- GroEL (side)
- GroEL (top)
- GroES/GroEL complex (side)
- GroES/GroEL complex (top)
The key to the activity of GroEL is in the structure of the monomer. The Hsp60 monomer has three distinct sections separated by two hinge regions. The apical section contains a large number of hydrophobic binding sites for unfolded protein substrates. Many globular proteins won't bind to the apical domain because their hydrophobic parts are clustered inside, away from the aqueous medium since this is the thermodynamically optimal conformation. Thus, these "substrate sites" will only bind to proteins which are not optimally folded. The apical domain also has binding sites for the Hsp10 monomers of GroES.
The equatorial domain has a slot near the hinge point for binding ATP, as well as two attachment points for the other half of the GroEL molecule. The rest of the equatorial section is moderately hydrophilic.
The addition of ATP and GroES has a drastic effect on the conformation of the cis domain. This effect is caused by flexion and rotation at the two hinge points on the Hsp60 monomers. The intermediate domain folds down and inward about 25° on the lower hinge. This effect, multiplied through the cooperative flexing of all monomers, increases the equatorial diameter of the GroEL cage. But the apical domain rotates a full 60° up and out on the upper hinge, and also rotates 90° around the hinge axis. This motion opens the cage very widely at the top of the cis domain, but completely removes the substrate binding sites from the inside of the cage.
# Interactions
GroEL has been shown to interact with GroES, ALDH2, Caspase 3 and Dihydrofolate reductase. | GroEL
GroEL belongs to the chaperonin family of molecular chaperones, and is found in a large number of bacteria.[1] It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively.
# Mechanism
Within the cell, the process of GroEL/ES mediated protein folding involves multiple rounds of binding, encapsulation, and release of substrate protein. Unfolded substrate proteins bind to a hydrophobic binding patch on the interior rim of the open cavity of GroEL, forming a binary complex with the chaperonin. Binding of substrate protein in this manner, in addition to binding of ATP, induces a conformational change that allows association of the binary complex with a separate lid structure, GroES. Binding of GroES to the open cavity of the chaperonin induces the individual subunits of the chaperonin to rotate such that the hydrophobic substrate binding site is removed from the interior of the cavity, causing the substrate protein to be ejected from the rim into the now largely hydrophilic chamber. The hydrophilic environment of the chamber favors the burying of hydrophobic residues of the substrate, inducing substrate folding. Hydrolysis of ATP and binding of a new substrate protein to the opposite cavity sends an allosteric signal causing GroES and the encapsulated protein to be released into the cytosol. A given protein will undergo multiple rounds of folding, returning each time to its original unfolded state, until the native conformation or an intermediate structure committed to reaching the native state is achieved. Alternatively, the substrate may succumb to a competing reaction, such as misfolding and aggregation with other misfolded proteins.[2]
## Thermodynamics
The constricted nature of the interior of the molecular complex strongly favors compact molecular conformations of the substrate protein. Free in solution, long-range, non-polar interactions can only occur at a high cost in entropy. In the close quarters of the GroEL complex, the relative loss of entropy is much smaller. The method of capture also tends to concentrate the non-polar binding sites separately from the polar sites. When the GroEL non-polar surfaces are removed, the chance that any given non-polar group will encounter a non-polar intramolecular site are much greater than in bulk solution. The hydrophobic sites which were on the outside are gathered together at the top of the cis domain and bind each other. The geometry of GroEL requires that the polar structures lead, and they envelop the non-polar core as it emerges from the trans side.
# Structure
Structurally, GroEL is a dual-ringed tetradecamer, with both the cis and trans rings consisting of seven subunits each. The conformational changes that occur within the central cavity of GroEL cause for the inside of GroEL to become hydrophilic, rather than hydrophobic, and is likely what facilitates protein folding.
- GroEL (side)
- GroEL (top)
- GroES/GroEL complex (side)
- GroES/GroEL complex (top)
The key to the activity of GroEL is in the structure of the monomer. The Hsp60 monomer has three distinct sections separated by two hinge regions. The apical section contains a large number of hydrophobic binding sites for unfolded protein substrates. Many globular proteins won't bind to the apical domain because their hydrophobic parts are clustered inside, away from the aqueous medium since this is the thermodynamically optimal conformation. Thus, these "substrate sites" will only bind to proteins which are not optimally folded. The apical domain also has binding sites for the Hsp10 monomers of GroES.
The equatorial domain has a slot near the hinge point for binding ATP, as well as two attachment points for the other half of the GroEL molecule. The rest of the equatorial section is moderately hydrophilic.
The addition of ATP and GroES has a drastic effect on the conformation of the cis domain. This effect is caused by flexion and rotation at the two hinge points on the Hsp60 monomers. The intermediate domain folds down and inward about 25° on the lower hinge. This effect, multiplied through the cooperative flexing of all monomers, increases the equatorial diameter of the GroEL cage. But the apical domain rotates a full 60° up and out on the upper hinge, and also rotates 90° around the hinge axis. This motion opens the cage very widely at the top of the cis domain, but completely removes the substrate binding sites from the inside of the cage.
# Interactions
GroEL has been shown to interact with GroES,[3][4] ALDH2,[4] Caspase 3[3][5] and Dihydrofolate reductase.[6] | https://www.wikidoc.org/index.php/GroEL | |
db38980a9bcf3dbac013adda7a1dc588fd531d6f | wikidoc | GroES | GroES
Heat shock 10 kDa protein 1 (Hsp10) also known as chaperonin 10 (cpn10) or early-pregnancy factor (EPF) is a protein that in humans is encoded by the HSPE1 gene. The homolog in E. coli is GroES that is a chaperonin which usually works in conjunction with GroEL.
# Structure and function
GroES exists as a ring-shaped oligomer of between six and eight identical subunits, while the 60 kDa chaperonin (cpn60 - or groEL in bacteria) forms a structure comprising 2 stacked rings, each ring containing 7 identical subunits. These ring structures assemble by self-stimulation in the presence of Mg2+-ATP. The central cavity of the cylindrical cpn60 tetradecamer provides an isolated environment for protein folding whilst cpn-10 binds to cpn-60 and synchronizes the release of the folded protein in an Mg2+-ATP dependent manner. The binding of cpn10 to cpn60 inhibits the weak ATPase activity of cpn60.
Escherichia coli GroES has also been shown to bind ATP cooperatively, and with an affinity comparable to that of GroEL. Each GroEL subunit contains three structurally distinct domains: an apical, an intermediate and an equatorial domain. The apical domain contains the binding sites for both GroES and the unfolded protein substrate. The equatorial domain contains the ATP-binding site and most of the oligomeric contacts. The intermediate domain links the apical and equatorial domains and transfers allosteric information between them. The GroEL oligomer is a tetradecamer, cylindrically shaped, that is organised in two heptameric rings stacked back to back. Each GroEL ring contains a central cavity, known as the `Anfinsen cage', that provides an isolated environment for protein folding. The identical 10 kDa subunits of GroES form a dome-like heptameric oligomer in solution. ATP binding to GroES may be important in charging the seven subunits of the interacting GroEL ring with ATP, to facilitate cooperative ATP binding and hydrolysis for substrate protein release.
# Interactions
GroES has been shown to interact with GroEL.
# Detection
Early pregnancy factor is tested for rosette inhibition assay. EPF is present in the maternal serum (blood plasma) shortly after fertilization; EPF is also present in cervical mucus
and in amniotic fluid.
EPF may be detected in sheep within 72 hours of mating, in mice within 24 hours of mating, and in samples from media surrounding human embryos fertilized in vitro within 48 hours of fertilization (although another study failed to duplicate this finding for in vitro embryos). EPF has been detected as soon as within six hours of mating.
Because the rosette inhibition assay for EPF is indirect, substances that have similar effects may confound the test. Pig semen, like EPF, has been shown to inhibit rosette formation - the rosette inhibition test was positive for one day in sows mated with a vasectomized boar, but not in sows similarly stimulated without semen exposure. A number of studies in the years after the discovery of EPF were unable to reproduce the consistent detection of EPF in post-conception females, and the validity of the discovery experiments was questioned. However, progress in characterization of EPF has been made and its existence is well-accepted in the scientific community.
# Origin
Early embryos are not believed to directly produce EPF. Rather, embryos are believed to produce some other chemical that induces the maternal system to create EPF. After implantation, EPF may be produced by the conceptus directly.
EPF is an immunosuppressant. Along with other substances associated with early embryos, EPF is believed to play a role in preventing the immune system of the pregnant female from attacking the embryo. Injecting anti-EPF antibodies into mice after mating significantly reduced the number of successful pregnancies and number of pups; no effect on growth was seen when mice embryos were cultured in media containing anti-EPF antibodies. While some actions of EPF are the same in all mammals (namely rosette inhibition), other immunosuppressant mechanism vary between species.
In mice, EPF levels are high in early pregnancy, but on day 15 decline to levels found in non-pregnant mice. In humans, EPF levels are high for about the first twenty weeks, then decline, becoming undetectable within eight weeks of delivery.
# Clinical utility
## Pregnancy testing
It has been suggested that EPF could be used as a marker for a very early pregnancy test, and as a way to monitor the viability of ongoing pregnancies in livestock. Interest in EPF for this purpose has continued, although current test methods have not proved sufficiently accurate for the requirements of livestock management.
In humans, modern pregnancy tests detect human chorionic gonadotropin (hCG). hCG is not present until after implantation, which occurs six to twelve days after fertilization. In contrast, EPF is present within hours of fertilization. While several other pre-implantation signals have been identified, EPF is believed to be the earliest possible marker of pregnancy. The accuracy of EPF as a pregnancy test in humans has been found to be high by several studies.
## Birth control research
EPF may also be used to determine whether pregnancy prevention mechanism of birth control methods act before or after fertilization. A 1982 study evaluating EPF levels in women with IUDs concluded that post-fertilization mechanisms contribute significantly to the effectiveness of these devices. However, more recent evidence, such as tubal flushing studies indicates that IUDs work by inhibiting fertilization, acting earlier in the reproductive process than previously thought.
For groups that define pregnancy as beginning with fertilization, birth control methods that have postfertilization mechanisms are regarded as abortifacient. There is currently contention over whether hormonal contraception methods have post-fertilization methods, specifically the most popular hormonal method - the combined oral contraceptive pill (COCP). The group Pharmacists for Life has called for a large-scale clinical trial to evaluate EPF in women taking COCPs; this would be the most conclusive evidence available to determine whether COCPs have postfertilization mechanisms.
## Infertility and early pregnancy loss
EPF is useful when investigating embryo loss prior to implantation. One study in healthy human women seeking pregnancy detected fourteen pregnancies with EPF. Of these, six were lost within ten days of ovulation (43% rate of early conceptus loss).
Use of EPF has been proposed to distinguish infertility caused by failure to conceive versus infertility caused by failure to implant. EPF has also been proposed as a marker of viable pregnancy, more useful in distinguishing ectopic or other nonviable pregnancies than other chemical markers such as hCG and progesterone.
## As a tumour marker
Although almost exclusively associated with pregnancy, EPF-like activity has also been detected in tumors of germ cell origin and in other types of tumors. Its utility as a tumour marker, to evaluate the success of surgical treatment, has been suggested. | GroES
Heat shock 10 kDa protein 1 (Hsp10) also known as chaperonin 10 (cpn10) or early-pregnancy factor (EPF) is a protein that in humans is encoded by the HSPE1 gene. The homolog in E. coli is GroES that is a chaperonin which usually works in conjunction with GroEL.[1]
# Structure and function
GroES exists as a ring-shaped oligomer of between six and eight identical subunits, while the 60 kDa chaperonin (cpn60 - or groEL in bacteria) forms a structure comprising 2 stacked rings, each ring containing 7 identical subunits.[2] These ring structures assemble by self-stimulation in the presence of Mg2+-ATP. The central cavity of the cylindrical cpn60 tetradecamer provides an isolated environment for protein folding whilst cpn-10 binds to cpn-60 and synchronizes the release of the folded protein in an Mg2+-ATP dependent manner.[3] The binding of cpn10 to cpn60 inhibits the weak ATPase activity of cpn60.
Escherichia coli GroES has also been shown to bind ATP cooperatively, and with an affinity comparable to that of GroEL.[4] Each GroEL subunit contains three structurally distinct domains: an apical, an intermediate and an equatorial domain. The apical domain contains the binding sites for both GroES and the unfolded protein substrate. The equatorial domain contains the ATP-binding site and most of the oligomeric contacts. The intermediate domain links the apical and equatorial domains and transfers allosteric information between them. The GroEL oligomer is a tetradecamer, cylindrically shaped, that is organised in two heptameric rings stacked back to back. Each GroEL ring contains a central cavity, known as the `Anfinsen cage', that provides an isolated environment for protein folding. The identical 10 kDa subunits of GroES form a dome-like heptameric oligomer in solution. ATP binding to GroES may be important in charging the seven subunits of the interacting GroEL ring with ATP, to facilitate cooperative ATP binding and hydrolysis for substrate protein release.
# Interactions
GroES has been shown to interact with GroEL.[5][6]
# Detection
Early pregnancy factor is tested for rosette inhibition assay. EPF is present in the maternal serum (blood plasma) shortly after fertilization; EPF is also present in cervical mucus
[7] and in amniotic fluid.[8]
EPF may be detected in sheep within 72 hours of mating,[9] in mice within 24 hours of mating,[10] and in samples from media surrounding human embryos fertilized in vitro within 48 hours of fertilization[11] (although another study failed to duplicate this finding for in vitro embryos).[12] EPF has been detected as soon as within six hours of mating.[13]
Because the rosette inhibition assay for EPF is indirect, substances that have similar effects may confound the test. Pig semen, like EPF, has been shown to inhibit rosette formation - the rosette inhibition test was positive for one day in sows mated with a vasectomized boar, but not in sows similarly stimulated without semen exposure.[14] A number of studies in the years after the discovery of EPF were unable to reproduce the consistent detection of EPF in post-conception females, and the validity of the discovery experiments was questioned.[15] However, progress in characterization of EPF has been made and its existence is well-accepted in the scientific community.[16][17]
# Origin
Early embryos are not believed to directly produce EPF. Rather, embryos are believed to produce some other chemical that induces the maternal system to create EPF.[18][19][20][21][22] After implantation, EPF may be produced by the conceptus directly.[12]
EPF is an immunosuppressant. Along with other substances associated with early embryos, EPF is believed to play a role in preventing the immune system of the pregnant female from attacking the embryo.[13][23] Injecting anti-EPF antibodies into mice after mating significantly[quantify] reduced the number of successful pregnancies and number of pups;[24][25] no effect on growth was seen when mice embryos were cultured in media containing anti-EPF antibodies.[26] While some actions of EPF are the same in all mammals (namely rosette inhibition), other immunosuppressant mechanism vary between species.[27]
In mice, EPF levels are high in early pregnancy, but on day 15 decline to levels found in non-pregnant mice.[28] In humans, EPF levels are high for about the first twenty weeks, then decline, becoming undetectable within eight weeks of delivery.[29][30]
# Clinical utility
## Pregnancy testing
It has been suggested that EPF could be used as a marker for a very early pregnancy test, and as a way to monitor the viability of ongoing pregnancies in livestock.[9] Interest in EPF for this purpose has continued,[31] although current test methods have not proved sufficiently accurate for the requirements of livestock management.[32][33][34][35]
In humans, modern pregnancy tests detect human chorionic gonadotropin (hCG). hCG is not present until after implantation, which occurs six to twelve days after fertilization.[36] In contrast, EPF is present within hours of fertilization. While several other pre-implantation signals have been identified, EPF is believed to be the earliest possible marker of pregnancy.[10][37] The accuracy of EPF as a pregnancy test in humans has been found to be high by several studies.[38][39][40][41]
## Birth control research
EPF may also be used to determine whether pregnancy prevention mechanism of birth control methods act before or after fertilization. A 1982 study evaluating EPF levels in women with IUDs concluded that post-fertilization mechanisms contribute significantly[quantify] to the effectiveness of these devices.[42] However, more recent evidence, such as tubal flushing studies indicates that IUDs work by inhibiting fertilization, acting earlier in the reproductive process than previously thought.[43]
For groups that define pregnancy as beginning with fertilization, birth control methods that have postfertilization mechanisms are regarded as abortifacient. There is currently contention over whether hormonal contraception methods have post-fertilization methods, specifically the most popular hormonal method - the combined oral contraceptive pill (COCP). The group Pharmacists for Life has called for a large-scale clinical trial to evaluate EPF in women taking COCPs; this would be the most conclusive evidence available to determine whether COCPs have postfertilization mechanisms.[44]
## Infertility and early pregnancy loss
EPF is useful when investigating embryo loss prior to implantation. One study in healthy human women seeking pregnancy detected fourteen pregnancies with EPF. Of these, six were lost within ten days of ovulation (43% rate of early conceptus loss).[45]
Use of EPF has been proposed to distinguish infertility caused by failure to conceive versus infertility caused by failure to implant.[46] EPF has also been proposed as a marker of viable pregnancy, more useful in distinguishing ectopic or other nonviable pregnancies than other chemical markers such as hCG and progesterone.[47][48][49][50]
## As a tumour marker
Although almost exclusively associated with pregnancy, EPF-like activity has also been detected in tumors of germ cell origin[51][52] and in other types of tumors.[53] Its utility as a tumour marker, to evaluate the success of surgical treatment, has been suggested.[54] | https://www.wikidoc.org/index.php/GroES | |
d4d5289909e99c79e2fba1fbb6b4ad18ef4a40a1 | wikidoc | Gutka | Gutka
Gutka (also spelled gutkha, guttkha, guthka) is a preparation of crushed betel nut, tobacco, and sweet or savory flavorings. It is manufactured in India and exported to a few other countries. A mild stimulant, it is sold across India in small, individual-size packets that cost between 1 and 4 rupees apiece. It is consumed much like chewing tobacco, and like chewing tobacco it is considered responsible for oral cancer and other severe negative health effects.
Used by millions of adults, it is also marketed to children. Some packaging does not mention tobacco as an ingredient, and some brands are pitched as candies - featuring packaging with children's faces and are brightly colored. Some are chocolate-flavored, and some are marketed as breath fresheners.
The gutka, a powdery, granular white substance, is placed between the bottom lip and the gum, or under the tongue. Within moments, the gutka begins to dissolve and turn deep red in color. It imparts upon its user a "buzz" somewhat more intense than that of tobacco.
Highly addictive and a known carcinogen, gutka is currently the subject of much controversy in India. Many states have sought to curb its immense popularity by taxing sales of gutka heavily or by banning it outright.
Gutka use can begin at a very young age. Due to its often sweet taste, easy availability and cheapness, it is popular with poor children, who can exhibit precancerous lesions at a very early age as a result. Some children consider it as a type of candy. Symptoms of cancer often appear by high school or college age. Social custom does not permit children in India to smoke cigarettes, so gutka use, being all but invisible to others, is the method of choice.
After it is consumed, it is generally spat onto a wall or the ground, causing an unsightly red stain that is quite resistant to the elements. Some building owners have taken to combating this unpleasantness by painting murals of gods on their walls, with the idea that gutkha-chewers would not spit on a god.
On 1 August 2002, Maharashtra State took the unusual step of placing a five year ban on all use of gutka (as a potentially hazardous foodstuff), an active black market persisted till the time the High Court of Judicature at Mumbai overturned the order on the grounds of unfair trade practice.
# Sources
- Sweet but Deadly Addiction is Seizing the Young in India, The New York Times, 13 August 2002
- Chewing tobacco cancer warning, BBC News, July 26, 1999
- Health: Children Buy Cancerous Sweets, BBC News, March 3, 1999
# Activist links
- Anti Gutkha Campaign, Cancer Patients Aid Association
sv:Gutka | Gutka
Gutka (also spelled gutkha, guttkha, guthka) is a preparation of crushed betel nut, tobacco, and sweet or savory flavorings. It is manufactured in India and exported to a few other countries. A mild stimulant, it is sold across India in small, individual-size packets that cost between 1 and 4 rupees apiece. It is consumed much like chewing tobacco, and like chewing tobacco it is considered responsible for oral cancer and other severe negative health effects.
Used by millions of adults, it is also marketed to children. Some packaging does not mention tobacco as an ingredient, and some brands are pitched as candies - featuring packaging with children's faces and are brightly colored. Some are chocolate-flavored, and some are marketed as breath fresheners.[1]
The gutka, a powdery, granular white substance, is placed between the bottom lip and the gum, or under the tongue. Within moments, the gutka begins to dissolve and turn deep red in color. It imparts upon its user a "buzz" somewhat more intense than that of tobacco.
Highly addictive and a known carcinogen, gutka is currently the subject of much controversy in India. Many states have sought to curb its immense popularity by taxing sales of gutka heavily or by banning it outright.
Gutka use can begin at a very young age. Due to its often sweet taste, easy availability and cheapness, it is popular with poor children, who can exhibit precancerous lesions at a very early age as a result. Some children consider it as a type of candy. Symptoms of cancer often appear by high school or college age. Social custom does not permit children in India to smoke cigarettes, so gutka use, being all but invisible to others, is the method of choice.
After it is consumed, it is generally spat onto a wall or the ground, causing an unsightly red stain that is quite resistant to the elements. Some building owners have taken to combating this unpleasantness by painting murals of gods on their walls, with the idea that gutkha-chewers would not spit on a god.
On 1 August 2002, Maharashtra State took the unusual step of placing a five year ban on all use of gutka (as a potentially hazardous foodstuff), an active black market persisted till the time the High Court of Judicature at Mumbai overturned the order on the grounds of unfair trade practice.
# Sources
- Sweet but Deadly Addiction is Seizing the Young in India, The New York Times, 13 August 2002
- Chewing tobacco cancer warning, BBC News, July 26, 1999
- Health: Children Buy Cancerous Sweets, BBC News, March 3, 1999
# Activist links
- Anti Gutkha Campaign, Cancer Patients Aid Association
sv:Gutka
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Gutka | |
2c22720ec60f23900627376ed16976d2834ca7cb | wikidoc | Human | Human
# Overview
Humans, or human beings, are bipedal primates belonging to the mammalian species Homo sapiens (Latin: "wise human" or "knowing human") in the family Hominidae (the great apes). DNA evidence indicates that modern humans originated in Africa about 200,000 years ago. Compared to other species, humans have a highly developed brain, capable of abstract reasoning, language, introspection, and emotional suffering. This mental capability, combined with an erect body carriage that frees the forelimbs (arms) for manipulating objects, has allowed humans to make far greater use of tools than any other species. Humans now inhabit every continent on Earth, except Antarctica (although several governments maintain permanent research stations there, inhabited for short periods by scientists and other researchers). Humans also now have a continuous presence in low Earth orbit, occupying the International Space Station. The human population on Earth now amounts to over 6.6 billion, as of May 2008.
Like most primates, humans are social by nature. However, they are particularly adept at utilizing systems of communication for self-expression, exchanging of ideas, and organization. Humans create complex social structures composed of many cooperating and competing groups, from families to nations. Social interactions between humans have established an extremely wide variety of traditions, rituals, ethics, values, social norms, and laws, which together form the basis of human society. Humans have a marked appreciation for beauty and aesthetics, which, combined with the desire for self-expression, has led to cultural innovations such as art, literature and music.
Humans are notable for their desire to understand and influence the world around them, seeking to explain and manipulate natural phenomena through science, philosophy, mythology and religion. This natural curiosity has led to the development of advanced tools and skills; humans are the only extant species known to build fires, cook their food, clothe themselves, and manipulate and develop numerous other technologies. Humans pass down their skills and knowledge to the next generations through education whether it is formal or informal.
# History
## Origin
The scientific study of human evolution encompasses the development of the genus Homo, but usually involves studying other hominids and hominines as well, such as Australopithecus. "Modern humans" are defined as the Homo sapiens species, of which the only extant subspecies - our own - was formerly known as Homo sapiens sapiens (now simply known as Homo sapiens). Homo sapiens idaltu (roughly translated as "elder wise human"), the other known subspecies, is now extinct. Anatomically modern humans first appear in the fossil record in Africa about 200,000 years ago.
The closest living relatives of Homo sapiens are the two chimpanzee species: the Common Chimpanzee and the Bonobo. Full genome sequencing has resulted in the conclusion that "after 6.5 years of separate evolution, the differences between chimpanzee and human are just 10 times greater than those between two unrelated people and 10 times less than those between rats and mice". Suggested differences between human and chimpanzee DNA sequences range between 95% and 99%. It has been estimated that the human lineage diverged from that of chimpanzees about five million years ago, and from that of gorillas about eight million years ago. However, a hominid skull discovered in Chad in 2001, classified as Sahelanthropus tchadensis, is approximately seven million years old, which may indicate an earlier divergence.
The Recent African Origin (RAO), or "out-of-Africa", hypothesis proposes that modern humans evolved in Africa before later migrating outwards to replace hominids in other parts of the world. Evidence from archaeogenetics accumulating since the 1990s has lent strong support to RAO, and has marginalized the competing multiregional hypothesis, which proposed that modern humans evolved, at least in part, from independent hominid populations. Geneticists Lynn Jorde and Henry Harpending of the University of Utah propose that the variation in human DNA is minute compared to that of other species. They also propose that during the Late Pleistocene, the human population was reduced to a small number of breeding pairs – no more than 10,000, and possibly as few as 1,000 – resulting in a very small residual gene pool. Various reasons for this hypothetical bottleneck have been postulated, one being the Toba catastrophe theory.
Human evolution is characterized by a number of important morphological, developmental, physiological and behavioural changes, which have taken place since the split between the last common ancestor of humans and chimpanzees. The first major morphological change was the evolution of a bipedal locomotor adaptation from an arboreal or semi-arboreal one, with all its attendant adaptations, such as a valgus knee, low intermembral index (long legs relative to the arms), and reduced upper-body strength.
Later, ancestral humans developed a much larger brain – typically 1,400 cm³ in modern humans, over twice the size of that of a chimpanzee or gorilla. The pattern of human postnatal brain growth differs from that of other apes (heterochrony), and allows for extended periods of social learning and language acquisition in juvenile humans. Physical anthropologists argue that the differences between the structure of human brains and those of other apes are even more significant than their differences in size.
Other significant morphological changes included: the evolution of a power and precision grip; a reduced masticatory system; a reduction of the canine tooth; and the descent of the larynx and hyoid bone, making speech possible. An important physiological change in humans was the evolution of hidden oestrus, or concealed ovulation, which may have coincided with the evolution of important behavioural changes, such as pair bonding. Another significant behavioural change was the development of material culture, with human-made objects becoming increasingly common and diversified over time. The relationship between all these changes is the subject of ongoing debate.
## Rise of civilization
The most widely accepted view among current anthropologists is that Homo sapiens originated in the African savanna around 200,000 BP (Before Present), descending from Homo erectus, had inhabited Eurasia and Oceania by 40,000 BP, and finally inhabited the Americas approximately 14,500 years ago. They displaced Homo neanderthalensis and other species descended from Homo erectus (which had inhabited Eurasia as early as 2 million years ago) through more successful reproduction and competition for resources.
Until c. 10,000 years ago, most humans lived as hunter-gatherers. They generally lived in small nomadic groups known as band societies. The advent of agriculture prompted the Neolithic Revolution, when access to food surplus led to the formation of permanent human settlements, the domestication of animals and the use of metal tools. Agriculture encouraged trade and cooperation, and led to complex society. Because of the significance of this date for human society, it is the epoch of the Holocene calendar or Human Era.
About 6,000 years ago, the first proto-states developed in Mesopotamia, Egypt and the Indus Valley. Military forces were formed for protection, and government bureaucracies for administration. States cooperated and competed for resources, in some cases waging wars. Around 2,000–3,000 years ago, some states, such as Persia, India, China and Rome, developed through conquest into the first expansive empires. Influential religions, such as Judaism, originating in the Middle East, and Hinduism, a religious tradition that originated in South Asia, also rose to prominence at this time.
The late Middle Ages saw the rise of revolutionary ideas and technologies. In China, an advanced and urbanized economy promoted innovations such as printing and the compass, while the Islamic Golden Age saw major scientific advancements in Muslim empires. In Europe, the rediscovery of classical learning and inventions such as the printing press led to the Renaissance in the 14th century. Over the next 500 years, exploration and imperialistic conquest brought much of the Americas, Asia, and Africa under European control, leading to later struggles for independence. The Scientific Revolution in the 17th century and the Industrial Revolution in the 18th – 19th centuries promoted major innovations in transport, such as the railway and automobile; energy development, such as coal and electricity; and government, such as representative democracy and Communism.
As a result of such changes, modern humans live in a world that has become increasingly globalized and interconnected. Although this has encouraged the growth of science, art, and technology, it has also led to culture clashes, the development and use of weapons of mass destruction, and increased environmental destruction and pollution, affecting not only themselves but also most other life forms on the planet.
# Habitat and population
Early human settlements were dependent on proximity to water and, depending on the lifestyle, other natural resources, such as fertile land for growing crops and grazing livestock, or seasonally by hunting populations of prey. However, humans have a great capacity for altering their habitats by various methods, such as through irrigation, urban planning, construction, transport, manufacturing goods, deforestation and desertification. With the advent of large-scale trade and transport infrastructure, proximity to these resources has become unnecessary, and in many places these factors are no longer a driving force behind the growth and decline of a population. Nonetheless, the manner in which a habitat is altered is often a major determinant in population change.
Technology has allowed humans to colonize all of the continents and adapt to all climates. Within the last few decades, humans have explored Antarctica, the ocean depths, and space, although long-term habitation of these environments is not yet possible. With a population of over six billion, humans are among the most numerous of the large mammals. Most humans (61%) live in Asia. The vast majority of the remainder live in the Americas (14%), Africa (14%) and Europe (11%), with 0.5% in Oceania.
Human habitation within closed ecological systems in hostile environments, such as Antarctica and outer space, is expensive, typically limited in duration, and restricted to scientific, military, or industrial expeditions. Life in space has been very sporadic, with no more than thirteen humans in space at any given time. Between 1969 and 1972, two humans at a time spent brief intervals on the Moon. As of early 2008, no other celestial body has been visited by human beings, although there has been a continuous human presence in space since the launch of the initial crew to inhabit the International Space Station on October 31, 2000. Other celestial bodies have, however, been visited by human-made objects.
Since 1800, the human population increased from one billion to over six billion. In 2004, some 2.5 billion out of 6.3 billion people (39.7%) lived in urban areas, and this percentage is expected to rise throughout the 21st century. Problems for humans living in cities include various forms of pollution and crime, especially in inner city and suburban slums. Benefits of urban living include increased literacy, access to the global canon of human knowledge and decreased susceptibility to rural famines.
Humans have had a dramatic effect on the environment. It has been hypothesized that human predation has contributed to the extinction of numerous species. As humans stand at the top of the food chain and are not generally preyed upon, they have been described as superpredators. Currently, through land development and pollution, humans are thought to be the main contributor to global climate change. This is believed to be a major contributor to the ongoing Holocene extinction event, a mass extinction which, if it continues at its current rate, is predicted to wipe out half of all species over the next century.
# Biology
## Physiology and genetics
Human body types vary substantially. Although body size is largely determined by genes, it is also significantly influenced by environmental factors such as diet and exercise. The average height of an adult human is about 1.5 to 1.8 m (5 to 6 feet) tall, although this varies significantly from place to place. Unlike most other primates, humans are capable of fully bipedal locomotion, thus leaving their arms available for manipulating objects using their hands, aided especially by opposable thumbs.
Although humans appear relatively hairless compared to other primates, with notable hair growth occurring chiefly on the top of the head, underarms and pubic area, the average human has more hair follicles on his or her body than the average chimpanzee. The main distinction is that human hairs are shorter, finer, and less heavily pigmented than the average chimpanzee's, thus making them harder to see.
The hue of human hair and skin is determined by the presence of pigments called melanins. Human skin hues can range from very dark brown to very pale pink, while human hair ranges from blond to brown to red to, most commonly, black, depending on the amount of melanin (an effective sun blocking pigment) in the skin. Most researchers believe that skin darkening was an adaptation that evolved as a protection against ultraviolet solar radiation. More recently, however, it has been argued that particular skin colors are an adaptation to balance folate, which is destroyed by ultraviolet radiation, and vitamin D, which requires sunlight to form. The skin pigmentation of contemporary humans is geographically stratified, and in general correlates with the level of ultraviolet radiation. Human skin also has a capacity to darken (sun tanning) in response to exposure to ultraviolet radiation. Humans tend to be physically weaker than other similairly sized primates, with young, conditioned male humans having been shown to be unable to match the strength of female orangutans which are at least three times stronger.
Humans have proportionately shorter palates and much smaller teeth than other primates. They are the only primates to have short 'flush' canine teeth. Humans have characteristically crowded teeth, with gaps from lost teeth usually closing up quickly in young specimens. Humans are gradually losing their wisdom teeth, with some individuals having them congenitally absent.
The average sleep requirement is between seven and eight hours a day for an adult and nine to ten hours for a child; elderly people usually sleep for six to seven hours. Experiencing less sleep than this is common in modern societies; this sleep deprivation can lead to negative effects. A sustained restriction of adult sleep to four hours per day has been shown to correlate with changes in physiology and mental state, including fatigue, aggression, and bodily discomfort.
Humans are an eukaryotic species. Each diploid cell has two sets of 23 chromosomes, each set received from one parent. There are 22 pairs of autosomes and one pair of sex chromosomes. By present estimates, humans have approximately 20,000 – 25,000 genes. Like other mammals, humans have an XY sex-determination system, so that females have the sex chromosomes XX and males have XY. The X chromosome is larger and carries many genes not on the Y chromosome, which means that recessive diseases associated with X-linked genes, such as hemophilia, affect men more often than women.
## Life cycle
The human life cycle is similar to that of other placental mammals. The fertilized egg divides inside the female's uterus to become an embryo, which over a period of thirty-eight weeks (9 months) of gestation becomes a human fetus. After this span of time, the fully-grown fetus is birthed from the woman's body and breathes independently as an infant for the first time. At this point, most modern cultures recognize the baby as a person entitled to the full protection of the law, though some jurisdictions extend personhood earlier to human fetuses while they remain in the uterus.
Compared with other species, human childbirth is dangerous. Painful labors lasting twenty-four hours or more are not uncommon and often leads to the death of the mother, or the child. This is because of both the relatively large fetal head circumference (for housing the brain) and the mother's relatively narrow pelvis (a trait required for successful bipedalism, by way of natural selection). The chances of a successful labor increased significantly during the 20th century in wealthier countries with the advent of new medical technologies. In contrast, pregnancy and natural childbirth remain relatively hazardous ordeals in developing regions of the world, with maternal death rates approximately 100 times more common than in developed countries.
In developed countries, infants are typically 3 – 4 kg (6 – 9 pounds) in weight and 50 – 60 cm (20 – 24 inches) in height at birth. However, low birth weight is common in developing countries, and contributes to the high levels of infant mortality in these regions. Helpless at birth, humans continue to grow for some years, typically reaching sexual maturity at 12 to 15 years of age. Females continue to develop physically until around the age of 18, whereas male development continues until around age 21. The human life span can be split into a number of stages: infancy, childhood, adolescence, young adulthood, adulthood and old age. The lengths of these stages, however, have varied across cultures and time periods. Compared to other primates, humans experience an unusually rapid growth spurt during adolescence, where the body grows 25% in size. Chimpanzees, for example, grow only 14%.
There are significant differences in life expectancy around the world. The developed world generally aging, with the median age around 40 years (highest in Monaco at 45.1 years). In the developing world the median age is between 15 and 20 years. Life expectancy at birth in Hong Kong, China is 84.8 years for a female and 78.9 for a male, while in Swaziland, primarily because of AIDS, it is 31.3 years for both sexes. While one in five Europeans is 60 years of age or older, only one in twenty Africans is 60 years of age or older. The number of centenarians (humans of age 100 years or older) in the world was estimated by the United Nations at 210,000 in 2002. At least one person, Jeanne Calment, is known to have reached the age of 122 years; higher ages have been claimed but they are not well substantiated. Worldwide, there are 81 men aged 60 or older for every 100 women of that age group, and among the oldest, there are 53 men for every 100 women.
Humans are unique in the widespread onset of female menopause during the latter stage of life. Menopause is believed to have arisen due to the Grandmother hypothesis, in which it is in the mother's reproductive interest to forgo the risks of death from childbirth at older ages in exchange for investing in the viability of her already living offspring.
The philosophical questions of when human personhood begins and whether it persists after death are the subject of considerable debate. The prospect of death causes unease or fear for most humans, distinct from the immediate awareness of a threat. Burial ceremonies are characteristic of human societies, often accompanied by beliefs in an afterlife or immortality.
## Diet
Early Homo sapiens employed a hunter-gatherer method as their primary means of food collection, involving combining stationary plant and fungal food sources (such as fruits, grains, tubers, and mushrooms) with wild game, which must be hunted and killed in order to be consumed. It is believed that humans have used fire to prepare and cook food prior to eating since the time of their divergence from Homo erectus.
Humans are omnivorous, capable of consuming both plant and animal products. A view of humans as omnivores is supported by the evidence that both a pure animal and a pure vegetable diet can lead to deficiency diseases in humans. A pure animal diet can, for instance, lead to scurvy, a vitamin C deficiency, while a pure plant diet may lead to vitamin B12 deficiency. The biggest problem posed by a vitamin B12 deficiency is that it severely limits the body's ability to synthesize folic acid, a main source of B group carriage. In order to counter the constant folic acid deficiency, one must regularly consume large amounts of folic acid, as may be found in green, leafy vegetables. Properly planned vegetarian and vegan diets, however, have been found to completely satisfy nutritional needs in every stage of life.
The human diet is prominently reflected in human culture, and has led to the development of food science.
In general, humans can survive for two to eight weeks without food, depending on stored body fat. Survival without water is usually limited to three or four days. Lack of food remains a serious problem, with about 300,000 people starving to death every year. Childhood malnutrition is also common and contributes to the global burden of disease. However global food distribution is not even, and obesity among some human populations has increased to almost epidemic proportions, leading to health complications and increased mortality in some developed, and a few developing countries. The United States Centers for Disease Control (CDC) state that 32% of American adults over the age of 20 are obese, while 66.5% are obese or overweight. Obesity is caused by consuming more calories than are expended, with many attributing excessive weight gain to a combination of overeating and insufficient exercise.
At least ten thousand years ago, humans developed agriculture, which has substantially altered the kind of food people eat. This has led to increased populations, the development of cities, and because of increased population density, the wider spread of infectious diseases. The types of food consumed, and the way in which they are prepared, has varied widely by time, location, and culture.
# Psychology
The human brain is the center of the central nervous system in humans, and acts as the primary control center for the peripheral nervous system. The brain controls "lower", or involuntary, autonomic activities such as the respiration, and digestion. The brain also controls "higher" order, conscious activities, such as thought, reasoning, and abstraction. These cognitive processes constitute the mind, and, along with their behavioral consequences, are studied in the field of psychology.
Generally regarded as more capable of these higher order activities, the human brain is believed to be more "intelligent" in general than that of any other known species. While many animals are capable of creating structures and using simple tools — mostly through instinct and mimicry — human technology is vastly more complex, and is constantly evolving and improving through time. Even the most ancient human tools and structures are far more advanced than any structure or tool created by any other animal. Modern anthropology has tended to bear out Darwin's proposition that "the difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind".
## Consciousness and thought
The human ability to think abstractly may be unparalleled in the animal kingdom. Humans are one of only six species to pass the mirror test — which tests whether an animal recognizes its reflection as an image of itself — along with chimpanzees, orangutans, dolphins, and pigeons. In October 2006, three elephants at the Bronx Zoo also passed this test. Most human children will pass the mirror test at 18 months old. However, the usefulness of this test as a true test of consciousness has been disputed (see mirror test), and this may be a matter of degree rather than a sharp divide. Monkeys have been trained to apply abstract rules in tasks. The human brain perceives the external world through the senses, and each individual human is influenced greatly by his or her experiences, leading to subjective views of existence and the passage of time. Humans are variously said to possess consciousness, self-awareness, and a mind, which correspond roughly to the mental processes of thought. These are said to possess qualities such as self-awareness, sentience, sapience, and the ability to perceive the relationship between oneself and one's environment. The extent to which the mind constructs or experiences the outer world is a matter of debate, as are the definitions and validity of many of the terms used above. The philosopher of cognitive science Daniel Dennett, for example, argues that there is no such thing as a narrative centre called the "mind", but that instead there is simply a collection of sensory inputs and outputs: different kinds of "software" running in parallel. Psychologist B.F. Skinner has argued that the mind is an explanatory fiction that diverts attention from environmental causes of behavior, and that what are commonly seen as mental processes may be better conceived of as forms of covert verbal behavior.
Humans study the more physical aspects of the mind and brain, and by extension of the nervous system, in the field of neurology, the more behavioral in the field of psychology, and a sometimes loosely-defined area between in the field of psychiatry, which treats mental illness and behavioral disorders. Psychology does not necessarily refer to the brain or nervous system, and can be framed purely in terms of phenomenological or information processing theories of the mind. Increasingly, however, an understanding of brain functions is being included in psychological theory and practice, particularly in areas such as artificial intelligence, neuropsychology, and cognitive neuroscience.
The nature of thought is central to psychology and related fields. Cognitive psychology studies cognition, the mental processes underlying behavior. It uses information processing as a framework for understanding the mind. Perception, learning, problem solving, memory, attention, language and emotion are all well-researched areas as well. Cognitive psychology is associated with a school of thought known as cognitivism, whose adherents argue for an information processing model of mental function, informed by positivism and experimental psychology. Techniques and models from cognitive psychology are widely applied and form the mainstay of psychological theories in many areas of both research and applied psychology. Largely focusing on the development of the human mind through the life span, developmental psychology seeks to understand how people come to perceive, understand, and act within the world and how these processes change as they age. This may focus on intellectual, cognitive, neural, social, or moral development.
Some philosophers divide consciousness into phenomenal consciousness, which is experience itself, and access consciousness, which is the processing of the things in experience. Phenomenal consciousness is the state of being conscious, such as when they say "I am conscious." Access consciousness is being conscious of something in relation to abstract concepts, such as when one says "I am conscious of these words." Various forms of access consciousness include awareness, self-awareness, conscience, stream of consciousness, Husserl's phenomenology, and intentionality. The concept of phenomenal consciousness, in modern history, according to some, is closely related to the concept of qualia. Social psychology links sociology with psychology in their shared study of the nature and causes of human social interaction, with an emphasis on how people think towards each other and how they relate to each other. The behavior and mental processes, both human and non-human, can be described through animal cognition, ethology, evolutionary psychology, and comparative psychology as well. Human ecology is an academic discipline that investigates how humans and human societies interact with both their natural environment and the human social environment.
## Motivation and emotion
Motivation is the driving force of desire behind all deliberate actions of human beings. Motivation is based on emotion — specifically, on the search for satisfaction (positive emotional experiences), and the avoidance of conflict. Positive and negative is defined by the individual brain state, which may be influenced by social norms: a person may be driven to self-injury or violence because their brain is conditioned to create a positive response to these actions. Motivation is important because it is involved in the performance of all learned responses. Within psychology, conflict avoidance and the libido are seen to be primary motivators. Within economics motivation is often seen to be based on financial incentives, moral incentives, or coercive incentives. Religions generally posit divine or demonic influences.
Happiness, or the state of being happy, is a human emotional condition. The definition of happiness is a common philosophical topic. Some people might define it as the best condition which a human can have — a condition of mental and physical health. Others define it as freedom from want and distress; consciousness of the good order of things; assurance of one's place in the universe or society.
Emotion has a significant influence on, or can even be said to control, human behavior, though historically many cultures and philosophers have for various reasons discouraged allowing this influence to go unchecked. Emotional experiences perceived as pleasant, such as love, admiration, or joy, contrast with those perceived as unpleasant, like hate, envy, or sorrow. There is often a distinction made between refined emotions which are socially learned and survival oriented emotions, which are thought to be innate. Human exploration of emotions as separate from other neurological phenomena is worthy of note, particularly in cultures where emotion is considered separate from physiological state. In some cultural medical theories emotion is considered so synonymous with certain forms of physical health that no difference is thought to exist. The Stoics believed excessive emotion was harmful, while some Sufi teachers (in particular, the poet and astronomer Omar Khayyám) felt certain extreme emotions could yield a conceptual perfection, what is often translated as ecstasy.
In modern scientific thought, certain refined emotions are considered to be a complex neural trait innate in a variety of domesticated and on-domesticated mammals. These were commonly developed in reaction to superior survival mechanisms and intelligent interaction with each other and the environment; as such, refined emotion is not in all cases as discrete and separate from natural neural function as was once assumed. However, when humans function in civilized tandem, it has been noted that uninhibited acting on extreme emotion can lead to social disorder and crime.
## Sexuality and love
Human sexuality, besides ensuring biological reproduction, has important social functions: it creates physical intimacy, bonds, and hierarchies among individuals; may be directed to spiritual transcendence (according to some traditions); and in a hedonistic sense to the enjoyment of activity involving sexual gratification. Sexual desire, or libido, is experienced as a bodily urge, often accompanied by strong emotions such as love, ecstasy and jealousy. The extreme importance of sexuality in the human species can be seen in a number of physical features, among them hidden ovulation, strong sexual dimorphism when compared to the chimpanzees, permanent secondary sexual characteristics, the forming of pair bonds based on sexual attraction as a common social structure and sexual ability in females outside of ovulation. These adaptations indicate that the importance of sexuality in humans is on par with that found in the Bonobo, and that the complex human sexual behaviour has a long evolutionary history.
As with other human self-descriptions, humans propose that it is high intelligence and complex societies of humans that have produced the most complex sexual behaviors of any animal, including a great many behaviors that are not directly connected with reproduction.
Human sexual choices are usually made in reference to cultural norms, which vary widely. Restrictions are sometimes determined by religious beliefs or social customs. The pioneering researcher Sigmund Freud believed that humans are born polymorphously perverse, which means that any number of objects could be a source of pleasure. According to Freud, humans then pass through five stages of psychosexual development (and can fixate on any stage because of various traumas during the process). For Alfred Kinsey, another influential sex researcher, people can fall anywhere along a continuous scale of sexual orientation (with only small minorities fully heterosexual or homosexual). Recent studies of neurology and genetics suggest people may be born with one sexual orientation or another, so there is not currently a clear consensus among sex researchers.
# Culture
Culture is defined here as a set of distinctive material, intellectual, emotional, and spiritual features of a social group, including art, literature, lifestyles, value systems, traditions, rituals, and beliefs. The link between human biology and human behavior and culture is often very close, making it difficult to clearly divide topics into one area or the other; as such, the placement of some subjects may be based primarily on convention. Culture consists of values, social norms, and artifacts. A culture's values define what it holds to be important or ethical. Closely linked are norms, expectations of how people ought to behave, bound by tradition. Artifacts, or material culture, are objects derived from the culture's values, norms, and understanding of the world. The mainstream anthropological view of culture implies that most experience a strong resistance when reminded that there is an animal as well as a spiritual aspect to human nature.
## Language
The capacity humans have to transfer concepts, ideas and notions through speech and writing is unrivaled in known species. Unlike the call systems of other primates which are closed, human language is far more open, and gains variety in different situations. The human language has the quality of displacement, using words to represent things and happenings that are not presently or locally occurring, but elsewhere or at a different time. Technology has even advanced so as to allow the communication of mass data upon request and over great distance through data-nets and programs such as Wikipedia. In this way data networks are important to the continuing development of language; changing it as just as Gutenberg did with the printing press. The faculty of speech is a defining feature of humanity, possibly predating phylogenetic separation of the modern population. Language is central to the communication between humans, as well as being central to the sense of identity that unites nations, cultures and ethnic groups. The invention of writing systems at least 5,000 years ago allowed the preservation of language on material objects, and was a major step in cultural evolution. Language is closely tied to ritual and religion (cf. mantra, sacred text). The science of linguistics describes the structure of language and the relationship between languages. There are approximately 6,000 different languages currently in use, including sign languages, and many thousands more that are considered extinct.
## Spirituality and religion
Religion—sometimes used interchangeably with "faith"—is generally defined as a belief system concerning the supernatural, sacred or divine, and moral codes, practices, values, institutions and rituals associated with such belief. In the course of its development, religion has taken on many forms that vary by culture and individual perspective. Some of the chief questions and issues religions are concerned with include life after death (commonly involving belief in an afterlife), the origin of life (the source of a variety of creation myths), the nature of the universe (religious cosmology) and its ultimate fate (eschatology), and what is moral or immoral. A common source in religions for answers to these questions are transcendent divine beings such as deities or a singular God, although not all religions are theistic — many are nontheistic or ambiguous on the topic, particularly among the Eastern religions. Spirituality, belief or involvement in matters of the soul or spirit, is one of the many different approaches humans take in trying to answer fundamental questions about humankind's place in the universe, the meaning of life, and the ideal way to live one's life. Though these topics have also been addressed by philosophy, and to some extent by science, spirituality is unique in that it focuses on mystical or supernatural concepts such as karma and God.
Although a majority of humans profess some variety of religious or spiritual belief, some are irreligious, that is lacking or rejecting belief in the supernatural or spiritual. Additionally, although most religions and spiritual beliefs are clearly distinct from science on both a philosophical and methodological level, the two are not generally considered to be mutually exclusive; a majority of humans hold a mix of both scientific and religious views. The distinction between philosophy and religion, on the other hand, is at times less clear, and the two are linked in such fields as the philosophy of religion and theology. Other humans have no religious beliefs and are atheists, scientific skeptics, agnostics or simply non-religious.
## Philosophy and self-reflection
Philosophy is a discipline or field of study involving the investigation, analysis, and development of ideas at a general, abstract, or fundamental level. It is the discipline searching for a general understanding of values and reality by chiefly speculative means. The core philosophical disciplines are logic, ontology or metaphysics, epistemology, and axiology, which includes the branches of ethics and aesthetics. Philosophy covers a very wide range of approaches, and is also used to refer to a worldview, to a perspective on an issue, or to the positions argued for by a particular philosopher or school of philosophy.
Metaphysics is a branch of philosophy concerned with the study of first principles, being and existence (ontology). In between the doctrines of religion and science, stands the philosophical perspective of metaphysical cosmology. This ancient field of study seeks to draw logical conclusions about the nature of the universe, humanity, god, and/or their connections based on the extension of some set of presumed facts borrowed from religion and/or observation. Humans often consider themselves to be the dominant species on Earth, and the most advanced in intelligence and ability to manage their environment. This belief is especially strong in modern Western culture. Alongside such claims of dominance is often found radical pessimism because of the frailty and brevity of human life.
Humanism is a philosophy which defines a socio-political doctrine the bounds of which are not constrained by those of locally developed cultures, but which seeks to include all of humanity and all issues common to human beings. Because spiritual beliefs of a community often manifests as religious doctrine, the history of which is as factious as it is unitive, secular humanism grew as an answer to the need for a common philosophy that transcended the cultural boundaries of local moral codes and religions. Many humanists are religious, however, and see humanism as simply a mature expression of a common truth present in most religions. Humanists affirm the possibility of an objective truth and accept that human perception of that truth is imperfect. The most basic tenets of humanism are that humans matter and can solve human problems, and that science, freedom of speech, rational thought, democracy, and freedom in the arts are worthy pursuits or goals for all peoples. Humanism depends chiefly on reason and logic without consideration for the supernatural.
## Art, music, and literature
Artistic works have existed for almost as long as humankind, from early pre-historic art to contemporary art. Art is one of the most unusual aspects of human behavior and a key distinguishing feature of humans from other species, In fact the only species to do so. Art has only been around for the last 35,000 years which could suggest that this was the time when humans started to 'think'.
As a form of cultural expression by humans, art may be defined by the pursuit of diversity and the usage of narratives of liberation and exploration (i.e. art history, art criticism, and art theory) to mediate its boundaries. This distinction may be applied to objects or performances, current or historical, and its prestige extends to those who made, found, exhibit, or own them. In the modern use of the word, art is commonly understood to be the process or result of making material works which, from concept to creation, adhere to the "creative impulse" of human beings. Art is distinguished from other works by being in large part unprompted by necessity, by biological drive, or by any undisciplined pursuit of recreation.
Music is a natural intuitive phenomenon based on the three distinct and interrelated organization structures of rhythm, harmony, and melody. Listening to music is perhaps the most common and universal form of entertainment for humans, while learning and understanding it are popular disciplines. There are a wide variety of music genres and ethnic musics. Literature, the body of written — and possibly oral — works, especially creative ones, includes prose, poetry and drama, both fiction and non-fiction. Literature includes such genres as epic, legend, myth, ballad, and folklore.
## Science and technology
Science is the discovery of knowledge about the world by verifiable means. Technology is the objects humans make to serve their purposes. Human cultures are both characterized and differentiated by the objects that they make and use. Archaeology attempts to tell the story of past or lost cultures in part by close examination of the artifacts they produced. Early humans left stone tools, pottery and jewelry that are particular to various regions and times. Improvements in technology are passed from one culture to another. For instance, the cultivation of crops arose in several different locations, but quickly spread to be an almost ubiquitous feature of human life. Similarly, advances in weapons, architecture and metallurgy are quickly disseminated.
Although such techniques can be passed on by oral tradition, the development of writing, itself a kind of technology, made it possible to pass information from generation to generation and from region to region with greater accuracy. Together, these developments made possible the commencement of civilization and urbanization, with their inherently complex social arrangements. Eventually this led to the institutionalization of the development of new technology, and the associated understanding of the way the world functions. This science now forms a central part of human culture. In recent times, physics and astrophysics have come to play a central role in shaping what is now known as physical cosmology, that is, the understanding of the universe through scientific observation and experiment. This discipline, which focuses on the universe as it exists on the largest scales and at the earliest times, begins by arguing for the big bang, a sort of cosmic expansion from which the universe itself is said to have erupted ~13.7 ± 0.2 billion (109) years ago. After its violent beginnings and until its very end, scientists then propose that the entire history of the universe has been an orderly progression governed by physical laws.
## Race and ethnicity
Humans often categorize themselves in terms of race or ethnicity, although the validity of human races as true biological categories is questionable. Human racial categories are based on both ancestry and visible traits, especially skin color and facial features. These categories may also carry some information on non-visible biological traits, such as the risk of developing particular diseases such as sickle-cell disease. Currently available genetic and archaeological evidence is generally interpreted as supportive of a recent single origin of modern humans in East Africa. Current genetic studies have demonstrated that humans on the African continent are most genetically diverse. However, compared to many other animals, human gene sequences are remarkably homogeneous. It has been repeatedly demonstrated that the great majority of genetic variation occurs within "racial groups", with only 5 to 15% of total variation occurring between racial groups. However, this remains an area of active debate.
Ethnic groups, on the other hand, are more often linked by linguistic, cultural, ancestral, and national or regional ties. Self-identification with an ethnic group is based on kinship and descent. Race and ethnicity can lead to variant treatment and impact social identity, giving rise to racism and the theory of identity politics.
## Society, government, and politics
Society is the system of organizations and institutions arising from interaction between humans. A state is an organized political community occupying a definite territory, having an organized government, and possessing internal and external sovereignty. Recognition of the state's claim to independence by other states, enabling it to enter into international agreements, is often important to the establishment of its statehood. The "state" can also be defined in terms of domestic conditions, specifically, as conceptualized by Max Weber, "a state is a human community that (successfully) claims the monopoly of the 'legitimate' use of physical force within a given territory."
Government can be defined as the political means of creating and enforcing laws; typically via a bureaucratic hierarchy. Politics is the process by which decisions are made within groups. Although the term is generally applied to behavior within governments, politics is also observed in all human group interactions, including corporate, academic, and religious institutions. Many different political systems exist, as do many different ways of understanding them, and many definitions overlap. The most common form of government worldwide is a republic, however other examples include monarchy, social democracy, military dictatorship and theocracy. All of these issues have a direct relationship with economics.
## War
War is a state of widespread conflict between states, organizations, or relatively large groups of people, which is characterized by the use of lethal violence between combatants or upon civilians. It is estimated that during the 20th century between 167 and 188 million humans died as a result of war. A common perception of war is a series of military campaigns between at least two opposing sides involving a dispute over sovereignty, territory, resources, religion or other issues. A war said to liberate an occupied country is sometimes characterized as a "war of liberation", while a war between internal elements of a state is a civil war. Full scale pitched-battle wars between adversaries of comparable strength appear to have nearly disappeared from human activity, with the last major one in the Congo region winding down in the late 1990s. Nearly all war now is asymmetric warfare, in which campaigns of sabotage, guerrilla warfare and sometimes acts of terrorism disrupt control and supply of better-equipped occupying forces, resulting in long low-intensity wars of attrition.
War is one of the main catalysts for human advances in technology. Throughout human history there has been a constant struggle between defense and offence, including the technologies behind armour and weapons designed to penetrate it. Modern examples include the bunker buster bomb and the bunkers which they are designed to destroy. Important inventions such as medicine, navigation, metallurgy, mass production, nuclear power, rocketry and computers have been completely or partially driven by war.
There have been a wide variety of rapidly advancing tactics throughout the history of war, ranging from conventional war to asymmetric warfare to total war and unconventional warfare. Techniques include hand to hand combat, the use of ranged weapons, and ethnic cleansing. Military intelligence has often played a key role in determining victory and defeat. Propaganda, which often includes factual information, slanted opinion and disinformation, plays a key role in maintaining unity within a warring group, and/or sowing discord among opponents. In modern warfare, soldiers and armoured fighting vehicles are used to control the land, warships the sea, and air power the sky. These fields have also overlapped in the forms of marines, paratroopers, naval aircraft carriers, and surface-to-air missiles, among others. Satellites in low Earth orbit have made outer space a factor in warfare as well, although no actual warfare is currently carried out in space.
## Trade and economics
Trade is the voluntary exchange of goods, services and a form of economics. A mechanism that allows trade is called a market. The original form of trade was barter, the direct exchange of goods and services. Modern traders instead generally negotiate through a medium of exchange, such as money. As a result, buying can be separated from selling, or earning. The invention of money (and later credit, paper money and non-physical money) greatly simplified and promoted trade. Because of specialization and division of labor, most people concentrate on a small aspect of manufacturing or service, trading their labour for products. Trade exists between regions because different regions have an absolute or comparative advantage in the production of some tradeable commodity, or because different regions' size allows for the benefits of mass production.
Economics is a social science which studies the production, distribution, trade and consumption of goods and services. Economics focuses on measurable variables, and is broadly divided into two main branches: microeconomics, which deals with individual agents, such as households and businesses, and macroeconomics, which considers the economy as a whole, in which case it considers aggregate supply and demand for money, capital and commodities. Aspects receiving particular attention in economics are resource allocation, production, distribution, trade, and competition. Economic logic is increasingly applied to any problem that involves choice under scarcity or determining economic value. Mainstream economics focuses on how prices reflect supply and demand, and uses equations to predict consequences of decisions. | Human
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Humans, or human beings, are bipedal primates belonging to the mammalian species Homo sapiens (Latin: "wise human" or "knowing human"[2]) in the family Hominidae (the great apes).[3][4] DNA evidence indicates that modern humans originated in Africa about 200,000 years ago.[5] Compared to other species, humans have a highly developed brain, capable of abstract reasoning, language, introspection, and emotional suffering. This mental capability, combined with an erect body carriage that frees the forelimbs (arms) for manipulating objects, has allowed humans to make far greater use of tools than any other species. Humans now inhabit every continent on Earth, except Antarctica (although several governments maintain permanent research stations there, inhabited for short periods by scientists and other researchers). Humans also now have a continuous presence in low Earth orbit, occupying the International Space Station. The human population on Earth now amounts to over 6.6 billion, as of May 2008.[6]
Like most primates, humans are social by nature. However, they are particularly adept at utilizing systems of communication for self-expression, exchanging of ideas, and organization. Humans create complex social structures composed of many cooperating and competing groups, from families to nations. Social interactions between humans have established an extremely wide variety of traditions, rituals, ethics, values, social norms, and laws, which together form the basis of human society. Humans have a marked appreciation for beauty and aesthetics, which, combined with the desire for self-expression, has led to cultural innovations such as art, literature and music.
Humans are notable for their desire to understand and influence the world around them, seeking to explain and manipulate natural phenomena through science, philosophy, mythology and religion. This natural curiosity has led to the development of advanced tools and skills; humans are the only extant species known to build fires, cook their food, clothe themselves, and manipulate and develop numerous other technologies. Humans pass down their skills and knowledge to the next generations through education whether it is formal or informal.
# History
## Origin
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The scientific study of human evolution encompasses the development of the genus Homo, but usually involves studying other hominids and hominines as well, such as Australopithecus. "Modern humans" are defined as the Homo sapiens species, of which the only extant subspecies - our own - was formerly known as Homo sapiens sapiens (now simply known as Homo sapiens). Homo sapiens idaltu (roughly translated as "elder wise human"), the other known subspecies, is now extinct.[7] Anatomically modern humans first appear in the fossil record in Africa about 200,000 years ago.[8][9]
The closest living relatives of Homo sapiens are the two chimpanzee species: the Common Chimpanzee and the Bonobo. Full genome sequencing has resulted in the conclusion that "after 6.5 [million] years of separate evolution, the differences between chimpanzee and human are just 10 times greater than those between two unrelated people and 10 times less than those between rats and mice". Suggested differences between human and chimpanzee DNA sequences range between 95% and 99%.[10][11][12][13] It has been estimated that the human lineage diverged from that of chimpanzees about five million years ago, and from that of gorillas about eight million years ago. However, a hominid skull discovered in Chad in 2001, classified as Sahelanthropus tchadensis, is approximately seven million years old, which may indicate an earlier divergence.[14]
The Recent African Origin (RAO), or "out-of-Africa", hypothesis proposes that modern humans evolved in Africa before later migrating outwards to replace hominids in other parts of the world. Evidence from archaeogenetics accumulating since the 1990s has lent strong support to RAO, and has marginalized the competing multiregional hypothesis, which proposed that modern humans evolved, at least in part, from independent hominid populations.[15] Geneticists Lynn Jorde and Henry Harpending of the University of Utah propose that the variation in human DNA is minute compared to that of other species. They also propose that during the Late Pleistocene, the human population was reduced to a small number of breeding pairs – no more than 10,000, and possibly as few as 1,000 – resulting in a very small residual gene pool. Various reasons for this hypothetical bottleneck have been postulated, one being the Toba catastrophe theory.
Human evolution is characterized by a number of important morphological, developmental, physiological and behavioural changes, which have taken place since the split between the last common ancestor of humans and chimpanzees. The first major morphological change was the evolution of a bipedal locomotor adaptation from an arboreal or semi-arboreal one,[16] with all its attendant adaptations, such as a valgus knee, low intermembral index (long legs relative to the arms), and reduced upper-body strength.
Later, ancestral humans developed a much larger brain – typically 1,400 cm³ in modern humans, over twice the size of that of a chimpanzee or gorilla. The pattern of human postnatal brain growth differs from that of other apes (heterochrony), and allows for extended periods of social learning and language acquisition in juvenile humans. Physical anthropologists argue that the differences between the structure of human brains and those of other apes are even more significant than their differences in size.
Other significant morphological changes included: the evolution of a power and precision grip;[17] a reduced masticatory system; a reduction of the canine tooth; and the descent of the larynx and hyoid bone, making speech possible. An important physiological change in humans was the evolution of hidden oestrus, or concealed ovulation, which may have coincided with the evolution of important behavioural changes, such as pair bonding. Another significant behavioural change was the development of material culture, with human-made objects becoming increasingly common and diversified over time. The relationship between all these changes is the subject of ongoing debate.[18][19]
## Rise of civilization
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The most widely accepted view among current anthropologists is that Homo sapiens originated in the African savanna around 200,000 BP (Before Present), descending from Homo erectus, had inhabited Eurasia and Oceania by 40,000 BP, and finally inhabited the Americas approximately 14,500 years ago.[20] They displaced Homo neanderthalensis and other species descended from Homo erectus (which had inhabited Eurasia as early as 2 million years ago) through more successful reproduction and competition for resources.
Until c. 10,000 years ago, most humans lived as hunter-gatherers. They generally lived in small nomadic groups known as band societies. The advent of agriculture prompted the Neolithic Revolution, when access to food surplus led to the formation of permanent human settlements, the domestication of animals and the use of metal tools. Agriculture encouraged trade and cooperation, and led to complex society. Because of the significance of this date for human society, it is the epoch of the Holocene calendar or Human Era.
About 6,000 years ago, the first proto-states developed in Mesopotamia, Egypt and the Indus Valley. Military forces were formed for protection, and government bureaucracies for administration. States cooperated and competed for resources, in some cases waging wars. Around 2,000–3,000 years ago, some states, such as Persia, India, China and Rome, developed through conquest into the first expansive empires. Influential religions, such as Judaism, originating in the Middle East, and Hinduism, a religious tradition that originated in South Asia, also rose to prominence at this time.
The late Middle Ages saw the rise of revolutionary ideas and technologies. In China, an advanced and urbanized economy promoted innovations such as printing and the compass, while the Islamic Golden Age saw major scientific advancements in Muslim empires. In Europe, the rediscovery of classical learning and inventions such as the printing press led to the Renaissance in the 14th century. Over the next 500 years, exploration and imperialistic conquest brought much of the Americas, Asia, and Africa under European control, leading to later struggles for independence. The Scientific Revolution in the 17th century and the Industrial Revolution in the 18th – 19th centuries promoted major innovations in transport, such as the railway and automobile; energy development, such as coal and electricity; and government, such as representative democracy and Communism.
As a result of such changes, modern humans live in a world that has become increasingly globalized and interconnected. Although this has encouraged the growth of science, art, and technology, it has also led to culture clashes, the development and use of weapons of mass destruction, and increased environmental destruction and pollution, affecting not only themselves but also most other life forms on the planet.
# Habitat and population
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Early human settlements were dependent on proximity to water and, depending on the lifestyle, other natural resources, such as fertile land for growing crops and grazing livestock, or seasonally by hunting populations of prey. However, humans have a great capacity for altering their habitats by various methods, such as through irrigation, urban planning, construction, transport, manufacturing goods, deforestation and desertification. With the advent of large-scale trade and transport infrastructure, proximity to these resources has become unnecessary, and in many places these factors are no longer a driving force behind the growth and decline of a population. Nonetheless, the manner in which a habitat is altered is often a major determinant in population change.
Technology has allowed humans to colonize all of the continents and adapt to all climates. Within the last few decades, humans have explored Antarctica, the ocean depths, and space, although long-term habitation of these environments is not yet possible. With a population of over six billion, humans are among the most numerous of the large mammals. Most humans (61%) live in Asia. The vast majority of the remainder live in the Americas (14%), Africa (14%) and Europe (11%), with 0.5% in Oceania.
Human habitation within closed ecological systems in hostile environments, such as Antarctica and outer space, is expensive, typically limited in duration, and restricted to scientific, military, or industrial expeditions. Life in space has been very sporadic, with no more than thirteen humans in space at any given time. Between 1969 and 1972, two humans at a time spent brief intervals on the Moon. As of early 2008, no other celestial body has been visited by human beings, although there has been a continuous human presence in space since the launch of the initial crew to inhabit the International Space Station on October 31, 2000. Other celestial bodies have, however, been visited by human-made objects.
Since 1800, the human population increased from one billion to over six billion.[21] In 2004, some 2.5 billion out of 6.3 billion people (39.7%) lived in urban areas, and this percentage is expected to rise throughout the 21st century. Problems for humans living in cities include various forms of pollution and crime,[22] especially in inner city and suburban slums. Benefits of urban living include increased literacy, access to the global canon of human knowledge and decreased susceptibility to rural famines.
Humans have had a dramatic effect on the environment. It has been hypothesized that human predation has contributed to the extinction of numerous species. As humans stand at the top of the food chain and are not generally preyed upon, they have been described as superpredators.[23] Currently, through land development and pollution, humans are thought to be the main contributor to global climate change.[24] This is believed to be a major contributor to the ongoing Holocene extinction event, a mass extinction which, if it continues at its current rate, is predicted to wipe out half of all species over the next century.[25][26]
# Biology
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## Physiology and genetics
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Human body types vary substantially. Although body size is largely determined by genes, it is also significantly influenced by environmental factors such as diet and exercise. The average height of an adult human is about 1.5 to 1.8 m (5 to 6 feet) tall, although this varies significantly from place to place.[27][28] Unlike most other primates, humans are capable of fully bipedal locomotion, thus leaving their arms available for manipulating objects using their hands, aided especially by opposable thumbs.
Although humans appear relatively hairless compared to other primates, with notable hair growth occurring chiefly on the top of the head, underarms and pubic area, the average human has more hair follicles on his or her body than the average chimpanzee. The main distinction is that human hairs are shorter, finer, and less heavily pigmented than the average chimpanzee's, thus making them harder to see.[29]
The hue of human hair and skin is determined by the presence of pigments called melanins. Human skin hues can range from very dark brown to very pale pink, while human hair ranges from blond to brown to red to, most commonly, black,[30] depending on the amount of melanin (an effective sun blocking pigment) in the skin. Most researchers believe that skin darkening was an adaptation that evolved as a protection against ultraviolet solar radiation. More recently, however, it has been argued that particular skin colors are an adaptation to balance folate, which is destroyed by ultraviolet radiation, and vitamin D, which requires sunlight to form.[31] The skin pigmentation of contemporary humans is geographically stratified, and in general correlates with the level of ultraviolet radiation. Human skin also has a capacity to darken (sun tanning) in response to exposure to ultraviolet radiation.[32][33] Humans tend to be physically weaker than other similairly sized primates, with young, conditioned male humans having been shown to be unable to match the strength of female orangutans which are at least three times stronger.[34]
Humans have proportionately shorter palates and much smaller teeth than other primates. They are the only primates to have short 'flush' canine teeth. Humans have characteristically crowded teeth, with gaps from lost teeth usually closing up quickly in young specimens. Humans are gradually losing their wisdom teeth, with some individuals having them congenitally absent.[35]
The average sleep requirement is between seven and eight hours a day for an adult and nine to ten hours for a child; elderly people usually sleep for six to seven hours. Experiencing less sleep than this is common in modern societies; this sleep deprivation can lead to negative effects. A sustained restriction of adult sleep to four hours per day has been shown to correlate with changes in physiology and mental state, including fatigue, aggression, and bodily discomfort.
Humans are an eukaryotic species. Each diploid cell has two sets of 23 chromosomes, each set received from one parent. There are 22 pairs of autosomes and one pair of sex chromosomes. By present estimates, humans have approximately 20,000 – 25,000 genes. Like other mammals, humans have an XY sex-determination system, so that females have the sex chromosomes XX and males have XY. The X chromosome is larger and carries many genes not on the Y chromosome, which means that recessive diseases associated with X-linked genes, such as hemophilia, affect men more often than women.
## Life cycle
The human life cycle is similar to that of other placental mammals. The fertilized egg divides inside the female's uterus to become an embryo, which over a period of thirty-eight weeks (9 months) of gestation becomes a human fetus. After this span of time, the fully-grown fetus is birthed from the woman's body and breathes independently as an infant for the first time. At this point, most modern cultures recognize the baby as a person entitled to the full protection of the law, though some jurisdictions extend personhood earlier to human fetuses while they remain in the uterus.
Compared with other species, human childbirth is dangerous. Painful labors lasting twenty-four hours or more are not uncommon and often leads to the death of the mother, or the child.[36] This is because of both the relatively large fetal head circumference (for housing the brain) and the mother's relatively narrow pelvis (a trait required for successful bipedalism, by way of natural selection).[37][38] The chances of a successful labor increased significantly during the 20th century in wealthier countries with the advent of new medical technologies. In contrast, pregnancy and natural childbirth remain relatively hazardous ordeals in developing regions of the world, with maternal death rates approximately 100 times more common than in developed countries.[39]
In developed countries, infants are typically 3 – 4 kg (6 – 9 pounds) in weight and 50 – 60 cm (20 – 24 inches) in height at birth.[41] However, low birth weight is common in developing countries, and contributes to the high levels of infant mortality in these regions.[42] Helpless at birth, humans continue to grow for some years, typically reaching sexual maturity at 12 to 15 years of age. Females continue to develop physically until around the age of 18, whereas male development continues until around age 21. The human life span can be split into a number of stages: infancy, childhood, adolescence, young adulthood, adulthood and old age. The lengths of these stages, however, have varied across cultures and time periods. Compared to other primates, humans experience an unusually rapid growth spurt during adolescence, where the body grows 25% in size. Chimpanzees, for example, grow only 14%.[43]
There are significant differences in life expectancy around the world. The developed world generally aging, with the median age around 40 years (highest in Monaco at 45.1 years). In the developing world the median age is between 15 and 20 years. Life expectancy at birth in Hong Kong, China is 84.8 years for a female and 78.9 for a male, while in Swaziland, primarily because of AIDS, it is 31.3 years for both sexes.[44] While one in five Europeans is 60 years of age or older, only one in twenty Africans is 60 years of age or older.[45] The number of centenarians (humans of age 100 years or older) in the world was estimated by the United Nations at 210,000 in 2002.[46] At least one person, Jeanne Calment, is known to have reached the age of 122 years; higher ages have been claimed but they are not well substantiated. Worldwide, there are 81 men aged 60 or older for every 100 women of that age group, and among the oldest, there are 53 men for every 100 women.
Humans are unique in the widespread onset of female menopause during the latter stage of life. Menopause is believed to have arisen due to the Grandmother hypothesis, in which it is in the mother's reproductive interest to forgo the risks of death from childbirth at older ages in exchange for investing in the viability of her already living offspring.[47]
The philosophical questions of when human personhood begins and whether it persists after death are the subject of considerable debate. The prospect of death causes unease or fear for most humans, distinct from the immediate awareness of a threat. Burial ceremonies are characteristic of human societies, often accompanied by beliefs in an afterlife or immortality.
## Diet
Early Homo sapiens employed a hunter-gatherer method as their primary means of food collection, involving combining stationary plant and fungal food sources (such as fruits, grains, tubers, and mushrooms) with wild game, which must be hunted and killed in order to be consumed. It is believed that humans have used fire to prepare and cook food prior to eating since the time of their divergence from Homo erectus.
Humans are omnivorous, capable of consuming both plant and animal products. A view of humans as omnivores is supported by the evidence that both a pure animal and a pure vegetable diet can lead to deficiency diseases in humans. A pure animal diet can, for instance, lead to scurvy, a vitamin C deficiency, while a pure plant diet may lead to vitamin B12 deficiency.[48] The biggest problem posed by a vitamin B12 deficiency is that it severely limits the body's ability to synthesize folic acid, a main source of B group carriage. In order to counter the constant folic acid deficiency, one must regularly consume large amounts of folic acid, as may be found in green, leafy vegetables. Properly planned vegetarian and vegan diets, however, have been found to completely satisfy nutritional needs in every stage of life. [49]
The human diet is prominently reflected in human culture, and has led to the development of food science.
In general, humans can survive for two to eight weeks without food, depending on stored body fat. Survival without water is usually limited to three or four days. Lack of food remains a serious problem, with about 300,000 people starving to death every year.[50] Childhood malnutrition is also common and contributes to the global burden of disease.[51] However global food distribution is not even, and obesity among some human populations has increased to almost epidemic proportions, leading to health complications and increased mortality in some developed, and a few developing countries. The United States Centers for Disease Control (CDC) state that 32% of American adults over the age of 20 are obese, while 66.5% are obese or overweight. Obesity is caused by consuming more calories than are expended, with many attributing excessive weight gain to a combination of overeating and insufficient exercise.
At least ten thousand years ago, humans developed agriculture,[52] which has substantially altered the kind of food people eat. This has led to increased populations, the development of cities, and because of increased population density, the wider spread of infectious diseases. The types of food consumed, and the way in which they are prepared, has varied widely by time, location, and culture.
# Psychology
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The human brain is the center of the central nervous system in humans, and acts as the primary control center for the peripheral nervous system. The brain controls "lower", or involuntary, autonomic activities such as the respiration, and digestion. The brain also controls "higher" order, conscious activities, such as thought, reasoning, and abstraction.[53] These cognitive processes constitute the mind, and, along with their behavioral consequences, are studied in the field of psychology.
Generally regarded as more capable of these higher order activities, the human brain is believed to be more "intelligent" in general than that of any other known species. While many animals are capable of creating structures and using simple tools — mostly through instinct and mimicry — human technology is vastly more complex, and is constantly evolving and improving through time. Even the most ancient human tools and structures are far more advanced than any structure or tool created by any other animal.[54] Modern anthropology has tended to bear out Darwin's proposition that "the difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind".[55]
## Consciousness and thought
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The human ability to think abstractly may be unparalleled in the animal kingdom. Humans are one of only six species to pass the mirror test — which tests whether an animal recognizes its reflection as an image of itself — along with chimpanzees, orangutans, dolphins, and pigeons.[56] In October 2006, three elephants at the Bronx Zoo also passed this test.[57] Most human children will pass the mirror test at 18 months old.[58] However, the usefulness of this test as a true test of consciousness has been disputed (see mirror test), and this may be a matter of degree rather than a sharp divide. Monkeys have been trained to apply abstract rules in tasks.[59] The human brain perceives the external world through the senses, and each individual human is influenced greatly by his or her experiences, leading to subjective views of existence and the passage of time. Humans are variously said to possess consciousness, self-awareness, and a mind, which correspond roughly to the mental processes of thought. These are said to possess qualities such as self-awareness, sentience, sapience, and the ability to perceive the relationship between oneself and one's environment. The extent to which the mind constructs or experiences the outer world is a matter of debate, as are the definitions and validity of many of the terms used above. The philosopher of cognitive science Daniel Dennett, for example, argues that there is no such thing as a narrative centre called the "mind", but that instead there is simply a collection of sensory inputs and outputs: different kinds of "software" running in parallel.[60] Psychologist B.F. Skinner has argued that the mind is an explanatory fiction that diverts attention from environmental causes of behavior,[61] and that what are commonly seen as mental processes may be better conceived of as forms of covert verbal behavior.[62]
Humans study the more physical aspects of the mind and brain, and by extension of the nervous system, in the field of neurology, the more behavioral in the field of psychology, and a sometimes loosely-defined area between in the field of psychiatry, which treats mental illness and behavioral disorders. Psychology does not necessarily refer to the brain or nervous system, and can be framed purely in terms of phenomenological or information processing theories of the mind. Increasingly, however, an understanding of brain functions is being included in psychological theory and practice, particularly in areas such as artificial intelligence, neuropsychology, and cognitive neuroscience.
The nature of thought is central to psychology and related fields. Cognitive psychology studies cognition, the mental processes underlying behavior. It uses information processing as a framework for understanding the mind. Perception, learning, problem solving, memory, attention, language and emotion are all well-researched areas as well. Cognitive psychology is associated with a school of thought known as cognitivism, whose adherents argue for an information processing model of mental function, informed by positivism and experimental psychology. Techniques and models from cognitive psychology are widely applied and form the mainstay of psychological theories in many areas of both research and applied psychology. Largely focusing on the development of the human mind through the life span, developmental psychology seeks to understand how people come to perceive, understand, and act within the world and how these processes change as they age. This may focus on intellectual, cognitive, neural, social, or moral development.
Some philosophers divide consciousness into phenomenal consciousness, which is experience itself, and access consciousness, which is the processing of the things in experience.[63] Phenomenal consciousness is the state of being conscious, such as when they say "I am conscious." Access consciousness is being conscious of something in relation to abstract concepts, such as when one says "I am conscious of these words." Various forms of access consciousness include awareness, self-awareness, conscience, stream of consciousness, Husserl's phenomenology, and intentionality. The concept of phenomenal consciousness, in modern history, according to some, is closely related to the concept of qualia. Social psychology links sociology with psychology in their shared study of the nature and causes of human social interaction, with an emphasis on how people think towards each other and how they relate to each other. The behavior and mental processes, both human and non-human, can be described through animal cognition, ethology, evolutionary psychology, and comparative psychology as well. Human ecology is an academic discipline that investigates how humans and human societies interact with both their natural environment and the human social environment.
## Motivation and emotion
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Motivation is the driving force of desire behind all deliberate actions of human beings. Motivation is based on emotion — specifically, on the search for satisfaction (positive emotional experiences), and the avoidance of conflict. Positive and negative is defined by the individual brain state, which may be influenced by social norms: a person may be driven to self-injury or violence because their brain is conditioned to create a positive response to these actions. Motivation is important because it is involved in the performance of all learned responses. Within psychology, conflict avoidance and the libido are seen to be primary motivators. Within economics motivation is often seen to be based on financial incentives, moral incentives, or coercive incentives. Religions generally posit divine or demonic influences.
Happiness, or the state of being happy, is a human emotional condition. The definition of happiness is a common philosophical topic. Some people might define it as the best condition which a human can have — a condition of mental and physical health. Others define it as freedom from want and distress; consciousness of the good order of things; assurance of one's place in the universe or society.
Emotion has a significant influence on, or can even be said to control, human behavior, though historically many cultures and philosophers have for various reasons discouraged allowing this influence to go unchecked. Emotional experiences perceived as pleasant, such as love, admiration, or joy, contrast with those perceived as unpleasant, like hate, envy, or sorrow. There is often a distinction made between refined emotions which are socially learned and survival oriented emotions, which are thought to be innate. Human exploration of emotions as separate from other neurological phenomena is worthy of note, particularly in cultures where emotion is considered separate from physiological state. In some cultural medical theories emotion is considered so synonymous with certain forms of physical health that no difference is thought to exist. The Stoics believed excessive emotion was harmful, while some Sufi teachers (in particular, the poet and astronomer Omar Khayyám) felt certain extreme emotions could yield a conceptual perfection, what is often translated as ecstasy.
In modern scientific thought, certain refined emotions are considered to be a complex neural trait innate in a variety of domesticated and on-domesticated mammals. These were commonly developed in reaction to superior survival mechanisms and intelligent interaction with each other and the environment; as such, refined emotion is not in all cases as discrete and separate from natural neural function as was once assumed. However, when humans function in civilized tandem, it has been noted that uninhibited acting on extreme emotion can lead to social disorder and crime.
## Sexuality and love
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Human sexuality, besides ensuring biological reproduction, has important social functions: it creates physical intimacy, bonds, and hierarchies among individuals; may be directed to spiritual transcendence (according to some traditions); and in a hedonistic sense to the enjoyment of activity involving sexual gratification. Sexual desire, or libido, is experienced as a bodily urge, often accompanied by strong emotions such as love, ecstasy and jealousy. The extreme importance of sexuality in the human species can be seen in a number of physical features, among them hidden ovulation, strong sexual dimorphism when compared to the chimpanzees, permanent secondary sexual characteristics, the forming of pair bonds based on sexual attraction as a common social structure and sexual ability in females outside of ovulation. These adaptations indicate that the importance of sexuality in humans is on par with that found in the Bonobo, and that the complex human sexual behaviour has a long evolutionary history.
As with other human self-descriptions, humans propose that it is high intelligence and complex societies of humans that have produced the most complex sexual behaviors of any animal, including a great many behaviors that are not directly connected with reproduction.
Human sexual choices are usually made in reference to cultural norms, which vary widely. Restrictions are sometimes determined by religious beliefs or social customs. The pioneering researcher Sigmund Freud believed that humans are born polymorphously perverse, which means that any number of objects could be a source of pleasure. According to Freud, humans then pass through five stages of psychosexual development (and can fixate on any stage because of various traumas during the process). For Alfred Kinsey, another influential sex researcher, people can fall anywhere along a continuous scale of sexual orientation (with only small minorities fully heterosexual or homosexual). Recent studies of neurology and genetics suggest people may be born with one sexual orientation or another, so there is not currently a clear consensus among sex researchers.[64][65]
# Culture
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Culture is defined here as a set of distinctive material, intellectual, emotional, and spiritual features of a social group, including art, literature, lifestyles, value systems, traditions, rituals, and beliefs. The link between human biology and human behavior and culture is often very close, making it difficult to clearly divide topics into one area or the other; as such, the placement of some subjects may be based primarily on convention. Culture consists of values, social norms, and artifacts. A culture's values define what it holds to be important or ethical. Closely linked are norms, expectations of how people ought to behave, bound by tradition. Artifacts, or material culture, are objects derived from the culture's values, norms, and understanding of the world. The mainstream anthropological view of culture implies that most experience a strong resistance when reminded that there is an animal as well as a spiritual aspect to human nature.[55]
## Language
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The capacity humans have to transfer concepts, ideas and notions through speech and writing is unrivaled in known species. Unlike the call systems of other primates which are closed, human language is far more open, and gains variety in different situations. The human language has the quality of displacement, using words to represent things and happenings that are not presently or locally occurring, but elsewhere or at a different time.[35] Technology has even advanced so as to allow the communication of mass data upon request and over great distance through data-nets and programs such as Wikipedia. In this way data networks are important to the continuing development of language; changing it as just as Gutenberg did with the printing press. The faculty of speech is a defining feature of humanity, possibly predating phylogenetic separation of the modern population. Language is central to the communication between humans, as well as being central to the sense of identity that unites nations, cultures and ethnic groups. The invention of writing systems at least 5,000 years ago allowed the preservation of language on material objects, and was a major step in cultural evolution. Language is closely tied to ritual and religion (cf. mantra, sacred text). The science of linguistics describes the structure of language and the relationship between languages. There are approximately 6,000 different languages currently in use, including sign languages, and many thousands more that are considered extinct.
## Spirituality and religion
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Religion—sometimes used interchangeably with "faith"—is generally defined as a belief system concerning the supernatural, sacred or divine, and moral codes, practices, values, institutions and rituals associated with such belief. In the course of its development, religion has taken on many forms that vary by culture and individual perspective. Some of the chief questions and issues religions are concerned with include life after death (commonly involving belief in an afterlife), the origin of life (the source of a variety of creation myths), the nature of the universe (religious cosmology) and its ultimate fate (eschatology), and what is moral or immoral. A common source in religions for answers to these questions are transcendent divine beings such as deities or a singular God, although not all religions are theistic — many are nontheistic or ambiguous on the topic, particularly among the Eastern religions. Spirituality, belief or involvement in matters of the soul or spirit, is one of the many different approaches humans take in trying to answer fundamental questions about humankind's place in the universe, the meaning of life, and the ideal way to live one's life. Though these topics have also been addressed by philosophy, and to some extent by science, spirituality is unique in that it focuses on mystical or supernatural concepts such as karma and God.
Although a majority of humans profess some variety of religious or spiritual belief, some are irreligious, that is lacking or rejecting belief in the supernatural or spiritual. Additionally, although most religions and spiritual beliefs are clearly distinct from science on both a philosophical and methodological level, the two are not generally considered to be mutually exclusive; a majority of humans hold a mix of both scientific and religious views. The distinction between philosophy and religion, on the other hand, is at times less clear, and the two are linked in such fields as the philosophy of religion and theology. Other humans have no religious beliefs and are atheists, scientific skeptics, agnostics or simply non-religious.
## Philosophy and self-reflection
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Philosophy is a discipline or field of study involving the investigation, analysis, and development of ideas at a general, abstract, or fundamental level. It is the discipline searching for a general understanding of values and reality by chiefly speculative means. The core philosophical disciplines are logic, ontology or metaphysics, epistemology, and axiology, which includes the branches of ethics and aesthetics. Philosophy covers a very wide range of approaches, and is also used to refer to a worldview, to a perspective on an issue, or to the positions argued for by a particular philosopher or school of philosophy.
Metaphysics is a branch of philosophy concerned with the study of first principles, being and existence (ontology). In between the doctrines of religion and science, stands the philosophical perspective of metaphysical cosmology. This ancient field of study seeks to draw logical conclusions about the nature of the universe, humanity, god, and/or their connections based on the extension of some set of presumed facts borrowed from religion and/or observation. Humans often consider themselves to be the dominant species on Earth, and the most advanced in intelligence and ability to manage their environment. This belief is especially strong in modern Western culture. Alongside such claims of dominance is often found radical pessimism because of the frailty and brevity of human life.
Humanism is a philosophy which defines a socio-political doctrine the bounds of which are not constrained by those of locally developed cultures, but which seeks to include all of humanity and all issues common to human beings. Because spiritual beliefs of a community often manifests as religious doctrine, the history of which is as factious as it is unitive, secular humanism grew as an answer to the need for a common philosophy that transcended the cultural boundaries of local moral codes and religions. Many humanists are religious, however, and see humanism as simply a mature expression of a common truth present in most religions. Humanists affirm the possibility of an objective truth and accept that human perception of that truth is imperfect. The most basic tenets of humanism are that humans matter and can solve human problems, and that science, freedom of speech, rational thought, democracy, and freedom in the arts are worthy pursuits or goals for all peoples. Humanism depends chiefly on reason and logic without consideration for the supernatural.
## Art, music, and literature
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Artistic works have existed for almost as long as humankind, from early pre-historic art to contemporary art. Art is one of the most unusual aspects of human behavior and a key distinguishing feature of humans from other species, In fact the only species to do so. Art has only been around for the last 35,000 years which could suggest that this was the time when humans started to 'think'.
As a form of cultural expression by humans, art may be defined by the pursuit of diversity and the usage of narratives of liberation and exploration (i.e. art history, art criticism, and art theory) to mediate its boundaries. This distinction may be applied to objects or performances, current or historical, and its prestige extends to those who made, found, exhibit, or own them. In the modern use of the word, art is commonly understood to be the process or result of making material works which, from concept to creation, adhere to the "creative impulse" of human beings. Art is distinguished from other works by being in large part unprompted by necessity, by biological drive, or by any undisciplined pursuit of recreation.
Music is a natural intuitive phenomenon based on the three distinct and interrelated organization structures of rhythm, harmony, and melody. Listening to music is perhaps the most common and universal form of entertainment for humans, while learning and understanding it are popular disciplines. There are a wide variety of music genres and ethnic musics. Literature, the body of written — and possibly oral — works, especially creative ones, includes prose, poetry and drama, both fiction and non-fiction. Literature includes such genres as epic, legend, myth, ballad, and folklore.
## Science and technology
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Science is the discovery of knowledge about the world by verifiable means. Technology is the objects humans make to serve their purposes. Human cultures are both characterized and differentiated by the objects that they make and use. Archaeology attempts to tell the story of past or lost cultures in part by close examination of the artifacts they produced. Early humans left stone tools, pottery and jewelry that are particular to various regions and times. Improvements in technology are passed from one culture to another. For instance, the cultivation of crops arose in several different locations, but quickly spread to be an almost ubiquitous feature of human life. Similarly, advances in weapons, architecture and metallurgy are quickly disseminated.
Although such techniques can be passed on by oral tradition, the development of writing, itself a kind of technology, made it possible to pass information from generation to generation and from region to region with greater accuracy. Together, these developments made possible the commencement of civilization and urbanization, with their inherently complex social arrangements. Eventually this led to the institutionalization of the development of new technology, and the associated understanding of the way the world functions. This science now forms a central part of human culture. In recent times, physics and astrophysics have come to play a central role in shaping what is now known as physical cosmology, that is, the understanding of the universe through scientific observation and experiment. This discipline, which focuses on the universe as it exists on the largest scales and at the earliest times, begins by arguing for the big bang, a sort of cosmic expansion from which the universe itself is said to have erupted ~13.7 ± 0.2 billion (109) years ago. After its violent beginnings and until its very end, scientists then propose that the entire history of the universe has been an orderly progression governed by physical laws.
## Race and ethnicity
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Humans often categorize themselves in terms of race or ethnicity, although the validity of human races as true biological categories is questionable.[66] Human racial categories are based on both ancestry and visible traits, especially skin color and facial features. These categories may also carry some information on non-visible biological traits, such as the risk of developing particular diseases such as sickle-cell disease.[67] Currently available genetic and archaeological evidence is generally interpreted as supportive of a recent single origin of modern humans in East Africa.[68] Current genetic studies have demonstrated that humans on the African continent are most genetically diverse.[69] However, compared to many other animals, human gene sequences are remarkably homogeneous.[70][71][72][73] It has been repeatedly demonstrated that the great majority of genetic variation occurs within "racial groups", with only 5 to 15% of total variation occurring between racial groups.[74] However, this remains an area of active debate.[75][76]
Ethnic groups, on the other hand, are more often linked by linguistic, cultural, ancestral, and national or regional ties. Self-identification with an ethnic group is based on kinship and descent. Race and ethnicity can lead to variant treatment and impact social identity, giving rise to racism and the theory of identity politics.
## Society, government, and politics
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Society is the system of organizations and institutions arising from interaction between humans. A state is an organized political community occupying a definite territory, having an organized government, and possessing internal and external sovereignty. Recognition of the state's claim to independence by other states, enabling it to enter into international agreements, is often important to the establishment of its statehood. The "state" can also be defined in terms of domestic conditions, specifically, as conceptualized by Max Weber, "a state is a human community that (successfully) claims the monopoly of the 'legitimate' use of physical force within a given territory."[77]
Government can be defined as the political means of creating and enforcing laws; typically via a bureaucratic hierarchy. Politics is the process by which decisions are made within groups. Although the term is generally applied to behavior within governments, politics is also observed in all human group interactions, including corporate, academic, and religious institutions. Many different political systems exist, as do many different ways of understanding them, and many definitions overlap. The most common form of government worldwide is a republic, however other examples include monarchy, social democracy, military dictatorship and theocracy. All of these issues have a direct relationship with economics.
## War
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War is a state of widespread conflict between states, organizations, or relatively large groups of people, which is characterized by the use of lethal violence between combatants or upon civilians. It is estimated that during the 20th century between 167 and 188 million humans died as a result of war.[78] A common perception of war is a series of military campaigns between at least two opposing sides involving a dispute over sovereignty, territory, resources, religion or other issues. A war said to liberate an occupied country is sometimes characterized as a "war of liberation", while a war between internal elements of a state is a civil war. Full scale pitched-battle wars between adversaries of comparable strength appear to have nearly disappeared from human activity, with the last major one in the Congo region winding down in the late 1990s. Nearly all war now is asymmetric warfare, in which campaigns of sabotage, guerrilla warfare and sometimes acts of terrorism disrupt control and supply of better-equipped occupying forces, resulting in long low-intensity wars of attrition.
War is one of the main catalysts for human advances in technology. Throughout human history there has been a constant struggle between defense and offence, including the technologies behind armour and weapons designed to penetrate it. Modern examples include the bunker buster bomb and the bunkers which they are designed to destroy. Important inventions such as medicine, navigation, metallurgy, mass production, nuclear power, rocketry and computers have been completely or partially driven by war.
There have been a wide variety of rapidly advancing tactics throughout the history of war, ranging from conventional war to asymmetric warfare to total war and unconventional warfare. Techniques include hand to hand combat, the use of ranged weapons, and ethnic cleansing. Military intelligence has often played a key role in determining victory and defeat. Propaganda, which often includes factual information, slanted opinion and disinformation, plays a key role in maintaining unity within a warring group, and/or sowing discord among opponents. In modern warfare, soldiers and armoured fighting vehicles are used to control the land, warships the sea, and air power the sky. These fields have also overlapped in the forms of marines, paratroopers, naval aircraft carriers, and surface-to-air missiles, among others. Satellites in low Earth orbit have made outer space a factor in warfare as well, although no actual warfare is currently carried out in space.
## Trade and economics
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Trade is the voluntary exchange of goods, services and a form of economics. A mechanism that allows trade is called a market. The original form of trade was barter, the direct exchange of goods and services. Modern traders instead generally negotiate through a medium of exchange, such as money. As a result, buying can be separated from selling, or earning. The invention of money (and later credit, paper money and non-physical money) greatly simplified and promoted trade. Because of specialization and division of labor, most people concentrate on a small aspect of manufacturing or service, trading their labour for products. Trade exists between regions because different regions have an absolute or comparative advantage in the production of some tradeable commodity, or because different regions' size allows for the benefits of mass production.
Economics is a social science which studies the production, distribution, trade and consumption of goods and services. Economics focuses on measurable variables, and is broadly divided into two main branches: microeconomics, which deals with individual agents, such as households and businesses, and macroeconomics, which considers the economy as a whole, in which case it considers aggregate supply and demand for money, capital and commodities. Aspects receiving particular attention in economics are resource allocation, production, distribution, trade, and competition. Economic logic is increasingly applied to any problem that involves choice under scarcity or determining economic value. Mainstream economics focuses on how prices reflect supply and demand, and uses equations to predict consequences of decisions. | https://www.wikidoc.org/index.php/H._sapiens | |
7589c32326098fc8cfc7b9b8fa26354374fcad61 | wikidoc | H2AFZ | H2AFZ
Histone H2A.Z is a protein that in humans is encoded by the H2AFZ gene.
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. The H2AFZ gene encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality.
Histone H2AZ is a variant of histone H2A, and is used to mediate the thermosensory response, and is essential to perceive the ambient temperature. Nucleosome occupancy of H2A.Z decreases with temperature, and in vitro assays show that H2A.Z-containing nucleosomes wrap DNA more tightly than canonical H2A nucleosomes in Arabidopsis.(Cell 140: 136–147, 2010) However, in some of the other studies (Nat. Genet. 41, 941–945 and Genes Dev., 21, 1519–1529) have shown that incorporation of H2A.Z in nucleosomes, when it co-occurs with H3.3, makes them weaker. Positioning of H2A.Z containing nucleosomes around transcription start sites has now been shown to affect the downstream gene expression.
Recent evidence also points to a role for H2A.Z in repressing a subset of ncRNAs, derepressing CUTs, as well as mediation higher order chromatin structure formation. | H2AFZ
Histone H2A.Z is a protein that in humans is encoded by the H2AFZ gene.[1][2]
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. The H2AFZ gene encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality.[2]
Histone H2AZ is a variant of histone H2A, and is used to mediate the thermosensory response, and is essential to perceive the ambient temperature. Nucleosome occupancy of H2A.Z decreases with temperature, and in vitro assays show that H2A.Z-containing nucleosomes wrap DNA more tightly than canonical H2A nucleosomes in Arabidopsis.(Cell 140: 136–147, 2010) However, in some of the other studies (Nat. Genet. 41, 941–945 and Genes Dev., 21, 1519–1529) have shown that incorporation of H2A.Z in nucleosomes, when it co-occurs with H3.3, makes them weaker. Positioning of H2A.Z containing nucleosomes around transcription start sites has now been shown to affect the downstream gene expression.[3]
Recent evidence also points to a role for H2A.Z in repressing a subset of ncRNAs, derepressing CUTs, as well as mediation higher order chromatin structure formation.[4] | https://www.wikidoc.org/index.php/H2AFZ | |
263ffe6c8efd4406288f78be58dd66fd1c863e4b | wikidoc | H3F3A | H3F3A
Histone H3.3 is a protein that in humans is encoded by the H3F3A gene.
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family.
Mutation of H3F3A are also linked to certain cancers. p.Lys27Met were discovered in Diffuse Intrinsic Pontine Glioma (DIPG), where they are present 65-75% of tumors and confer a worse prognosis. p.Lys27Met alterations in HIST1H3B and HIST1H3C, which code for histone H3.1 have also been reported in ~10% of DIPG. H3F3A is also mutated in a smaller portion of pediatric and young adult high grade astrocytomas but more frequently as p.Gly34Arg/Val. Mutations in H3F3A and H3F3B are also found in chondroblastoma and giant cell tumor of bone. | H3F3A
Histone H3.3 is a protein that in humans is encoded by the H3F3A gene.[1]
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family.[2]
Mutation of H3F3A are also linked to certain cancers. p.Lys27Met were discovered in Diffuse Intrinsic Pontine Glioma (DIPG),[3] where they are present 65-75% of tumors and confer a worse prognosis.[4] p.Lys27Met alterations in HIST1H3B and HIST1H3C, which code for histone H3.1 have also been reported in ~10% of DIPG.[5] H3F3A is also mutated in a smaller portion of pediatric and young adult high grade astrocytomas but more frequently as p.Gly34Arg/Val. Mutations in H3F3A and H3F3B are also found in chondroblastoma and giant cell tumor of bone.[6] | https://www.wikidoc.org/index.php/H3F3A | |
45137b4d21be57cfd7a3fd0a82b860c04ec8b98a | wikidoc | HADHA | HADHA
Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.
# Structure
HADHA is an 82.9 kDa protein composed of 763 amino acids.
The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.
# Function
This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The enzyme converts medium- and long-chain 2-enoyl-CoA compounds into the following 3-ketoacyl-CoA when NAD is solely present, and acetyl-CoA when NAD and CoASH are present. The alpha subunit catalyzes this reaction, and is attached to HADHB, which catalyzes the last step of the reaction.
# Clinical significance
Mutations in this gene result in trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.
The most common form of the mutation is G1528C, in which the guanine at the 1528th position is changed to a cytosine. The gene mutation creates a protein deficiency that is associated with impaired oxidation of long-chain fatty acids that can lead to sudden infant death. Clinical manifestations of this deficiency can include myopathy, cardiomyopathy, episodes of coma, and hypoglycemia. Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum, acute fatty liver of pregnancy, and maternal floor infarct of the placenta. Additionally, it has been correlated with Acute fatty liver of pregnancy (AFLP) disease.
From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of chemotherapy in patients with lung cancer.
# Interactions
HADHA has been shown to have 142 binary protein-protein interactions including 117 co-complex interactions. HADHA appears to interact with GABARAP, MAP1LC3B, TRAF6, GABARAPL2, GABARAPL1, GAST, BCAR3, EPB41, TNFRSF1A, HLA-B, NFKB2, MAP3K1, IKBKE, PRKAB1, RIPK3, CD74, NR4A1, cdsA, mtaD, ATXN2L, ABCF2, and MAPK3. | HADHA
Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[1]
# Structure
HADHA is an 82.9 kDa protein composed of 763 amino acids.[2][3]
The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.[1]
# Function
This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids.[1] The enzyme converts medium- and long-chain 2-enoyl-CoA compounds into the following 3-ketoacyl-CoA when NAD is solely present, and acetyl-CoA when NAD and CoASH are present.[4] The alpha subunit catalyzes this reaction, and is attached to HADHB, which catalyzes the last step of the reaction.[5]
# Clinical significance
Mutations in this gene result in trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[1]
The most common form of the mutation is G1528C, in which the guanine at the 1528th position is changed to a cytosine. The gene mutation creates a protein deficiency that is associated with impaired oxidation of long-chain fatty acids that can lead to sudden infant death.[6] Clinical manifestations of this deficiency can include myopathy, cardiomyopathy, episodes of coma, and hypoglycemia.[7] Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum, acute fatty liver of pregnancy, and maternal floor infarct of the placenta.[8][9] Additionally, it has been correlated with Acute fatty liver of pregnancy (AFLP) disease.[10]
From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of chemotherapy in patients with lung cancer.[11]
# Interactions
HADHA has been shown to have 142 binary protein-protein interactions including 117 co-complex interactions. HADHA appears to interact with GABARAP, MAP1LC3B, TRAF6, GABARAPL2, GABARAPL1, GAST, BCAR3, EPB41, TNFRSF1A, HLA-B, NFKB2, MAP3K1, IKBKE, PRKAB1, RIPK3, CD74, NR4A1, cdsA, mtaD, ATXN2L, ABCF2, and MAPK3.[12] | https://www.wikidoc.org/index.php/HADHA | |
84be58941ecc57caaa378384cd83a5f8d8425d9e | wikidoc | HADHB | HADHB
Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.
HADHB is a subunit of the mitochondrial trifunctional protein and has thiolase activity.
# Structure
The HADHB gene is located on chromosome 2, with its specific location being 2p23. The gene contains 17 exons. HADHB encodes a 51.2 kDa protein that is composed of 474 amino acids; 124 peptides have been observed through mass spectrometry data.
# Function
This gene encodes the beta subunit of the mitochondrial trifunctional protein, a catalyst of mitochondrial beta-oxidation of long chain fatty acids. The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the thiol group of another molecule of Coenzyme A. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, which is two carbons shorter.
The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.
# Clinical significance
Mutations in this gene, along with mutations in HADHA, result in trifunctional protein deficiency. Mutations in either gene have similar clinical presentations. Trifunctional protein deficiency is characterized by decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase. This deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden infant death syndrome (SIDS), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy. Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy. In some cases, symptoms of the deficiency can present as dilated cardiomyopathy, congestive heart failure, and respiratory failure. The deficiency has presented as hydrops fetalis and HELLP syndrome in fetuses. A compound heterozygous mutation of the HADHB gene can causes axonal Charcot-Marie-tooth disease, which is a neurological disorder, which shows that mutations in this gene can result in deficiencies that present in new forms not currently described.
# Interactions
HADHB is a functional molecular target of ERα in the mitochondria, and the interaction may play an important role in the estrogen-mediated lipid metabolism in animals and humans. Additionally, HADHB has been shown to bind to the distal 3’ untranslated region of renin mRNA, thereby regulating renin protein expression. | HADHB
Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.[1]
HADHB is a subunit of the mitochondrial trifunctional protein and has thiolase activity.
# Structure
The HADHB gene is located on chromosome 2, with its specific location being 2p23.[1] The gene contains 17 exons. HADHB encodes a 51.2 kDa protein that is composed of 474 amino acids; 124 peptides have been observed through mass spectrometry data.[2][3]
# Function
This gene encodes the beta subunit of the mitochondrial trifunctional protein, a catalyst of mitochondrial beta-oxidation of long chain fatty acids. The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the thiol group of another molecule of Coenzyme A. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, which is two carbons shorter.
The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.[1]
# Clinical significance
Mutations in this gene, along with mutations in HADHA, result in trifunctional protein deficiency.[1] Mutations in either gene have similar clinical presentations.[4] Trifunctional protein deficiency is characterized by decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase. This deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden infant death syndrome (SIDS),[5] infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy.[6] Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy.[7] In some cases, symptoms of the deficiency can present as dilated cardiomyopathy, congestive heart failure, and respiratory failure. The deficiency has presented as hydrops fetalis and HELLP syndrome in fetuses.[8] A compound heterozygous mutation of the HADHB gene can causes axonal Charcot-Marie-tooth disease, which is a neurological disorder, which shows that mutations in this gene can result in deficiencies that present in new forms not currently described.[9]
# Interactions
HADHB is a functional molecular target of ERα in the mitochondria, and the interaction may play an important role in the estrogen-mediated lipid metabolism in animals and humans.[10] Additionally, HADHB has been shown to bind to the distal 3’ untranslated region of renin mRNA, thereby regulating renin protein expression.[11] | https://www.wikidoc.org/index.php/HADHB | |
601eb850a0c21863466543174e1c36f7418651aa | wikidoc | HAND1 | HAND1
Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.
A member of the HAND subclass of basic Helix-loop-helix (bHLH) transcription factors, the Heart and neural crest-derived transcript-1 (HAND1) gene is vital for the development and differentiation of three distinct embryological lineages including the cardiac muscle cells of the heart, trophoblast of the placenta, and yolk sac vasculogenesis. Most highly related to twist-like bHLH genes in amino acid identity and embryonic expression, HAND1 can form homo- and heterodimer combinations with multiple bHLH partners, mediating transcriptional activity in the nucleus.
# Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins are expressed within the developing ventricular chambers, cardiac neural crest, endocardium (HAND2 only) and epicardium (HAND2 only). HAND1 is expressed with myocardium of the primary heart field and plays an essential but poorly understood role in cardiac morphogenesis.
HAND1 works jointly with HAND2 in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities. Knock-out experimentation on mice caused death and severe cardiac malformations such as failed cardiac looping, impaired ventricular development and defective chamber septation. This aids in the implication that HAND1 expression is a factor to patients suffering from congenital heart disease. However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation. Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease. The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.
HAND factors function in the formation of the right ventricle, left ventricle, aortic arch arteries, epicardium, and endocardium implicating them as mediators of congenital heart disease. In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast differentiation.
## Cardiac morphogenesis
In the third week of fetal development the rudimentary heart (bilaterally symmetrical cardiac tube) undergoes a characteristic dextral looping, forming an asymmetrical structure with bulges that represent the incipient ventricular and atrial chambers of the heart. Arising from cells derived from the primary heart field in the cardiac crescent, HAND1 goes from being expressed on both sides of the heart tube to the ventral surface of the caudal heart segment and the aortic sac, then being restricted to the outer curvature of the left ventricle in the looped heart. In conjunction with HAND2 (a fellow bHLH transcription factor), complementary and overlapping expression patterns are thought to play a role in interpreting asymmetrical signals in the developing heart which leads to the characteristic looping. The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.
HAND1 mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where HAND1-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities. In humans, evidence of a frameshift mutation in the bHLH domain of HAND1 has been correlated with hypoplastic left heart syndrome (a serious form of congenital heart disease where the left side of the heart is severely underdeveloped), aiding in the implication that HAND1 expression is a factor to patients suffering from the disease.
However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation. Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease. The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.
## Trophoblast differentiation
In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast giant cell differentiation. Trophoblast giant cells are necessary in order for placental development to proceed, participating in vital processes such as blastocyst implantation, remodeling of the maternal decidua, and secretion of hormones. The importance of this relationship is demonstrated in HAND1-null mutant mice, which display significant abnormalities in trophoblast development, such as a reduced ectoplacental cone, thin parietal yolk sac, and reduced density of trophoblast giant cells. These homozygous HAND1-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.
## Yolk sac vasculogenesis
Expressed in high levels in the extraembryonic membranes throughout development, HAND1 also plays a functional role in vascular development of the yolk sac. Though not strictly required for vasculogenesis, data has shown that HAND1 contributes to the fine-tuning of the vasculogenic response in the yolk sac, recruiting smooth muscle cells to the endothelial network in order to refine the primitive endothelial plexus to a functional vascular system. This relationship has been demonstrated in the HAND1-null mouse model, where embryos lacking the HAND1 gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of hematopoietic cells between the yolk sac and the amnion. | HAND1
Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.[1][2][3]
A member of the HAND subclass of basic Helix-loop-helix (bHLH) transcription factors, the Heart and neural crest-derived transcript-1 (HAND1) gene is vital for the development and differentiation of three distinct embryological lineages including the cardiac muscle cells of the heart, trophoblast of the placenta, and yolk sac vasculogenesis.[4][5] Most highly related to twist-like bHLH genes in amino acid identity and embryonic expression, HAND1 can form homo- and heterodimer combinations with multiple bHLH partners, mediating transcriptional activity in the nucleus.[5][6]
# Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins are expressed within the developing ventricular chambers, cardiac neural crest, endocardium (HAND2 only) and epicardium (HAND2 only). HAND1 is expressed with myocardium of the primary heart field and plays an essential but poorly understood role in cardiac morphogenesis.
HAND1 works jointly with HAND2 in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.[7] Knock-out experimentation on mice caused death and severe cardiac malformations such as failed cardiac looping, impaired ventricular development and defective chamber septation. This aids in the implication that HAND1 expression is a factor to patients suffering from congenital heart disease.[8] However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.[7] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.[9] The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.[7]
HAND factors function in the formation of the right ventricle, left ventricle, aortic arch arteries, epicardium, and endocardium implicating them as mediators of congenital heart disease. In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast differentiation.[3]
## Cardiac morphogenesis
In the third week of fetal development the rudimentary heart (bilaterally symmetrical cardiac tube) undergoes a characteristic dextral looping, forming an asymmetrical structure with bulges that represent the incipient ventricular and atrial chambers of the heart.[10] Arising from cells derived from the primary heart field in the cardiac crescent, HAND1 goes from being expressed on both sides of the heart tube to the ventral surface of the caudal heart segment and the aortic sac, then being restricted to the outer curvature of the left ventricle in the looped heart.[10][11][12] In conjunction with HAND2 (a fellow bHLH transcription factor), complementary and overlapping expression patterns are thought to play a role in interpreting asymmetrical signals in the developing heart which leads to the characteristic looping.[10][13] The two are implemented in cardiac development of embryos based on a crucial HAND gene dosage system. If HAND1 is over or under expressed then morphological abnormalities can form; most notable are cleft lips and palates. Expression was modeled with a knock-in of phosphorylation to turn on and off gene expression which induced the craniofacial abnormalities.[7]
HAND1 mutants also appear to develop a spectrum of cardiac abnormalities, as demonstrated in knock-out experimentation in the mouse model, where HAND1-null mice displayed defects in the ventral septum, malformation of the AV valve, hypoplastic ventricles, and outflow tract abnormalities.[13][14] In humans, evidence of a frameshift mutation in the bHLH domain of HAND1 has been correlated with hypoplastic left heart syndrome (a serious form of congenital heart disease where the left side of the heart is severely underdeveloped), aiding in the implication that HAND1 expression is a factor to patients suffering from the disease.[8][15]
However, a lack of HAND1 in the distal regions of the Neural Crest has no effect on cranial feature formation.[7] Mutation of HAND1 has been shown to hinder the effect of GATA4, another vital cardiac transcription factor, and is associated with congenital heart disease.[9] The lack of HAND1 detection in the developing embryo leads to many of the structural defects that causes heart disease and facial deformities while the dosage of HAND1 relates to the severity of these maladies.[7]
## Trophoblast differentiation
In addition, HAND1 is uniquely expressed in trophoblasts and is essential for early trophoblast giant cell differentiation.[16] Trophoblast giant cells are necessary in order for placental development to proceed, participating in vital processes such as blastocyst implantation, remodeling of the maternal decidua, and secretion of hormones.[16] The importance of this relationship is demonstrated in HAND1-null mutant mice, which display significant abnormalities in trophoblast development, such as a reduced ectoplacental cone, thin parietal yolk sac, and reduced density of trophoblast giant cells.[17] These homozygous HAND1-null mutant embryos were arrested by E7.5 of gestation, though could be saved by contribution of wild-type cells to the trophoblast.[17]
## Yolk sac vasculogenesis
Expressed in high levels in the extraembryonic membranes throughout development, HAND1 also plays a functional role in vascular development of the yolk sac.[18] Though not strictly required for vasculogenesis, data has shown that HAND1 contributes to the fine-tuning of the vasculogenic response in the yolk sac, recruiting smooth muscle cells to the endothelial network in order to refine the primitive endothelial plexus to a functional vascular system.[18][5] This relationship has been demonstrated in the HAND1-null mouse model, where embryos lacking the HAND1 gene had a yolk sac vasculature defect caused by lack of vasculature refinement leading to the accumulation of hematopoietic cells between the yolk sac and the amnion.[18] | https://www.wikidoc.org/index.php/HAND1 | |
afd9268507e6b5c752805f7218ef6f04bae1b9c9 | wikidoc | HAND2 | HAND2
Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.
# Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins Hand1 and Hand2, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development. In one study, it was found that a missense mutation of the Hand2 protein in patients with the congenital heart disease (CHD) Tetralogy of Fallot experienced significantly decreased Hand2 interactions with other key developmental genes such as GATA4 and NKX2.5. Hand2 mutations have the potential to be genes for the future study of right ventricle stenosis and its pathogenesis. In avian species, Hand2 has been shown to be expressed in developing gut tissue and is believed to contribute to the formation of enteric neurons.
Hand2 also plays a critical role in the establishment of a proper implantation environment for pregnancy in mice. The induction of Hand2 by progesterone-dependent mechanisms in uterine stromal tissue suppresses fibroblast growth factors (FGFs) that would otherwise stimulate estrogen producing pathways and impair embryo implantation.
Hand2 plays a role in lower jaw formation and tongue morphogenesis in mice by suppressing the homeobox genes Dlx5 and Dlx6.
# Interactions
HAND2 has been shown to interact with GATA4, NKX2.5, PPP2R5D, PHOX2A., TWIST1, and TWIST2.
# Clinical significance
Hand2 interactions with TWIST1 and TWIST2 genes are critical for proper limb development. Recent literature shows over dosage of Hand2 can result in many defects in the limbs, face, heart, and lower lumbar vertebrae. In this instance, trisomy of the hand2 gene can directly cause human congenital heart disease.
Hand2 gene hypermethylation and epigenetic silencing has also been implicated to increase the development of endometrial cancer. Mounting evidence showing its methylation increased chances of premalignant endometrial lesions. Hand2, in addition to its other functions in the developing heart and limbs, has been found to be an important transcription factor seen in the endometrial stroma. In fact, in mice with the Hand2 gene knocked out, they developed premaligant lesions as they grew older, further providing evidence of its role in endometrial cancer development. These findings have led to Hand2 becoming a potentially promising biomarker for early detection of endometrial cancer and may be used to predict its treatment. | HAND2
Heart- and neural crest derivatives-expressed protein 2 is a protein that in humans is encoded by the HAND2 gene.[1][2]
# Function
The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins Hand1 and Hand2, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development.[2] In one study, it was found that a missense mutation of the Hand2 protein in patients with the congenital heart disease (CHD) Tetralogy of Fallot experienced significantly decreased Hand2 interactions with other key developmental genes such as GATA4 and NKX2.5.[3] Hand2 mutations have the potential to be genes for the future study of right ventricle stenosis and its pathogenesis.[4] In avian species, Hand2 has been shown to be expressed in developing gut tissue and is believed to contribute to the formation of enteric neurons.[5]
Hand2 also plays a critical role in the establishment of a proper implantation environment for pregnancy in mice. The induction of Hand2 by progesterone-dependent mechanisms in uterine stromal tissue suppresses fibroblast growth factors (FGFs) that would otherwise stimulate estrogen producing pathways and impair embryo implantation.[6]
Hand2 plays a role in lower jaw formation and tongue morphogenesis in mice by suppressing the homeobox genes Dlx5 and Dlx6.[7]
# Interactions
HAND2 has been shown to interact with GATA4,[8] NKX2.5,[3] PPP2R5D,[9] PHOX2A.,[10] TWIST1, and TWIST2.
# Clinical significance
Hand2 interactions with TWIST1 and TWIST2 genes are critical for proper limb development. Recent literature shows over dosage of Hand2 can result in many defects in the limbs, face, heart, and lower lumbar vertebrae. In this instance, trisomy of the hand2 gene can directly cause human congenital heart disease.[4]
Hand2 gene hypermethylation and epigenetic silencing has also been implicated to increase the development of endometrial cancer. Mounting evidence showing its methylation increased chances of premalignant endometrial lesions. Hand2, in addition to its other functions in the developing heart and limbs, has been found to be an important transcription factor seen in the endometrial stroma. In fact, in mice with the Hand2 gene knocked out, they developed premaligant lesions as they grew older, further providing evidence of its role in endometrial cancer development. These findings have led to Hand2 becoming a potentially promising biomarker for early detection of endometrial cancer and may be used to predict its treatment.[11] | https://www.wikidoc.org/index.php/HAND2 | |
bd52a66f6113faaad359923faaf461586edc0375 | wikidoc | HAR1F | HAR1F
HAR1F is a RNA gene which is part of a human accelerated region of the human genome. HAR1F is found on the long arm of chromosome 20 and the RNA product is expressed in Cajal-Retzius cells, where it colocalizes with the protein reelin.
HAR1F was identified in August 2006 when human accelerated regions (HARs) were first investigated. These 49 regions represent parts of the human genome which differ significantly from highly conserved regions of our closest ancestors evolutionarily. Because many of the HARs are associated with genes known to play a role in neurodevelopment, HARs are believed to be responsible for the language, brain size, and complex thought which separate humans from other species. One particularly altered region, HAR1, was found in a stretch of genome with no known protein coding RNA sequences. Two RNA genes, HAR1F and HAR1R were identified partly within the region. The RNA structure of HAR1F has been shown to be stable, with a three–dimensional structure unlike those previously described.
HAR1F is active in the developing human brain between the 7th and 18th gestational weeks. It is found in the dorsal telencephalon in fetuses. In adult humans, it is found throughout the cerebellum and forebrain; it is also found in the testes. The function of HAR1F is unknown. | HAR1F
HAR1F is a RNA gene which is part of a human accelerated region of the human genome. HAR1F is found on the long arm of chromosome 20 and the RNA product is expressed in Cajal-Retzius cells, where it colocalizes with the protein reelin.
HAR1F was identified in August 2006 when human accelerated regions (HARs) were first investigated. These 49 regions represent parts of the human genome which differ significantly from highly conserved regions of our closest ancestors evolutionarily. Because many of the HARs are associated with genes known to play a role in neurodevelopment, HARs are believed to be responsible for the language, brain size, and complex thought which separate humans from other species. One particularly altered region, HAR1, was found in a stretch of genome with no known protein coding RNA sequences. Two RNA genes, HAR1F and HAR1R were identified partly within the region. The RNA structure of HAR1F has been shown to be stable, with a three–dimensional structure unlike those previously described.
HAR1F is active in the developing human brain between the 7th and 18th gestational weeks. It is found in the dorsal telencephalon in fetuses. In adult humans, it is found throughout the cerebellum and forebrain; it is also found in the testes. The function of HAR1F is unknown.[1] | https://www.wikidoc.org/index.php/HAR1F | |
2ccedc813013cf50ec07e2340cd526a98f442be9 | wikidoc | HDAC1 | HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.
# Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 MTA2, it deacetylates p53 and modulates its effect on cell growth and apoptosis.
# Model organisms
Model organisms have been used in the study of HDAC1 function. A conditional knockout mouse line, called Hdac1tm1a(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 — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals.
# Interactions
HDAC1 has been shown to interact with:
- Androgen receptor,
- BCL6,
- BTG2,
- BUB1B,
- BUB1,
- BUB3,
- CBFA2T3,
- CDC20,
- CDH1,
- CHD3,
- CHD4,
- COUP-TFII,
- CTBP1,
- DDX17,
- DDX5,
- DNMT3A,
- DNMT3L,
- Death-associated protein 6,
- EED,
- EVI1,
- EZH2,
- FKBP3,
- GATA1,
- HMG20B,
- HSPA4,
- HUS1,
- Histone deacetylase 2,
- Homeobox protein TGIF1,
- Host cell factor C1,
- IFRD1,
- IKZF1,
- ING1,
- MBD3,
- MIER1,
- MLL,
- MTA1,
- MTA2,
- Mad1,
- Mdm2,
- Methyl-CpG-binding domain protein 2,
- Mothers against decapentaplegic homolog 2,
- MyoD,
- NFKB1,
- Nuclear receptor co-repressor 2,
- P21,
- PCNA,
- PHF21A,
- Prohibitin,
- Promyelocytic leukemia protein,
- RAD9A,
- RBBP4,
- RBBP7,
- RCOR1,
- RELA,
- RFC1,
- Retinoblastoma protein,
- Retinoblastoma-like protein 1,
- Retinoblastoma-like protein 2,
- SAP30,
- SATB1,
- SIN3A,
- SIN3B,
- SPEN,
- SUDS3,
- SUV39H1,
- Sp1 transcription factor,
- TOP2A,
- TOP2B, and
- Zinc finger and BTB domain-containing protein 16. | HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.[1]
# Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 MTA2, it deacetylates p53 and modulates its effect on cell growth and apoptosis.[2]
# Model organisms
Model organisms have been used in the study of HDAC1 function. A conditional knockout mouse line, called Hdac1tm1a(EUCOMM)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 — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty five tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals.[5]
# Interactions
HDAC1 has been shown to interact with:
- Androgen receptor,[13]
- BCL6,[14][15]
- BTG2,[16] [17]
- BUB1B,[18]
- BUB1,[18]
- BUB3,[18]
- CBFA2T3,[19][20]
- CDC20,[18]
- CDH1,[18]
- CHD3,[21][22]
- CHD4,[21][23][24]
- COUP-TFII,[25]
- CTBP1,[26][27][28]
- DDX17,[29]
- DDX5,[29]
- DNMT3A,[30]
- DNMT3L,[31][32]
- Death-associated protein 6,[33]
- EED,[34]
- EVI1,[35][36]
- EZH2,[34]
- FKBP3,[37]
- GATA1,[38]
- HMG20B,[39]
- HSPA4,[40]
- HUS1,[41]
- Histone deacetylase 2,[21][23][34][39][40][42][43][44][45][46][47][48][49]
- Homeobox protein TGIF1,[26][50]
- Host cell factor C1,[51]
- IFRD1,[52]
- IKZF1,[53][54]
- ING1,[22][55]
- MBD3,[47][56][57]
- MIER1,[58]
- MLL,[59]
- MTA1,[23][60]
- MTA2,[23][47][61][62]
- Mad1,[18]
- Mdm2,[63]
- Methyl-CpG-binding domain protein 2,[47][64][65]
- Mothers against decapentaplegic homolog 2,[66]
- MyoD,[67][68]
- NFKB1,[69]
- Nuclear receptor co-repressor 2,[42][70]
- P21, [71]
- PCNA,[72]
- PHF21A,[39][73]
- Prohibitin,[74][75]
- Promyelocytic leukemia protein,[76][77]
- RAD9A,[41]
- RBBP4,[23][24][47][48][49][61][64][78][79][80][81]
- RBBP7,[23][47][49][64]
- RCOR1,[39][61]
- RELA,[46][69][82]
- RFC1,[83]
- Retinoblastoma protein,[67][75][84][85][86][87][88]
- Retinoblastoma-like protein 1,[84][85]
- Retinoblastoma-like protein 2,[84][89]
- SAP30,[22][47][90][91][92][93]
- SATB1,[62]
- SIN3A,[21][22][23][24][47][48][61][62][78][79][94][95][96][97]
- SIN3B,[47][53]
- SPEN,[98]
- SUDS3,[94][99]
- SUV39H1,[100]
- Sp1 transcription factor,[79][101][102][103]
- TOP2A,[104][105]
- TOP2B,[104][105] and
- Zinc finger and BTB domain-containing protein 16.[14][106][107] | https://www.wikidoc.org/index.php/HDAC1 | |
35392ae33cbd761a28b52375f6ad29eafee131c5 | wikidoc | HDAC3 | HDAC3
Histone deacetylase 3 is an enzyme encoded by the HDAC3 gene in both humans and mice.
# Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein component of chromatin. The posttranslational and enzymatically mediated lysine acetylation and deacetylation of histone tails changes the local chromatin structure through altering the electrostatic attraction between the negatively charged DNA backbone and histones. HDAC3 is a Class I member of the histone deacetylase superfamily (comprising four classes based on function and DNA sequence homology) that is recruited to enhancers to modulate both the epigenome and nearby gene expression. HDAC3 is found exclusively in the cell nucleus where it is the sole endogenous histone deacetylase biochemically purified in the nuclear-receptor corepressor complex containing NCOR and SMRT (NCOR2). Thus, HDAC3 unlike other HDACs, has a unique role in modulating the transcriptional activities of nuclear receptors.
# Alternative functions
Histone deacetylases can be regulated by endogenous factors, dietary components, synthetic inhibitors and bacteria-derived signals. Studies in mice with a specific
deletion of HDAC3 in intestinal epithelial cells (IECs) show a deregulated IEC's gene expression. In these deletion-mutant mice, loss of Paneth cells, impaired IEC function and alterations in intestinal composition of commensal bacteria were observed. These negative effects were not observed in germ-free mice, indicating that the effects of the deletion are only seen in the presence of intestinal microbial colonization. But the negative effects of HDAC3 deletion are not due to the presence of an altered microbiota because normal germ-free mice colonized with the altered microbiota did not show the negative effects seen in deletion mutants.
Although the precise mechanism and the specific signals are not known it is clear that HDAC3 interacts with derived signals of commensal bacteria of the gut microbiota. These interactions are responsible of calibrating epithelial cells responses necessary to establish a normal relationship between the host and the commensal as well as to maintain intestinal homeostasis.
# Model organisms
Model organisms have been used in the study of HDAC3 function. A conditional knockout mouse line, called Hdac3tm1a(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 two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and in a separate study none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.
# Interactions
HDAC3 has been shown to interact with:
- CBFA2T3,
- CCND1,
- GATA1,
- GATA2,
- GPS2,
- GTF2I,
- HDAC4,
- HDAC5,
- HDAC7A,
- HDAC9,
- MAP3K7IP2,
- MAPK11,
- NCOR1,
- NCOR2,
- PPARD,
- PPARG,
- PML
- RBBP4,
- RELA,
- RP,
- RUNX2,
- SUV39H1,
- TCP1,
- TBL1X,
- TR2,
- UBC,
- YY1, and
- ZBTB33. | HDAC3
Histone deacetylase 3 is an enzyme encoded by the HDAC3 gene in both humans and mice.[1][2][3][4]
# Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein component of chromatin. The posttranslational and enzymatically mediated lysine acetylation and deacetylation of histone tails changes the local chromatin structure through altering the electrostatic attraction between the negatively charged DNA backbone and histones. HDAC3 is a Class I member of the histone deacetylase superfamily (comprising four classes based on function and DNA sequence homology) that is recruited to enhancers to modulate both the epigenome and nearby gene expression. HDAC3 is found exclusively in the cell nucleus where it is the sole endogenous histone deacetylase biochemically purified in the nuclear-receptor corepressor complex containing NCOR and SMRT (NCOR2). Thus, HDAC3 unlike other HDACs, has a unique role in modulating the transcriptional activities of nuclear receptors.
# Alternative functions
Histone deacetylases can be regulated by endogenous factors, dietary components, synthetic inhibitors and bacteria-derived signals. Studies in mice with a specific
deletion of HDAC3 in intestinal epithelial cells (IECs) show a deregulated IEC's gene expression. In these deletion-mutant mice, loss of Paneth cells, impaired IEC function and alterations in intestinal composition of commensal bacteria were observed. These negative effects were not observed in germ-free mice, indicating that the effects of the deletion are only seen in the presence of intestinal microbial colonization. But the negative effects of HDAC3 deletion are not due to the presence of an altered microbiota because normal germ-free mice colonized with the altered microbiota did not show the negative effects seen in deletion mutants.
Although the precise mechanism and the specific signals are not known it is clear that HDAC3 interacts with derived signals of commensal bacteria of the gut microbiota. These interactions are responsible of calibrating epithelial cells responses necessary to establish a normal relationship between the host and the commensal as well as to maintain intestinal homeostasis.[5][6][7][8]
# Model organisms
Model organisms have been used in the study of HDAC3 function. A conditional knockout mouse line, called Hdac3tm1a(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 two significant abnormalities were observed.[11] No homozygous mutant embryos were identified during gestation, and in a separate study none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals.[11]
# Interactions
HDAC3 has been shown to interact with:
- CBFA2T3,[19][20]
- CCND1,[21][22]
- GATA1,[23]
- GATA2,[24]
- GPS2,[25]
- GTF2I,[26][27]
- HDAC4,[28][29][30][31]
- HDAC5,[25][29][30][31]
- HDAC7A,[28]
- HDAC9,[32][33]
- MAP3K7IP2,[34]
- MAPK11,[35]
- NCOR1,[25][28][30][36][37][38][39]
- NCOR2,[30][36][37][38][39][40][41]
- PPARD,[42][43]
- PPARG,[42][44]
- PML[45]
- RBBP4,[46]
- RELA,[47]
- RP,[44][48]
- RUNX2,[49]
- SUV39H1,[50]
- TCP1,[41]
- TBL1X,[25][40]
- TR2,[42][51][52]
- UBC,[53]
- YY1,[54][55] and
- ZBTB33.[36] | https://www.wikidoc.org/index.php/HDAC3 | |
2167fedcfadf81d579d262608bcb859a245b7bbc | wikidoc | HDAC4 | HDAC4
Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. Furthermore, HDAC4 is required for TGFbeta1-induced myofibroblastic differentiation.
# Clinical significance
Studies have shown that HDAC4 regulates bone and muscle development. Harvard University researchers also concluded that it promotes healthy vision: Reduced levels of the protein led to the death of the rod photoreceptors and bipolar cells in the retinas of mice.
# Interactions
HDAC4 has been shown to interact with:
- BCL6,
- BTG2,
- CBX5,
- GATA1,
- HDAC3,
- MAPK1,
- MAPK3,
- MEF2C,
- Myocyte-specific enhancer factor 2A,
- Nuclear receptor co-repressor 1,
- Nuclear receptor co-repressor 2,
- Testicular receptor 2,
- YWHAB,
- YWHAE, and
- Zinc finger and BTB domain-containing protein 16. | HDAC4
Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.[1][2]
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3.[3] Furthermore, HDAC4 is required for TGFbeta1-induced myofibroblastic differentiation.[4]
# Clinical significance
Studies have shown that HDAC4 regulates bone and muscle development. Harvard University researchers also concluded that it promotes healthy vision: Reduced levels of the protein led to the death of the rod photoreceptors and bipolar cells in the retinas of mice.[5][6]
# Interactions
HDAC4 has been shown to interact with:
- BCL6,[7]
- BTG2,[8] [9]
- CBX5,[10]
- GATA1,[11]
- HDAC3,[1][12][13][14]
- MAPK1,[15]
- MAPK3,[15]
- MEF2C,[16][17]
- Myocyte-specific enhancer factor 2A,[18][19]
- Nuclear receptor co-repressor 1,[12][20]
- Nuclear receptor co-repressor 2,[12][20]
- Testicular receptor 2,[21][22]
- YWHAB,[13]
- YWHAE,[13][23] and
- Zinc finger and BTB domain-containing protein 16.[7][24] | https://www.wikidoc.org/index.php/HDAC4 | |
656649efc6f4014d2a268dc250d0f66b49c20629 | wikidoc | HDAC6 | HDAC6
Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromatin structure and affects transcription. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains that appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription.
# Clinical relevance
Mutations in this gene have been associated to Alzheimer's disease.
Over expression of this protein correlates with tumorigenesis and cell survival. HDAC6 also encourages metastasis of cancer cells.
# Functions
Retracts the Cilium of the cell, which is necessary prior to mitosis of the cell.
HDAC also encourages cell motility and catalyzes α-tubulin deacetylation. as a result the enzyme also encourages cancer cell metastasis.
HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90) and stress granules (SGs), respectively.
HDAC6 is also known to bond with high affinity to ubiquitinated proteins. HDAC6 is also required in the formation of SG (Stress granule proteins and is instrumental in SG formation; pharmacological inhibition or genetic removal of HDAC6 abolished SG formation.
# Interactions
HDAC6 has been shown to interact with HDAC11 and Zinc finger and BTB domain-containing protein 16.
HDAC6 interacts with SG (Stress granule) protein G3BP1. | HDAC6
Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.[1][2]
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromatin structure and affects transcription. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains that appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription.[3]
# Clinical relevance
Mutations in this gene have been associated to Alzheimer's disease.[4]
Over expression of this protein correlates with tumorigenesis and cell survival. HDAC6 also encourages metastasis of cancer cells.[5]
# Functions
Retracts the Cilium of the cell, which is necessary prior to mitosis of the cell.[6]
HDAC also encourages cell motility and catalyzes α-tubulin deacetylation.[7] as a result the enzyme also encourages cancer cell metastasis.[5]
HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90) and stress granules (SGs), respectively.[5]
HDAC6 is also known to bond with high affinity to ubiquitinated proteins.[8] HDAC6 is also required in the formation of SG (Stress granule proteins and is instrumental in SG formation; pharmacological inhibition or genetic removal of HDAC6 abolished SG formation.
# Interactions
HDAC6 has been shown to interact with HDAC11[9] and Zinc finger and BTB domain-containing protein 16.[10]
HDAC6 interacts with SG (Stress granule) protein G3BP1.[8] | https://www.wikidoc.org/index.php/HDAC6 | |
6992469fa01fb9d4e750f4f0c78933b77c8c0091 | wikidoc | HDAC7 | HDAC7
Histone deacetylase 7 is an enzyme that in humans is encoded by the HDAC7 gene.
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene has sequence homology to members of the histone deacetylase family. This gene is orthologous to mouse HDAC7 gene whose protein promotes repression mediated via transcriptional corepressor SMRT. Multiple alternatively spliced transcript variants encoding several isoforms have been found for this gene. HDAC7 has both structural and functional similarity to HDACs 4, 5, and 9, as these four HDACs make up the Class IIa of HDACs in higher eukaryotes. Class IIa HDACs are phosphorylated by calcium/calmodulin dependent-kindase (CaMK) and protein kinase D (PKD) in response to kinase-dependent signaling. HDAC7 possesses little intrinsic deacetylase activity and therefore requires association with the class I HDAC, HDAC3 in order to suppress gene expression. It has been demonstrated through crystal structures of the human HDAC7 that the catalytic domain of HDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site. This is most likely to allow for substrate recognition and protein-protein interactions that are necessary for class IIa HDAC enzymes.
# Alternative functions
Although HDAC7 has shown to have little intrinsic deacetylase activity, studies have shown that HDAC7 may have various alternative functions related to development, proliferation, and inflammation.
One study showed that HDAC7 suppresses proliferation and β-catenin activity in chondrocytes. This was shown by knocking out HDAC7 in mice, which then resulted in increased levels of the cell cycle regulator, cyclin D3; decreased levels of the tumor suppressor, p21; and increased levels of active beta-catenin. Since each of these contribute to regulating cell proliferation, deletion of HDAC7 increased chondrocyte proliferation. This study also showed that signaling via the insulin/Insulin-like growth factor 1 receptor led to increased levels of HDAC7 in the cytosol than the nucleus and increased levels of active β-catenin, indicating that HDAC7 associates with β-catenin. During chondrogenesis, HDAC7 is translocated to the cytosol to be degraded, indicating that generally HDAC7 represses β-catenin activity in chondrocytes.
Another study supported the conclusion that HDAC7 and β-catenin associate together by demonstrating that HDAC7 controls endothelial cell growth through modulation of β-catenin. This was shown in the opposite way from the previous study, in that HDAC7 was overexpressed rather than removed. They found that overexpression of HDAC7 prevented nuclear translocation of β-catenin which then coincided with downregulation of the cell cycle regulator, cyclin D1. Overall, this study demonstrated that HDAC7 once again interacts with β-catenin to keep endothelial cells in a low proliferation stage.
Not only does HDAC7 play a role in the proliferation of cell growth in chondrocytes and endothelial cells, but it has also been demonstrated that HDAC7 is a crucial player in cancer cell proliferation through a study that showed mechanistic insight into the contribution of HDAC7 to tumor progression. This study showed that knockdown of HDAC7 resulted in significant cell arrest between the G(1) and S phases of the cell cycle. Subsequently, HDAC7 knockdown suppressed c-Myc expression which in turn blocked cell cycle progression. Through chromatin immunoprecipitation assays, it was shown that HDAC7 directly binds with the c-Myc gene and therefore HDAC7 silencing decreased c-Myc mRNA levels.
Outside of proliferation, an additional study demonstrated that HDAC7 promotes inflammatory responses in macrophages. This was shown by overexpression of HDAC7 in inflammatory macrophages in mice. This overexpression promoted lipopolysaccharide (LPS)-inducible expression of HDAC-dependent genes via a HIF-1alpha-dependent mechanism. This demonstrated that HDAC7 may be a viable target for developing new anti-inflammatory drugs.
# Interactions
HDAC7A has been shown to interact with:
- BCL6,
- Endothelin receptor type A,
- HDAC3,
- HTATIP,
- IKZF1, and
- Nuclear receptor co-repressor 1. | HDAC7
Histone deacetylase 7 is an enzyme that in humans is encoded by the HDAC7 gene.[1][2][3]
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene has sequence homology to members of the histone deacetylase family. This gene is orthologous to mouse HDAC7 gene whose protein promotes repression mediated via transcriptional corepressor SMRT. Multiple alternatively spliced transcript variants encoding several isoforms have been found for this gene.[3] HDAC7 has both structural and functional similarity to HDACs 4, 5, and 9, as these four HDACs make up the Class IIa of HDACs in higher eukaryotes. Class IIa HDACs are phosphorylated by calcium/calmodulin dependent-kindase (CaMK) and protein kinase D (PKD) in response to kinase-dependent signaling. HDAC7 possesses little intrinsic deacetylase activity and therefore requires association with the class I HDAC, HDAC3 in order to suppress gene expression. It has been demonstrated through crystal structures of the human HDAC7 that the catalytic domain of HDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site.[4] This is most likely to allow for substrate recognition and protein-protein interactions that are necessary for class IIa HDAC enzymes.
# Alternative functions
Although HDAC7 has shown to have little intrinsic deacetylase activity, studies have shown that HDAC7 may have various alternative functions related to development, proliferation, and inflammation.
One study showed that HDAC7 suppresses proliferation and β-catenin activity in chondrocytes. This was shown by knocking out HDAC7 in mice, which then resulted in increased levels of the cell cycle regulator, cyclin D3; decreased levels of the tumor suppressor, p21; and increased levels of active beta-catenin. Since each of these contribute to regulating cell proliferation, deletion of HDAC7 increased chondrocyte proliferation. This study also showed that signaling via the insulin/Insulin-like growth factor 1 receptor led to increased levels of HDAC7 in the cytosol than the nucleus and increased levels of active β-catenin, indicating that HDAC7 associates with β-catenin. During chondrogenesis, HDAC7 is translocated to the cytosol to be degraded, indicating that generally HDAC7 represses β-catenin activity in chondrocytes.[5]
Another study supported the conclusion that HDAC7 and β-catenin associate together by demonstrating that HDAC7 controls endothelial cell growth through modulation of β-catenin. This was shown in the opposite way from the previous study, in that HDAC7 was overexpressed rather than removed. They found that overexpression of HDAC7 prevented nuclear translocation of β-catenin which then coincided with downregulation of the cell cycle regulator, cyclin D1. Overall, this study demonstrated that HDAC7 once again interacts with β-catenin to keep endothelial cells in a low proliferation stage.[6]
Not only does HDAC7 play a role in the proliferation of cell growth in chondrocytes and endothelial cells, but it has also been demonstrated that HDAC7 is a crucial player in cancer cell proliferation through a study that showed mechanistic insight into the contribution of HDAC7 to tumor progression. This study showed that knockdown of HDAC7 resulted in significant cell arrest between the G(1) and S phases of the cell cycle. Subsequently, HDAC7 knockdown suppressed c-Myc expression which in turn blocked cell cycle progression. Through chromatin immunoprecipitation assays, it was shown that HDAC7 directly binds with the c-Myc gene and therefore HDAC7 silencing decreased c-Myc mRNA levels.[7]
Outside of proliferation, an additional study demonstrated that HDAC7 promotes inflammatory responses in macrophages. This was shown by overexpression of HDAC7 in inflammatory macrophages in mice. This overexpression promoted lipopolysaccharide (LPS)-inducible expression of HDAC-dependent genes via a HIF-1alpha-dependent mechanism. This demonstrated that HDAC7 may be a viable target for developing new anti-inflammatory drugs.[8]
# Interactions
HDAC7A has been shown to interact with:
- BCL6,[9]
- Endothelin receptor type A,[10]
- HDAC3,[11]
- HTATIP,[12]
- IKZF1,[13] and
- Nuclear receptor co-repressor 1.[11] | https://www.wikidoc.org/index.php/HDAC7 | |
24283c0da175c216da1009df86f59517d83e83d8 | wikidoc | HDAC8 | HDAC8
Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene.
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation / deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter.
Histone deacetylase 8 is involved in skull morphogenesis and metabolic control of the ERR-alpha / PGC1-alpha transcriptional complex.
# Clinical significance
HDAC8 has been linked to number of disease states notably to acute myeloid leukemia and is related to actin cytoskeleton in smooth muscle cells. siRNA targeting HDAC8 showed anticancer effects. Inhibition of HDAC8 induced apoptosis has been observed in T cell lymphomas. In addition the HDAC8 enzyme has been implicated in the pathogenesis of neuroblastoma. Therefore, there has been interest in developing HDAC8 selective inhibitors.
# Interactions
- ERR-alpha. | HDAC8
Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene.[1][2][3]
# Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation / deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter.[3]
Histone deacetylase 8 is involved in skull morphogenesis[4] and metabolic control of the ERR-alpha / PGC1-alpha transcriptional complex.[5]
# Clinical significance
HDAC8 has been linked to number of disease states notably to acute myeloid leukemia and is related to actin cytoskeleton in smooth muscle cells. siRNA targeting HDAC8 showed anticancer effects.[6] Inhibition of HDAC8 induced apoptosis has been observed in T cell lymphomas.[7] In addition the HDAC8 enzyme has been implicated in the pathogenesis of neuroblastoma.[8] Therefore, there has been interest in developing HDAC8 selective inhibitors.[9][10]
# Interactions
- ERR-alpha.[5] | https://www.wikidoc.org/index.php/HDAC8 | |
174cffb5afbbafcbbae13ad0766aa4feb7e55fd2 | wikidoc | HECW2 | HECW2
HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 is a protein that in humans is encoded by the HECW2 gene.
# Model organisms
Model organisms have been used in the study of HECW2 function. A conditional knockout mouse line called Hecw2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping
# Clinical significance
Mutations in the HECW2 gene have been associated to epilepsy and intellectual disability. These mutations affect one copy of the HECW2 gene and are believed to change the function of the HECW2 protein. | HECW2
HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 is a protein that in humans is encoded by the HECW2 gene.[1]
# Model organisms
Model organisms have been used in the study of HECW2 function. A conditional knockout mouse line called Hecw2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[2] Male and female animals underwent a standardized phenotypic screen[3] to determine the effects of deletion.[4][5][6][7] Additional screens performed: - In-depth immunological phenotyping[8]
# Clinical significance
Mutations in the HECW2 gene have been associated to epilepsy and intellectual disability. These mutations affect one copy of the HECW2 gene and are believed to change the function of the HECW2 protein.[9] | https://www.wikidoc.org/index.php/HECW2 | |
72397ab52c29e4d5d471ead526734123df8a1d31 | wikidoc | HERC5 | HERC5
Probable E3 ubiquitin-protein ligase HERC5 is an enzyme that in humans is encoded by the HERC5 gene.
This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells. The protein localizes to the cytoplasm and perinuclear region and functions as an interferon-induced E3 protein ligase that mediates ISGylation of protein targets. The gene lies in a cluster of HERC family genes on chromosome 4. HERC5 has been shown to exhibit antiviral activity towards HIV-1, influenza A virus and human papillomavirus.
# Interactions
HERC5 has been shown to interact with NME2 and Cyclin E1. | HERC5
Probable E3 ubiquitin-protein ligase HERC5 is an enzyme that in humans is encoded by the HERC5 gene.[1][2]
This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells. The protein localizes to the cytoplasm and perinuclear region and functions as an interferon-induced E3 protein ligase that mediates ISGylation of protein targets. The gene lies in a cluster of HERC family genes on chromosome 4.[2] HERC5 has been shown to exhibit antiviral activity towards HIV-1, influenza A virus and human papillomavirus.[3][4][5]
# Interactions
HERC5 has been shown to interact with NME2[6] and Cyclin E1.[1] | https://www.wikidoc.org/index.php/HERC5 | |
991a3ac4e579b52c90ccaa14242d1b1cab6c3929 | wikidoc | HESX1 | HESX1
Homeobox expressed in ES cells 1, also known as homeobox protein ANF, is a homeobox protein that in humans is encoded by the HESX1 gene.
Expression of HEX1 and HESX1 marks the anterior visceral endoderm of the embryo. The AVE is an extra-embryonic tissue, key to the establishment of the anterior-posterior body axis.
# Clinical significance
Mutations in the HESX1 gene are associated with some cases of septo-optic dysplasia or Pickardt-Fahlbusch syndrome. | HESX1
Homeobox expressed in ES cells 1, also known as homeobox protein ANF, is a homeobox protein that in humans is encoded by the HESX1 gene.[1]
Expression of HEX1 and HESX1 marks the anterior visceral endoderm of the embryo. The AVE is an extra-embryonic tissue, key to the establishment of the anterior-posterior body axis.
# Clinical significance
Mutations in the HESX1 gene are associated with some cases of septo-optic dysplasia[2] or Pickardt-Fahlbusch syndrome.[3] | https://www.wikidoc.org/index.php/HESX1 | |
19e71a2710e4b28ecd2f1d58e9bab4a47aadc66d | wikidoc | HIF1A | HIF1A
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. It is a basic helix-loop-helix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. Two other alternative transcripts encoding different isoforms have been identified.
# Structure
HIF1 is a heterodimeric basic helix-loop-helix structure that is composed of HIF1A, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. HIF1A contains a basic helix-loop-helix domain near the C-terminal, followed by two distinct PAS (PER-ARNT-SIM) domains, and a PAC (PAS-associated C-terminal) domain. The HIF1A polypeptide also contains a nuclear localization signal motif, two transactivating domains CTAD and NTAD, and an intervening inhibitory domain (ID) that can repress the transcriptional activities of CTAD and NTAD. There are a total of three HIF1A isoforms formed by alternative splicing, however isoform1 has been chosen as the canonical structure, and is the most extensively studied isoform in structure and function.
# Gene and expression
The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1). HIF1A expression level is dependent on its GC-rich promoter activation. In most cells, HIF1A gene is constitutively expressed in low levels under normoxic conditions, however, under hypoxia, HIF1A transcription is often significantly upregulated. Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation. In hypoxia-independent ways, HIF1A expression may be upregulated through a redox-sensitive mechanism.
# Function
The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals. HIF1A activity is regulated by a host of post-translational modifications: hydroxylation, acetylation, and phosphorylation. HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions. HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism. In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription. HIF1A stability, subcellular localization, as well as transcriptional activity are especially affected by oxygen level. The alpha subunit forms a heterodimer with the beta subunit. Under normoxic conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes Enzymes prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A. The enzymatic activity of oxygen sensor dioxygenase PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the proline residue of HIF1A. The hydroxylated proline residue of HIF1A is then recognized and buried in the hydrophobic core of von Hippel-Lindau tumor suppressor protein (VHL), which itself is part of a ubiquitin ligase enzyme. The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia. Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.
## Repair and regeneration
In normal circumstances after injury HIF1A is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1A via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of HIF1A results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF1A can either turn off, or turn on the key processes of mammalian regeneration. One such regenerative process in which HIF1A is involved is peripheral nerve regeneration. Following axon injury, HIF1A activates VEGFA to promote regeneration and functional recovery.
# Regulation
HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner. In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.
PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF1A stabilization. HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized.
Factors increasing HIF1A
- Modulator of Degradation:
Oxygen-Dependent:
EPF UCP (degrades pHVL)
VDU2 (de-ubiquitinates HIF1A)
SUMOylation (via RSUME)
DeSUMOylation ( via SENP1)
Oxygen-independent:
Calcineurin A ( Ca2+-dependent via RACK1)
- Oxygen-Dependent:
EPF UCP (degrades pHVL)
VDU2 (de-ubiquitinates HIF1A)
SUMOylation (via RSUME)
DeSUMOylation ( via SENP1)
- EPF UCP (degrades pHVL)
- VDU2 (de-ubiquitinates HIF1A)
- SUMOylation (via RSUME)
- DeSUMOylation ( via SENP1)
- Oxygen-independent:
Calcineurin A ( Ca2+-dependent via RACK1)
- Calcineurin A ( Ca2+-dependent via RACK1)
- Modulators of translation:
RNA-binding proteins, PTB, and HuR
PtdIns3K and MAPK pathways
IRES-mediated translation
calcium signaling
miRNAs
- RNA-binding proteins, PTB, and HuR
- PtdIns3K and MAPK pathways
- IRES-mediated translation
- calcium signaling
- miRNAs
Factors decreasing HIF1A
- Modulator of Degradation:
Oxygen-Dependent:
PHD, VHL, OS-9 and SSAT2
SUMOylation
Oxygen-independent
RACK1 and SSAT1
GSK3β
FOXO4
- Oxygen-Dependent:
PHD, VHL, OS-9 and SSAT2
SUMOylation
- PHD, VHL, OS-9 and SSAT2
- SUMOylation
- Oxygen-independent
RACK1 and SSAT1
GSK3β
FOXO4
- RACK1 and SSAT1
- GSK3β
- FOXO4
- Modulators of translation:
Calcium signaling
miRNAs
- Calcium signaling
- miRNAs
# Role in cancer
HIF-1 is overexpressed in many human cancers. HIF-1 overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia. Hypoxia promotes apoptosis in both normal and tumor cells. However, hypoxic conditions in tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF-1 overexpression.
Significant HIF-1 expression has been noted in most solid tumors studied, which include cancers of the colon, breast, pancreas, kidneys, prostate, ovary, brain, and bladder. Clinically, elevated Hif-1a levels in a number of cancers, including cervical cancer, non-small-cell lung carcinoma, breast cancer (LV-positive and negative), oligodendroglioma, oropharyngeal cancer, ovarian cancer, endometrial cancer, esophageal cancer, head and neck cancer, and stomach cancer, have been associated with aggressive tumor progression, and thus has been implicated as a predictive and prognostic marker for resistance to radiation treatment, chemotherapy, and increased mortality.
HIF1A expression may also regulate breast tumor progression. Elevated HIF1A levels may be detected in early cancer development, and have been found in early ductal carcinoma in situ, a pre-invasive stage in breast cancer development, and is also associated with increased microvasculature density in tumor lesions. Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy. Similar findings have been reported in brain cancer and ovarian cancer studies as well, and suggest at regulatory role of HIF1A in initiating angiogenesis through interactions with pro-angiogenic factors such as VEGF. Studies of glioblastoma multiforme show striking similarity between HIF1A expression pattern and that of VEGF gene transcription level. In addition, high-grade glioblastoma multiform tumors with high VEGF expression pattern, similar to breast cancer with HIF1A overexpression, display significant signs of tumor neovascularization. This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.
HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemagioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor. Although in both renal carcinoma and hemagioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels. In addition to VEGF overexpression in response elevated HIF1A levels, the PI3K/AKT pathway is also involved in tumor growth. In prostate cancers, the commonly occurring PTEN mutation is associated with tumor progression toward aggressive stage, increased vascular density and angiogenesis.
During hypoxia, tumor suppressor p53 overexpression may be associated with HIF1A-dependent pathway to initiate apoptosis. Moreover, p53-independent pathway may also induce apoptosis through the Bcl-2 pathway. However, overexpression of HIF1A is cancer- and individual-specific, and depends on the accompanying genetic alternations and levels of pro- and anti-apoptotic factors present. One study on epithelial ovarian cancer shows HIF1A and nonfunctional tumor suppressor p53 is correlated with low levels of tumor cell apoptosis and poor prognosis. Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy. Studies of glioblastoma multiforme show striking similarity between HIF1A protein expression pattern and that of VEGF gene transcription level.
While research efforts to develop therapeutic drugs to target hypoxia-associated tumor cells have been ongoing for many years, there has not yet been any breakthrough that has shown selectivity and effectiveness at targeting HIF1A pathways to decrease tumor progression and angiogenesis. Successful therapeutic approaches in the future may also be highly case-specific to particular cancers and individuals, and seem unlikely to be widely applicable due to the genetically heterogenous nature of the many cancer types and subtypes.
# Interactions
HIF1A has been shown to interact with:
- ARNTL,
- ARNT,
- CREBB,
- EP300,
- HIF1AN,
- Mdm2,
- NR4A,
- P53,
- PSMA7,
- STAT3,
- UBC,
- VH and
- VHL.
- GR (NR3C1). | HIF1A
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene.[1][2][3] It is a basic helix-loop-helix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia.[4][5] The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion.[3][6] Two other alternative transcripts encoding different isoforms have been identified.[3]
# Structure
HIF1 is a heterodimeric basic helix-loop-helix structure[7] that is composed of HIF1A, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. HIF1A contains a basic helix-loop-helix domain near the C-terminal, followed by two distinct PAS (PER-ARNT-SIM) domains, and a PAC (PAS-associated C-terminal) domain.[4][8] The HIF1A polypeptide also contains a nuclear localization signal motif, two transactivating domains CTAD and NTAD, and an intervening inhibitory domain (ID) that can repress the transcriptional activities of CTAD and NTAD.[9] There are a total of three HIF1A isoforms formed by alternative splicing, however isoform1 has been chosen as the canonical structure, and is the most extensively studied isoform in structure and function.[10][11]
# Gene and expression
The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1).[12] HIF1A expression level is dependent on its GC-rich promoter activation.[13] In most cells, HIF1A gene is constitutively expressed in low levels under normoxic conditions, however, under hypoxia, HIF1A transcription is often significantly upregulated.[13][14][15][16][17][18] Typically, oxygen-independent pathway regulates protein expression, and oxygen-dependent pathway regulates degradation.[19] In hypoxia-independent ways, HIF1A expression may be upregulated through a redox-sensitive mechanism.[20]
# Function
The transcription factor HIF-1 plays an important role in cellular response to systemic oxygen levels in mammals.[21][22] HIF1A activity is regulated by a host of post-translational modifications: hydroxylation, acetylation, and phosphorylation.[23] HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions.[6][24][25] HIF-1 also induces transcription of genes involved in cell proliferation and survival, as well as glucose and iron metabolism.[25] In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription.[26][27][28][29][30] HIF1A stability, subcellular localization, as well as transcriptional activity are especially affected by oxygen level. The alpha subunit forms a heterodimer with the beta subunit. Under normoxic conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1a; however, under hypoxia, HIF1A protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes [31][32] Enzymes prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A.[33] The enzymatic activity of oxygen sensor dioxygenase PHD is dependent on oxygen level as it requires oxygen as one of its main substrates to transfer to the proline residue of HIF1A.[27][34] The hydroxylated proline residue of HIF1A is then recognized and buried in the hydrophobic core of von Hippel-Lindau tumor suppressor protein (VHL), which itself is part of a ubiquitin ligase enzyme.[35][36] The hydroxylation of HIF1A proline residue also regulates its ability to associate with co-activators under hypoxia.[37][38] Function of HIF1A gene can be effectively examined by siRNA knockdown based on an independent validation.[39]
## Repair and regeneration
In normal circumstances after injury HIF1A is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF1A via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of HIF1A results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF1A can either turn off, or turn on the key processes of mammalian regeneration.[40][41] One such regenerative process in which HIF1A is involved is peripheral nerve regeneration. Following axon injury, HIF1A activates VEGFA to promote regeneration and functional recovery. [42][43]
# Regulation
HIF1A abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner.[44] In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in the post-translation phase.[45]
PHDs rely on iron among other molecules to hydroxylate HIF1A; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF1A stabilization.[46] HBO (Hyperbaric oxygen therapy) and HIF1A imitators such as cobalt chloride have also been successfully utilized.[46]
Factors increasing HIF1A[47]
- Modulator of Degradation:
Oxygen-Dependent:
EPF UCP (degrades pHVL)
VDU2 (de-ubiquitinates HIF1A)
SUMOylation (via RSUME)
DeSUMOylation ( via SENP1)
Oxygen-independent:
Calcineurin A ( Ca2+-dependent via RACK1)
- Oxygen-Dependent:
EPF UCP (degrades pHVL)
VDU2 (de-ubiquitinates HIF1A)
SUMOylation (via RSUME)
DeSUMOylation ( via SENP1)
- EPF UCP (degrades pHVL)
- VDU2 (de-ubiquitinates HIF1A)
- SUMOylation (via RSUME)
- DeSUMOylation ( via SENP1)
- Oxygen-independent:
Calcineurin A ( Ca2+-dependent via RACK1)
- Calcineurin A ( Ca2+-dependent via RACK1)
- Modulators of translation:
RNA-binding proteins, PTB, and HuR
PtdIns3K and MAPK pathways
IRES-mediated translation
calcium signaling
miRNAs
- RNA-binding proteins, PTB, and HuR
- PtdIns3K and MAPK pathways
- IRES-mediated translation
- calcium signaling
- miRNAs
Factors decreasing HIF1A[47]
- Modulator of Degradation:
Oxygen-Dependent:
PHD, VHL, OS-9 and SSAT2
SUMOylation
Oxygen-independent
RACK1 and SSAT1
GSK3β
FOXO4
- Oxygen-Dependent:
PHD, VHL, OS-9 and SSAT2
SUMOylation
- PHD, VHL, OS-9 and SSAT2
- SUMOylation
- Oxygen-independent
RACK1 and SSAT1
GSK3β
FOXO4
- RACK1 and SSAT1
- GSK3β
- FOXO4
- Modulators of translation:
Calcium signaling
miRNAs
- Calcium signaling
- miRNAs
# Role in cancer
HIF-1 is overexpressed in many human cancers.[48][49] HIF-1 overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.[50] Hypoxia promotes apoptosis in both normal and tumor cells.[51] However, hypoxic conditions in tumor microenvironment especially, along with accumulation of genetic alternations often contribute to HIF-1 overexpression.[6]
Significant HIF-1 expression has been noted in most solid tumors studied, which include cancers of the colon, breast, pancreas, kidneys, prostate, ovary, brain, and bladder.[52][53] Clinically, elevated Hif-1a levels in a number of cancers, including cervical cancer, non-small-cell lung carcinoma, breast cancer (LV-positive and negative), oligodendroglioma, oropharyngeal cancer, ovarian cancer, endometrial cancer, esophageal cancer, head and neck cancer, and stomach cancer, have been associated with aggressive tumor progression, and thus has been implicated as a predictive and prognostic marker for resistance to radiation treatment, chemotherapy, and increased mortality.[19][54][55][56][57][58][59]
HIF1A expression may also regulate breast tumor progression. Elevated HIF1A levels may be detected in early cancer development, and have been found in early ductal carcinoma in situ, a pre-invasive stage in breast cancer development, and is also associated with increased microvasculature density in tumor lesions.[60] Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy.[61] Similar findings have been reported in brain cancer and ovarian cancer studies as well, and suggest at regulatory role of HIF1A in initiating angiogenesis through interactions with pro-angiogenic factors such as VEGF.[62][63] Studies of glioblastoma multiforme show striking similarity between HIF1A expression pattern and that of VEGF gene transcription level.[64][65] In addition, high-grade glioblastoma multiform tumors with high VEGF expression pattern, similar to breast cancer with HIF1A overexpression, display significant signs of tumor neovascularization.[66] This further suggests the regulatory role of HIF1A in promoting tumor progression, likely through hypoxia-induced VEGF expression pathways.[67]
HIF1A overexpression in tumors may also occur in a hypoxia-independent pathway. In hemagioblastoma, HIF1A expression is found in most cells sampled from the well-vascularized tumor.[68] Although in both renal carcinoma and hemagioblastoma, the von Hippel-Lindau gene is inactivated, HIF1A is still expressed at high levels.[63][68][69] In addition to VEGF overexpression in response elevated HIF1A levels, the PI3K/AKT pathway is also involved in tumor growth. In prostate cancers, the commonly occurring PTEN mutation is associated with tumor progression toward aggressive stage, increased vascular density and angiogenesis.[70]
During hypoxia, tumor suppressor p53 overexpression may be associated with HIF1A-dependent pathway to initiate apoptosis. Moreover, p53-independent pathway may also induce apoptosis through the Bcl-2 pathway.[71] However, overexpression of HIF1A is cancer- and individual-specific, and depends on the accompanying genetic alternations and levels of pro- and anti-apoptotic factors present. One study on epithelial ovarian cancer shows HIF1A and nonfunctional tumor suppressor p53 is correlated with low levels of tumor cell apoptosis and poor prognosis.[72] Further, early-stage esophageal cancer patients with demonstrated overexpression of HIF1 and absence of BCL2 expression also failed photodynamic therapy.[73] Studies of glioblastoma multiforme show striking similarity between HIF1A protein expression pattern and that of VEGF gene transcription level.
While research efforts to develop therapeutic drugs to target hypoxia-associated tumor cells have been ongoing for many years, there has not yet been any breakthrough that has shown selectivity and effectiveness at targeting HIF1A pathways to decrease tumor progression and angiogenesis.[74] Successful therapeutic approaches in the future may also be highly case-specific to particular cancers and individuals, and seem unlikely to be widely applicable due to the genetically heterogenous nature of the many cancer types and subtypes.
# Interactions
HIF1A has been shown to interact with:
- ARNTL,[75]
- ARNT,[2][76]
- CREBB,[77][78][79]
- EP300,[80][81]
- HIF1AN,[82]
- Mdm2,[83][84]
- NR4A,[85]
- P53,[83][84][86][87]
- PSMA7,[88]
- STAT3,[89]
- UBC,[79][85][90]
- VH[79][82][85][89][90][91][92][93][94][95] and
- VHL.[96]
- GR (NR3C1).[97][98] | https://www.wikidoc.org/index.php/HIF1A | |
ac0c7f0cd660651b952ce7938d0823c73c1044f7 | wikidoc | HIF3A | HIF3A
Hypoxia-inducible factor 3 alpha is a protein that in humans is encoded by the HIF3A gene.
# Function
The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. At least three transcript variants encoding three different isoforms have been found for this gene.
In rats, it plays a negative role in the adaptation to hypoxia, because the inhibition of HIF-3α expression leads to an increase in physical endurance.
# Clinical significance
DNA methylation in the introns of HIF3A is associated with BMI an adiposity. | HIF3A
Hypoxia-inducible factor 3 alpha is a protein that in humans is encoded by the HIF3A gene.[1][2][3]
# Function
The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. At least three transcript variants encoding three different isoforms have been found for this gene.[3]
In rats, it plays a negative role in the adaptation to hypoxia, because the inhibition of HIF-3α expression leads to an increase in physical endurance.[4]
# Clinical significance
DNA methylation in the introns of HIF3A is associated with BMI an adiposity.[5] | https://www.wikidoc.org/index.php/HIF3A | |
e7338a24d1fef63deb510197de5feb4fee2ced42 | wikidoc | HINT2 | HINT2
Histidine triad nucleotide binding protein 2 (HINT2) is a mitochondrial protein that in humans is encoded by the HINT2 gene on chromosome 9. This protein is an AMP-lysine hydrolase and phosphoamidase and may contribute to tumor suppression.
# Structure
As a member of the histidine triad nucleotide-binding (Hint) protein family, which is a subfamily of the histidine triad (HIT) family, HINT2 contains a conserved histidine and HIT sequence motif (His-X-His-X-His-X-X), and the latter two histidines contribute to a catalytic triad.
The 163-amino acid protein encoded by this gene forms a 17-kDa homodimer. Compared to other members of the Hint family, HINT2 has a 61% sequence homology to HINT1 and 28% sequence homology to HINT3. When compared with HINT1, the 35–amino acid extension at the HINT2 N-terminal corresponds to a predicted mitochondria import signal.
# Function
HINT2 is a member of the HIT superfamily and Hint subfamily, which are characterized as nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides. The Hint family is the oldest within the HIT superfamily and thus, its members are highly conserved among eukaryotes and archaebacteria. The Hint proteins function as AMP-lysine hydrolases and phosphoramidases. In mammals, HINT2 is expressed in the liver, adrenal cortex, and pancreas and localizes to the mitochondria within their cells. Specifically, the protein is located in the inner mitochondrial membrane, facing the mitochondrial matrix. This positioning likely facilitates the transport of cholesterol from the cytosol to the matrix, which is necessary for steroidogenesis, by providing a contact site for the hydrophobic molecule and allowing it to cross the mitochondrial intermembrane space. HINT2 regulates steroidogenesis through calcium-dependent and calcium-independent signalling pathways that may serve to maintain a favorable mitochondrial potential. Its role in calcium homeostasis may also contribute to its proapoptotic function in hepatocytes and other non-steroidogenic cells, though the exact mechanism remains unclear.
# Clinical significance
Hint2, one of the three members of the Hint family of proteins, is localized to mitochondria of various cell types. In human adrenocarcinoma cells, Hint2 modulates Ca2+ handling by mitochondria. In all living organisms, intracellular calcium controls a wide variety of physiological processes. Extracellular stimuli generate temporally organized Ca2+ signals, which most of the time occur as repetitive spikes. The frequency of these oscillations controls the nature and the extent of the cellular response. Ca2+ oscillations originate from the repetitive opening of the inositol 1,4,5-trisphosphate (InsP3) receptors that are Ca2+ channels embedded in the membrane of the endoplasmic reticulum (ER). Opening of these channels is initiated by the stimulus-induced rise in InsP3; because their activity is biphasically regulated by the level of cytoplasmic Ca2+, oscillations can occur. Mitochondria also affect cytoplasmic Ca2+ signals. They can both buffer cytosolic Ca2+ changes (7 and 8) and release Ca2+. At rest, intramitochondrial (m) and cytosolic Ca2+ concentration (i) are similar, of the order of 100 nM (9).
The Hint family has been implicated in tumor suppression. Int2, a member of the superfamily of histidine triad proteins, has been localized exclusively in mitochondria, near the contact sites of the inner membrane. This enzyme is highly expressed in the liver, where it has been shown to stimulate mitochondrial lipid metabolism, respiration, and glucose homeostasis. Hint2 modulates cytoplasmic and mitochondrial Ca2+ dynamics by stimulating the activity of the mitochondrial respiratory chain. It appears that the absence of Hint2 leads to a premature opening of the mitochondrial permeability transition pore (mPTP) in mitochondrial suspensions. As such, HINT2 plays a prominent role in mitochondrial cell death signaling (e.g. apoptosis) and in ischemia-reperfusion injury (for instance during heart attacks) through calcium homeostasis.
In particular, HINT2 is also observed to be upregulated in breast, pancreatic, and colon cancer cells, while it is downregulated in hepatocellular carcinoma and endometrial cancer. Its exact role in tumor suppression remains unknown, though studies suggest it may promote apoptosis in hepatocellular carcinoma and endometrial cancer. In double knockout Hint2 mice, higher acylation and morphological alterations were observed in the mitochondria, suggesting that Hint2 may regulate glucose and lipid metabolism.
# Interactions
Currently, HINT2 has no known protein-protein interaction partners. | HINT2
Histidine triad nucleotide binding protein 2 (HINT2) is a mitochondrial protein that in humans is encoded by the HINT2 gene on chromosome 9. This protein is an AMP-lysine hydrolase and phosphoamidase and may contribute to tumor suppression.[1][2][3][4][5]
# Structure
As a member of the histidine triad nucleotide-binding (Hint) protein family, which is a subfamily of the histidine triad (HIT) family, HINT2 contains a conserved histidine and HIT sequence motif (His-X-His-X-His-X-X), and the latter two histidines contribute to a catalytic triad.[2][4]
The 163-amino acid protein encoded by this gene forms a 17-kDa homodimer.[2][3][4] Compared to other members of the Hint family, HINT2 has a 61% sequence homology to HINT1 and 28% sequence homology to HINT3.[2] When compared with HINT1, the 35–amino acid extension at the HINT2 N-terminal corresponds to a predicted mitochondria import signal.[4]
# Function
HINT2 is a member of the HIT superfamily and Hint subfamily, which are characterized as nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides.[1] The Hint family is the oldest within the HIT superfamily and thus, its members are highly conserved among eukaryotes and archaebacteria.[2] The Hint proteins function as AMP-lysine hydrolases and phosphoramidases.[2][3][4][5] In mammals, HINT2 is expressed in the liver, adrenal cortex, and pancreas and localizes to the mitochondria within their cells.[3][4] Specifically, the protein is located in the inner mitochondrial membrane, facing the mitochondrial matrix. This positioning likely facilitates the transport of cholesterol from the cytosol to the matrix, which is necessary for steroidogenesis, by providing a contact site for the hydrophobic molecule and allowing it to cross the mitochondrial intermembrane space. HINT2 regulates steroidogenesis through calcium-dependent and calcium-independent signalling pathways that may serve to maintain a favorable mitochondrial potential. Its role in calcium homeostasis may also contribute to its proapoptotic function in hepatocytes and other non-steroidogenic cells, though the exact mechanism remains unclear.[3]
# Clinical significance
Hint2, one of the three members of the Hint family of proteins, is localized to mitochondria of various cell types. In human adrenocarcinoma cells, Hint2 modulates Ca2+ handling by mitochondria. In all living organisms, intracellular calcium controls a wide variety of physiological processes. Extracellular stimuli generate temporally organized Ca2+ signals, which most of the time occur as repetitive spikes. The frequency of these oscillations controls the nature and the extent of the cellular response. Ca2+ oscillations originate from the repetitive opening of the inositol 1,4,5-trisphosphate (InsP3) receptors that are Ca2+ channels embedded in the membrane of the endoplasmic reticulum (ER). Opening of these channels is initiated by the stimulus-induced rise in InsP3; because their activity is biphasically regulated by the level of cytoplasmic Ca2+, oscillations can occur. Mitochondria also affect cytoplasmic Ca2+ signals. They can both buffer cytosolic Ca2+ changes (7 and 8) and release Ca2+. At rest, intramitochondrial ([Ca2+]m) and cytosolic Ca2+ concentration ([Ca2+]i) are similar, of the order of 100 nM (9).
The Hint family has been implicated in tumor suppression.[2] Int2, a member of the superfamily of histidine triad proteins, has been localized exclusively in mitochondria, near the contact sites of the inner membrane. This enzyme is highly expressed in the liver, where it has been shown to stimulate mitochondrial lipid metabolism, respiration, and glucose homeostasis. Hint2 modulates cytoplasmic and mitochondrial Ca2+ dynamics by stimulating the activity of the mitochondrial respiratory chain. It appears that the absence of Hint2 leads to a premature opening of the mitochondrial permeability transition pore (mPTP) in mitochondrial suspensions. As such, HINT2 plays a prominent role in mitochondrial cell death signaling (e.g. apoptosis) and in ischemia-reperfusion injury (for instance during heart attacks) through calcium homeostasis.
In particular, HINT2 is also observed to be upregulated in breast, pancreatic, and colon cancer cells, while it is downregulated in hepatocellular carcinoma and endometrial cancer. Its exact role in tumor suppression remains unknown, though studies suggest it may promote apoptosis in hepatocellular carcinoma and endometrial cancer.[2][3][4][5] In double knockout Hint2 mice, higher acylation and morphological alterations were observed in the mitochondria, suggesting that Hint2 may regulate glucose and lipid metabolism.[6]
# Interactions
Currently, HINT2 has no known protein-protein interaction partners.[2] | https://www.wikidoc.org/index.php/HINT2 | |
aa5009b6447946e19274a437ca4a9e01d3f81a17 | wikidoc | HIPK2 | HIPK2
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene. HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors. It belongs to a family of protein kinases known as the DYRK kinases. Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3. HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.
# Discovery
HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed, yielded products that interacted with transcription factors related to the NK homeodomain . HIPKs were discovered using a technique called Two-hybrid screening. Two-hybrid screening is in conjunction with cDNA cloning, in which embryonic mouse cDNA libraries were used with mouse homeoprotein Nkx-1.2 to find genes involved with homeodomain transcription factors. The researchers found two clones that were similar in protein sequence, demonstrated a strong interaction with the homeoprotein, and an active site characteristic of protein kinases. These characteristics led to the name "HIPK". In 2000, the location of the HIPK2 gene was discovered to be on the long arm of Chromosome 7 (human) in the human genome. In mice, HIPK2 was discovered to be on Chromosome 6.
# Homology
There is evidence to suggest that HIPKs including HIPK2 are evolutionarily conserved proteins across a wide array of species. The human sequence shares a close similarity to a sequence from the genome of Caenorhabditis elegans. HIPKs also share a close similarity with YAK1 in yeast and are in the same family as a kinase from Dictyostelium. Furthermore, HIPKs are able to interact with homeoproteins from other species, such as NK-1 and NK-3 in Drosophila as well as Nkx-2.5 in mice. HIPK2 can also be found in dogs, cats, sheep, and zebrafish as well as many other species.
# Localization
## Expression in tissues
HIPK2 is expressed in nearly all tissue types, however it is highly expressed in the heart, muscle and kidneys. HIPK2 has been shown to be expressed at the highest levels in the brain and neuronal tissues. In addition to adult tissues, HIPK2 is also expressed late in the development of the Human embryo, specifically in the retina, muscles, and neural tissues.
## Sub-cellular localization
HIPK2 is found in the nucleus within structures called nuclear speckles. It is also associated with PML bodies, which are also structures found in the nucleus. Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic.
# Structure
## Gene
The HIPK2 gene contains 13 exons and 13 introns within the entire 59.1 Kilo-base pair sequence. Along with the other HIPKs, it contains three conserved sequences: a protein kinase domain, an interaction domain, a PEST sequence, and a YH domain. Alternative splicing produces three different messenger RNAs, which subsequently lead to the production of three Protein isoforms.
## Protein
The HIPK2 protein is 1198 amino acids in length and has a molecular weight of 130.97 kilodaltons. The most abundant amino acids in the protein are serine, threonine and alanine, which make up approximately 30 percent of the proteins total amino acid count. The structure of the protein in its native form is unstable. The protein is made up of several regions which directly relate to its function, regulation, and localization. The protein kinase domain is 330 amino acids long and is located near the N-terminus of the protein. In addition to its kinase domain, HIPK2 has two nuclear localization signals, a SUMO interaction motif, an auto-inhibitory domain a transcriptional co-repression domain, and several interaction domains, including one for p53. While there are signals targeting HIPK2 to nuclear speckles, there is also a speckle retention sequence that causes HIPK2 to remain in the nuclear speckles. The auto-inhibitory domain, which contains an ubiquitylation site at the K1182 residue is located at the C-terminus.
# Function
HIPK2 has two major functions. It acts as a co-repressor for NK homeodomain transcription factors, increasing their DNA binding affinity and their repressive effect on transcription. HIPK2 participates in the regulation of gene expression through its contribution to regulating homeobox genes.These genes encode transcription factors that act to regulate target genes. HIPK2 also acts in signal transduction, specifically the pathway leading to programmed cell death (apoptosis). HIPK2 can promote apoptosis either in association with p53 or by a separate mechanism. HIPK2 phosphorylates the S46 residue of p53, leading to its activation, which in turn leads to the transcription of factors that induce apoptosis. Phosphorylation of p53 by HIPK2 prevents the association of negative regulator Mdm2 to p53 and is necessary for the acetylation of the K382 residue in p53, which also serves as a functionally important modification. Proper folding of p53 is essential for p53 function. The folding of p53 depends on the presence of zinc , and HIPK2 plays a role in zinc regulation. Consequently, the absence of HIPK2 leads to p53 misfolding. HIPK2 indirectly enhances p53 activity by phosphorylating negative regulators of p53, such as CtBP1 and Mdm2, leading to their degradation by the proteasome. HIPK2 also has the ability to regulate cellular response to reactive oxygen species by regulating the expression of both oxidant and antioxidant genes.
# Regulation
HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications.
## Positive
Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation.The activity of HIPK2 is increased through the action of caspase 6. Caspase 6 cleaves HIPK2 at residue D916 and D977. As a result, the auto-inhibitory domain is removed and the activity of HIPK2 increases. HIPK2 activity can also be increased through the action of checkpoint kinases. These kinases phosphorylate HIPK2 associated ubiquitin ligases and prevent their binding to HIPK2. As a result, the degradation of HIPK2 through the ubiquitin proteasome pathway is inhibited. In conditions of oxidative stress, sumoylation of HIPK2 prevents acetylation, and as a result maintains its function in facilitating apoptosis. Under normal physiological conditions however, acetylation of HIPK2 by a protein called p300 again stabilizes HIPK2 but, increases its ability to induce apoptosis. Phosphorylation of HIPK2 at residues T880 and S882, via another kinase or through auto-phosphorylation, leads to the recruitment of PIN1 and stabilization of HIPK2. This results in increased apoptotic function of HIPK2.
## Negative
Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation. The PEST sequence found in HIPK2 is also linked to protein degradation. HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm. In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis.
## p53
p53 regulates HIPK2 using both positive and negative mechanisms. p53 binds to the third intron of the caspase 6 gene, and promotes the activation of the gene. Caspase 6 in turn activates HIPK2. Conversly, p53 down regulates HIPK2 by activating the ubiquitin ligase mdm2. An interaction of mdm2 and HIPK2 leads to the ubiquitination and eventual degradation of HIPK2.
# Mutations
Two mutations have been discovered in the speckle retention sequence, both of which are missense. One of which was named R868W, meaning that at residue 868 where the wild type amino acid sequence would have contained an arginine residue, it now contains a tryptophan residue. The other mutation was named N958I, meaning that at residue 958 where the wild type amino acid sequence would have contained an asparagine residue, it now contains an isoleucine residue. The R868W mutation is the result of cytosine to thymine point mutation and the N985I mutation resulted from an adenine to thymine point mutation. The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13. These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles. The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function.
# Interactions
HIPK2 interacts with several other proteins:
- CREB binding protein
- p53
- p300
- SKI protein
- TP53INP1
- ATM kinase
- PIN1
- HMGA1
- SIAH1
- WSB1
- caspase 6
- Tachykinin receptor 3
- Mdm2
- CtBP
# Clinical significance
Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia, myelodysplastic syndrome through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2. Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis and cardiovascular disease. | HIPK2
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.[1] HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors.[2] It belongs to a family of protein kinases known as the DYRK kinases.[3] Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3.[4] HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.
# Discovery
HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed, yielded products that interacted with transcription factors related to the NK homeodomain .[4] HIPKs were discovered using a technique called Two-hybrid screening.[4] Two-hybrid screening is in conjunction with cDNA cloning, in which embryonic mouse cDNA libraries were used with mouse homeoprotein Nkx-1.2 to find genes involved with homeodomain transcription factors.[4] The researchers found two clones that were similar in protein sequence, demonstrated a strong interaction with the homeoprotein, and an active site characteristic of protein kinases.[4] These characteristics led to the name "HIPK". In 2000, the location of the HIPK2 gene was discovered to be on the long arm of Chromosome 7 (human) in the human genome.[3] In mice, HIPK2 was discovered to be on Chromosome 6.[3]
# Homology
There is evidence to suggest that HIPKs including HIPK2 are evolutionarily conserved proteins across a wide array of species. The human sequence shares a close similarity to a sequence from the genome of Caenorhabditis elegans.[4] HIPKs also share a close similarity with YAK1 in yeast and are in the same family as a kinase from Dictyostelium.[3][4] Furthermore, HIPKs are able to interact with homeoproteins from other species, such as NK-1 and NK-3 in Drosophila as well as Nkx-2.5 in mice.[4] HIPK2 can also be found in dogs,[5] cats,[6] sheep,[7] and zebrafish[8] as well as many other species.
# Localization
## Expression in tissues
HIPK2 is expressed in nearly all tissue types, however it is highly expressed in the heart, muscle and kidneys.[9] HIPK2 has been shown to be expressed at the highest levels in the brain and neuronal tissues.[10] In addition to adult tissues, HIPK2 is also expressed late in the development of the Human embryo, specifically in the retina, muscles, and neural tissues.[10]
## Sub-cellular localization
HIPK2 is found in the nucleus within structures called nuclear speckles.[3][11] It is also associated with PML bodies, which are also structures found in the nucleus.[12] Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic.[13]
# Structure
## Gene
The HIPK2 gene contains 13 exons and 13 introns within the entire 59.1 Kilo-base pair sequence.[14][15] Along with the other HIPKs, it contains three conserved sequences: a protein kinase domain, an interaction domain, a PEST sequence, and a YH domain.[4] Alternative splicing produces three different messenger RNAs, which subsequently lead to the production of three Protein isoforms.[16]
## Protein
The HIPK2 protein is 1198 amino acids in length and has a molecular weight of 130.97 kilodaltons.[17][18] The most abundant amino acids in the protein are serine, threonine and alanine, which make up approximately 30 percent of the proteins total amino acid count.[17] The structure of the protein in its native form is unstable.[17] The protein is made up of several regions which directly relate to its function, regulation, and localization. The protein kinase domain is 330 amino acids long and is located near the N-terminus of the protein.[19][20] In addition to its kinase domain, HIPK2 has two nuclear localization signals,[21] a SUMO interaction motif,[21] an auto-inhibitory domain[19] a transcriptional co-repression domain,[9] and several interaction domains, including one for p53.[22] While there are signals targeting HIPK2 to nuclear speckles, there is also a speckle retention sequence that causes HIPK2 to remain in the nuclear speckles.[13] The auto-inhibitory domain, which contains an ubiquitylation site at the K1182 residue is located at the C-terminus.[20]
# Function
HIPK2 has two major functions. It acts as a co-repressor for NK homeodomain transcription factors, increasing their DNA binding affinity and their repressive effect on transcription.[4] HIPK2 participates in the regulation of gene expression through its contribution to regulating homeobox genes.These genes encode transcription factors that act to regulate target genes.[4] HIPK2 also acts in signal transduction, specifically the pathway leading to programmed cell death (apoptosis). HIPK2 can promote apoptosis either in association with p53 or by a separate mechanism. HIPK2 phosphorylates the S46 residue of p53, leading to its activation, which in turn leads to the transcription of factors that induce apoptosis.[23] Phosphorylation of p53 by HIPK2 prevents the association of negative regulator Mdm2 to p53 and is necessary for the acetylation of the K382 residue in p53, which also serves as a functionally important modification.[23] Proper folding of p53 is essential for p53 function. The folding of p53 depends on the presence of zinc , and HIPK2 plays a role in zinc regulation.[24] Consequently, the absence of HIPK2 leads to p53 misfolding.[23] HIPK2 indirectly enhances p53 activity by phosphorylating negative regulators of p53, such as CtBP1 and Mdm2, leading to their degradation by the proteasome.[23][25] HIPK2 also has the ability to regulate cellular response to reactive oxygen species by regulating the expression of both oxidant and antioxidant genes.[26]
# Regulation
HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications.[27][26][28][29]
## Positive
Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation.The activity of HIPK2 is increased through the action of caspase 6.[13] Caspase 6 cleaves HIPK2 at residue D916 and D977.[13] As a result, the auto-inhibitory domain is removed and the activity of HIPK2 increases. HIPK2 activity can also be increased through the action of checkpoint kinases. These kinases phosphorylate HIPK2 associated ubiquitin ligases and prevent their binding to HIPK2. As a result, the degradation of HIPK2 through the ubiquitin proteasome pathway is inhibited.[13][27] In conditions of oxidative stress, sumoylation of HIPK2 prevents acetylation, and as a result maintains its function in facilitating apoptosis.[26] Under normal physiological conditions however, acetylation of HIPK2 by a protein called p300 again stabilizes HIPK2 but, increases its ability to induce apoptosis.[28] Phosphorylation of HIPK2 at residues T880 and S882, via another kinase or through auto-phosphorylation, leads to the recruitment of PIN1 and stabilization of HIPK2.[29] This results in increased apoptotic function of HIPK2.[29]
## Negative
Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation.[13][27] The PEST sequence found in HIPK2 is also linked to protein degradation.[30] HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm.[13] In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis.[26]
## p53
p53 regulates HIPK2 using both positive and negative mechanisms.[13] p53 binds to the third intron of the caspase 6 gene, and promotes the activation of the gene.[31] Caspase 6 in turn activates HIPK2. Conversly, p53 down regulates HIPK2 by activating the ubiquitin ligase mdm2. An interaction of mdm2 and HIPK2 leads to the ubiquitination and eventual degradation of HIPK2.[13]
# Mutations
Two mutations have been discovered in the speckle retention sequence, both of which are missense.[32] One of which was named R868W, meaning that at residue 868 where the wild type amino acid sequence would have contained an arginine residue, it now contains a tryptophan residue. The other mutation was named N958I, meaning that at residue 958 where the wild type amino acid sequence would have contained an asparagine residue, it now contains an isoleucine residue. The R868W mutation is the result of cytosine to thymine point mutation and the N985I mutation resulted from an adenine to thymine point mutation.[32] The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13.[32] These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles.[32] The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function.[32]
# Interactions
HIPK2 interacts with several other proteins:
- CREB binding protein[33]
- p53[23]
- p300[28]
- SKI protein[34]
- TP53INP1[35]
- ATM kinase[13]
- PIN1[29]
- HMGA1[13]
- SIAH1[13]
- WSB1[13]
- caspase 6[31]
- Tachykinin receptor 3[4]
- Mdm2[30]
- CtBP[25]
# Clinical significance
Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia,[32] myelodysplastic syndrome[32] through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2.[36] Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis[37] and cardiovascular disease.[38] | https://www.wikidoc.org/index.php/HIPK2 | |
e096e9607a702dfbe6bcafdd4cc835a0fba28596 | wikidoc | HKDC1 | HKDC1
Hexokinase domain containing 1 (HKDC1) is an enzyme which in humans is encoded by the HKDC1 gene on chromosome 10. It is a recently discovered hexokinase isoform that likely phosphorylates glucose in maternal metabolism during pregnancy.
# Structure
The HKDC1 gene is oriented in a head-to-tail arrangement next to the HK1 gene on chromosome 10. This arrangement, along with its amino acid sequence similarity to HK1, suggests that HKDC1 and HK1 derived from the same precursor via a tandem gene duplication event. The similarity between HKDC1 and HK1 may have obscured its discovery in earlier screens for vertebrate hexokinases. Unlike the HK2 pseudogene, HKDC1 contains an intact open reading frame of 917 residues and is conserved across animal species, indicating that it encodes a functional protein. Moreover, the encoded protein contains conserved glucose-binding sites in its N- and C-terminal domains as well as an ATP-binding site in its C-terminal domain, indicating that its C-terminal is capable of hexokinase activity.
# Function
As the recently identified fifth isoform of hexokinase, HKDC1 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. Though its particular biological function remains unclear, HKDC1 has been suggested to play a more major role in glucose metabolism during pregnancy, as the mother would need to provide enough energy for both herself and the fetus. HKDC1 is ubiquitously expressed, with the highest levels of expression in pharynx, thymus, colon, esophagus, and eye tissue.
# Clinical Significance
## Cancer
Compared to the other hexokinases, HKDC1 was dramatically overexpressed in cancer tissues, indicating that this isoform might play an important and different role in cancer growth. Further experiments clarifying this role will be required for developing HKDC1 as a therapeutic target.
## Gestational hyperglycemia
Several regulatory variants, including various enhancers, targeting HKDC1 expression have been associated with gestational hyperglycemia in pregnant women. Considering that maternal glucose levels during pregnancy impact the both fetal and later health outcomes, a greater understanding of the genetic mechanisms underlying maternal glycemia during pregnancy may help identify and aid such women at risk. | HKDC1
Hexokinase domain containing 1 (HKDC1) is an enzyme which in humans is encoded by the HKDC1 gene on chromosome 10.[1] It is a recently discovered hexokinase isoform that likely phosphorylates glucose in maternal metabolism during pregnancy.[2][3]
# Structure
The HKDC1 gene is oriented in a head-to-tail arrangement next to the HK1 gene on chromosome 10.[3][4] This arrangement, along with its amino acid sequence similarity to HK1, suggests that HKDC1 and HK1 derived from the same precursor via a tandem gene duplication event.[2][3][4] The similarity between HKDC1 and HK1 may have obscured its discovery in earlier screens for vertebrate hexokinases.[2] Unlike the HK2 pseudogene, HKDC1 contains an intact open reading frame of 917 residues and is conserved across animal species, indicating that it encodes a functional protein. Moreover, the encoded protein contains conserved glucose-binding sites in its N- and C-terminal domains as well as an ATP-binding site in its C-terminal domain, indicating that its C-terminal is capable of hexokinase activity.[3][4]
# Function
As the recently identified fifth isoform of hexokinase, HKDC1 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P.[5] Though its particular biological function remains unclear, HKDC1 has been suggested to play a more major role in glucose metabolism during pregnancy, as the mother would need to provide enough energy for both herself and the fetus.[2][3] HKDC1 is ubiquitously expressed, with the highest levels of expression in pharynx, thymus, colon, esophagus, and eye tissue.[3][4]
# Clinical Significance
## Cancer
Compared to the other hexokinases, HKDC1 was dramatically overexpressed in cancer tissues, indicating that this isoform might play an important and different role in cancer growth. Further experiments clarifying this role will be required for developing HKDC1 as a therapeutic target.[5]
## Gestational hyperglycemia
Several regulatory variants, including various enhancers, targeting HKDC1 expression have been associated with gestational hyperglycemia in pregnant women.[2] Considering that maternal glucose levels during pregnancy impact the both fetal and later health outcomes, a greater understanding of the genetic mechanisms underlying maternal glycemia during pregnancy may help identify and aid such women at risk.[2][3] | https://www.wikidoc.org/index.php/HKDC1 | |
e93bc9bdf8b1fc7d105a8d0ed6e142fcc177c990 | wikidoc | HLA-A | HLA-A
HLA-A is a group of human leukocyte antigens (HLA) that are coded for by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I cell surface receptors. The others are HLA-B and HLA-C. The receptor is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is coded for by a separate region of the human genome.
MHC Class I molecules such as HLA-A are part of a process that presents short polypeptides to the immune system. These polypeptides are typically 7-11 amino acids in length and originate from proteins being expressed by the cell. There are two classes of polypeptide that can be presented by an HLA protein: those that are supposed to be expressed by the cell (self) and those of foreign derivation (non-self). Under normal conditions cytotoxic T cells, which normally patrol the body in the blood, "read" the peptide presented by the complex. T cells, if functioning properly, only bind to non-self peptides. If binding occurs, a series of events is initiated culminating in cell death via apoptosis. In this manner, the human body eliminates any cells infected by a virus or expressing proteins they shouldn't be (e.g. cancerous cells).
For humans, as in most mammalian populations, MHC Class I molecules are extremely variable in their primary structure, and HLA-A is ranked among the genes in humans with the fastest-evolving coding sequence. As of December 2013, there are 2432 known HLA-A alleles coding for 1740 active proteins and 117 null proteins. This level of variation on MHC Class I is the primary cause of transplant rejection, as random transplantation between donor and host is unlikely to result in a matching of HLA-A, B or C antigens. Evolutionary biologists also believe that the wide variation in HLAs is a result of a balancing act between conflicting pathogenic pressures. Greater variety of HLAs decreases the probability that the entire population will be wiped out by a single pathogen as certain individuals will be highly resistant to each pathogen. The effect of HLA-A variation on HIV/AIDS progression is discussed below.
# HLA-A gene
The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, α-chain, constituent of HLA-A. Variation of HLA-A α-chain is key to HLA function. This variation promotes genetic diversity in the population. Since each HLA has a different affinity for peptides of certain structures, greater variety of HLAs means greater variety of antigens to be 'presented' on the cell surface, enhancing the likelihood that a subset of the population will be resistant to a given foreign invader. This decreases the likelihood that a single pathogen has the capability to wipe out the entire human population.
Each individual can express up to two types of HLA-A, one from each of their parents. Some individuals will inherit the same HLA-A from both parents, decreasing their individual HLA diversity; however, the majority of individuals will receive two different copies of HLA-A. This same pattern follows for all HLA groups. In other words, every single person can only express either one or two of the 2432 known HLA-A alleles.
## Alleles
All HLAs are assigned a name by the World Health Organization Naming Committee for Factors of the HLA System. This name is organized to provide the most information about the particular allele while keeping the name as short as possible. An HLA name looks something like this:
HLA-A*02:01:01:02L
All alleles receive at least a four digit classification (HLA-A*02:12). The A signifies which HLA gene the allele belongs to. There are many HLA-A alleles, so that classification by serotype simplifies categorization. The next pair of digits indicates this assignment. For example, HLA-A*02:02, HLA-A*02:04, and HLA-A*02:324 are all members of the A2 serotype (designated by the *02 prefix). This group is the primary factor responsible for HLA compatibility. All numbers after this cannot be determined by serotyping and are designated through gene sequencing. The second set of digits indicates what HLA protein is produced. These are assigned in order of discovery and as of December 2013 there are 456 different HLA-A*02 proteins known (assigned names HLA-A*02:01 to HLA-A*02:456). The shortest possible HLA name includes both of these details. Each extension beyond that signifies synonymous mutations within the coding region and mutations outside the coding region. The interpretation of the extensions is covered in greater detail in current HLA naming system.
## Protein
The protein coded for by the HLA-A gene is 365 amino acids long and weighs roughly 41,000 Daltons (Da). It contains 8 exons.
The HLA-A signal peptide is a series of hydrophobic amino acids present at the N-terminus of the protein that directs it to the endoplasmic reticulum where the remaining seven domains are translated. The three α domains form the binding groove that holds a peptide for presentation to CD8+ t-cells. The transmembrane region is the region that is embedded in the phospholipid bilayer surrounding the ER lumen. The HLA-A protein is a single-pass transmembrane protein. In other words, the first four domains of the protein are inside the ER lumen, while the last three domains are present outside the lumen, giving the protein the orientation required for proper function. The last three domains of the protein form a tail of primarily β-sheets that remains in the cell's cytosol.
Once the HLA-A protein is completely translated, it must be folded into the proper shape. A molecular chaperone protein called calnexin and an enzyme called ERp57 assist in the folding process. Calnexin holds the HLA-A heavy chain while Erp57 catalyzes disulfide bonds between the heavy chain and the light, β2-microglobulin chain. This bond induces a conformational change in the heavy chain, forming the binding groove. Calnexin then dissociates with the complex, now referred to as a peptide loading complex, and is replaced by calreticulin, another chaperone protein. Short peptides are continually transported from around the cell into the ER lumen by a specialized transport protein called TAP. TAP then binds to the peptide loading complex along with another protein, called tapasin. At this point the peptide loading complex consists of HLA-A (heavy chain), β2-microglobulin (light chain), an ERp57 enzyme, calreticulin chaperone protein, TAP (with a bound peptide fragment), and tapasin. Tapasin increases the stability of TAP, in addition to stabilizing the entire peptide loading complex. At this point TAP releases the peptide it transported into the ER lumen. The proximity of the HLA-A binding groove to TAP is ensured by the peptide loading complex. This increases the likelihood that the peptide will find the groove. If the peptide's affinity for the HLA-A protein is great enough, it binds in the groove. Research suggests that tapasin may actively load peptides from TAP into the HLA-A complex while also holding class I molecules in the ER lumen until a high affinity peptide has been bound.
After a peptide of high enough affinity has bonded to the class I MHC, calreticulin, ERp57, TAP, and tapasin release the molecule. At this point the class I complex consists of an HLA-A protein bonded to a β2-microglobulin and a short peptide. It is still anchored in the ER membrane by the transmembrane domain. At some point the ER will receive a signal and the portion of the membrane holding the complex will bud off and be transported to the golgi bodies for further processing. From the golgi bodies, the complex is transported, again via vesicle transport, to the cell membrane. This is the point at which the orientation mentioned previously becomes important. The portion of the HLA-A complex holding the peptide must be on the exterior surface of the cell membrane. This is accomplished by vesicle fusion with the cell membrane.
# Function
## Natural function
MHC Class I molecules present small peptides, typically 7-10 amino acids in length, to the immune system. A glycoprotein called CD8 binds to residues 223-229 in the α3 domain of HLA-A and this glycoprotein stabilizes interactions between the t-cell receptor on cytotoxic (CD8+) T-lymphocytes and the Class I MHC. The T-cell receptor also has the potential to bind to the peptide being presented by the MHC. In a properly functioning immune system, only t-cells that do not bind self peptides are allowed out of the thymus, thus, if a T-cell binds to the peptide, it must be a foreign or abnormal peptide. The t-cell then initiates apoptosis, or programmed cell death. This process can happen as quickly as 5 minutes after initial foreign antigen presentation, although typically it takes several hours for death to become apparent. This process is the basis of acquired immunity and serves as the primary defense against viruses and other intracellular pathogens.
## Other activities
By the 1960s, it became evident that factors on donated organs and tissues often resulted in destruction of the donated tissue by the host's immune system. MHCs were originally discovered as a result of this observation (see history of HLAs for more details). There are two types of peptide presenting complexes, Class I and Class II MHCs. Each of these has multiple HLA genes, of which HLA-A is but one. There are three major HLAs that should be matched between donors and recipients. They are HLA-A, HLA-B, (both Class I MHCs) and HLA-DR (a Class II MHC). If the two tissues have the same genes coding for these three HLAs, the likelihood and severity of rejection is minimized.
# Role in disease
HLAs serve as the sole link between the immune system and what happens inside cells. Thus any alteration on the part of the HLA, be it decreased binding to a certain peptide or increased binding to a certain peptide, is expressed as, respectively, increased susceptibility to disease or decreased susceptibility to disease. In other words, certain HLAs may be incapable of binding any of the short peptides produced by proteolysis of pathogenic proteins. If this is the case, there is no way for the immune system to tell that a cell is infected. Thus the infection can proliferate largely unchecked. It works the other way too. Some HLAs bind pathogenic peptide fragments with very high affinity. This in essence "supercharges" their immune system in regards to that particular pathogen, allowing them to manage an infection that might otherwise be devastating.
## HIV/AIDS
One of the most researched examples of differential immune regulation of a pathogen is that of human immunodeficiency virus. Because HIV is an RNA virus, it mutates incredibly quickly. This changes the peptides produced via proteolysis, which changes the peptides able to be presented to the immune system by the infected cell's MHCs. Any virus with a mutation that creates a peptide with high affinity for a particular HLA is quickly killed by the immune system, and thus does not survive and that high affinity peptide is no longer produced. However, it turns out that even HIV has some conserved regions in its genome, and if a HLA is capable of binding to a peptide produced from a conserved region, there is little the HIV can do to avoid immune detection and destruction. This is the principle behind HLA-mediated differential HIV loads.
With over 2000 variations of the HLA-A coded MHC, it is difficult to determine the impact of all variants upon HIV loads. However, a select few have been implicated. HLA-A*30 has been shown to decrease viral load to less than 10,000 copies/cubic millimeter, considered quite low. On the other hand, HLA-A*02 has been implicated in high viral load (greater than 100,000 copies/cubic millimeter) when associated with HLA-B*45. Additionally, the haplotypes HLA-A*23-C*07 and HLA-A*02-C*16 typically expressed increased viral loads within the sample population of Zambians. One of the most effective HIV-inhibiting haplotypes was HLA-A*30-C*03 while one of the least effective was HLA-A*23*B*14. In summation, HLA-A*23 was highly correlated with increased HIV load among the sample population, although it is important to note that across samples of differing ethnicity this correlation decreases significantly.
Although classification of the effect of individual HLA genes and alleles on the presence of HIV is difficult, there are still some strong conclusions that can be made. Individuals who are homozygous in one or more Class I HLA genes typically progress to AIDS much more rapidly than heterozygotes. In some homozygous individuals the rate of progression is double that of heterozygotes. This differential progression is correlated fairly tightly with the degree of heterozygosity. In summation, certain HLA-A alleles are associated with differing viral loads in HIV infected patients; however, due to the diversity amongst those alleles, it is difficult to classify each and every allele's impact upon immune regulation of HIV. Nevertheless, it is possible to correlate heterozygosity in HLA-A alleles to decreased rate of progression to AIDS.
Not only do certain HLA alleles prescribe increased or decreased resistance to HIV, but HIV is able to alter HLA expression, and does so selectively leading to reduced elimination by natural killer cells (NK cells). Research has shown that HIV downregulates Class I MHC expression in infected cells. However, doing so indiscriminately opens up the opportunity for attack by NK cells, because NK cells respond to downregulation of HLA-C and HLA-E. Obviously, this mechanism has put selective pressure on the HIV virus. Thus, HIV has evolved the capability to downregulate HLA-A and HLA-B without significantly disturbing the expression of HLA-C and HLA-E. A protein coded for by the HIV genome, negative regulatory factor (Nef), induces this change by binding to the cytoplasmic tail of the Class I MHC while it is still in the endoplasmic reticulum or occasionally while it is in the early stages of trafficking through the golgi bodies. This complex of MHC and Nef then causes adaptor protein 1 (AP-1) to direct the MHC to the lysosomes for degradation instead of to the cell membrane where it normally functions. In addition to selective HLA downregulation, negative regulatory factor (Nef) enables HIV to downregulate CD4 and CD8. These glycoproteins are essential for, respectively, helper t-cell and cytotoxic t-cell binding to MHCs. Without these cofactors, both types of t-cells are less likely to bind to HLAs and initiate apoptosis, even if the HLA is expressing an HIV derived (non-self) peptide. Both of these proteins are also targeted at their cytoplasmic tail domain. The combination of these abilities greatly enhances HIV's ability to avoid detection by the immune system.
# Summary
HLA-A is one particular group of the human Class I MHCs. It consists of several hundred different genes and several thousand variant alleles. HLA-A is critical to the cytotoxic t-cell controlled immune response to viruses and other intracellular pathogens. Because each HLA-A gene has a high affinity for slightly different peptides, certain HLA-As are associated with increased risk, more rapid progression, and/or increased severity of many diseases. For similar reasons, HLA-A matching is essential to successful tissue transplants. | HLA-A
HLA-A is a group of human leukocyte antigens (HLA) that are coded for by the HLA-A locus, which is located at human chromosome 6p21.3.[1] HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I cell surface receptors. The others are HLA-B and HLA-C.[2] The receptor is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule.[3] The β2 microglobulin protein is coded for by a separate region of the human genome.[4]
MHC Class I molecules such as HLA-A are part of a process that presents short polypeptides to the immune system. These polypeptides are typically 7-11 amino acids in length and originate from proteins being expressed by the cell. There are two classes of polypeptide that can be presented by an HLA protein: those that are supposed to be expressed by the cell (self) and those of foreign derivation (non-self).[5] Under normal conditions cytotoxic T cells, which normally patrol the body in the blood, "read" the peptide presented by the complex. T cells, if functioning properly, only bind to non-self peptides. If binding occurs, a series of events is initiated culminating in cell death via apoptosis.[6] In this manner, the human body eliminates any cells infected by a virus or expressing proteins they shouldn't be (e.g. cancerous cells).
For humans, as in most mammalian populations, MHC Class I molecules are extremely variable in their primary structure, and HLA-A is ranked among the genes in humans with the fastest-evolving coding sequence. As of December 2013, there are 2432 known HLA-A alleles coding for 1740 active proteins and 117 null proteins.[2] This level of variation on MHC Class I is the primary cause of transplant rejection, as random transplantation between donor and host is unlikely to result in a matching of HLA-A, B or C antigens. Evolutionary biologists also believe that the wide variation in HLAs is a result of a balancing act between conflicting pathogenic pressures. Greater variety of HLAs decreases the probability that the entire population will be wiped out by a single pathogen as certain individuals will be highly resistant to each pathogen.[5] The effect of HLA-A variation on HIV/AIDS progression is discussed below.
# HLA-A gene
The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, α-chain, constituent of HLA-A. Variation of HLA-A α-chain is key to HLA function. This variation promotes genetic diversity in the population. Since each HLA has a different affinity for peptides of certain structures, greater variety of HLAs means greater variety of antigens to be 'presented' on the cell surface, enhancing the likelihood that a subset of the population will be resistant to a given foreign invader. This decreases the likelihood that a single pathogen has the capability to wipe out the entire human population.
Each individual can express up to two types of HLA-A, one from each of their parents. Some individuals will inherit the same HLA-A from both parents, decreasing their individual HLA diversity; however, the majority of individuals will receive two different copies of HLA-A. This same pattern follows for all HLA groups.[7] In other words, every single person can only express either one or two of the 2432 known HLA-A alleles.
## Alleles
All HLAs are assigned a name by the World Health Organization Naming Committee for Factors of the HLA System. This name is organized to provide the most information about the particular allele while keeping the name as short as possible. An HLA name looks something like this:
HLA-A*02:01:01:02L
All alleles receive at least a four digit classification (HLA-A*02:12). The A signifies which HLA gene the allele belongs to. There are many HLA-A alleles, so that classification by serotype simplifies categorization. The next pair of digits indicates this assignment. For example, HLA-A*02:02, HLA-A*02:04, and HLA-A*02:324 are all members of the A2 serotype (designated by the *02 prefix).[2] This group is the primary factor responsible for HLA compatibility. All numbers after this cannot be determined by serotyping and are designated through gene sequencing. The second set of digits indicates what HLA protein is produced. These are assigned in order of discovery and as of December 2013 there are 456 different HLA-A*02 proteins known (assigned names HLA-A*02:01 to HLA-A*02:456). The shortest possible HLA name includes both of these details.[1] Each extension beyond that signifies synonymous mutations within the coding region and mutations outside the coding region. The interpretation of the extensions is covered in greater detail in current HLA naming system.
## Protein
The protein coded for by the HLA-A gene is 365 amino acids long and weighs roughly 41,000 Daltons (Da).[8] It contains 8 exons.[9]
The HLA-A signal peptide is a series of hydrophobic amino acids present at the N-terminus of the protein that directs it to the endoplasmic reticulum where the remaining seven domains are translated.[8][9][10] The three α domains form the binding groove that holds a peptide for presentation to CD8+ t-cells. The transmembrane region is the region that is embedded in the phospholipid bilayer surrounding the ER lumen.[9] The HLA-A protein is a single-pass transmembrane protein.[8] In other words, the first four domains of the protein are inside the ER lumen, while the last three domains are present outside the lumen, giving the protein the orientation required for proper function. The last three domains of the protein form a tail of primarily β-sheets that remains in the cell's cytosol.[9]
Once the HLA-A protein is completely translated, it must be folded into the proper shape. A molecular chaperone protein called calnexin and an enzyme called ERp57 assist in the folding process. Calnexin holds the HLA-A heavy chain while Erp57 catalyzes disulfide bonds between the heavy chain and the light, β2-microglobulin chain. This bond induces a conformational change in the heavy chain, forming the binding groove. Calnexin then dissociates with the complex, now referred to as a peptide loading complex, and is replaced by calreticulin, another chaperone protein. Short peptides are continually transported from around the cell into the ER lumen by a specialized transport protein called TAP. TAP then binds to the peptide loading complex along with another protein, called tapasin. At this point the peptide loading complex consists of HLA-A (heavy chain), β2-microglobulin (light chain), an ERp57 enzyme, calreticulin chaperone protein, TAP (with a bound peptide fragment), and tapasin. Tapasin increases the stability of TAP, in addition to stabilizing the entire peptide loading complex. At this point TAP releases the peptide it transported into the ER lumen. The proximity of the HLA-A binding groove to TAP is ensured by the peptide loading complex. This increases the likelihood that the peptide will find the groove. If the peptide's affinity for the HLA-A protein is great enough, it binds in the groove.[12] Research suggests that tapasin may actively load peptides from TAP into the HLA-A complex while also holding class I molecules in the ER lumen until a high affinity peptide has been bound.[13]
After a peptide of high enough affinity has bonded to the class I MHC, calreticulin, ERp57, TAP, and tapasin release the molecule.[12] At this point the class I complex consists of an HLA-A protein bonded to a β2-microglobulin and a short peptide. It is still anchored in the ER membrane by the transmembrane domain. At some point the ER will receive a signal and the portion of the membrane holding the complex will bud off and be transported to the golgi bodies for further processing. From the golgi bodies, the complex is transported, again via vesicle transport, to the cell membrane. This is the point at which the orientation mentioned previously becomes important. The portion of the HLA-A complex holding the peptide must be on the exterior surface of the cell membrane. This is accomplished by vesicle fusion with the cell membrane.[10]
# Function
## Natural function
MHC Class I molecules present small peptides, typically 7-10 amino acids in length, to the immune system. A glycoprotein called CD8 binds to residues 223-229 in the α3 domain of HLA-A and this glycoprotein stabilizes interactions between the t-cell receptor on cytotoxic (CD8+) T-lymphocytes and the Class I MHC.[14] The T-cell receptor also has the potential to bind to the peptide being presented by the MHC. In a properly functioning immune system, only t-cells that do not bind self peptides are allowed out of the thymus, thus, if a T-cell binds to the peptide, it must be a foreign or abnormal peptide. The t-cell then initiates apoptosis, or programmed cell death. This process can happen as quickly as 5 minutes after initial foreign antigen presentation, although typically it takes several hours for death to become apparent.[15] This process is the basis of acquired immunity and serves as the primary defense against viruses and other intracellular pathogens.
## Other activities
By the 1960s, it became evident that factors on donated organs and tissues often resulted in destruction of the donated tissue by the host's immune system. MHCs were originally discovered as a result of this observation (see history of HLAs for more details).[5] There are two types of peptide presenting complexes, Class I and Class II MHCs. Each of these has multiple HLA genes, of which HLA-A is but one. There are three major HLAs that should be matched between donors and recipients. They are HLA-A, HLA-B, (both Class I MHCs) and HLA-DR (a Class II MHC).[7] If the two tissues have the same genes coding for these three HLAs, the likelihood and severity of rejection is minimized.[16]
# Role in disease
HLAs serve as the sole link between the immune system and what happens inside cells. Thus any alteration on the part of the HLA, be it decreased binding to a certain peptide or increased binding to a certain peptide, is expressed as, respectively, increased susceptibility to disease or decreased susceptibility to disease. In other words, certain HLAs may be incapable of binding any of the short peptides produced by proteolysis of pathogenic proteins. If this is the case, there is no way for the immune system to tell that a cell is infected. Thus the infection can proliferate largely unchecked. It works the other way too. Some HLAs bind pathogenic peptide fragments with very high affinity. This in essence "supercharges" their immune system in regards to that particular pathogen, allowing them to manage an infection that might otherwise be devastating.[5]
## HIV/AIDS
One of the most researched examples of differential immune regulation of a pathogen is that of human immunodeficiency virus. Because HIV is an RNA virus, it mutates incredibly quickly. This changes the peptides produced via proteolysis, which changes the peptides able to be presented to the immune system by the infected cell's MHCs. Any virus with a mutation that creates a peptide with high affinity for a particular HLA is quickly killed by the immune system, and thus does not survive and that high affinity peptide is no longer produced. However, it turns out that even HIV has some conserved regions in its genome, and if a HLA is capable of binding to a peptide produced from a conserved region, there is little the HIV can do to avoid immune detection and destruction.[5] This is the principle behind HLA-mediated differential HIV loads.
With over 2000 variations of the HLA-A coded MHC, it is difficult to determine the impact of all variants upon HIV loads. However, a select few have been implicated. HLA-A*30 has been shown to decrease viral load to less than 10,000 copies/cubic millimeter, considered quite low. On the other hand, HLA-A*02 has been implicated in high viral load (greater than 100,000 copies/cubic millimeter) when associated with HLA-B*45. Additionally, the haplotypes HLA-A*23-C*07 and HLA-A*02-C*16 typically expressed increased viral loads within the sample population of Zambians. One of the most effective HIV-inhibiting haplotypes was HLA-A*30-C*03 while one of the least effective was HLA-A*23*B*14. In summation, HLA-A*23 was highly correlated with increased HIV load among the sample population, although it is important to note that across samples of differing ethnicity this correlation decreases significantly.[18]
Although classification of the effect of individual HLA genes and alleles on the presence of HIV is difficult, there are still some strong conclusions that can be made. Individuals who are homozygous in one or more Class I HLA genes typically progress to AIDS much more rapidly than heterozygotes. In some homozygous individuals the rate of progression is double that of heterozygotes. This differential progression is correlated fairly tightly with the degree of heterozygosity.[19] In summation, certain HLA-A alleles are associated with differing viral loads in HIV infected patients; however, due to the diversity amongst those alleles, it is difficult to classify each and every allele's impact upon immune regulation of HIV. Nevertheless, it is possible to correlate heterozygosity in HLA-A alleles to decreased rate of progression to AIDS.
Not only do certain HLA alleles prescribe increased or decreased resistance to HIV, but HIV is able to alter HLA expression, and does so selectively leading to reduced elimination by natural killer cells (NK cells). Research has shown that HIV downregulates Class I MHC expression in infected cells. However, doing so indiscriminately opens up the opportunity for attack by NK cells, because NK cells respond to downregulation of HLA-C and HLA-E. Obviously, this mechanism has put selective pressure on the HIV virus. Thus, HIV has evolved the capability to downregulate HLA-A and HLA-B without significantly disturbing the expression of HLA-C and HLA-E.[20] A protein coded for by the HIV genome, negative regulatory factor (Nef), induces this change by binding to the cytoplasmic tail of the Class I MHC while it is still in the endoplasmic reticulum or occasionally while it is in the early stages of trafficking through the golgi bodies. This complex of MHC and Nef then causes adaptor protein 1 (AP-1) to direct the MHC to the lysosomes for degradation instead of to the cell membrane where it normally functions.[21] In addition to selective HLA downregulation, negative regulatory factor (Nef) enables HIV to downregulate CD4 and CD8. These glycoproteins are essential for, respectively, helper t-cell and cytotoxic t-cell binding to MHCs. Without these cofactors, both types of t-cells are less likely to bind to HLAs and initiate apoptosis, even if the HLA is expressing an HIV derived (non-self) peptide. Both of these proteins are also targeted at their cytoplasmic tail domain.[21] The combination of these abilities greatly enhances HIV's ability to avoid detection by the immune system.
# Summary
HLA-A is one particular group of the human Class I MHCs. It consists of several hundred different genes and several thousand variant alleles. HLA-A is critical to the cytotoxic t-cell controlled immune response to viruses and other intracellular pathogens. Because each HLA-A gene has a high affinity for slightly different peptides, certain HLA-As are associated with increased risk, more rapid progression, and/or increased severity of many diseases. For similar reasons, HLA-A matching is essential to successful tissue transplants. | https://www.wikidoc.org/index.php/HLA-A | |
3d6f8ccc9ec72d99b38bab309d883c89c49d4f95 | wikidoc | HLA-B | HLA-B
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.
HLA is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. Genes in this complex are separated into three basic groups: class I, class II, and class III. In humans, the HLA-B gene and two related genes, HLA-A and HLA-C, are the major genes in MHC class I.
MHC class I genes provide instructions for making proteins that are present on the surface of almost all cells. On the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from within the cell. MHC class I proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by destroying the infected cell.
The HLA-B gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign invaders. Hundreds of versions (alleles) of HLA-B are known, each of which is given a particular number (such as HLA-B27). Closely related alleles are categorized together; for example, at least 28 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2728.
The HLA-B gene is located on the short (p) arm of chromosome 6 at cytoband 21.3, from base pair 31,353,871 to 31,357,211
# Related conditions
Ankylosing spondylitis: A version of the HLA-B gene called HLA-B27 increases the risk of developing ankylosing spondylitis. It is uncertain how HLA-B27 causes this increased risk. Researchers speculate that HLA-B27 may abnormally display to the immune system peptides that trigger arthritis. Other research suggests that joint inflammation characteristic of this disorder may result from improper folding of the HLA-B27 protein or the presence of abnormal forms of the protein on the cell surface. Although most patients with ankylosing spondylitis have the HLA-B27 variation, many people with this particular variation never develop the disorder. Other genetic and environmental factors are likely to affect the chances of developing ankylosing spondylitis and influence its progression.
HLA-B27 is associated with the spondyloarthropathies, a group of disorders that includes ankylosing spondylitis and other inflammatory joint diseases. Some of these diseases are associated with a common skin condition called psoriasis or chronic inflammatory bowel disorders (Crohn's disease and ulcerative colitis). One of the spondyloarthropathies, reactive arthritis, is typically triggered by bacterial infections of the gastrointestinal or genital tract. Following an infection, affected individuals may develop arthritis, back pain, and eye inflammation. Like ankylosing spondylitis, many factors probably contribute to the development of reactive arthritis and other spondyloarthropathies.
Other disorders: Several variations of the HLA-B gene are associated with adverse reactions to certain drugs. For example, two specific versions of this gene are related to increased drug sensitivity among the Han Chinese population. Individuals who have HLA-B*1502 are more likely to experience a severe skin disorder called Stevens–Johnson syndrome in response to carbamazepine (a drug used to treat seizures). Another version, HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol (a drug used to treat gout, which is a form of arthritis caused by uric acid in the joints).
Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B*5701 is associated with an extreme sensitivity to abacavir. This drug is a treatment for HIV-1 that slows the spread of the virus in the body. People with abacavir hypersensitivity often develop a fever, chills, rash, upset stomach, and other symptoms when treated with this drug.
Several other variations of the HLA-B gene appear to play a role in the progression of HIV infection to acquired immunodeficiency syndrome (AIDS). AIDS is a disease that damages the immune system, preventing it from effectively defending the body against infections. The signs and symptoms of AIDS may not appear until 10 years or more after infection with HIV. Studies suggest that people with HIV infection who have HLA-B27 or HLA-B57 tend to progress more slowly than usual to AIDS. On the other hand, researchers believe that HIV-positive individuals who have HLA-B35 tend to develop the signs and symptoms of AIDS more quickly than usual. Other factors also influence the progression of HIV to AIDS.
Another version of the HLA-B gene, HLA-B53, has been shown to help protect against severe malaria. HLA-B53 is most common in West African populations, where malaria is a frequent cause of death in children. Researchers suggest that this version of the HLA-B gene may help the immune system respond more effectively to the parasite that causes malaria.
# HLA-B and graft compatibility
HLA-B is one of three major HLAs that should be matched between donors and recipients. They are HLA-A, HLA-B, (both Class I MHCs) and HLA-DR (a Class II MHC). If the two tissues have the same genes coding for these three HLAs, the likelihood and severity of rejection is minimized. | HLA-B
HLA-B (major histocompatibility complex, class I, B) is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.
HLA is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. Genes in this complex are separated into three basic groups: class I, class II, and class III. In humans, the HLA-B gene and two related genes, HLA-A and HLA-C, are the major genes in MHC class I.
MHC class I genes provide instructions for making proteins that are present on the surface of almost all cells. On the cell surface, these proteins are bound to protein fragments (peptides) that have been exported from within the cell. MHC class I proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by destroying the infected cell.
The HLA-B gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign invaders. Hundreds of versions (alleles) of HLA-B are known, each of which is given a particular number (such as HLA-B27). Closely related alleles are categorized together; for example, at least 28 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2728.
The HLA-B gene is located on the short (p) arm of chromosome 6 at cytoband 21.3, from base pair 31,353,871 to 31,357,211 [1]
# Related conditions
Ankylosing spondylitis: A version of the HLA-B gene called HLA-B27 increases the risk of developing ankylosing spondylitis. It is uncertain how HLA-B27 causes this increased risk. Researchers speculate that HLA-B27 may abnormally display to the immune system peptides that trigger arthritis. Other research suggests that joint inflammation characteristic of this disorder may result from improper folding of the HLA-B27 protein or the presence of abnormal forms of the protein on the cell surface. Although most patients with ankylosing spondylitis have the HLA-B27 variation, many people with this particular variation never develop the disorder. Other genetic and environmental factors are likely to affect the chances of developing ankylosing spondylitis and influence its progression.
HLA-B27 is associated with the spondyloarthropathies, a group of disorders that includes ankylosing spondylitis and other inflammatory joint diseases. Some of these diseases are associated with a common skin condition called psoriasis or chronic inflammatory bowel disorders (Crohn's disease and ulcerative colitis). One of the spondyloarthropathies, reactive arthritis, is typically triggered by bacterial infections of the gastrointestinal or genital tract. Following an infection, affected individuals may develop arthritis, back pain, and eye inflammation. Like ankylosing spondylitis, many factors probably contribute to the development of reactive arthritis and other spondyloarthropathies.
Other disorders: Several variations of the HLA-B gene are associated with adverse reactions to certain drugs. For example, two specific versions of this gene are related to increased drug sensitivity among the Han Chinese population. Individuals who have HLA-B*1502 are more likely to experience a severe skin disorder called Stevens–Johnson syndrome in response to carbamazepine (a drug used to treat seizures). Another version, HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol (a drug used to treat gout, which is a form of arthritis caused by uric acid in the joints).
Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B*5701 is associated with an extreme sensitivity to abacavir. This drug is a treatment for HIV-1 that slows the spread of the virus in the body. People with abacavir hypersensitivity often develop a fever, chills, rash, upset stomach, and other symptoms when treated with this drug.
Several other variations of the HLA-B gene appear to play a role in the progression of HIV infection to acquired immunodeficiency syndrome (AIDS). AIDS is a disease that damages the immune system, preventing it from effectively defending the body against infections. The signs and symptoms of AIDS may not appear until 10 years or more after infection with HIV. Studies suggest that people with HIV infection who have HLA-B27 or HLA-B57 tend to progress more slowly than usual to AIDS. On the other hand, researchers believe that HIV-positive individuals who have HLA-B35 tend to develop the signs and symptoms of AIDS more quickly than usual. Other factors also influence the progression of HIV to AIDS.
Another version of the HLA-B gene, HLA-B53, has been shown to help protect against severe malaria.[2] HLA-B53 is most common in West African populations, where malaria is a frequent cause of death in children. Researchers suggest that this version of the HLA-B gene may help the immune system respond more effectively to the parasite that causes malaria.
# HLA-B and graft compatibility
HLA-B is one of three major HLAs that should be matched between donors and recipients. They are HLA-A, HLA-B, (both Class I MHCs) and HLA-DR (a Class II MHC).[3] If the two tissues have the same genes coding for these three HLAs, the likelihood and severity of rejection is minimized.[4] | https://www.wikidoc.org/index.php/HLA-B | |
81f714f54440968cf70cd6743c0ec2ed95c0465c | wikidoc | HLA-E | HLA-E
HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23.
# Structure
Like other MHC class I molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain (β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8 exons. Exon one encodes the signal peptide, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the transmembrane domain, and exons 6 and 7 encode the cytoplasmic tail.
# Function
HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells). HLA-E binds a restricted subset of peptides derived from signal peptides of classical MHC class I molecules, namely HLA-A, B, C, G. These peptides are released from the membrane of the endoplasmic reticulum (ER) by the signal peptide peptidase and trimmed by the cytosolic proteasome. Upon transport into the ER lumen by the transporter associated with antigen processing (TAP), these peptides bind to a peptide binding groove on the HLA-E molecule. This allows HLA-E to assemble correctly and to be expressed on the cell surface. NK cells recognize the HLA-E+peptide complex using the heterodimeric receptor CD94/NKG2A/B/C. When CD94/NKG2A or CD94/NKG2B is engaged, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis. However, binding of HLA-E to CD94/NKG2C results in NK cell activation. This interaction has been shown to trigger expansion of NK cell subsets in antiviral responses. | HLA-E
HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene.[1] The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23.
# Structure
Like other MHC class I molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain (β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8 exons. Exon one encodes the signal peptide, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the transmembrane domain, and exons 6 and 7 encode the cytoplasmic tail.[2]
# Function
HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells).[3] HLA-E binds a restricted subset of peptides derived from signal peptides of classical MHC class I molecules, namely HLA-A, B, C, G.[4] These peptides are released from the membrane of the endoplasmic reticulum (ER) by the signal peptide peptidase and trimmed by the cytosolic proteasome.[5][6] Upon transport into the ER lumen by the transporter associated with antigen processing (TAP), these peptides bind to a peptide binding groove on the HLA-E molecule.[7] This allows HLA-E to assemble correctly and to be expressed on the cell surface. NK cells recognize the HLA-E+peptide complex using the heterodimeric receptor CD94/NKG2A/B/C.[3] When CD94/NKG2A or CD94/NKG2B is engaged, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis. However, binding of HLA-E to CD94/NKG2C results in NK cell activation. This interaction has been shown to trigger expansion of NK cell subsets in antiviral responses.[8] | https://www.wikidoc.org/index.php/HLA-E | |
d49a9b6c602cce6ce017690060ab18229084e4d1 | wikidoc | HLA-F | HLA-F
HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.
# HLA-F
The Major Histocompatibility Complex (MHC) is a group of cell surface proteins that in humans is also called the Human Leukocyte Antigen (HLA) complex. These proteins are encoded by a cluster of genes known as the HLA locus. The HLA locus occupies a ~ 3Mbp stretch that is located on the short arm of chromosome 6, specifically on 6p21.1-21.3. The MHC proteins are classified into three main categories, namely class I, II, and III. There are over 140 genes within the HLA locus and they are often called HLA genes. HLA-A, B, and C are the classical class I genes and HLA-E, F and G are the nonclassical class I genes. The protein encoded from the gene HLA-F was originally isolated from the human lymphoblastoid cell line 721.
# Gene
The HLA-F gene is located on the short arm of chromosome 6, telomeric to the HLA-A locus. HLA-F has little allelic polymorphism and is highly conserved in other primates. HLA-F appears to be a recombinant between two multigene families, one that comprises conserved sequences found in all class I proteins (single transmembrane span) and another distinct family of genes with a conserved 3’ UTR. Many of these genes are highly transcribed and differentially expressed.
# Protein
The HLA-F protein is a ~40-41 kDa molecule with conserved domains. Exon 7 is absent from the mRNA of HLA-F. The absence of this exon produces a modification in the cytoplasmic tail of the protein making it shorter relative to classical HLA class-I proteins. The cytoplasmic tail helps HLA-F exit the endoplasmic reticulum, and that function is primarily done by the amino acid valine found at the C-terminal end of the tail.
# Expression
Classic HLA class I molecules interact with HLA-F through their heavy chain. However, HLA class I molecules only interact with HLA-F when they are in the form of an open conformer (free of peptide). Thus, HLA-F is expressed independently of bound peptide.
## Intracellular expression
HLA-F is expressed intracellularly in peripheral blood lymphocytes (PBL), resting lymphocyte cells (B, T, NK, and monocytes), tonsils, spleen, thymus, bladder, brain, colon, kidney, liver, lymphoblast, T cell leukemia, choriocarcinoma, and carcinoma.
## Extracellular expression
HLA-F is expressed on the cell surface of activated lymphocytes, HeLa cells, EBV-transformed lymphoblastoid cells, and in some activated monocyte cell lines. The surface expression of HLA-F coincides with the activated immune response since HLA-F is mostly found on the surface of stimulated T memory cells but not on circulating regulatory T cells.
## Expression during pregnancy
HLA-F is expressed on the cells that surround the forming placenta (called extravillous trophoblasts), which are in direct contact with the maternal uterine cells. In these cells, HLA-F is expressed both intracellularly and on the surface.
# Function
HLA-F belongs to the non-classical HLA class I heavy chain paralogues. Compared to classical HLA class I molecules, it exhibits very few polymorphisms. This class I molecule mainly exists as a heterodimer associated with the invariant light chain beta-2 microglobulin. The heavy chain is approximately 42 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, the putative peptide binding sites, exon 4 encodes the alpha3 domain, exon 5 and 6 encode the transmembrane region and exons 7 and 8 the cytoplasmic tail. However, exons 7 and 8 (the cytoplasmic tail) are not translated due to an in-frame translation termination codon in exon 6.
HLA-F is currently the most enigmatic of the HLA molecules. Hence, its precise functions still remain to be resolved. Though, in contrast to other HLA molecules, it mainly resides intracellularly and rarely reaches the cell surface, e.g. upon activation of NK, B and T cells. Unlike classical HLA class I molecules, which possess ten highly conserved amino acids responsible for antigen recognition, HLA-F only has 5, suggesting a biological function different from peptide presentation. Upon immune cell activation, HLA-F binds free forms of HLA class I molecules and reaches the cell surface as heterodimer. In this way HLA-F stabilizes HLA class I molecules that haven't yet bound peptides, thereby acting as a chaperone and transporting the free HLA class I to, on, and from the cell surface.
## Association with specialized ligands
HLA-F has been observed only in a subset of cell membranes, mostly B cells and activated lymphocytes. As a result, it has been suggested that its role involves association with specialized ligands that become available in the cell membrane of activated cells. For example, HLA-F can act as a peptide binding of ILT2 and ILT4. HLA-F can associate with TAP (transporter associated with antigen processing) and with the multimeric complex involved in peptide loading.
## Maternal immunity tolerance
It has been observed that all three non-classical HLA class I proteins are expressed in placental trophoblasts in contact with maternal immune cells. This suggests that these proteins collaborate in the immune response and that HLA-F plays a fundamental role in both normal and maternal immune response. HLA-F is also expressed in decidual extravillous trophoblasts. During pregnancy, HLA-F interacts with T reg cells and extravillous trophoblasts mediating maternal tolerance to the fetus.
## Intermolecular communication
During the interaction between HLA-F and the heavy chain (HC) of HLA class I molecules in activated lymphocytes, HLA-F plays a role as a chaperone, escorting HLA class I HC to the cell surface and stabilizing its expression in the absence of peptide. HLA-F binds most allelic forms of HLA class I open conformers, but it does not bind peptide complexes.
The expression patterns of HLA-F in T cells suggest that HLA-F is involved in the communication pathway between T reg and activated T cells, where HLA-F signals that the immune response has been activated. During this communication, either HLA-F invokes secretion of inhibitory cytokines by the regulatory T cells or it provides a simple inhibitory signal to the regulatory T cells, allowing a normal immune response to proceed.
## Exogenous antigen cross-presentation
Viral proteins and other exogenous antigens decrease surface HLA-F expression because the exogenous proteins interact with HLA class I molecules at the same sites where HLA-F interacts, producing crosslinking. The exogenous proteins trigger an internal co-localization of both HLA-F and HLA class I molecules. Exogenous proteins with higher affinity will interact more readily with HLA class I molecules triggering a dissociation of HLA class I/HLA-F, thereby reducing the surface levels of HLA-F. HLA-F interacts with the open conformer (OC) of HLA class I and they function together in cross-presentation of exogenous antigen. Exogenous antigen binds to a structure on the surface of activated cells; this structure is composed of HLA class I open conformer and HLA-F; the peptide-binding point of contact is a specific HLA class I epitope on the exogenous antigen.
## Ligand during inflammatory response
The complex HLA-F/HLA class I OC has two distinct roles that are central to the inflammatory response: first, it is a ligand for KIR receptors and can both activate and inhibit KIR; second, it is involved in cross-presentation of exogenous antigen.
The complex HLA-F/HLA class-I OC is a ligand for a subset of KIR (Killer-cell immunoglobulin-like receptor) receptors. Specifically, it was demonstrated that HLA-F interacts physically and functionally with three KIR receptors: KIR3DL2, KIR2DS4, and KIR3DS1, particularly during the inflammatory response. KIR directly interacts with both HLA-F and HLA class-I individually (i.e. no dimerization between HLA-F and HLA class-I is necessary).
# Disease association
HLA-F has been linked to several diseases (Table). For cancer and tumors, HLA-F expression has been found to be enhanced in gastric adenocarcinoma, breast cancer, esophageal carcinoma, lung cancer, hepatocellular carcinoma, and neuroblastoma. HLA-F has also been associated with susceptibility to several diseases: hepatitis B, Systemic Lupus Erythematosus, and Type 1 diabetes (T1D). | HLA-F
HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.[1][2]
# HLA-F
The Major Histocompatibility Complex (MHC) is a group of cell surface proteins that in humans is also called the Human Leukocyte Antigen (HLA) complex. These proteins are encoded by a cluster of genes known as the HLA locus. The HLA locus occupies a ~ 3Mbp stretch that is located on the short arm of chromosome 6, specifically on 6p21.1-21.3.[3] The MHC proteins are classified into three main categories, namely class I, II, and III. There are over 140 genes within the HLA locus and they are often called HLA genes.[4][5] HLA-A, B, and C are the classical class I genes and HLA-E, F and G are the nonclassical class I genes.[6][7] The protein encoded from the gene HLA-F was originally isolated from the human lymphoblastoid cell line 721.[8]
# Gene
The HLA-F gene is located on the short arm of chromosome 6, telomeric to the HLA-A locus.[6] HLA-F has little allelic polymorphism[9] and is highly conserved in other primates.[10] HLA-F appears to be a recombinant between two multigene families, one that comprises conserved sequences found in all class I proteins (single transmembrane span) and another distinct family of genes with a conserved 3’ UTR. Many of these genes are highly transcribed and differentially expressed.[1]
# Protein
The HLA-F protein is a ~40-41 kDa molecule with conserved domains.[11] Exon 7 is absent from the mRNA of HLA-F.[1][12] The absence of this exon produces a modification in the cytoplasmic tail of the protein making it shorter relative to classical HLA class-I proteins.[1] The cytoplasmic tail helps HLA-F exit the endoplasmic reticulum,[13] and that function is primarily done by the amino acid valine found at the C-terminal end of the tail.[13][14]
# Expression
Classic HLA class I molecules interact with HLA-F through their heavy chain.[14] However, HLA class I molecules only interact with HLA-F when they are in the form of an open conformer (free of peptide). Thus, HLA-F is expressed independently of bound peptide.[14][15]
## Intracellular expression
HLA-F is expressed intracellularly in peripheral blood lymphocytes (PBL), resting lymphocyte cells (B, T, NK, and monocytes), tonsils, spleen, thymus, bladder, brain, colon, kidney, liver, lymphoblast, T cell leukemia, choriocarcinoma, and carcinoma.[11][16][17]
## Extracellular expression
HLA-F is expressed on the cell surface of activated lymphocytes, HeLa cells, EBV-transformed lymphoblastoid cells, and in some activated monocyte cell lines.[13][16] The surface expression of HLA-F coincides with the activated immune response since HLA-F is mostly found on the surface of stimulated T memory cells but not on circulating regulatory T cells.[18]
## Expression during pregnancy
HLA-F is expressed on the cells that surround the forming placenta (called extravillous trophoblasts), which are in direct contact with the maternal uterine cells.[19] In these cells, HLA-F is expressed both intracellularly and on the surface.[19]
# Function
HLA-F belongs to the non-classical HLA class I heavy chain paralogues. Compared to classical HLA class I molecules, it exhibits very few polymorphisms. This class I molecule mainly exists as a heterodimer associated with the invariant light chain beta-2 microglobulin. The heavy chain is approximately 42 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, the putative peptide binding sites, exon 4 encodes the alpha3 domain, exon 5 and 6 encode the transmembrane region and exons 7 and 8 the cytoplasmic tail. However, exons 7 and 8 (the cytoplasmic tail) are not translated due to an in-frame translation termination codon in exon 6.[2]
HLA-F is currently the most enigmatic of the HLA molecules. Hence, its precise functions still remain to be resolved. Though, in contrast to other HLA molecules, it mainly resides intracellularly and rarely reaches the cell surface, e.g. upon activation of NK, B and T cells. Unlike classical HLA class I molecules, which possess ten highly conserved amino acids responsible for antigen recognition, HLA-F only has 5, suggesting a biological function different from peptide presentation. Upon immune cell activation, HLA-F binds free forms of HLA class I molecules and reaches the cell surface as heterodimer. In this way HLA-F stabilizes HLA class I molecules that haven't yet bound peptides, thereby acting as a chaperone and transporting the free HLA class I to, on, and from the cell surface.[20]
## Association with specialized ligands
HLA-F has been observed only in a subset of cell membranes, mostly B cells and activated lymphocytes.[19] As a result, it has been suggested that its role involves association with specialized ligands that become available in the cell membrane of activated cells.[11] For example, HLA-F can act as a peptide binding of ILT2 and ILT4.[17][21] HLA-F can associate with TAP (transporter associated with antigen processing) and with the multimeric complex involved in peptide loading.[11][17][16][18]
## Maternal immunity tolerance
It has been observed that all three non-classical HLA class I proteins are expressed in placental trophoblasts in contact with maternal immune cells.[9] This suggests that these proteins collaborate in the immune response and that HLA-F plays a fundamental role in both normal and maternal immune response.[9] HLA-F is also expressed in decidual extravillous trophoblasts.[19] During pregnancy, HLA-F interacts with T reg cells and extravillous trophoblasts mediating maternal tolerance to the fetus.[18]
## Intermolecular communication
During the interaction between HLA-F and the heavy chain (HC) of HLA class I molecules in activated lymphocytes, HLA-F plays a role as a chaperone, escorting HLA class I HC to the cell surface and stabilizing its expression in the absence of peptide.[14] HLA-F binds most allelic forms of HLA class I open conformers, but it does not bind peptide complexes.[15]
The expression patterns of HLA-F in T cells suggest that HLA-F is involved in the communication pathway between T reg and activated T cells, where HLA-F signals that the immune response has been activated. During this communication, either HLA-F invokes secretion of inhibitory cytokines by the regulatory T cells or it provides a simple inhibitory signal to the regulatory T cells, allowing a normal immune response to proceed.[18]
## Exogenous antigen cross-presentation
Viral proteins and other exogenous antigens decrease surface HLA-F expression because the exogenous proteins interact with HLA class I molecules at the same sites where HLA-F interacts, producing crosslinking. The exogenous proteins trigger an internal co-localization of both HLA-F and HLA class I molecules.[15] Exogenous proteins with higher affinity will interact more readily with HLA class I molecules triggering a dissociation of HLA class I/HLA-F, thereby reducing the surface levels of HLA-F.[15] HLA-F interacts with the open conformer (OC) of HLA class I and they function together in cross-presentation of exogenous antigen. Exogenous antigen binds to a structure on the surface of activated cells; this structure is composed of HLA class I open conformer and HLA-F; the peptide-binding point of contact is a specific HLA class I epitope on the exogenous antigen.[15]
## Ligand during inflammatory response
The complex HLA-F/HLA class I OC has two distinct roles that are central to the inflammatory response: first, it is a ligand for KIR receptors and can both activate and inhibit KIR; second, it is involved in cross-presentation of exogenous antigen.[22][23][24]
The complex HLA-F/HLA class-I OC is a ligand for a subset of KIR (Killer-cell immunoglobulin-like receptor) receptors.[22] Specifically, it was demonstrated that HLA-F interacts physically and functionally with three KIR receptors: KIR3DL2, KIR2DS4, and KIR3DS1, particularly during the inflammatory response.[22][23][24] KIR directly interacts with both HLA-F and HLA class-I individually (i.e. no dimerization between HLA-F and HLA class-I is necessary).
# Disease association
HLA-F has been linked to several diseases (Table). For cancer and tumors, HLA-F expression has been found to be enhanced in gastric adenocarcinoma,[25] breast cancer,[26] esophageal carcinoma,[27] lung cancer,[28] hepatocellular carcinoma,[29] and neuroblastoma.[30] HLA-F has also been associated with susceptibility to several diseases: hepatitis B,[31] Systemic Lupus Erythematosus,[32] and Type 1 diabetes (T1D).[33] | https://www.wikidoc.org/index.php/HLA-F | |
12f20013086f03bdc4a0e00a32e56bfb9a5ec400 | wikidoc | HLA-G | HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.
HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. Exon 7 and 8 are not translated due to a stop codon present in exon 6.
# Function
HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not. As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss. its downregulation is related to HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.
However, a large family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors. It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations. Also, some higher primates do not show all MHC-G isoforms. In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA. All of these anomalies must be studied.
The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos. However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.
# Interactions
HLA-G has been shown to interact with CD8A. | HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.[1]
HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.[1] Exon 7 and 8 are not translated due to a stop codon present in exon 6.[2]
# Function
HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not.[3] As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.[4] its downregulation is related to HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.[5]
However, a large family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors.[6][7] It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations.[8] Also, some higher primates do not show all MHC-G isoforms.[9] In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA.[10] All of these anomalies must be studied.
The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.[11] However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.[11]
# Interactions
HLA-G has been shown to interact with CD8A.[12][13] | https://www.wikidoc.org/index.php/HLA-G | |
2a3fb9815fe352c53130023271a6590d5386f832 | wikidoc | HLA E | HLA E
Major histocompatibility complex, class I, E, also known as HLA-E, is a human gene.
HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail.
HLA-E is a protein that is a member of the HLA family. It is one of a family of molecules known as MHC class Ib and has a very specialized role in cell recognition by NK cells (Natural Killer). HLA-E is very highly conserved and presents a small repertoire of peptides of various origins. HLA-E is expressed ubiquitously. The primary peptides HLA-E binds are derived from the leader sequence of other HLA class Ia molecules, such as HLA-A, B, C, G.These proteins bind to the Peptide binding groove of the HLA-E molecule, and this allows it to be expressed on on the surface. NK cells recognise bound HLA-E+Peptide combination using the heterodimeric inhibitory receptor CD94/NKG2A or the activating receptor NKG2C/CD94 . When CD94/NKG2A is stimulated, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis.
A number of viruses have evolved to express proteins that inhibit the expression of MHC I molecules on cell surface of cells they infect, thereby preventing Antigen presentation that would allow the Immune system to recognise infection. NK cells therefore identify cells that are exhibiting such characteristics of viral infection.
HLA E is also reported to interact with the T-cell receptor. HLA-E presents a peptide (VMAPRTLIL) derived from the UL40 protein from cytomegalovirus. This peptide is highly similar to the leader peptides derived from other HLA molecules and acts as a surrogate "leader peptide" and interacts with CD94/NKG2 receptors. This engagement relays into an overall inhibitory effect on NK-cell meditated cytotoxicity. | HLA E
Major histocompatibility complex, class I, E, also known as HLA-E, is a human gene.
HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail.[1]
HLA-E is a protein that is a member of the HLA family. It is one of a family of molecules known as MHC class Ib and has a very specialized role in cell recognition by NK cells (Natural Killer). HLA-E is very highly conserved and presents a small repertoire of peptides of various origins.[2] HLA-E is expressed ubiquitously. The primary peptides HLA-E binds are derived from the leader sequence of other HLA class Ia molecules, such as HLA-A, B, C, G.These proteins bind to the Peptide binding groove of the HLA-E molecule, and this allows it to be expressed on on the surface. NK cells recognise bound HLA-E+Peptide combination using the heterodimeric inhibitory receptor CD94/NKG2A or the activating receptor NKG2C/CD94 . When CD94/NKG2A is stimulated, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis.
A number of viruses have evolved to express proteins that inhibit the expression of MHC I molecules on cell surface of cells they infect, thereby preventing Antigen presentation that would allow the Immune system to recognise infection. NK cells therefore identify cells that are exhibiting such characteristics of viral infection.
HLA E is also reported to interact with the T-cell receptor.[3] HLA-E presents a peptide (VMAPRTLIL) derived from the UL40 protein from cytomegalovirus. This peptide is highly similar to the leader peptides derived from other HLA molecules and acts as a surrogate "leader peptide" and interacts with CD94/NKG2 receptors. This engagement relays into an overall inhibitory effect on NK-cell meditated cytotoxicity. | https://www.wikidoc.org/index.php/HLA_E | |
3d5bcb750024b94393874868f6d589cea9700158 | wikidoc | HMGA1 | HMGA1
High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.
# Function
This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transcription, DNA replication, heterochromatin organization, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells.
HMGA1 proteins are quite small (~10-12 kDa) and basic molecules, and consist of three AT-hooks with the RGRP (Arg-Gly-Arg-Pro) core motif, a novel cross-linking domain located between the second and third AT-hook, and a C-terminal acidic tail characteristic for the HMG family comprising HMGA, HMGB and HMGN proteins.
HMGA1-GFP fusion proteins are highly dynamic in vivo (determined using FRAP analysis), but in contrast also show nanomolar affinity to AT-rich DNA in vitro (determined biochemically), which might be explained due to the extensive post-transcriptional modifications in vivo. HMGA1 preferentially binds to the minor groove of AT-rich regions in double-stranded DNA using its AT-hooks. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverse posttranslational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm.
Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibers in vitro and can induce chromatin clustering in vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization.
At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene. The splice variant HMGA1c with only two AT hooks and no acidic tail is in discussion to be a real member of the HMGA family.
Mice lacking their variant of HMGA1, i.e., Hmga1-/- mice, are diabetic, show a cardiac hypertrophy and express low levels of the insulin receptor.
# Interactions
HMGA1 has been shown to interact with CEBPB and Sp1 transcription factor. | HMGA1
High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.[1][2]
# Function
This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transcription, DNA replication, heterochromatin organization, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells.
HMGA1 proteins are quite small (~10-12 kDa) and basic molecules, and consist of three AT-hooks with the RGRP (Arg-Gly-Arg-Pro) core motif, a novel cross-linking domain located between the second and third AT-hook, and a C-terminal acidic tail characteristic for the HMG family comprising HMGA, HMGB and HMGN proteins.
HMGA1-GFP fusion proteins are highly dynamic in vivo (determined using FRAP analysis), but in contrast also show nanomolar affinity to AT-rich DNA in vitro (determined biochemically), which might be explained due to the extensive post-transcriptional modifications in vivo. HMGA1 preferentially binds to the minor groove of AT-rich regions in double-stranded DNA using its AT-hooks. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverse posttranslational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm.
Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibers in vitro and can induce chromatin clustering in vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization.[3]
At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene.[4] The splice variant HMGA1c with only two AT hooks and no acidic tail is in discussion to be a real member of the HMGA family.
Mice lacking their variant of HMGA1, i.e., Hmga1-/- mice, are diabetic, show a cardiac hypertrophy and express low levels of the insulin receptor.[5]
# Interactions
HMGA1 has been shown to interact with CEBPB[6] and Sp1 transcription factor.[6] | https://www.wikidoc.org/index.php/HMGA1 | |
9449b214203a6ac95bfe9c03a41d39414eedde5f | wikidoc | HMGA2 | HMGA2
High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.
# Function
This gene encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhanceosome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with lipomas suggests a role in adipogenesis and mesenchymal differentiation. A gene knock-out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
The expression of HMGA2 in adult tissues is commonly associated with both malignant and benign tumor formation, as well as certain characteristic cancer-promoting mutations. Homologous proteins with highly conserved sequences are found in other mammalian species, including lab mice (Mus musculus).
HMGA2 contains three basic DNA-binding domains (AT-hooks) that cause the protein to bind to adenine-thymine (AT)-rich regions of nuclear DNA. HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. With few exceptions, HMGA2 is expressed in humans only during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues. The microRNA let-7 is largely responsible for this time-dependent regulation of HMGA2. The apparent function of HMGA2 in proliferation and differentiation of cells during development is supported by the observation that mice with mutant HMGA2 genes are unusually small (pygmy phenotype), and genome-wide association studies linking HMGA2-associated SNPs to variation in human height.
# Regulation by let-7
Let-7 inhibits production of specific proteins by complementary binding to their mRNA transcripts. The HMGA2 mature mRNA transcript contains seven regions complementary or nearly complementary to let-7 in its 3' untranslated region (UTR). Let-7 expression is very low during early human development, which coincides with the greatest transcription of HMGA2. The time-dependent drop in HMGA2 expression is caused by a rise in let-7 expression.
# Clinical significance
## Relationship with cancer
Heightened expression of HMGA2 is found in a variety of human cancers, but the precise mechanism by which HMGA2 contributes to the formation of cancer is unknown. The same mutations that lead to pituitary adenomas in mice can be found in similar cancers in humans. Its presence is associated with poor prognosis for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy. To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by radiation therapy and some forms of chemotherapy. Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood. However, the expression of HMGA2 is also associated with increased rates of metastasis in breast cancer, and both metastasis and recurrence of squamous cell carcinoma. These properties are responsible for patients' poor prognoses. As with HMGA2's effects on the response to radiation and chemotherapy, the mechanism by which HMGA2 exerts these effects is unknown.
## Characteristic mutations in HMGA2-high cancers
A very common finding in HMGA2-high cancers is the under-expression of let-7. This is not unexpected, given let-7's natural role in the regulation of HMGA2. However, many cancers are found with normal levels of let-7 that are also HMGA2 high. Many of these cancers express the normal HMGA2 protein, but the mature mRNA transcript is truncated, missing a portion of the 3'UTR that contains the critical let-7 complementary regions. Without these, let-7 is unable to bind to HMGA2 mRNA, and, thus, is unable to repress it. The truncated mRNAs may arise from a chromosomal translocation that results in loss of a portion of the HMGA2 gene.
## ERCC1
Overexpressed HMGA2 may play a role in the frequent repression of ERCC1 in cancers. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present. (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. As shown by Borrmann et al., HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. These authors noted that repression of ERCC1 (by HGMA2) can reduce DNA repair, leading to increased genome instability.
ERCC1 protein expression is reduced or absent in 84% to 100% of human colorectal cancers. ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer. As indicated in the ERCC1 article, however, two other epigenetic mechanisms of repression of ERCC1 also may have a role in reducing expression of ERCC1 (promoter DNA methylation and microRNA repression).
## Chromatin immunoprecipitation
Genome-wide analysis of HMGA2 target genes was performed by chromatin immunoprecipitation in a gastric cell line with overexpressed HMGA2, and 1,366 genes were identified as potential targets. The pathways they identified as associated with malignant neoplasia progression were the adherens junction pathway, MAPK signaling pathway, Wnt signaling pathway, p53 signaling pathway, VEGF signaling pathway, Notch signaling pathway, and TGF beta signaling pathway.
## Non-homologous end joining DNA repair
Li et al. showed that overexpression of HMGA2 delayed the release of DNA-PKcs (needed for non-homologous end joining DNA repair) from double strand break sites. Overexpression of HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. These properties implicate HMGA2 in the promotion of genome instability and tumorigenesis.
## Base excision repair pathway
Summer et al. found that HGMA2 protein can efficiently cleave DNA containing apurinic/apyrimidinic (AP) sites (is an AP lyase). In addition, this protein also possesses the related 5’-deoxyribosyl phosphate (dRP) lyase activity. They demonstrated an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, indicating that HMGA2 can be incorporated into the cellular base excision repair (BER) machinery. Increased expression of HMGA2 increased BER, and allowed cells with increased HMGA2 to be resistant to hydroxyurea, a chemotherapeutic agent for solid tumors.
# Interactions
HMGA2 has been shown to interact with PIAS3 and NFKB1.
The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and importin-α2. | HMGA2
High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.[1][2][3]
# Function
This gene encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhanceosome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with lipomas suggests a role in adipogenesis and mesenchymal differentiation. A gene knock-out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3]
The expression of HMGA2 in adult tissues is commonly associated with both malignant and benign tumor formation, as well as certain characteristic cancer-promoting mutations. Homologous proteins with highly conserved sequences are found in other mammalian species, including lab mice (Mus musculus).
HMGA2 contains three basic DNA-binding domains (AT-hooks) that cause the protein to bind to adenine-thymine (AT)-rich regions of nuclear DNA. HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. With few exceptions, HMGA2 is expressed in humans only during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues.[4] The microRNA let-7 is largely responsible for this time-dependent regulation of HMGA2.[5] The apparent function of HMGA2 in proliferation and differentiation of cells during development is supported by the observation that mice with mutant HMGA2 genes are unusually small (pygmy phenotype),[6] and genome-wide association studies linking HMGA2-associated SNPs to variation in human height.[7]
# Regulation by let-7
Let-7 inhibits production of specific proteins by complementary binding to their mRNA transcripts. The HMGA2 mature mRNA transcript contains seven regions complementary or nearly complementary to let-7 in its 3' untranslated region (UTR).[8] Let-7 expression is very low during early human development, which coincides with the greatest transcription of HMGA2. The time-dependent drop in HMGA2 expression is caused by a rise in let-7 expression.[5]
# Clinical significance
## Relationship with cancer
Heightened expression of HMGA2 is found in a variety of human cancers, but the precise mechanism by which HMGA2 contributes to the formation of cancer is unknown.[9][10] The same mutations that lead to pituitary adenomas in mice can be found in similar cancers in humans.[9] Its presence is associated with poor prognosis for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy.[11] To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by radiation therapy and some forms of chemotherapy. Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood.[11] However, the expression of HMGA2 is also associated with increased rates of metastasis in breast cancer, and both metastasis and recurrence of squamous cell carcinoma. These properties are responsible for patients' poor prognoses. As with HMGA2's effects on the response to radiation and chemotherapy, the mechanism by which HMGA2 exerts these effects is unknown.[11]
## Characteristic mutations in HMGA2-high cancers
A very common finding in HMGA2-high cancers is the under-expression of let-7.[12] This is not unexpected, given let-7's natural role in the regulation of HMGA2. However, many cancers are found with normal levels of let-7 that are also HMGA2 high. Many of these cancers express the normal HMGA2 protein, but the mature mRNA transcript is truncated, missing a portion of the 3'UTR that contains the critical let-7 complementary regions. Without these, let-7 is unable to bind to HMGA2 mRNA, and, thus, is unable to repress it. The truncated mRNAs may arise from a chromosomal translocation that results in loss of a portion of the HMGA2 gene.[8]
## ERCC1
Overexpressed HMGA2 may play a role in the frequent repression of ERCC1 in cancers. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present.[13] (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. As shown by Borrmann et al.,[14] HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. These authors noted that repression of ERCC1 (by HGMA2) can reduce DNA repair, leading to increased genome instability.
ERCC1 protein expression is reduced or absent in 84% to 100% of human colorectal cancers.[15][16] ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer.[17] As indicated in the ERCC1 article, however, two other epigenetic mechanisms of repression of ERCC1 also may have a role in reducing expression of ERCC1 (promoter DNA methylation and microRNA repression).
## Chromatin immunoprecipitation
Genome-wide analysis of HMGA2 target genes was performed by chromatin immunoprecipitation in a gastric cell line with overexpressed HMGA2, and 1,366 genes were identified as potential targets.[18] The pathways they identified as associated with malignant neoplasia progression were the adherens junction pathway, MAPK signaling pathway, Wnt signaling pathway, p53 signaling pathway, VEGF signaling pathway, Notch signaling pathway, and TGF beta signaling pathway.
## Non-homologous end joining DNA repair
Li et al.[19] showed that overexpression of HMGA2 delayed the release of DNA-PKcs (needed for non-homologous end joining DNA repair) from double strand break sites. Overexpression of HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. These properties implicate HMGA2 in the promotion of genome instability and tumorigenesis.
## Base excision repair pathway
Summer et al.[20] found that HGMA2 protein can efficiently cleave DNA containing apurinic/apyrimidinic (AP) sites (is an AP lyase). In addition, this protein also possesses the related 5’-deoxyribosyl phosphate (dRP) lyase activity. They demonstrated an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, indicating that HMGA2 can be incorporated into the cellular base excision repair (BER) machinery. Increased expression of HMGA2 increased BER, and allowed cells with increased HMGA2 to be resistant to hydroxyurea, a chemotherapeutic agent for solid tumors.
# Interactions
HMGA2 has been shown to interact with PIAS3[21] and NFKB1.[22]
The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and importin-α2.[6] | https://www.wikidoc.org/index.php/HMGA2 | |
08c194d1b45a7edae0b99603f480c67577bf5be0 | wikidoc | HMGB1 | HMGB1
High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.
HMG-1 belongs to the high mobility group and contains a HMG-box domain.
# Function
Like the histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with nucleosomes, transcription factors, and histones. This nuclear protein organizes the DNA and regulates transcription. After binding, HMGB1 bends DNA, which facilitates the binding of other proteins. HMGB1 supports transcription of many genes in interactions with many transcription factors. It also interacts with nucleosomes to loosen packed DNA and remodel the chromatin. Contact with core histones changes the structure of nucleosomes.
The presence of HMGB1 in the nucleus depends on posttranslational modifications. When the protein is not acetylated, it stays in the nucleus, but hyperacetylation on lysine residues causes it to translocate into the cytosol.
HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during V(D)J recombination.
# Role in inflammation
HMGB1 is secreted by immune cells (like macrophages, monocytes and dendritic cells) through leaderless secretory pathway. Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of Inflammation. Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus. The mechanism of inflammation and damage consists of binding to TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses.
HMGB1 has been proposed as a DNA vaccine adjuvant. HMGB1 released from tumour cells was demonstrated to mediate anti-tumour immune responses by activating Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.
# Interactions
HMGB1 has to interact with P53.
HMGB1 is an intracellular protein that can translocate to the nucleus where it binds DNA and regulates gene expression. It can also be released from cells, in which extracellular form it can bind the inflammatory receptor RAGE (Receptor for Advanced Glycation End-products). Release from cells seems to involve two distinct processes: necrosis, in which case cell membranes are permeabilized and intracellular constituents may diffuse out of the cell; and some form of active or facilitated secretion induced by signaling through the NF-κB.
HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.
## Interaction via TLR4
Some actions of HMGB1 are mediated through the toll-like receptors (TLRs). Interaction between HMGB1 and TLR4 results in upregulation of NF-κB, which leads to increased production and release of cytokines. HMGB1 is also able to interact with TLR4 on neutrophils to stimulate the production of reactive oxygen species by NADPH oxidase. HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading to signal transduction and the activation of various signaling cascades. The downstream effect of this signaling is to activate MAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.
# Clinical significance
HMGB1 has been proposed as a target for cancer therapy.
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by mutation in the ataxin 1 gene. In a mouse model of SCA1, mutant ataxin 1 protein mediated the reduction or inhibition of HMGB1 in the mitochondria of neurons. HMGB1 regulates DNA architectural changes essential for repair of DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitated repair of the mitochondrial DNA damage, ameliorated the neuropathology and the motor defects of the SCA1 mice, and also extended their lifespan. Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1. | HMGB1
High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.[1][2]
HMG-1 belongs to the high mobility group and contains a HMG-box domain.
# Function
Like the histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with nucleosomes, transcription factors, and histones.[3] This nuclear protein organizes the DNA and regulates transcription.[4] After binding, HMGB1 bends[5] DNA, which facilitates the binding of other proteins. HMGB1 supports transcription of many genes in interactions with many transcription factors. It also interacts with nucleosomes to loosen packed DNA and remodel the chromatin. Contact with core histones changes the structure of nucleosomes.
The presence of HMGB1 in the nucleus depends on posttranslational modifications. When the protein is not acetylated, it stays in the nucleus, but hyperacetylation on lysine residues causes it to translocate into the cytosol.[4]
HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during V(D)J recombination.[6]
# Role in inflammation
HMGB1 is secreted by immune cells (like macrophages, monocytes and dendritic cells) through leaderless secretory pathway.[4] Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of Inflammation.[7] Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus.[citation needed] The mechanism of inflammation and damage consists of binding to TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses.[8][9]
HMGB1 has been proposed as a DNA vaccine adjuvant.[10] HMGB1 released from tumour cells was demonstrated to mediate anti-tumour immune responses by activating Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.[11]
# Interactions
HMGB1 has to interact with P53.[12][13]
HMGB1 is an intracellular protein that can translocate to the nucleus where it binds DNA and regulates gene expression. It can also be released from cells, in which extracellular form it can bind the inflammatory receptor RAGE (Receptor for Advanced Glycation End-products). Release from cells seems to involve two distinct processes: necrosis, in which case cell membranes are permeabilized and intracellular constituents may diffuse out of the cell; and some form of active or facilitated secretion induced by signaling through the NF-κB.
HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.[14]
## Interaction via TLR4
Some actions of HMGB1 are mediated through the toll-like receptors (TLRs).[15] Interaction between HMGB1 and TLR4 results in upregulation of NF-κB, which leads to increased production and release of cytokines. HMGB1 is also able to interact with TLR4 on neutrophils to stimulate the production of reactive oxygen species by NADPH oxidase.[4][16] HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading to signal transduction and the activation of various signaling cascades. The downstream effect of this signaling is to activate MAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.[17][18]
# Clinical significance
HMGB1 has been proposed as a target for cancer therapy.[19]
The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by mutation in the ataxin 1 gene. In a mouse model of SCA1, mutant ataxin 1 protein mediated the reduction or inhibition of HMGB1 in the mitochondria of neurons.[20] HMGB1 regulates DNA architectural changes essential for repair of DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitated repair of the mitochondrial DNA damage, ameliorated the neuropathology and the motor defects of the SCA1 mice, and also extended their lifespan.[20] Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1. | https://www.wikidoc.org/index.php/HMGB1 | |
9247e8947f6409f87325d288ab531367a60962e0 | wikidoc | HMOX1 | HMOX1
HMOX1 (heme oxygenase (decycling) 1) is a human gene that encodes for the enzyme heme oxygenase 1 (EC 1.14.99.3). Heme oxygenase mediates the first step of heme catabolism, it cleaves heme to form biliverdin.
Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, carbon monoxide, and ferrous iron. The biliverdin is subsequently converted to bilirubin by biliverdin reductase. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2. HMOX1 and HMOX2 belong to the heme oxygenase family.
The HMOX gene is located on the long (q) arm of chromosome 22 at position 12.3, from base pair 34,101,636 to base pair 34,114,748.
# Related conditions
- Heme oxygenase-1 deficiency
# Anti-inflammatory effect
The ability of oxygenase 1 to catabolize free heme and produce carbon monoxide (CO) gives its anti-inflammatory properties by up-regulation of interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1RA) expression. | HMOX1
HMOX1 (heme oxygenase (decycling) 1) is a human gene that encodes for the enzyme heme oxygenase 1 (EC 1.14.99.3). Heme oxygenase mediates the first step of heme catabolism, it cleaves heme to form biliverdin.
Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, carbon monoxide, and ferrous iron.[1] The biliverdin is subsequently converted to bilirubin by biliverdin reductase. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2. HMOX1 and HMOX2 belong to the heme oxygenase family.[2]
The HMOX gene is located on the long (q) arm of chromosome 22 at position 12.3, from base pair 34,101,636 to base pair 34,114,748.
# Related conditions
- Heme oxygenase-1 deficiency
# Anti-inflammatory effect
The ability of oxygenase 1 to catabolize free heme and produce carbon monoxide (CO) gives its anti-inflammatory properties by up-regulation of interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1RA) expression.[3] | https://www.wikidoc.org/index.php/HMOX1 | |
e2e917e77d13906fd3290c1b4454f587d1855f9a | wikidoc | HNF1A | HNF1A
HNF1 homeobox A (hepatocyte nuclear factor 1 homeobox A), also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
## Gene
The HNF1A gene resides on chromosome 12 at the band 12q24.2 and contains 9 exons. This gene produces 8 isoforms through alternative splicing.
## Protein
This protein belongs to the HNF1 homeobox family. It contains 3 functional domains: an N-terminal dimerization domain (residues 1–32), a bipartite DNA-binding motif containing an atypical POU-homeodomain (residues 98–280), and a C-terminal transactivation domain (residues 281–631). There is also a flexible linker (residues 33–97) which connects the dimerization and DNA binding domains. Crystal structures have been solved for the dimerization domain, which forms a four-helix bundle where two α helices are separated by a turn; the DNA-binding motif, which forms a helix-turn-helix structure; and the POU-homeodomain, which is composed of three α helices, contained in the motif. This homeodomain is considered atypical due to an extended loop inserted between the second and third helices relative to the canonical homeodomain fold. The atypical insertion is thought to stabilize the interface to improve transcriptional efficiency. Meanwhile, the dimerization domain is responsible for the homo- and heterodimerization of HNF-1α. The resulting dimer contains a rigid “mini-zipper”, comprising α-helices 1 and 1′, linked by a non-canonical tight turn to a flexible C-terminal comprising α-helices 2 and 2′.
# Function
HNF-1α is a transcription factor expressed in organs of endoderm origin, including liver, kidneys, pancreas, intestines, stomach, spleen, thymus, testis, and keratinocytes and melanocytes in human skin. It has been shown to affect intestinal epithelial cell growth and cell lineages differentiation. For instance, HNF1A is an important cell-intrinsic transcription factor in adult B lymphopoiesis. The participation of HNF-1α in glucose metabolism and diabetes has been reported, including the involvement in GLUT1 and GLUT2 transporter expression in pancreatic β-cells and angiotensin-converting enzyme 2 gene expression in pancreatic islets. HNF-1α could promote the transcription of several proteins involved in the management of type II diabetes including dipeptidyl peptidase-IV (DPP-IV/CD26). HNF-1α is also involved in various metabolic pathways of other organs, such as being a transcriptional regulator of bile acid transporters in the intestine and kidneys. HNF-1α is involved in the promotion of hepatic organic cation transporters, which uptake certain classes of pharmaceuticals; hence, the loss of its function can lead to drug metabolism problems. In addition, HNF-1α regulates the expression of acute phase proteins, such as fibrinogen, c-reactive protein, and interleukin 1 receptor, which are involved with inflammation. Moreover, significantly lower levels of HNF-1α in pancreatic tumors and hepatocellular adenomas than in normal adjacent tissues was observed, suggesting that HNF-1α might play a possible tumor suppressor role.
# Clinical significance
HNF1A mutations can cause maturity onset diabetes of the young type 3, one of the forms of "monogenic diabetes", as well as hepatocellular adenoma. HNF-1 protein is present in clear cell carcinoma of ovary
In humans, mutations in HNF1A cause diabetes that responds to low dose sulfonylurea agents. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A presents a clear example of the relevance of HNF1A in diabetes patients and how pharmacogenetics can contribute in patient care. For example, patients with maturity onset diabetes of the young owing to mutations in HNF1A (which accounts for ~3% of all diabetes mellitus cases diagnosed under the age of 30 years) are extremely sensitive to sulfonylurea treatment and can successfully transition off insulin treatment. Likewise, patients with diabetes caused by mutations in the HNF1A gene have been described as sensitive to the hypoglycemic effects of sulphonylureas. The cause of hyperglycemia appears to alter the response to hypoglycemic drugs. Accordingly, HNF-1α-induced diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, and the genetic basis of hyperglycemia may have implications for patient management.
## Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the HNF1A 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
HNF1A has been shown to interact with:
- CREB-binding protein and
- EP300,
- PCAF,
- PCBD1,
- RAC3, and
- Src. | HNF1A
HNF1 homeobox A (hepatocyte nuclear factor 1 homeobox A), also known as HNF1A, is a human gene on chromosome 12.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes.[5] Mutations in the HNF1A gene have been known to cause diabetes.[6] The HNF1A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[7]
# Structure
## Gene
The HNF1A gene resides on chromosome 12 at the band 12q24.2 and contains 9 exons.[3] This gene produces 8 isoforms through alternative splicing.[8]
## Protein
This protein belongs to the HNF1 homeobox family.[8] It contains 3 functional domains: an N-terminal dimerization domain (residues 1–32), a bipartite DNA-binding motif containing an atypical POU-homeodomain (residues 98–280), and a C-terminal transactivation domain (residues 281–631).[9][10] There is also a flexible linker (residues 33–97) which connects the dimerization and DNA binding domains.[10] Crystal structures have been solved for the dimerization domain, which forms a four-helix bundle where two α helices are separated by a turn; the DNA-binding motif, which forms a helix-turn-helix structure; and the POU-homeodomain, which is composed of three α helices, contained in the motif. This homeodomain is considered atypical due to an extended loop inserted between the second and third helices relative to the canonical homeodomain fold. The atypical insertion is thought to stabilize the interface to improve transcriptional efficiency.[9] Meanwhile, the dimerization domain is responsible for the homo- and heterodimerization of HNF-1α. The resulting dimer contains a rigid “mini-zipper”, comprising α-helices 1 and 1′, linked by a non-canonical tight turn to a flexible C-terminal comprising α-helices 2 and 2′.[10]
# Function
HNF-1α is a transcription factor expressed in organs of endoderm origin, including liver, kidneys, pancreas, intestines, stomach, spleen, thymus, testis, and keratinocytes and melanocytes in human skin.[11] It has been shown to affect intestinal epithelial cell growth and cell lineages differentiation. For instance, HNF1A is an important cell-intrinsic transcription factor in adult B lymphopoiesis.[12][13][14] The participation of HNF-1α in glucose metabolism and diabetes has been reported, including the involvement in GLUT1 and GLUT2 transporter expression in pancreatic β-cells and angiotensin-converting enzyme 2 gene expression in pancreatic islets.[15][16] HNF-1α could promote the transcription of several proteins involved in the management of type II diabetes including dipeptidyl peptidase-IV (DPP-IV/CD26).[17][18] HNF-1α is also involved in various metabolic pathways of other organs, such as being a transcriptional regulator of bile acid transporters in the intestine and kidneys.[19] HNF-1α is involved in the promotion of hepatic organic cation transporters, which uptake certain classes of pharmaceuticals; hence, the loss of its function can lead to drug metabolism problems.[20] In addition, HNF-1α regulates the expression of acute phase proteins, such as fibrinogen, c-reactive protein, and interleukin 1 receptor, which are involved with inflammation.[21] Moreover, significantly lower levels of HNF-1α in pancreatic tumors and hepatocellular adenomas than in normal adjacent tissues was observed, suggesting that HNF-1α might play a possible tumor suppressor role.[22][23]
# Clinical significance
HNF1A mutations can cause maturity onset diabetes of the young type 3, one of the forms of "monogenic diabetes",[2] as well as hepatocellular adenoma. HNF-1 protein is present in clear cell carcinoma of ovary [24][25]
In humans, mutations in HNF1A cause diabetes that responds to low dose sulfonylurea agents.[26] The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A presents a clear example of the relevance of HNF1A in diabetes patients and how pharmacogenetics can contribute in patient care.[27] For example, patients with maturity onset diabetes of the young owing to mutations in HNF1A (which accounts for ~3% of all diabetes mellitus cases diagnosed under the age of 30 years) are extremely sensitive to sulfonylurea treatment and can successfully transition off insulin treatment.[6] Likewise, patients with diabetes caused by mutations in the HNF1A gene have been described as sensitive to the hypoglycemic effects of sulphonylureas. The cause of hyperglycemia appears to alter the response to hypoglycemic drugs. Accordingly, HNF-1α-induced diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, and the genetic basis of hyperglycemia may have implications for patient management.[6]
## Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the HNF1A 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).[7]
# Interactions
HNF1A has been shown to interact with:
- CREB-binding protein[28] and
- EP300,[29]
- PCAF,[28]
- PCBD1,[30][31]
- RAC3,[28] and
- Src.[28] | https://www.wikidoc.org/index.php/HNF1A | |
236f77d28c2319d076073228a4772b4c0a12a74c | wikidoc | HNRPD | HNRPD
Heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) also known as AU-rich element RNA-binding protein 1 (AUF1) is a protein that in humans is encoded by the HNRNPD gene. Alternative splicing of this gene results in four transcript variants.
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). The interaction sites on the RNA are frequently biased towards particular sequence motifs. 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 two repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability.
# Interactions
HNRPD has been shown to interact with SAFB and Hsp27. AUF1 also has been reported to interact with mRNAs such as Mef2c mRNA. | HNRPD
Heterogeneous nuclear ribonucleoprotein D0 (HNRNPD) also known as AU-rich element RNA-binding protein 1 (AUF1) is a protein that in humans is encoded by the HNRNPD gene.[1][2] Alternative splicing of this gene results in four transcript variants.
# Function
This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). The interaction sites on the RNA are frequently biased towards particular sequence motifs.[3] 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 two repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability.[2]
# Interactions
HNRPD has been shown to interact with SAFB[4] and Hsp27.[5] AUF1 also has been reported to interact with mRNAs such as Mef2c mRNA.[6] | https://www.wikidoc.org/index.php/HNRPD | |
41d16c1fa66c0c24ab05299e75fc3322cb57d5bb | wikidoc | HOSxP | HOSxP
HOSxP is a hospital information system, including Electronic health record (EHR), in use in over 70 hospitals across Thailand. The software aims to ease the healthcare workflow of health centers, for small sanitariums to central hospitals.
Before becoming HOSxP, the software was called KSK-HDBMS. Seeking a more friendly name, the development team opted for the name HOSxP, which comes from Hospital and Experience. The name also reflects the software's graphical user interface, which mimic the theme of Windows XP, no matter what actually the underlying operating system.
Distributed under GNU General Public License (GPL), HOSxP is free software.
# History
The development started in 1999. Emerged from a solo project by Chaiyaporn Suratemekul, a pharmacist by training, now main developers of the software are staffs from Bangkok Medical Software Co., Ltd., a company lead by Chaiyaporn. The development infrastructure, including source code repository, is hosted by SourceForge.net.
# Architecture and technical information
HOSxP uses a client-server architecture. For the database server, it is claimed to run on many RDBMS, like MySQL, Microsoft SQL Server, PostgreSQL, and Interbase/Firebird.
- Client-server (two-tier)
a server software can run on either Linux or Microsoft Windows
a client software can run only on Microsoft Windows
- a server software can run on either Linux or Microsoft Windows
- a client software can run only on Microsoft Windows
- Multi-tier technology (Borland DataSnap)
- Distributed Component Object Model (DCOM)
Borland Delphi and its Linux counterpart Kylix are the integrated development environments of choice in the project.
A user is allowed to write scripts in the Pascal programming language to automate tasks in HOSxP.
# Awards
- Thailand ICT Award 2004 2nd Healthcare Application
- Thailand ICT Award 2005 1st Healthcare Application
- Thailand ICT Award 2005 Popular Award | HOSxP
HOSxP is a hospital information system, including Electronic health record (EHR), in use in over 70 hospitals across Thailand. The software aims to ease the healthcare workflow of health centers, for small sanitariums to central hospitals.
Before becoming HOSxP, the software was called KSK-HDBMS. Seeking a more friendly name, the development team opted for the name HOSxP, which comes from Hospital and Experience. The name also reflects the software's graphical user interface, which mimic the theme of Windows XP, no matter what actually the underlying operating system.
Distributed under GNU General Public License (GPL), HOSxP is free software.
# History
The development started in 1999. Emerged from a solo project by Chaiyaporn Suratemekul, a pharmacist by training, now main developers of the software are staffs from Bangkok Medical Software Co., Ltd., a company lead by Chaiyaporn. The development infrastructure, including source code repository, is hosted by SourceForge.net.
# Architecture and technical information
HOSxP uses a client-server architecture. For the database server, it is claimed to run on many RDBMS, like MySQL, Microsoft SQL Server, PostgreSQL, and Interbase/Firebird.
- Client-server (two-tier)
a server software can run on either Linux or Microsoft Windows
a client software can run only on Microsoft Windows
- a server software can run on either Linux or Microsoft Windows
- a client software can run only on Microsoft Windows
- Multi-tier technology (Borland DataSnap)
- Distributed Component Object Model (DCOM)
Borland Delphi and its Linux counterpart Kylix are the integrated development environments of choice in the project.
A user is allowed to write scripts in the Pascal programming language to automate tasks in HOSxP.
# Awards
- Thailand ICT Award 2004 2nd Healthcare Application
- Thailand ICT Award 2005 1st Healthcare Application
- Thailand ICT Award 2005 Popular Award | https://www.wikidoc.org/index.php/HOSxP | |
31eaa3a7b6eabe00ec01b52c4625e1fc60fd7317 | wikidoc | HOT-2 | HOT-2
HOT-2, or 2,5-dimethoxy-4-(β-ethylthio)-N-hydroxyphenethylamine is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PIHKAL.
# Chemistry
HOT-2's full chemical name is 2-[4-(2-ethylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-2 and to other drugs in the HOT- series, with the most closely related compounds being HOT-7 and HOT-17.
# General Information
The dosage range of HOT-2 is typically 10-18 mg and its duration is approximately 6-10 hours according to Shulgin. HOT-2 produces visuals and moving, flowing lights. It also causes euphoria and increases blood pressure.
# Categorization | HOT-2
HOT-2, or 2,5-dimethoxy-4-(β-ethylthio)-N-hydroxyphenethylamine is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book PIHKAL.
# Chemistry
HOT-2's full chemical name is 2-[4-(2-ethylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-2 and to other drugs in the HOT- series, with the most closely related compounds being HOT-7 and HOT-17.
# General Information
The dosage range of HOT-2 is typically 10-18 mg and its duration is approximately 6-10 hours according to Shulgin. HOT-2 produces visuals and moving, flowing lights. It also causes euphoria and increases blood pressure.
# Categorization
Template:Hallucinogenic phenethylamines
Template:PiHKAL | https://www.wikidoc.org/index.php/HOT-2 | |
6f68e2d8edf1cc5778f7910f686e00f05b3bacbc | wikidoc | HOT-7 | HOT-7
HOT-7, or 2,5-dimethoxy-4-(β-propylthio)-N-hydroxyphenethylamine, is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book, PIHKAL.
# Chemistry
HOT-7's full chemical name is 2-[4-(2-propylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-7 and to other drugs in the HOT- series, with the most closely related compounds being HOT-2 and HOT-17.
# General Information
The dosage range of HOT-7 is typically 15-25 mg and its duration is approximately 6-8 hours according to Shulgin. HOT-7 produces closed-eye and open-eye visuals. It also induces a feeling similar to that of being drunk.
# Categorization | HOT-7
HOT-7, or 2,5-dimethoxy-4-(β-propylthio)-N-hydroxyphenethylamine, is a psychedelic phenethylamine of the 2C family. It was presumably first synthesized by Alexander Shulgin and reported in his book, PIHKAL.
# Chemistry
HOT-7's full chemical name is 2-[4-(2-propylthio)-2,5-dimethoxyphenyl-N-hydroxyethanamine. It has structural properties similar to 2C-T-7 and to other drugs in the HOT- series, with the most closely related compounds being HOT-2 and HOT-17.
# General Information
The dosage range of HOT-7 is typically 15-25 mg and its duration is approximately 6-8 hours according to Shulgin. HOT-7 produces closed-eye and open-eye visuals. It also induces a feeling similar to that of being drunk.
# Categorization
Template:Hallucinogenic phenethylamines
Template:PiHKAL | https://www.wikidoc.org/index.php/HOT-7 | |
e40bee096974d32ece19ebf32614a0c2de027571 | wikidoc | HOXA2 | HOXA2
Homeobox protein Hox-A2 is a protein that in humans is encoded by the HOXA2 gene.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.
HOXA2 controls the embryonic development of the lower and middle part of the face and of the middle ear. Mutations in it are known to cause microtia, hearing impairment, and cleft palate. | HOXA2
Homeobox protein Hox-A2 is a protein that in humans is encoded by the HOXA2 gene.[1]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.[2]
HOXA2 controls the embryonic development of the lower and middle part of the face and of the middle ear. Mutations in it are known to cause microtia, hearing impairment, and cleft palate. | https://www.wikidoc.org/index.php/HOXA2 | |
beca1ee548a3380a7c279623e69af95e76c25d08 | wikidoc | HOXA3 | HOXA3
Homeobox protein Hox-A3 is a protein that in humans is encoded by the HOXA3 gene.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Three transcript variants encoding two different isoforms have been found for this gene.
During normal fetal development, HoxA3 is expressed in mesenchymal neural crest cells and endodermal cells found in the third pharyngeal pouch. Expression of HoxA3 in these cells affects the proper formation of the thymus, thyroid, and parathyroid organs. While the gene does not seem to affect the proliferation or migration of the pharyngeal neural crest cells, it does appear to trigger cellular differentiation events required to form these organs. Knockout of HoxA3 leads to failure in forming the thymus (athymia) and parathyroid gland (aparthyroidism). Mutant HoxA3 also causes a reduction in thyroid size. While the follicular and parafollicular cells still differentiate, their numbers are reduced and they are not evenly distributed throughout the gland. Mutant HoxA3 models show similar phenotypes as those seen in DiGeorge’s Syndrome, and it is possible that the two are linked.
# Regulation
The HOXA3 gene is repressed by the microRNA miR-10a. | HOXA3
Homeobox protein Hox-A3 is a protein that in humans is encoded by the HOXA3 gene.[1][2][3]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Three transcript variants encoding two different isoforms have been found for this gene.[3]
During normal fetal development, HoxA3 is expressed in mesenchymal neural crest cells and endodermal cells found in the third pharyngeal pouch.[4] Expression of HoxA3 in these cells affects the proper formation of the thymus, thyroid, and parathyroid organs.[5][6] While the gene does not seem to affect the proliferation or migration of the pharyngeal neural crest cells, it does appear to trigger cellular differentiation events required to form these organs.[5] Knockout of HoxA3 leads to failure in forming the thymus (athymia) and parathyroid gland (aparthyroidism).[6] Mutant HoxA3 also causes a reduction in thyroid size. While the follicular and parafollicular cells still differentiate, their numbers are reduced and they are not evenly distributed throughout the gland.[5] Mutant HoxA3 models show similar phenotypes as those seen in DiGeorge’s Syndrome, and it is possible that the two are linked.[5]
# Regulation
The HOXA3 gene is repressed by the microRNA miR-10a.[7] | https://www.wikidoc.org/index.php/HOXA3 | |
4bfa040685059b25ee211439558faf408b0639ea | wikidoc | HOXA5 | HOXA5
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Methylation of this gene may result in the loss of its expression and, since the encoded protein upregulates the tumor suppressor p53, this protein may play an important role in tumorigenesis.
HoxA5 is controlled, at least in part, by DNA methylation. HoxA5 has been shown to upregulate the tumor suppressor p53 and AKT1 by downregulation of PTEN. Suppression of HoxA5 has been shown to attenuate hemangioma growth. HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFα-inducible monocyte binding to HUVECs.
Comparison of the HoxA5 promoter methylation profile across cell types from the least differentiated (human embryonic stem cells) to the most endothelial-like (human umbilical vein endothelial cells, or HUVECs) shows that the HoxA5 promoter is normally heavily methylated in non-differentiated cells and becomes demethylated as cells differentiate down the endothelial lineage. HoxA5 contains a C-Amp Response Elements (CRE) in its promoter. POL2 and CTCF binding are enriched at the CpG-dense HoxA5 promoter in HUVECs, demonstrating transcriptional activity.
# Clinical significance
HoxA5 is suppressed in acute myeloid leukemia (AML), and the DNMT inhibitor decitabine (5Aza) is used to treat this disease. While HoxA5 is known to be hypermethylated in AML, it has not yet been shown whether decitabine directly targets these genes for demethylation. | HOXA5
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.[1][2][3]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Methylation of this gene may result in the loss of its expression and, since the encoded protein upregulates the tumor suppressor p53, this protein may play an important role in tumorigenesis.[3]
HoxA5 is controlled, at least in part, by DNA methylation.[4] HoxA5 has been shown to upregulate the tumor suppressor p53 and AKT1 by downregulation of PTEN.[5] Suppression of HoxA5 has been shown to attenuate hemangioma growth.[6] HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines.[7] HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFα-inducible monocyte binding to HUVECs.[8][9]
Comparison of the HoxA5 promoter methylation profile across cell types from the least differentiated (human embryonic stem cells) to the most endothelial-like (human umbilical vein endothelial cells, or HUVECs) shows that the HoxA5 promoter is normally heavily methylated in non-differentiated cells and becomes demethylated as cells differentiate down the endothelial lineage.[10] HoxA5 contains a C-Amp Response Elements (CRE) in its promoter.[4] POL2 and CTCF binding are enriched at the CpG-dense HoxA5 promoter in HUVECs, demonstrating transcriptional activity.[10]
# Clinical significance
HoxA5 is suppressed in acute myeloid leukemia (AML), and the DNMT inhibitor decitabine (5Aza) is used to treat this disease. While HoxA5 is known to be hypermethylated in AML, it has not yet been shown whether decitabine directly targets these genes for demethylation.[11][12] | https://www.wikidoc.org/index.php/HOXA5 | |
631dc02fe6302c1ff4b2dfc5deab1220d9fea66a | wikidoc | HOXA6 | HOXA6
Homeobox protein Hox-A6 is a protein that in humans is encoded by the HOXA6 gene.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation.
# Clinical significance
## Leukemia
HOXA6 was examined to be preferentially expressed in primitive cells (e.g. hematopoietic progenitor cells), under the regulation of growth factors and cell cycles. Interleukin 3 and all-trans retinoic acid were found to be the inducing factors that can stimulate the expression of HOXA6. In mitotic process, HOXA6 was mainly expressed in S-phase and G2M phase cells. Overexpression of HoxA6 increased proliferation but inhibited differentiation of multipotential stem cells in the process of hemopoiesis, even had the capacity to transform primary hematopoietic cells into immortal cell lines. Transplantation of these cell lines may cause acute myeloid leukemia in recipient animals.Also in patients with acute myeloid leukemia, HOXA6 expression was upregulated. The comethylation of HOX genes, including HOXA6, leads to the dysfunction of tumor suppression genes by reducing gene expression. The methylation processes can be identified in adult chronic lymphocytic leukemia and childhood acute lymphocytic leukemia.
## Glioblastoma
HOXA6 may also contribute to the invasive tendency of glioblastoma multiforme cells. Suppressed expression of HOXA6 by introducing its antisense fragments can reduce the invasion of glioblastoma multiforme cells. | HOXA6
Homeobox protein Hox-A6 is a protein that in humans is encoded by the HOXA6 gene.[1][2][3]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation.[3]
# Clinical significance
## Leukemia
HOXA6 was examined to be preferentially expressed in primitive cells (e.g. hematopoietic progenitor cells), under the regulation of growth factors and cell cycles. Interleukin 3 and all-trans retinoic acid were found to be the inducing factors that can stimulate the expression of HOXA6. In mitotic process, HOXA6 was mainly expressed in S-phase and G2M phase cells. Overexpression of HoxA6 increased proliferation but inhibited differentiation of multipotential stem cells in the process of hemopoiesis,[4] even had the capacity to transform primary hematopoietic cells into immortal cell lines. Transplantation of these cell lines may cause acute myeloid leukemia in recipient animals.[5]Also in patients with acute myeloid leukemia, HOXA6 expression was upregulated. The comethylation of HOX genes, including HOXA6, leads to the dysfunction of tumor suppression genes by reducing gene expression. The methylation processes can be identified in adult chronic lymphocytic leukemia and childhood acute lymphocytic leukemia.[6]
## Glioblastoma
HOXA6 may also contribute to the invasive tendency of glioblastoma multiforme cells. Suppressed expression of HOXA6 by introducing its antisense fragments can reduce the invasion of glioblastoma multiforme cells.[7] | https://www.wikidoc.org/index.php/HOXA6 | |
eadc4ca16a2eb2204107436677445ae1ff2038fe | wikidoc | HOXA9 | HOXA9
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is highly similar to the abdominal-B (Abd-B) gene of Drosophila fly. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis.
As HOXA9 dysfunction has been implicated in acute myeloid leukemia, and expression of the gene has been shown to differ markedly between erythrocyte lineages of different stages of development, the gene is of particular interest from a hematopoietic perspective.
# Function
## Role in hematopoiesis
As HOXA9 is part of the homeobox family, involved in setting the body plans of animals, it is likely that HOXA9 would display increased expression in cells with higher differentiation potentials. Indeed in the hematopoietic lineage, it has been found that HOXA9 is preferentially expressed in hematopoietic stem cells (HSCs), and is down-regulated as the cell differentiates and matures further.
HOXA9 knockout mice have been shown to develop a reduction in the number of circulating common myeloid progenitor cells, which differentiate into erythroid progenitor cells. The same study indicated that HOXA9 deficiencies specifically affected the granulocyte lineage of the common myeloid progenitor, and it was in HOXA7 knockout mice where the erythroid lineage was affected; however, ErythronDB shows HOXA7 as being insignificantly expressed in all stages of each erythroid lineage. This is something that needs to be investigated further, and could shed light on the interactions between the genes in the HOXA family.
Another study found that HOXA9 knockout HSCs displayed a 5-fold impairment to proliferation rate in vitro, as well as delayed maturation to committed progenitors, specifically myeloid maturation, and that normal proliferation and differentiation rates could be reinstated by reintroducing a HOXA9 vector into the culture. In vivo, lethally irradiated mice with transplanted HOXA9 knockout HSCs displayed a 4-fold to 12-fold reduction in repopulating ability. Furthermore, they developed 60% less myeloid and erythroid colonies in the bone marrow when compared to the wild type. Furthermore, transgenic mice with overexpressed HOXA9 developed a 15-fold increase in the amount of committed progenitor cells in the bone marrow, indicating that overexpressed HOXA9 induces expansion of the HSC population without disrupting differentiation.
From these results, it appears that HOXA9 is important in maintaining HSC populations, as well as guiding their differentiation, especially towards myeloid (erythroid and granulocyte) lineages.
## Expression in adult, fetal and embryonic stages
Throughout the development of a mammal, there are three distinct stages of erythrocyte formation – embryonic, fetal and adult. Adult erythrocytes are the most common blood cell type in mammals, and their characteristic biconcave shape, 7-8 µm diameter and enucleation are amongst the greatest commonalities between mammalian species. However, primitive and fetal erythrocytes, which circulate during early stages of development, are markedly different from their adult counterparts, most obviously through their larger size, shorter lifespan, nucleation, containment of different hemoglobin chains, and higher oxygen affinity. The reasons for and functions of these differences are not well established.
HOXA9 is a candidate for one of the genes responsible for these morphological differences between the erythrocyte lineages, as it is expressed differently in each lineage. In primitive erythrocyte precursors, HOXA9 expression is almost zero. It increases slightly in the fetal stage, and then it is expressed highly in the adult erythrocyte precursors. This expression profile links to the importance of HOXA9 in the HSC, as it mirrors the fact that HSCs are absent in the developing embryo, undergoing initial production in the fetal stage, and are vital in the adult. Furthermore, in the fetal and adult precursors, not all precursor stages display HOXA9 expression. Most of the expression is in the proerythroblast (P) stage, and a minor amount in the basophilic erythroblast (B) stage. There is almost zero expression in the orthonormoblast (O) and reticulocyte (R) stages. P and B are the first two stages of committed differentiation in the erythrocyte lineage, and this implies that HOXA9 may only be involved in the differentiation and proliferation of HSCs, rather than the erythrocyte maturation process.
# Clinical significance
## Role in acute myeloid leukemia
Ordinarily, HOXA9 is expressed on chromosome 7 and the nucleoporin gene NUP98 is expressed on chromosome 11. However, a gene translocation which sometimes occurs in humans moves NUP98 onto chromosome 7, where it fuses with HOXA9 to form the NUP98-HOXA9 oncogene. This oncogene has been widely implicated in acute myeloid leukemia (AML), and expression of this oncogene is the single most highly correlating factor for poor AML prognosis. The oncogene has been found to increase proliferative rates of HSCs whilst impairing their differentiation.
The HOXA9 fusion oncogene causes an 8 times greater proliferation rate of HSCs after 5 weeks of cell culture when compared to control cells, and doubles the period of time over which HSCs can self-renew to an average of 54.3 days, compared to control human HSCs which stopped proliferating after 27.3 days.
There are conflicting results regarding the effect of the oncogene on the differentiation of HSCs into the erythroid lineage. One study observed that the oncogene had a detrimental effect on the differentiation of HSCs, especially in the erythroid lineage, as proerythroblast colonies derived in vitro from mutated HSCs were fewer in number when compared to those derived from control HSCs, regardless of growth factors such as erythropoietin and interleukins which were introduced into the cultures. However, another study noted that the erythroid colonies were twice as populated in cultures of oncogene HSCs when compared to control HSCs. It is possible that these differing observations are due to a delayed differentiation of HSCs affected by the oncogene. The study which observed an increase in erythroid cell number noted that this proliferative effect could only be observed after around 3 weeks, and before this, cell numbers were comparable if not lower for the oncogene culture. The study observing a decreased number of cells did not quote the time of measurement, so if it was within three weeks of the culture, the reduced number may be attributed to this delay.
## Morphology alteration
Proerythroblasts formed in the densely populated colonies of oncogene HSC cultures are strikingly different from those formed in the control colonies. By staining the colonies with giemsa, the oncogene-derived cells were shown to be non-hemoglobinized, larger, much less uniform in shape and had a distinctly large nucleus. These are some of the key morphological differences between primitive erythrocytes and adult erythrocytes. Thus, the NUP98-HOXA9 fusion may give rise to a new population of primitive erythrocytes in cases of AML, and by investigating the various proteins coded by this oncogene, it may be possible to not only establish some molecular causes of AML, but also identify some crucial proteins involved in early erythropoiesis which are absent during adult erythropoiesis.
## Pure erythroid leukemia
There exists a rare form of AML, pure erythroid leukemia, where only the erythroid precursors of myeloid progenitors are leukemic, and not the granulocyte precursors. In this form of AML, levels of erythroblasts can reach up to 94.8% of all nucleated cells in the bone marrow, and the immature forms of the erythroblasts, the proerythroblasts and basophilic erythroblasts, are more commonly found. One study noted that in control leukemic groups with general AML, immature erythroblasts accounted for 8% of all erythroid cells, but in a group with pure erythroid leukemia, this number was a minimum of 40%, and ranged up to 83%. Furthermore, in the case of pure erythroid leukemia, the immature erythrocytes are most morphologically affected, being larger and sometimes bi- or tri-nucleic. Hence the most affected stages of erythrocyte development in pure erythroid leukemia are the same stages in which HOXA9 expression is greatest.
# Interactions
HOXA9 has been shown to interact with:
- MEIS1,
- PBX2, and
- TRIP6.
HOXA9 expression is regulated by several genes, including UTX, WHSC1, MLL and MEN1. UTX, MLL and WHSC1 code for protein methylation and demethylation activity, specifically for the histone methyltransferase complex, of which increased levels have been shown to correlate with higher HOXA9 expression. MEN1 codes for the tumour suppressing protein menin, and lower menin levels as a result of MEN1 excision correlate with low HOXA9 expression. UTX and WHSC1 also display similar expression patterns to HOXA9, being lowest in the embryonic erythrocyte lineage, higher in the fetal stage and showing highest expression in the adult stage. MLL and MEN1, however, show consistent expression through each erythroid lineage, and it is possible that some other transcription factor may be interfering with the actions of these genes on HOXA9 during the embryonic stage.
HOXA9 itself regulates a vast array of genes, such as Flt3, Erg, Myb and Lmo2, all of which exhibit the characteristic increasing expression pattern through the erythroid lineages displayed by HOXA9. Furthermore, mutations in each of these genes have been implicated in cancers. Flt3 duplication is observed in 20% of AML cases, and along with NUP98 translocation, it is associated with a poor prognosis. Erg and Myb are part of two families of transcription factors which, when mutated, correlate strongly with prostate cancer and myeloblastosis respectively. Lmo2 is associated with T-cell leukemias, and is also essential to erythropoiesis in early developmental stages, as Lmo2 knockout mice experience yolk sac erythropoiesis failure and the embryo dies around 10.5 days post coitus. This seems to contradict with the observed expression of Lmo2 being significantly lower in embryonic stages compared to fetal and adult stages.
Other genes have already been shown to co-operate with NUP98-HOXA9 and increase their activity, such as Dnalc4, Fcgr2b, FcrI and Con1. This particular study utilized reverse transcription polymerase chain reaction to measure changes in gene expression. | HOXA9
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.[1][2]
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is highly similar to the abdominal-B (Abd-B) gene of Drosophila fly. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis.[3]
As HOXA9 dysfunction has been implicated in acute myeloid leukemia,[4] and expression of the gene has been shown to differ markedly between erythrocyte lineages of different stages of development,[5] the gene is of particular interest from a hematopoietic perspective.
# Function
## Role in hematopoiesis
As HOXA9 is part of the homeobox family, involved in setting the body plans of animals,[6] it is likely that HOXA9 would display increased expression in cells with higher differentiation potentials. Indeed in the hematopoietic lineage, it has been found that HOXA9 is preferentially expressed in hematopoietic stem cells (HSCs), and is down-regulated as the cell differentiates and matures further.[7]
HOXA9 knockout mice have been shown to develop a reduction in the number of circulating common myeloid progenitor cells, which differentiate into erythroid progenitor cells.[8] The same study indicated that HOXA9 deficiencies specifically affected the granulocyte lineage of the common myeloid progenitor, and it was in HOXA7 knockout mice where the erythroid lineage was affected; however, ErythronDB shows HOXA7 as being insignificantly expressed in all stages of each erythroid lineage.[5] This is something that needs to be investigated further, and could shed light on the interactions between the genes in the HOXA family.
Another study found that HOXA9 knockout HSCs displayed a 5-fold impairment to proliferation rate in vitro, as well as delayed maturation to committed progenitors, specifically myeloid maturation, and that normal proliferation and differentiation rates could be reinstated by reintroducing a HOXA9 vector into the culture.[9] In vivo, lethally irradiated mice with transplanted HOXA9 knockout HSCs displayed a 4-fold to 12-fold reduction in repopulating ability. Furthermore, they developed 60% less myeloid and erythroid colonies in the bone marrow when compared to the wild type.[10] Furthermore, transgenic mice with overexpressed HOXA9 developed a 15-fold increase in the amount of committed progenitor cells in the bone marrow,[11] indicating that overexpressed HOXA9 induces expansion of the HSC population without disrupting differentiation.
From these results, it appears that HOXA9 is important in maintaining HSC populations, as well as guiding their differentiation, especially towards myeloid (erythroid and granulocyte) lineages.
## Expression in adult, fetal and embryonic stages
Throughout the development of a mammal, there are three distinct stages of erythrocyte formation – embryonic, fetal and adult. Adult erythrocytes are the most common blood cell type in mammals, and their characteristic biconcave shape, 7-8 µm diameter and enucleation are amongst the greatest commonalities between mammalian species.[12] However, primitive and fetal erythrocytes, which circulate during early stages of development, are markedly different from their adult counterparts, most obviously through their larger size, shorter lifespan, nucleation, containment of different hemoglobin chains, and higher oxygen affinity.[13] The reasons for and functions of these differences are not well established.
HOXA9 is a candidate for one of the genes responsible for these morphological differences between the erythrocyte lineages, as it is expressed differently in each lineage.[5] In primitive erythrocyte precursors, HOXA9 expression is almost zero. It increases slightly in the fetal stage, and then it is expressed highly in the adult erythrocyte precursors. This expression profile links to the importance of HOXA9 in the HSC, as it mirrors the fact that HSCs are absent in the developing embryo, undergoing initial production in the fetal stage, and are vital in the adult. Furthermore, in the fetal and adult precursors, not all precursor stages display HOXA9 expression. Most of the expression is in the proerythroblast (P) stage, and a minor amount in the basophilic erythroblast (B) stage. There is almost zero expression in the orthonormoblast (O) and reticulocyte (R) stages.[5] P and B are the first two stages of committed differentiation in the erythrocyte lineage, and this implies that HOXA9 may only be involved in the differentiation and proliferation of HSCs, rather than the erythrocyte maturation process.
# Clinical significance
## Role in acute myeloid leukemia
Ordinarily, HOXA9 is expressed on chromosome 7 and the nucleoporin gene NUP98 is expressed on chromosome 11. However, a gene translocation which sometimes occurs in humans moves NUP98 onto chromosome 7, where it fuses with HOXA9 to form the NUP98-HOXA9 oncogene.[4] This oncogene has been widely implicated in acute myeloid leukemia (AML), and expression of this oncogene is the single most highly correlating factor for poor AML prognosis.[11] The oncogene has been found to increase proliferative rates of HSCs whilst impairing their differentiation.
The HOXA9 fusion oncogene causes an 8 times greater proliferation rate of HSCs after 5 weeks of cell culture when compared to control cells,[14] and doubles the period of time over which HSCs can self-renew to an average of 54.3 days, compared to control human HSCs which stopped proliferating after 27.3 days.[15]
There are conflicting results regarding the effect of the oncogene on the differentiation of HSCs into the erythroid lineage. One study observed that the oncogene had a detrimental effect on the differentiation of HSCs, especially in the erythroid lineage, as proerythroblast colonies derived in vitro from mutated HSCs were fewer in number when compared to those derived from control HSCs, regardless of growth factors such as erythropoietin and interleukins which were introduced into the cultures.[14] However, another study noted that the erythroid colonies were twice as populated in cultures of oncogene HSCs when compared to control HSCs.[15] It is possible that these differing observations are due to a delayed differentiation of HSCs affected by the oncogene. The study which observed an increase in erythroid cell number noted that this proliferative effect could only be observed after around 3 weeks, and before this, cell numbers were comparable if not lower for the oncogene culture.[15] The study observing a decreased number of cells did not quote the time of measurement, so if it was within three weeks of the culture, the reduced number may be attributed to this delay.
## Morphology alteration
Proerythroblasts formed in the densely populated colonies of oncogene HSC cultures are strikingly different from those formed in the control colonies. By staining the colonies with giemsa, the oncogene-derived cells were shown to be non-hemoglobinized, larger, much less uniform in shape and had a distinctly large nucleus.[15] These are some of the key morphological differences between primitive erythrocytes and adult erythrocytes. Thus, the NUP98-HOXA9 fusion may give rise to a new population of primitive erythrocytes in cases of AML, and by investigating the various proteins coded by this oncogene, it may be possible to not only establish some molecular causes of AML, but also identify some crucial proteins involved in early erythropoiesis which are absent during adult erythropoiesis.
## Pure erythroid leukemia
There exists a rare form of AML, pure erythroid leukemia, where only the erythroid precursors of myeloid progenitors are leukemic, and not the granulocyte precursors. In this form of AML, levels of erythroblasts can reach up to 94.8% of all nucleated cells in the bone marrow,[16] and the immature forms of the erythroblasts, the proerythroblasts and basophilic erythroblasts, are more commonly found.[17] One study noted that in control leukemic groups with general AML, immature erythroblasts accounted for 8% of all erythroid cells, but in a group with pure erythroid leukemia, this number was a minimum of 40%, and ranged up to 83%.[17] Furthermore, in the case of pure erythroid leukemia, the immature erythrocytes are most morphologically affected, being larger and sometimes bi- or tri-nucleic.[17] Hence the most affected stages of erythrocyte development in pure erythroid leukemia are the same stages in which HOXA9 expression is greatest.
# Interactions
HOXA9 has been shown to interact with:
- MEIS1,[18][19]
- PBX2,[19] and
- TRIP6.[20]
HOXA9 expression is regulated by several genes, including UTX, WHSC1, MLL and MEN1.[21] UTX, MLL and WHSC1 code for protein methylation and demethylation activity,[5] specifically for the histone methyltransferase complex, of which increased levels have been shown to correlate with higher HOXA9 expression.[22] MEN1 codes for the tumour suppressing protein menin, and lower menin levels as a result of MEN1 excision correlate with low HOXA9 expression.[23] UTX and WHSC1 also display similar expression patterns to HOXA9, being lowest in the embryonic erythrocyte lineage, higher in the fetal stage and showing highest expression in the adult stage.[5] MLL and MEN1, however, show consistent expression through each erythroid lineage,[5] and it is possible that some other transcription factor may be interfering with the actions of these genes on HOXA9 during the embryonic stage.
HOXA9 itself regulates a vast array of genes, such as Flt3, Erg, Myb and Lmo2,[24] all of which exhibit the characteristic increasing expression pattern through the erythroid lineages displayed by HOXA9.[5] Furthermore, mutations in each of these genes have been implicated in cancers. Flt3 duplication is observed in 20% of AML cases, and along with NUP98 translocation, it is associated with a poor prognosis.[25] Erg and Myb are part of two families of transcription factors which, when mutated, correlate strongly with prostate cancer and myeloblastosis respectively.[26] Lmo2 is associated with T-cell leukemias, and is also essential to erythropoiesis in early developmental stages, as Lmo2 knockout mice experience yolk sac erythropoiesis failure and the embryo dies around 10.5 days post coitus.[27] This seems to contradict with the observed expression of Lmo2 being significantly lower in embryonic stages compared to fetal and adult stages.[5]
Other genes have already been shown to co-operate with NUP98-HOXA9 and increase their activity, such as Dnalc4, Fcgr2b, FcrI and Con1.[28] This particular study utilized reverse transcription polymerase chain reaction to measure changes in gene expression. | https://www.wikidoc.org/index.php/HOXA9 | |
b6eee17e9ec3a8cc7031a5c12a9e9fb04025d4c2 | wikidoc | HOXB6 | HOXB6
Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.
# Function
This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development, including that of lung and skin, and has been localized to both the nucleus and cytoplasm. Altered expression of this gene or a change in the subcellular localization of its protein is associated with some cases of acute myeloid leukemia and colorectal cancer.
# During development
HOX B6 gene is only expressed in erythoid progenitor cells, which are the precursor to red blood cells used for transport of oxygen and carbon dioxide throughout the body. During development, the formation of the HOX gene factor happens in the first stages of fetal development, namely soon after the establishment of the mesoderm, which is the “middle layer” of the future embryo. However, HOX B6 is only expressed once the undifferentiated stem cells of the embryo distinguish themselves into the erythpoietic phase. The research has shown that HOX B6 is not expressed in hematopoietic stem cells located in the red bone marrow, which are the precursor cells to all types of blood cells, or primordial germ cells (PGCs), the precursor to cells passed on in each generation. Since it is a transcriptional factor, HOX B6 regulates erythpoigenesis (red blood cell formation) using mRNA as the basis for certain protein productions. The specific gene factor for erytopoigenesis has relatively been unobserved in the scientific community, and no known diseases have been associated with a defect HOX B6 gene. However, it has been shown in correlation with major skeletal deformations.
HOXB6 is a structural protein that has been shown to influence the growth and differentiation of the different blood lineages. This gene has also been shown to encourage the growth of granulocytes and monocytes, but at the cost of other blood cells. HOXB6 has the ability to cause the indefinite proliferation of murine marrow cells, as well as expand hematopoietic stem cells. When expressed abnormally, HOXB6 displays many characteristics of a potent oncoprotein. An oncoprotein can cause the transformation of a normal cell into a tumor cell. Overexpression of HOXB6, along with the addition of MEIS1 protein, has been implicated in the development of acute myeloid leukemia (AML). Acute myeloid leukemia is a cancer of the blood cells, specifically the leukocytes. The chromosomal irregularity most frequently seen in HOXB6 AML is a reappearing interstitial deletion of chromosome 2. Fundamental HOXB6 expression stops myeloid differentiation and debilitates erythropoiesis, megakaryopoiesis, and lymphopoiesis. | HOXB6
Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.[1][2][3]
# Function
This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development, including that of lung and skin, and has been localized to both the nucleus and cytoplasm. Altered expression of this gene or a change in the subcellular localization of its protein is associated with some cases of acute myeloid leukemia and colorectal cancer.[3]
# During development
HOX B6 gene is only expressed in erythoid progenitor cells, which are the precursor to red blood cells used for transport of oxygen and carbon dioxide throughout the body. During development, the formation of the HOX gene factor happens in the first stages of fetal development, namely soon after the establishment of the mesoderm, which is the “middle layer” of the future embryo. However, HOX B6 is only expressed once the undifferentiated stem cells of the embryo distinguish themselves into the erythpoietic phase. The research has shown that HOX B6 is not expressed in hematopoietic stem cells located in the red bone marrow, which are the precursor cells to all types of blood cells, or primordial germ cells (PGCs), the precursor to cells passed on in each generation.[4] Since it is a transcriptional factor, HOX B6 regulates erythpoigenesis (red blood cell formation) using mRNA as the basis for certain protein productions. The specific gene factor for erytopoigenesis has relatively been unobserved in the scientific community, and no known diseases have been associated with a defect HOX B6 gene. However, it has been shown in correlation with major skeletal deformations.[5]
HOXB6 is a structural protein that has been shown to influence the growth and differentiation of the different blood lineages. This gene has also been shown to encourage the growth of granulocytes and monocytes, but at the cost of other blood cells. HOXB6 has the ability to cause the indefinite proliferation of murine marrow cells, as well as expand hematopoietic stem cells. When expressed abnormally, HOXB6 displays many characteristics of a potent oncoprotein. An oncoprotein can cause the transformation of a normal cell into a tumor cell. Overexpression of HOXB6, along with the addition of MEIS1 protein, has been implicated in the development of acute myeloid leukemia (AML). Acute myeloid leukemia is a cancer of the blood cells, specifically the leukocytes. The chromosomal irregularity most frequently seen in HOXB6 AML is a reappearing interstitial deletion of chromosome 2. Fundamental HOXB6 expression stops myeloid differentiation and debilitates erythropoiesis, megakaryopoiesis, and lymphopoiesis.[6] | https://www.wikidoc.org/index.php/HOXB6 | |
ac2bc310b0973d5330a3188fdfd3bf9ac2530c63 | wikidoc | HOXB7 | HOXB7
Homeobox protein Hox-B7 is a protein that in humans is encoded by the HOXB7 gene.
# Function
This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded nuclear protein functions as a sequence-specific transcription factor that is involved in cell proliferation and differentiation. Increased expression of this gene is associated with some cases of melanoma and ovarian carcinoma.
# Interactions
HOXB7 has been shown to interact with PBX1 and CREB-binding protein. | HOXB7
Homeobox protein Hox-B7 is a protein that in humans is encoded by the HOXB7 gene.[1][2]
# Function
This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded nuclear protein functions as a sequence-specific transcription factor that is involved in cell proliferation and differentiation. Increased expression of this gene is associated with some cases of melanoma and ovarian carcinoma.[3]
# Interactions
HOXB7 has been shown to interact with PBX1[4] and CREB-binding protein.[5] | https://www.wikidoc.org/index.php/HOXB7 | |
31cf783f2d44a1a689050aa102e4a09986180d59 | wikidoc | HOXB8 | HOXB8
Homeobox protein Hox-B8 is a protein that in humans is encoded by the HOXB8 gene.
# Function
This gene is a member of the Antp homeobox family and encodes a nuclear protein with a homeobox DNA-binding domain. It is included in a cluster of Homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with colorectal cancer. Mice that have had the murine ortholog (see Homology (biology) § Orthology) of this gene knocked out exhibit an excessive pathologic grooming behavior. This behavior is similar to the behavior of humans suffering from the obsessive-compulsive spectrum disorder trichotillomania.
Transplantation of normal (wild-type) bone marrow into a Hoxb8 mutant mouse results in a reduction of compulsive grooming. | HOXB8
Homeobox protein Hox-B8 is a protein that in humans is encoded by the HOXB8 gene.[1][2][3]
# Function
This gene is a member of the Antp homeobox family and encodes a nuclear protein with a homeobox DNA-binding domain. It is included in a cluster of Homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with colorectal cancer. Mice that have had the murine ortholog (see Homology (biology) § Orthology) of this gene knocked out exhibit an excessive pathologic grooming behavior. This behavior is similar to the behavior of humans suffering from the obsessive-compulsive spectrum disorder trichotillomania.[3]
Transplantation of normal (wild-type) bone marrow into a Hoxb8 mutant mouse results in a reduction of compulsive grooming.[4] | https://www.wikidoc.org/index.php/HOXB8 | |
477a9870ffcfaa79053fa5d200068e767009a5df | wikidoc | KMT2A | KMT2A
Histone-lysine N-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the KMT2A gene.
MLL1 is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD and is involved in the epigenetic maintenance of transcriptional memory. Its role as an epigenetic regulator of neuronal function is an ongoing area of research.
# Function
## Transcriptional Regulation
KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the MLL1 enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa). These fragments then assemble into different multi-protein complexes that regulate the transcription of specific target genes, including many of the HOX genes.
Transcriptome profiling after deletion of MLL1 in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding. Among them were Meis2, a homeobox transcription factor critical for development of forebrain neurons and Satb2, a protein involved in neuronal differentiation.
Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.
## Cognition and emotion
MLL1 has been shown to be an important epigenetic regulator of complex behaviors. Rodent models of MLL1 dysfunction in forebrain neurons showed that conditional deletion results in elevated anxiety and defective cognition. Prefrontal cortex-specific knockout of MLL1 results in the same phenotypes, as well as working memory deficits.
## Stem Cells
MLL1 has been found to be an important regulator of epiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditional embryonic stem cells derived from inner cell mass prior to implantation. Suppression of MLL1 expression was shown to be adequate for inducing ESC-like morphology and behavior within 72 hours of treatment. It has been proposed that the small molecule inhibitor MM-401, which was used to inhibit MLL1, changes the distribution of H3K4me1, the single methylation of the histone H3 lysine 4, to be significantly downregulated at MLL1 targets thus leading to decreased expression of MLL1 targets, rather than a direct regulation of pluripotency core markers.
# Structure
## Gene
KMT2A gene has 37 exons and resides on chromosome 11 at q23.
## Protein
KMT2A has over a dozen of binding partners and is cleaved into two pieces, a larger N-terminal fragment, involved in gene repression, and a smaller C-terminal fragment, which is a transcriptional activator. The cleavage, followed by the association of the two fragments, is necessary for KMT2A to be fully active. Like many other methyltransferases, the KMT2 family members exist in multisubunit nuclear complexes (human COMPASS), where other subunits also mediate the enzymatic activity. The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP.
9aaTADs in the E protein family
E2A and MLL binding to the KIX domain of CBP
# Clinical significance
Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism. Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons. It also may participate in the process of GAD67 downregulation in schizophrenia.
Rearrangements of the MLL1 gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid. Despite being an aggressive leukemia, the MLL1 rearranged sub-type had the lowest mutation rates reported for any cancer.
Mutations in MLL1 cause Wiedemann-Steiner syndrome and Acute lymphoblastic leukemia. The leukemia cells of up to 80 percent of infants with ALL-1 have a chromosomal rearrangement that fuses the MLL1 gene to a gene on a different chromosome.
# Interactions
MLL (gene) has been shown to interact with:
- ASH2L,
- CREBBP,
- CTBP1,
- HDAC1,
- HCFC1,
- MEN1,
- PPIE,
- PPP1R15A,
- RBBP5, and
- WDR5. | KMT2A
Histone-lysine N-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the KMT2A gene.[1]
MLL1 is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD[2] and is involved in the epigenetic maintenance of transcriptional memory. Its role as an epigenetic regulator of neuronal function is an ongoing area of research.
# Function
## Transcriptional Regulation
KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the MLL1 enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4.[3] This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa).[4][5] These fragments then assemble into different multi-protein complexes that regulate the transcription of specific target genes, including many of the HOX genes.
Transcriptome profiling after deletion of MLL1 in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding.[6] Among them were Meis2, a homeobox transcription factor critical for development of forebrain neurons[7][8] and Satb2, a protein involved in neuronal differentiation.[9]
Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[10]
## Cognition and emotion
MLL1 has been shown to be an important epigenetic regulator of complex behaviors. Rodent models of MLL1 dysfunction in forebrain neurons showed that conditional deletion results in elevated anxiety and defective cognition. Prefrontal cortex-specific knockout of MLL1 results in the same phenotypes, as well as working memory deficits.[6]
## Stem Cells
MLL1 has been found to be an important regulator of epiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditional embryonic stem cells derived from inner cell mass prior to implantation. Suppression of MLL1 expression was shown to be adequate for inducing ESC-like morphology and behavior within 72 hours of treatment. It has been proposed that the small molecule inhibitor MM-401, which was used to inhibit MLL1, changes the distribution of H3K4me1, the single methylation of the histone H3 lysine 4, to be significantly downregulated at MLL1 targets thus leading to decreased expression of MLL1 targets, rather than a direct regulation of pluripotency core markers.[11]
# Structure
## Gene
KMT2A gene has 37 exons and resides on chromosome 11 at q23.[10]
## Protein
KMT2A has over a dozen of binding partners and is cleaved into two pieces, a larger N-terminal fragment, involved in gene repression, and a smaller C-terminal fragment, which is a transcriptional activator.[12] The cleavage, followed by the association of the two fragments, is necessary for KMT2A to be fully active. Like many other methyltransferases, the KMT2 family members exist in multisubunit nuclear complexes (human COMPASS), where other subunits also mediate the enzymatic activity.[13] The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP.[14][15]
9aaTADs in the E protein family
E2A and MLL binding to the KIX domain of CBP
# Clinical significance
Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism.[16] Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons.[16][17][18] It also may participate in the process of GAD67 downregulation in schizophrenia.[17]
Rearrangements of the MLL1 gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid.[19] Despite being an aggressive leukemia, the MLL1 rearranged sub-type had the lowest mutation rates reported for any cancer.[20]
Mutations in MLL1 cause Wiedemann-Steiner syndrome and Acute lymphoblastic leukemia.[21] The leukemia cells of up to 80 percent of infants with ALL-1 have a chromosomal rearrangement that fuses the MLL1 gene to a gene on a different chromosome.[20]
# Interactions
MLL (gene) has been shown to interact with:
- ASH2L,[22]
- CREBBP,[23][24]
- CTBP1,[25]
- HDAC1,[25]
- HCFC1,[22]
- MEN1,[22]
- PPIE,[26]
- PPP1R15A,[27]
- RBBP5,[22] and
- WDR5.[22] | https://www.wikidoc.org/index.php/HRX | |
73c52db7da3f62da76017a4cf848cec66435ffe7 | wikidoc | HSPA8 | HSPA8
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.
# Structure
This gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (Hsp70) family. As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain.
The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.
# Function
The heat shock protein 70 (Hsp70) family contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate (Hsc) proteins. The heat shock 70 kDa protein 8 also known as Hsc70 belongs to the heat-shock cognate subgroup. This protein binds to nascent polypeptides to facilitate correct protein folding. In order to properly fold non-native proteins, Hsp70 chaperones interact with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. Hsc70 is known to localize to the cytoplasm and lysosome, where it participates in chaperone-mediated autophagy by aiding the unfolding and translocation of substrate proteins across the membrane into the lysosomal lumen. Through this pathway, Hsc70 also contributes to the degradation of the proapoptotic BBC3/PUMA under normal conditions, thus conferring cytoprotection.
Hsc70 additionally serves as a positive regulator of cell cycle transition and carcinogenesis. For example, Hsc70 regulates the nuclear accumulation of cyclin D1, which is a key player in G1 to S phase cell cycle transition.
Another function of Hsc70 is as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. It works with auxilin to remove clathrin coated vesicles. In neurons, synaptojanin is also an important protein involved in vesicle uncoating. Hsc70 is a key component of chaperone-mediated autophagy wherein it imparts selectivity to the proteins being degraded by this lysosomal pathway.
## Hsc70 vs Hsp70 comparison
Human Hsc70 has 85% identity with human Hsp70 (SDSC workbench, blosom26 default analysis). The scientific community has long assumed that Hsp70 and Hsc70 have similar cellular roles, but this assumption proved incomplete. While Hsc70 also performed chaperone functions under normal conditions, unlike canonical heat shock proteins, Hsc70 is constitutively expressed and performs functions related to normal cellular processes, such as protein ubiquitylation and degradation.
# Clinical significance
The Hsp70 member proteins are important apoptotic constituents. 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.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation. As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials. One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma. Alternatively, overexpression of Hsp70 can mitigate damage from ischemia-reperfusion in cardiac muscle, as well damage from neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge. In particular, Hsc70 plays a protective role in the aforementioned diseases, as well as in other neuropsychiatric disorders such as schizophrenia. Its protective role was further highlighted in a study that identified HSPA8 alongside other HSP70 proteins in a core sub-network of the wider chaperome interactome that functions as a proteostasis safeguard and that is repressed in aging brains and in the brains of Alzheimer's, Parkinson's and Huntington's disease patients.
# Interactions
Hsc70 forms a chaperone complex by interacting with the heat shock protein of 40 kDa (Hsp40), the heat shock protein of 90 kDa (Hsp90), the hsc70-interacting protein (HIP), the hsc70-hsp90 organizing protein (HOP), and the Bcl2-associated athanogene 1 protein (BAG1).
HSPA8 has also been shown to interact with:
- BBC Three,
- BAG1,
- BAG2,
- BAG3,
- BAG4,
- CDC5L,
- CITED1,
- CCND1,
- DNAJA3,
- GJA1,
- HSPBP1,
- PARK2, and
- STUB1. | HSPA8
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11.[1] As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins.[1][2] Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation.[2][3][4] It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.[2][3]
# Structure
This gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (Hsp70) family.[1] As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain.[5][6][7]
The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation. The unstructured region at the very end of the C-terminal is believed to be the docking site for co-chaperones.[7]
# Function
The heat shock protein 70 (Hsp70) family contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate (Hsc) proteins. The heat shock 70 kDa protein 8 also known as Hsc70 belongs to the heat-shock cognate subgroup. This protein binds to nascent polypeptides to facilitate correct protein folding.[1] In order to properly fold non-native proteins, Hsp70 chaperones interact with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.[2][3] Hsc70 is known to localize to the cytoplasm and lysosome, where it participates in chaperone-mediated autophagy by aiding the unfolding and translocation of substrate proteins across the membrane into the lysosomal lumen.[8][9] Through this pathway, Hsc70 also contributes to the degradation of the proapoptotic BBC3/PUMA under normal conditions, thus conferring cytoprotection.[9]
Hsc70 additionally serves as a positive regulator of cell cycle transition and carcinogenesis. For example, Hsc70 regulates the nuclear accumulation of cyclin D1, which is a key player in G1 to S phase cell cycle transition.[10][11]
Another function of Hsc70 is as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell.[1][12] It works with auxilin to remove clathrin coated vesicles. In neurons, synaptojanin is also an important protein involved in vesicle uncoating.[1] Hsc70 is a key component of chaperone-mediated autophagy wherein it imparts selectivity to the proteins being degraded by this lysosomal pathway.[1][12]
## Hsc70 vs Hsp70 comparison
Human Hsc70 has 85% identity with human Hsp70 (SDSC workbench, blosom26 default analysis). The scientific community has long assumed that Hsp70 and Hsc70 have similar cellular roles, but this assumption proved incomplete. While Hsc70 also performed chaperone functions under normal conditions, unlike canonical heat shock proteins, Hsc70 is constitutively expressed and performs functions related to normal cellular processes, such as protein ubiquitylation and degradation.[12][13]
# Clinical significance
The Hsp70 member proteins are important apoptotic constituents. 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.[14] 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.
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporine, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colon cancers, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[3] Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[15][3] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[3] One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma.[3] Alternatively, overexpression of Hsp70 can mitigate damage from ischemia-reperfusion in cardiac muscle, as well damage from neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[15][16] In particular, Hsc70 plays a protective role in the aforementioned diseases, as well as in other neuropsychiatric disorders such as schizophrenia.[17] Its protective role was further highlighted in a study that identified HSPA8 alongside other HSP70 proteins in a core sub-network of the wider chaperome interactome that functions as a proteostasis safeguard and that is repressed in aging brains and in the brains of Alzheimer's, Parkinson's and Huntington's disease patients.[18]
# Interactions
Hsc70 forms a chaperone complex by interacting with the heat shock protein of 40 kDa (Hsp40), the heat shock protein of 90 kDa (Hsp90), the hsc70-interacting protein (HIP), the hsc70-hsp90 organizing protein (HOP), and the Bcl2-associated athanogene 1 protein (BAG1).[8]
HSPA8 has also been shown to interact with:
- BBC Three,[9]
- BAG1,[19][20]
- BAG2,[19]
- BAG3,[19]
- BAG4,[21]
- CDC5L,[22]
- CITED1,[23]
- CCND1,[24]
- DNAJA3,[25]
- GJA1,[24]
- HSPBP1,[26][27]
- PARK2,[28] and
- STUB1.[29] | https://www.wikidoc.org/index.php/HSPA8 | |
1a4cef3e1732fe85c44b1126dd924707db529c2d | wikidoc | HSPB6 | HSPB6
Heat shock protein beta-6 is a protein that in humans is encoded by the HSPB6 gene.
HSPB6 also known as hsp20 is a 17-kDa member of the small heat shock family of proteins. HSPB6 was first identified in 1994 when it was isolated from rat and human skeletal muscle as a complex with HSPB1 (also known as HSP27) and HSPB5 (also known as αB-crystallin).
HSPB6 is expressed in multiple tissues; however, HSPB6 is most highly and constitutively expressed in different types of muscle including vascular, airway, colonic, bladder, uterine smooth muscle, cardiac muscle and skeletal muscle. HSPB6 has specific functions for vasodilation, platelet function, and insulin resistance and in smooth and cardiac muscle. | HSPB6
Heat shock protein beta-6 is a protein that in humans is encoded by the HSPB6 gene.[1][2][3]
HSPB6 also known as hsp20 is a 17-kDa member of the small heat shock family of proteins. HSPB6 was first identified in 1994 when it was isolated from rat and human skeletal muscle as a complex with HSPB1 (also known as HSP27) and HSPB5 (also known as αB-crystallin).[4]
HSPB6 is expressed in multiple tissues; however, HSPB6 is most highly and constitutively expressed in different types of muscle including vascular, airway, colonic, bladder, uterine smooth muscle, cardiac muscle and skeletal muscle. HSPB6 has specific functions for vasodilation, platelet function, and insulin resistance[5] and in smooth and cardiac muscle.[6][7] | https://www.wikidoc.org/index.php/HSPB6 | |
8269a36eea781431ff6b1492d250163ac75c80e6 | wikidoc | HTRA1 | HTRA1
Serine protease HTRA1 is an enzyme that in humans is encoded by the HTRA1 gene. The HTRA1 protein is composed of four distinct protein domains. They are from amino-terminus to carboxyl-terminus an Insulin-like growth factor binding domain, a kazal domain, a trypsin-like peptidase domain and a PDZ domain.
This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth.
Mutations of this gene are responsible for the development of CARASIL, a genetic form of cerebral vasculopathy. | HTRA1
Serine protease HTRA1 is an enzyme that in humans is encoded by the HTRA1 gene.[1][2] The HTRA1 protein is composed of four distinct protein domains. They are from amino-terminus to carboxyl-terminus an Insulin-like growth factor binding domain, a kazal domain, a trypsin-like peptidase domain and a PDZ domain.
This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth.[2]
Mutations of this gene are responsible for the development of CARASIL, a genetic form of cerebral vasculopathy. | https://www.wikidoc.org/index.php/HTRA1 | |
48bd96be16b6738f724821b6d61fd7f7e1d4ce8b | wikidoc | HVCN1 | HVCN1
Voltage-gated hydrogen channel 1 is a protein that in humans is encoded by the HVCN1 gene.
Voltage-gated hydrogen channel 1 is a voltage-gated proton channel that has been shown to allow proton transport into phagosomes and out of many types of cells including spermatozoa, electrically excitable cells and respiratory epithelial cells. The proton-conducting HVCN1 channel has only transmembrane domains corresponding to the S1-S4 voltage sensing domains (VSD) of voltage-gated potassium channels and voltage-gated sodium channels. Molecular simulation is consistent with a water-filled pore that can function as a "water wire" for allowing hydrogen bonded H+ to cross the membrane. However, mutation of Asp112 in human Hv1 results in anion permeation, suggesting that obligatory protonation of Asp produces proton selectivity. Quantum mechanical calculations show that the Asp-Arg interaction can produce proton selective permeation. The HVCN1 protein has been shown to exist as a dimer with two functioning pores. Like other VSD channels, HVCN1 channels conduct ions about 1000-fold slower than channels formed by tetrameric S5-S6 central pores.
# As a drug target
Small molecule inhibitors of the HVCN1 channel are being developed as chemotherapeutics and anti-inflammatory agents. | HVCN1
Voltage-gated hydrogen channel 1 is a protein that in humans is encoded by the HVCN1 gene.
Voltage-gated hydrogen channel 1 is a voltage-gated proton channel that has been shown to allow proton transport into phagosomes[1][2] and out of many types of cells including spermatozoa, electrically excitable cells and respiratory epithelial cells.[3] The proton-conducting HVCN1 channel has only transmembrane domains corresponding to the S1-S4 voltage sensing domains (VSD) of voltage-gated potassium channels and voltage-gated sodium channels.[4] Molecular simulation is consistent with a water-filled pore that can function as a "water wire" for allowing hydrogen bonded H+ to cross the membrane.[5][6] However, mutation of Asp112 in human Hv1 results in anion permeation, suggesting that obligatory protonation of Asp produces proton selectivity.[7] Quantum mechanical calculations show that the Asp-Arg interaction can produce proton selective permeation.[8] The HVCN1 protein has been shown to exist as a dimer with two functioning pores.[9][10] Like other VSD channels, HVCN1 channels conduct ions about 1000-fold slower than channels formed by tetrameric S5-S6 central pores.[11]
# As a drug target
Small molecule inhibitors of the HVCN1 channel are being developed as chemotherapeutics and anti-inflammatory agents.[12] | https://www.wikidoc.org/index.php/HVCN1 | |
7012e763ac27a6215a5f62bed788a7a24327c6fd | wikidoc | HYAL2 | HYAL2
Hyaluronidase-2 is an enzyme that in humans is encoded by the HYAL2 gene.
This gene encodes a protein which is similar in structure to hyaluronidases. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. Varying functions have been described for this protein. It has been described as a lysosomal hyaluronidase which is active at a pH below 4 and specifically hydrolyzes high molecular weight hyaluronan. It has also been described as a GPI-anchored cell surface protein which does not display hyaluronidase activity but does serve as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.
One study found associations between cleft lip and palate and mutations in the HYAL2 gene.
An investigation published in 2017, attributed an additional function to the Hyaluronidase 2 (HYAL2) protein. The study found interactions between HYAL2 and proteins involved in the alternative splicing of CD44 pre-mRNA, suggesting a broader regulatory role for the HYAL2 protein in cell biology. | HYAL2
Hyaluronidase-2 is an enzyme that in humans is encoded by the HYAL2 gene.[1][2][3]
This gene encodes a protein which is similar in structure to hyaluronidases. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. Varying functions have been described for this protein. It has been described as a lysosomal hyaluronidase which is active at a pH below 4 and specifically hydrolyzes high molecular weight hyaluronan. It has also been described as a GPI-anchored cell surface protein which does not display hyaluronidase activity but does serve as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[3]
One study found associations between cleft lip and palate and mutations in the HYAL2 gene.[4]
An investigation published in 2017, attributed an additional function to the Hyaluronidase 2 (HYAL2) protein. The study found interactions between HYAL2 and proteins involved in the alternative splicing of CD44 pre-mRNA,[5] suggesting a broader regulatory role for the HYAL2 protein in cell biology. | https://www.wikidoc.org/index.php/HYAL2 | |
4aa2f36da4423f2eaf0704908d7f3c8a58b59a22 | wikidoc | Heave | Heave
Synonyms and Keywords: lift, parasternal heave, parasternal lift, left ventricular impulse, LV impulse
# Overview
A heave is felt as an upward displacement of the chest against the hand during palpation of the precordium. Heaves are best felt with the heel of the hand at the sternal border.
# Physical Examination
For more detailed information regarding the physical examination of the precordium, please consult the chapter on palpation of the precordium. | Heave
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and Keywords: lift, parasternal heave, parasternal lift, left ventricular impulse, LV impulse
# Overview
A heave is felt as an upward displacement of the chest against the hand during palpation of the precordium. Heaves are best felt with the heel of the hand at the sternal border.
# Physical Examination
For more detailed information regarding the physical examination of the precordium, please consult the chapter on palpation of the precordium. | https://www.wikidoc.org/index.php/Heave | |
ade36e27a47ae484fe00c71af02f79a828a4de4d | wikidoc | Hemin | Hemin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Hemin is an blood modifier agent that is FDA approved for the treatment of acute intermittent porphyria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include phlebitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hemin for injection is indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women.
- Manifestations such as pain, hypertension, tachycardia, abnormal mental status and mild to progressive neurologic signs may be controlled in selected patients with this disorder.
- Similar findings have been reported in other patients with acute intermittent porphyria, porphyria variegata and hereditary coproporphyria. Hemin is not indicated in porphyria cutanea tarda.
### Dosing Information
- Before administering Hemin, an appropriate period of alternate therapy (i.e., 400 g glucose/day for 1 to 2 days) must be considered. If improvement is unsatisfactory for the treatment of acute attacks of porphyria, an intravenous infusion of Hemin containing a dose of 1 to 4 mg/kg/day of hematin should be given over a period of 10 to 15 minutes for 3 to 14 days based on the clinical signs. In more severe cases this dose may be repeated no earlier than every 12 hours. No more than 6 mg/kg of hematin should be given in any 24 hour period.
- After reconstitution each mL of Hemin contains the equivalent of approximately 7 mg of hematin. The drug may be administered directly from the vial.
- Since reconstituted Hemin is not transparent, any undissolved particulate matter is difficult to see when inspected visually. Therefore, terminal filtration through a sterile 0.45 micron or smaller filter is recommended.
### Preparation of Solution:
- Reconstitute Hemin by aseptically adding 43 mL of Sterile Water for Injection, USP, to the dispensing vial. Immediately after adding diluent, the product should be shaken well for a period of 2 to 3 minutes to aid dissolution.
- NOTE: Because Hemin contains no preservative and because Hemin undergoes rapid chemical decomposition in solution, it should not be reconstituted until immediately before use. After the first withdrawal from the vial, any solution remaining must be discarded.
- No drug or chemical agent should be added to a Hemin fluid admixture unless its effect on the chemical and physical stability has first been determined.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hemin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hemin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients under 16 years of age have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Guideline-Supported off-Label Use of Hemin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hemin in pediatric patients.
# Contraindications
- Hemin is contraindicated in patients with known hypersensitivity to this drug.
# Warnings
- Hemin is made from human blood. Products made from human blood may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening blood donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Recordati Rare Diseases, (1-888-575-8344). The physician should discuss the risks and benefits of this product with the patient.
- Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
- Hemin therapy is intended to limit the rate of porphyria/heme biosynthesis possibly by inhibiting the enzyme δ-aminolevulinic acid synthetase. For this reason, drugs such as estrogens, barbituric acid derivatives and steroid metabolites which increase the activity of enzyme δ-aminolevulinic acid synthetase should be avoided.
- Also, because hemin for injection has exhibited transient, mild anticoagulant effects during clinical studies, concurrent anticoagulant therapy should be avoided. The extent and duration of the hypocoagulable state induced by Hemin has not been established.
### PRECAUTIONS
- Clinical benefit from Hemin depends on prompt administration. Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. Hemin therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. Hemin is not effective in repairing neuronal damage.
- Recommended dosage guidelines should be strictly followed. Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Oliguria and increased nitrogen retention occurred although the patient remained asymptomatic. No worsening of renal function has been seen with administration of recommended dosages of hematin.
- A large arm vein or a central venous catheter should be utilized for the administration of Hemin to avoid the possibility of phlebitis.
- Since reconstituted Hemin is not transparent, any undissolved particulate matter is difficult to see when inspected visually. Therefore, terminal filtration through a sterile 0.45 micron or smaller filter is recommended.
- Because increased levels of iron and serum ferritin have been reported in post-marketing experience, physicians should monitor iron and serum ferritin in patients receiving multiple administrations of Hemin.
# Adverse Reactions
## Clinical Trials Experience
- Phlebitis with or without leucocytosis and with or without mild pyrexia has occurred after administration of hematin through small arm veins.
## Postmarketing Experience
- Reversible renal shutdown has occurred with administration of excessive doses.
- There have been post-marketing literature reports of thrombocytopenia and coagulopathy (including prolonged prothrombin time and prolonged partial thromboplastin time) in patients receiving Hemin.Iron overload and serum ferritin increased have also been reported.
# Drug Interactions
There is limited information regarding Drug Interaction of Hemin in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with hematin. It is also not known whether hematin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. For this reason Hemin should not be given to a pregnant woman unless the expected benefits are sufficiently important to the health and welfare of the patient to outweigh the unknown hazard to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hemin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hemin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hemin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients under 16 years of age have not been established.
### Geriatic Use
- Clinical studies in Hemin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Hemin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hemin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hemin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hemin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hemin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hemin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
### Tests for Diagnosis and Monitoring of Therapy
- Before Hemin therapy is begun, the presence of acute porphyria must be diagnosed using the following criteria:
- Presence of clinical symptoms.
- Positive Watson-Schwartz or Hoesch test. (A negative Watson-Schwartz or Hoesch test indicates a porphyric attack is highly unlikely. When in doubt quantitative measures of δ-aminolevulinic acid and porphobilinogen in serum or urine may aid in diagnosis.)
- Urinary concentrations of the following compounds may be monitored during Hemin therapy. Drug effect will be demonstrated by a decrease in one or more of the following compounds.
- ALA - δ-aminolevulinic acid
- UPG - uroporphyrinogen
- PBG - porphobilinogen
- coproporphyrin
# IV Compatibility
There is limited information regarding the compatibility of Hemin and IV administrations.
# Overdosage
- Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Treatment of this case consisted of ethacrynic acid and mannitol
# Pharmacology
## Mechanism of Action
- Heme acts to limit the hepatic and/or marrow synthesis of porphyrin. This action is likely due to the inhibition of δ-aminolevulinic acid synthetase, the enzyme which limits the rate of the porphyrin/heme biosynthetic pathway. The exact mechanism by which hematin produces symptomatic improvement in patients with acute episodes of the hepatic porphyrias has not been elucidated
## Structure
- Hemin for injection) is an enzyme inhibitor derived from processed red blood cells. Hemin for injection was known previously as hematin. The term hematin has been used to describe the chemical reaction product of hemin and sodium carbonate solution. Hemin is an iron containing metalloporphyrin. Chemically hemin is represented as chloro iron. The structural formula for hemin is:
## Pharmacodynamics
There is limited information regarding Hemin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following intravenous administration of hematin in non-jaundiced human patients, an increase in fecal urobilinogen can be observed which is roughly proportional to the amount of hematin administered. This suggests an enterohepatic pathway as at least one route of elimination. Bilirubin metabolites are also excreted in the urine following hematin injections.
- Hemin for injection therapy for the acute porphyrias is not curative. After discontinuation of Hemin treatment, symptoms generally return although in some cases remission is prolonged. Some neurological symptoms have improved weeks to months after therapy although little or no response was noted at the time of treatment.
- Other aspects of human pharmacokinetics have not been defined.
## Nonclinical Toxicology
- Hemin was not mutagenic in bacteria systems in vitro and was not clastogenic in mammalian systems in vitro and in vivo. No data are available on potential for carcinogenicity or impairment of fertility in animals or humans.
# Clinical Studies
There is limited information regarding Hemin Clinical Studies in the drug label.
# How Supplied
- Hemin is supplied as a sterile, lyophilized black powder in single dose dispensing vials (NDC 55292-701-54) in a carton (NDC 55292-701-55). When mixed as directed with Sterile Water for Injection, USP, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
## Storage
- Store lyophilized powder at 20-25°C (68-77°F).
- Caution: The packaging (vial stopper) of this product contains natural rubber latex which may cause allergic reactions.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 55292-701-54
Single Dose Vial
Hemin For Injection Hemin®
313 mg Hemin per Vial
For Intravenous Infusion Only Sterile Powder for Injection
RECORDATI RARE DISEASES GROUP
Rx only
Each vial contains:
Hemin ......313 mg
Sodium Carbonate ..... 215 mg
Sorbitol ..... 300 mg
pH may have been adjusted with hydrochloric acid.
Contains no preservatives.
When mixed as directed, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
See package insert for full prescribing information and appropriate caution statements regarding administration.
Caution: Vial stopper contains latex.
The patient and physician should discuss the risks and benefits of this product.
Store powder at 20-25°C (68-77°F).
See USP controlled room temperature.
DIRECTIONS FOR MIXING:
Add 43 mL of Sterile Water for Injection, USP. Shake to aid dissolution. Infusion may be given from this vial.
USE IMMEDIATELY AFTER MIXING.
Discard any unused portion.
Mfd. by: Fresenius Kabi USA, LLC
Raleigh, NC 27616
For: Recordati Rare Diseases Inc.
Lebanon, NJ 08833, U.S.A.
U.S. Lic. No. 1899
Lot:
Exp.:
NDC 55292-701-55
Contains One Vial
Hemin For Injection Hemin®
313 mg Hemin per Vial
For Intravenous Infusion Only Sterile Powder for Injection
RECORDATI RARE DISEASES GROUP
Rx only
Each vial contains:
Hemin ..... 313 mg
Sodium Carbonate ...... 215 mg
Sorbitol ..... 300 mg
pH may have been adjusted with hydrochloric acid.
Contains no preservatives.
When mixed as directed, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
Manufactured by: Fresenius Kabi USA, LLC
Raleigh, NC 27616
For: Recordati Rare Diseases Inc.
Lebanon, NJ 08833, U.S.A.
U.S. Lic. No. 1899
® Trademark of Recordati Rare Diseases Inc.
Lot No.
Exp. Date
Store powder at 20-25°C (68-77°F).
See USP controlled room temperature.
Mixing directions:
1. Prep stopper.
2. Insert vent needle in “air” target.
3. Add 43 mL of Sterile Water for Injection, USP.
4. Immediately after adding diluent shake to aid dissolution.
5. May be administered directly from original single dose dispensing vial.
6. Administer by intermittent intravenous infusion over a period of from 10 to 15 minutes.
USE IMMEDIATELY AFTER MIXING.
Discard any unused portion.
See package insert for full prescribing information and appropriate caution statements regarding administration.
Caution: Vial stopper contains latex.
The patient and physician should discuss the risks and benefits of this product.
# Patient Counseling Information
There is limited information regarding Patient Counseling Information in this label
# Precautions with Alcohol
Alcohol-Hemin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Panhematin
# Look-Alike Drug Names
There is limited information regarding Hemin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Hemin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Hemin is an blood modifier agent that is FDA approved for the treatment of acute intermittent porphyria. There is a Black Box Warning for this drug as shown here. Common adverse reactions include phlebitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Hemin for injection is indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women.
- Manifestations such as pain, hypertension, tachycardia, abnormal mental status and mild to progressive neurologic signs may be controlled in selected patients with this disorder.
- Similar findings have been reported in other patients with acute intermittent porphyria, porphyria variegata and hereditary coproporphyria. Hemin is not indicated in porphyria cutanea tarda.
### Dosing Information
- Before administering Hemin, an appropriate period of alternate therapy (i.e., 400 g glucose/day for 1 to 2 days) must be considered. If improvement is unsatisfactory for the treatment of acute attacks of porphyria, an intravenous infusion of Hemin containing a dose of 1 to 4 mg/kg/day of hematin should be given over a period of 10 to 15 minutes for 3 to 14 days based on the clinical signs. In more severe cases this dose may be repeated no earlier than every 12 hours. No more than 6 mg/kg of hematin should be given in any 24 hour period.
- After reconstitution each mL of Hemin contains the equivalent of approximately 7 mg of hematin. The drug may be administered directly from the vial.
- Since reconstituted Hemin is not transparent, any undissolved particulate matter is difficult to see when inspected visually. Therefore, terminal filtration through a sterile 0.45 micron or smaller filter is recommended.
### Preparation of Solution:
- Reconstitute Hemin by aseptically adding 43 mL of Sterile Water for Injection, USP, to the dispensing vial. Immediately after adding diluent, the product should be shaken well for a period of 2 to 3 minutes to aid dissolution.
- NOTE: Because Hemin contains no preservative and because Hemin undergoes rapid chemical decomposition in solution, it should not be reconstituted until immediately before use. After the first withdrawal from the vial, any solution remaining must be discarded.
- No drug or chemical agent should be added to a Hemin fluid admixture unless its effect on the chemical and physical stability has first been determined.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hemin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hemin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients under 16 years of age have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Guideline-Supported off-Label Use of Hemin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hemin in pediatric patients.
# Contraindications
- Hemin is contraindicated in patients with known hypersensitivity to this drug.
# Warnings
- Hemin is made from human blood. Products made from human blood may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening blood donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Recordati Rare Diseases, (1-888-575-8344). The physician should discuss the risks and benefits of this product with the patient.
- Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
- Hemin therapy is intended to limit the rate of porphyria/heme biosynthesis possibly by inhibiting the enzyme δ-aminolevulinic acid synthetase. For this reason, drugs such as estrogens, barbituric acid derivatives and steroid metabolites which increase the activity of enzyme δ-aminolevulinic acid synthetase should be avoided.
- Also, because hemin for injection has exhibited transient, mild anticoagulant effects during clinical studies, concurrent anticoagulant therapy should be avoided. The extent and duration of the hypocoagulable state induced by Hemin has not been established.
### PRECAUTIONS
- Clinical benefit from Hemin depends on prompt administration. Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. Hemin therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. Hemin is not effective in repairing neuronal damage.
- Recommended dosage guidelines should be strictly followed. Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Oliguria and increased nitrogen retention occurred although the patient remained asymptomatic. No worsening of renal function has been seen with administration of recommended dosages of hematin.
- A large arm vein or a central venous catheter should be utilized for the administration of Hemin to avoid the possibility of phlebitis.
- Since reconstituted Hemin is not transparent, any undissolved particulate matter is difficult to see when inspected visually. Therefore, terminal filtration through a sterile 0.45 micron or smaller filter is recommended.
- Because increased levels of iron and serum ferritin have been reported in post-marketing experience, physicians should monitor iron and serum ferritin in patients receiving multiple administrations of Hemin.
# Adverse Reactions
## Clinical Trials Experience
- Phlebitis with or without leucocytosis and with or without mild pyrexia has occurred after administration of hematin through small arm veins.
## Postmarketing Experience
- Reversible renal shutdown has occurred with administration of excessive doses.
- There have been post-marketing literature reports of thrombocytopenia and coagulopathy (including prolonged prothrombin time and prolonged partial thromboplastin time) in patients receiving Hemin.Iron overload and serum ferritin increased have also been reported.
# Drug Interactions
There is limited information regarding Drug Interaction of Hemin in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with hematin. It is also not known whether hematin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. For this reason Hemin should not be given to a pregnant woman unless the expected benefits are sufficiently important to the health and welfare of the patient to outweigh the unknown hazard to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hemin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hemin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hemin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients under 16 years of age have not been established.
### Geriatic Use
- Clinical studies in Hemin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Hemin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hemin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hemin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hemin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hemin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hemin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
### Tests for Diagnosis and Monitoring of Therapy
- Before Hemin therapy is begun, the presence of acute porphyria must be diagnosed using the following criteria:
- Presence of clinical symptoms.
- Positive Watson-Schwartz or Hoesch test. (A negative Watson-Schwartz or Hoesch test indicates a porphyric attack is highly unlikely. When in doubt quantitative measures of δ-aminolevulinic acid and porphobilinogen in serum or urine may aid in diagnosis.)
- Urinary concentrations of the following compounds may be monitored during Hemin therapy. Drug effect will be demonstrated by a decrease in one or more of the following compounds.
- ALA - δ-aminolevulinic acid
- UPG - uroporphyrinogen
- PBG - porphobilinogen
- coproporphyrin
# IV Compatibility
There is limited information regarding the compatibility of Hemin and IV administrations.
# Overdosage
- Reversible renal shutdown has been observed in a case where an excessive hematin dose (12.2 mg/kg) was administered in a single infusion. Treatment of this case consisted of ethacrynic acid and mannitol
# Pharmacology
## Mechanism of Action
- Heme acts to limit the hepatic and/or marrow synthesis of porphyrin. This action is likely due to the inhibition of δ-aminolevulinic acid synthetase, the enzyme which limits the rate of the porphyrin/heme biosynthetic pathway. The exact mechanism by which hematin produces symptomatic improvement in patients with acute episodes of the hepatic porphyrias has not been elucidated
## Structure
- Hemin for injection) is an enzyme inhibitor derived from processed red blood cells. Hemin for injection was known previously as hematin. The term hematin has been used to describe the chemical reaction product of hemin and sodium carbonate solution. Hemin is an iron containing metalloporphyrin. Chemically hemin is represented as chloro [7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18-dipropanoato(2-)-N21,N22,N23,N24] iron. The structural formula for hemin is:
## Pharmacodynamics
There is limited information regarding Hemin Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following intravenous administration of hematin in non-jaundiced human patients, an increase in fecal urobilinogen can be observed which is roughly proportional to the amount of hematin administered. This suggests an enterohepatic pathway as at least one route of elimination. Bilirubin metabolites are also excreted in the urine following hematin injections.
- Hemin for injection therapy for the acute porphyrias is not curative. After discontinuation of Hemin treatment, symptoms generally return although in some cases remission is prolonged. Some neurological symptoms have improved weeks to months after therapy although little or no response was noted at the time of treatment.
- Other aspects of human pharmacokinetics have not been defined.
## Nonclinical Toxicology
- Hemin was not mutagenic in bacteria systems in vitro and was not clastogenic in mammalian systems in vitro and in vivo. No data are available on potential for carcinogenicity or impairment of fertility in animals or humans.
# Clinical Studies
There is limited information regarding Hemin Clinical Studies in the drug label.
# How Supplied
- Hemin is supplied as a sterile, lyophilized black powder in single dose dispensing vials (NDC 55292-701-54) in a carton (NDC 55292-701-55). When mixed as directed with Sterile Water for Injection, USP, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
## Storage
- Store lyophilized powder at 20-25°C (68-77°F).
- Caution: The packaging (vial stopper) of this product contains natural rubber latex which may cause allergic reactions.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 55292-701-54
Single Dose Vial
Hemin For Injection Hemin®
313 mg Hemin per Vial
For Intravenous Infusion Only Sterile Powder for Injection
RECORDATI RARE DISEASES GROUP
Rx only
Each vial contains:
Hemin ......313 mg
Sodium Carbonate ..... 215 mg
Sorbitol ..... 300 mg
pH may have been adjusted with hydrochloric acid.
Contains no preservatives.
When mixed as directed, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
See package insert for full prescribing information and appropriate caution statements regarding administration.
Caution: Vial stopper contains latex.
The patient and physician should discuss the risks and benefits of this product.
Store powder at 20-25°C (68-77°F).
See USP controlled room temperature.
DIRECTIONS FOR MIXING:
Add 43 mL of Sterile Water for Injection, USP. Shake to aid dissolution. Infusion may be given from this vial.
USE IMMEDIATELY AFTER MIXING.
Discard any unused portion.
Mfd. by: Fresenius Kabi USA, LLC
Raleigh, NC 27616
For: Recordati Rare Diseases Inc.
Lebanon, NJ 08833, U.S.A.
U.S. Lic. No. 1899
780-04245-4
Lot:
Exp.:
NDC 55292-701-55
Contains One Vial
Hemin For Injection Hemin®
313 mg Hemin per Vial
For Intravenous Infusion Only Sterile Powder for Injection
RECORDATI RARE DISEASES GROUP
Rx only
Each vial contains:
Hemin ..... 313 mg
Sodium Carbonate ...... 215 mg
Sorbitol ..... 300 mg
pH may have been adjusted with hydrochloric acid.
Contains no preservatives.
When mixed as directed, each 43 mL provides the equivalent of approximately 301 mg hematin (7 mg/mL).
Manufactured by: Fresenius Kabi USA, LLC
Raleigh, NC 27616
For: Recordati Rare Diseases Inc.
Lebanon, NJ 08833, U.S.A.
U.S. Lic. No. 1899
® Trademark of Recordati Rare Diseases Inc.
Lot No.
Exp. Date
Store powder at 20-25°C (68-77°F).
See USP controlled room temperature.
Mixing directions:
1. Prep stopper.
2. Insert vent needle in “air” target.
3. Add 43 mL of Sterile Water for Injection, USP.
4. Immediately after adding diluent shake to aid dissolution.
5. May be administered directly from original single dose dispensing vial.
6. Administer by intermittent intravenous infusion over a period of from 10 to 15 minutes.
USE IMMEDIATELY AFTER MIXING.
Discard any unused portion.
See package insert for full prescribing information and appropriate caution statements regarding administration.
Caution: Vial stopper contains latex.
The patient and physician should discuss the risks and benefits of this product.
# Patient Counseling Information
There is limited information regarding Patient Counseling Information in this label
# Precautions with Alcohol
Alcohol-Hemin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Panhematin
# Look-Alike Drug Names
There is limited information regarding Hemin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Hematin | |
382cafb1a3b28656c8298529f2e52edc7a7b8f2f | wikidoc | Henna | Henna
Henna or Hina (Lawsonia inermis, syn. L. alba) is a flowering plant, the sole species in the genus Lawsonia in the family Lythraceae. It is native to tropical and subtropical regions of Africa, southern Asia, and northern Australasia in semi-arid zones. Henna is a tall shrub or small tree, 2–6 m high. It is glabrous, multibranched with spine tipped branchlets. Leaves are opposite, entire, glabrous, sub-sessile, elliptical, and broadly lanceolate (1.5–5.0 cm x 0.5–2 cm), acuminate, having depressed veins on the dorsal surface.
During the onset of precipitation intervals, the plant grows rapidly; putting out new shoots, then growth slows. The leaves gradually yellow and fall during prolonged dry or cool intervals. Henna flowers have four sepals and a 2 mm calyx tube with 3 mm spread lobes. Petals are obvate, white or red stamens inserted in pairs on the rim of the calyx tube. Ovary is four celled, style up to 5 mm long and erect. Fruits are small, brownish capsules, 4–8 mm in diameter, with 32–49 seeds per fruit, and open irregularly into four splits. Lawsone content in leaves is negatively associated with the number of seeds in the fruits.
# Cultivation and uses
Henna, Lawsonia inermis, produces a red-orange dye molecule, lawsone. This molecule has an affinity for bonding with protein, and thus has been used to dye skin, hair, fingernails, leather, silk and wool. Henna's indigenous zone is the tropical savannah and tropical arid zone, in latitudes between 15° and 25° N and S from Africa to the western Pacific rim, and produces highest dye content in temperatures between 35°C and 45°C. It does not thrive where minimum temperatures are below 11°C. Temperatures below 5°C will kill the henna plant. The dye molecule, lawsone, is primarily concentrated in the leaves, and is in the highest levels in the petioles of the leaf. Products sold as "black henna" or "neutral henna" are not made from henna, but may be derived from indigo (in the plant Indigofera tinctoria) or Cassia obovata, and may contain unlisted dyes and chemicals.
Henna is commercially cultivated in western India, Pakistan, Morocco, Yemen, Iran, Sudan and Libya. Presently the Pali district of Rajasthan is the most heavily cultivated henna production area in India, with over 100 henna processors operating in Sojat City.
Though henna has been used for body art and hair dye since the Bronze Age, henna has had a recent renaissance in body art due to improvements in cultivation, processing, and the diasporas of people from traditional henna using regions.
The word "henna" comes from the Arabic name Hina for Lawsonia inermis. In the Bible's Song of Songs and Song of Solomon, henna is referred to as Camphire. In the Indian subcontinent, there are many variant words such as Mehndi in North India, Pakistan and Bangladesh. In Arabic-speaking countries in North Africa and the Middle East the Arabic word is "hina".
In Telugu (India, Malaysia, USA), it is known as Gorintaaku. In Tamil (South India, Singapore, Malaysia, Sri Lanka) it is called "Marudhaani" and is used as ground fresh leaves rather than as dried powder. It is used in various festivals and celebrations and used by women and children. It is left on overnight and will last one month or more depending on the plant and how well it was ground and how long it is left on.
Henna has many traditional and commercial uses, the most common being as a dye for hair, skin and fingernails, as a dye and preservative for leather and cloth, and as an anti-fungal. Henna was used as a hair dye in Indian court records around 400 CE, in Rome during the Roman Empire, and in Spain during Convivienca. It was listed in the medical texts of the Ebers Papyrus (16th c BCE Egypt) and by Ibn Qayyim al-Jawziyya (14th c CE (Syria and Egypt) as a medicinal herb. In Morocco, wool is dyed and ornamented with henna, as are drumheads and other leather goods. Henna will repel some insect pests and mildew.
The United States Food and Drug Administration has not approved henna for direct application to the skin. It is unconditionally approved as a hair dye, and can only be imported for that purpose. Henna imported into the USA which appears to be for use as body art is subject to seizure, and at present it is illegal to use henna for body art in the U.S., though prosecution is rare. The fast black stains of “black henna” are not made with henna, but are from p-phenylenediamine. This can cause severe allergic reactions and permanent scarring. No henna can make a black stain on a torso in ½ hour. P-phenylenediamine can stain skin black quickly, but the FDA specifically forbids PPD to be used for that purpose.
# Preparation and application of paste
Henna body art is made by applying henna paste to the skin: the lawsone in the paste migrates into the outermost layer of the skin and makes a red-brown stain.
Whole, unbroken henna leaves will not stain the skin. Henna will not stain skin until the lawsone molecules are made available (released) from the henna leaf. Fresh henna leaves will stain the skin if they are smashed with a mildly acidic liquid. This will stain skin within moments, but it is difficult to form intricate patterns from coarse crushed leaves. Dried ground, sifted henna leaves are easily worked into a paste that can used to make intricate body art. Commercially available henna powder is made by drying the henna leaves and milling them to powder, then the powder is sifted. This powder is mixed with lemon juice, strong tea, or other mildly acidic liquids. Essential oils with high levels of "terps", monoterpene alcohols such as tea tree, eucalyptus, cajeput, or lavender will improve skin stain characteristics. The henna mix must rest for 6 to 12 hours so the leaf cellulose is dissolved, making the lawsone available to stain the skin. This is mixed to a toothpaste consistency and applied with a one of many traditional tools, including resist techniques, shading techniques, and thicker paste techniques, or the modern cellowrap cone.
Once applied to the skin, lawsone molecules gradually migrate from the henna paste into the outer layer of the skin. Though henna's lawsone will stain the skin within minutes, the longer the paste is left on the skin, the more lawsone will migrate. Henna paste will yield as much dye as the skin can easily absorb in less than eight hours. Henna tends to crack and fall off the skin during these hours, so it is often sealed down by dabbing a sugar/lemon mix over the dried paste, or simply adding some form of sugar to the paste. This also adds to the colour of the end result, increasing the intensity of the shade.
When the paste has fallen off the skin or been removed by scraping, the stain will be orange, but should darken over the following three days to a reddish brown. Soles and palms have the thickest layer of skin and so take up the most lawsone, and take it to the greatest depth, so that hands and feet will have the darkest and most long-lasting stains. Steaming or warming the henna pattern will darken the stain, either during the time the paste is still on the skin, or after the paste has been removed. Chlorinated water and soaps may spoil the darkening process: alkaline may hasten the darkening process. After the stain reaches its peak color it will appear to fade. The henna stain is not actually fading, the skin is exfoliating: the lower, less stained cells, rise to the surface, until all stained cells are shed.
# Chemistry and allergic reactions
Allergic reactions to natural henna are rare. The onset of a reaction to natural henna occurs within a few hours, symptoms being itching, shortness of breath, and/or tightness in the chest. Some people have an allergic reaction to an essential oil used to "terp" the mix, and others are allergic to lemon juice often used to mix henna.
Lawsone, the dye molecule in henna, can cause hemolytic oxidation in people who have G6PD deficiency, an inherited enzyme deficiency. A large application of henna to a child with G6PD deficiency (such as scalp, palms and soles) may cause severe hemolytic crisis and may be fatal Ingestion of a henna by a person with G6PD deficiency can be fatal.
# Traditions of henna as body art
The different words for henna in ancient languages imply that henna had more than one point of discovery and origin, and different pathways of daily and ceremonial use.
Henna has been used to adorn young women’s bodies as part of social and holiday celebrations since the late Bronze Age in the eastern Mediterranean. The earliest text mentioning henna in the context of marriage and fertility celebrations comes from the Ugaritic legend of Baal and Anath , which has references to women marking themselves with henna in preparation to meet their husbands, and Anath adorning herself with henna to celebrate a victory over the enemies of Baal. Wall paintings excavated at Akrotiri (dating prior to the eruption of Thera in 1680 BCE) show women with markings consistent with henna on their nails, palms and soles, in a tableau consistent with the henna bridal description from Ugarit Many statuettes of young women dating between 1500 and 500 BCE along the Mediterranean coastline have raised hands with markings consistent with henna. This early connection between young, fertile women and henna seems to be the origin of the Night of the Henna, which is now celebrated world-wide.
The Night of the Henna was celebrated by most groups in the areas where henna grew naturally: Jews, , Muslims, Hindus, and Zoroastrians, among others, all celebrated marriages by adorning the bride, and often the groom, with henna.
Across the henna-growing region, Purim , Eid, Diwali, Karva Chauth, Passover, Nawruwz, Mawlid, and most saints’ days were celebrated with some henna. Favorite horses, donkeys, and salukis had their hooves, paws, and tails hennaed. Battle victories, births, circumcision, birthdays, Zar, as well as weddings, usually included some henna as part of the celebration. When there was joy, there was henna, as long as henna was available.
Henna was regarded as having “Barakah”, blessings, and was applied for luck as well as joy and beauty. Brides typically had the most henna, and the most complex patterns, to support their greatest joy, and wishes for luck. Some bridal traditions were very complex, such as those in Yemen, where the Jewish bridal henna process took four or five days to complete, with multiple applications and resist work.
The fashion of "Bridal Mehndi" in Northern Libya and in North Indian diasporas is currently growing in complexity and elaboration, with new innovations in glitter, gilding, and fine-line work. Recent technological innovations in grinding, sifting, temperature control, and packaging henna, as well as government encouragement for henna cultivation, have improved dye content and artistic potential for henna.
Though traditional henna artists were Nai caste in India, and barbering castes in other countries, (socially low classes) talented contemporary henna artists can command high fees for their work. Women in countries where women are discouraged from working outside the home can find socially acceptable, lucrative work doing henna. Morocco, Mauritania, Yemen, Libya, Somalia, Sudan, as well as India and many other countries have thriving women’s henna businesses. These businesses are often open all night for Eids, Diwali and Karva Chauth, and many women may work as a team for a large wedding where hundreds of guests will be hennaed as well as the bride and groom.
# Health Effects
Pre-mixed henna body art pastes may have ingredients added to darken stain, or to alter stain color. The FDA considers these to be adulterants and therefore illegal for use on skin. Some pastes have been found to include: silver nitrate, carmine, pyrogallol, disperse orange dye, and chromium. These have been found to cause allergic reactions, chronic inflammatory reactions, or late-onset allergic reactions to hairdressing products and textile dyes.
- Medical report of heavy metals such as nickel, cobalt, chromium, lead and mercury found in henna tattoos
- Allergies Associated with Body Piercing and Tattoos
- OSHA on silver nitrate
- CDC on silver nitrate
# Black henna
“Black Henna” is a misnomer arising from imports of plant-based hair dyes into the West in the late 19th century. Partly fermented, dried indigo was called “black henna” because it could be used in combination with henna to dye hair black. This gave rise to the belief that there was such a thing as “black henna” which could dye skin black. Indigo will not dye skin black. Pictures of indigenous people with black body art (either alkalized henna or from some other source) also fed the belief that there was such a thing as “black henna.”
In the 1990s, henna artists in Africa, India, the Arabian Peninsula and the West began to experiment with para-phenylenediamine (PPD) based black hair dye, applying it as a thick paste as they would apply henna, in an effort to find something that would quickly make jet black temporary body art. PPD can cause severe allergic reactions, with blistering, intense itching, permanent scarring, and permanent chemical sensitivities . Estimates of allergic reactions range between 3% and 15%. Henna does not cause these injuries. Henna boosted with PPD can cause life long health damage.
Para-phenylenediamine is illegal for use on skin in western countries, though enforcement is lax. When used in hair dye, the PPD amount must be below 6%, and application instructions warn that the dye not touch the scalp and the dye must be quickly rinsed away. “Black henna” pastes have PPD percentages from 10% to 60%, and are left on the skin for half an hour.
Para-phenylenediamine “black henna” use is widespread, particularly in tourist areas. Because the blistering reaction appears 3 to 12 days after the application, most tourists have left and do not return to show how much damage the artist has done. This permits the artists to continue injuring others, unaware they are causing severe injuries. The high profit margins of ‘black henna” and the demand for body art that emulates “tribal tattoos” further encourage artists to ignore the dangers.
It is not difficult to recognize and avoid para-phenylenediamine “black henna”:
- if a paste stains torso skin black in less than ½ hour, it has PPD in it, and little or no henna.
- if the paste is mixed with peroxide, or if peroxide is wiped over the design to bring out the color, it has PPD in it, and little or no henna.
Anyone who has an itching and blistering reaction to a black body stain should go to a doctor, and report that they have had an application of para-phenylenediamine to their skin.
PPD sensitivity is life-long and once sensitized, the use of synthetic hair dye can be life threatening . These injuries are not caused by henna, and a person can use henna as hair dye. | Henna
Template:Wiktionarypar
Template:Two other uses
Henna or Hina (Lawsonia inermis, syn. L. alba) is a flowering plant, the sole species in the genus Lawsonia in the family Lythraceae. It is native to tropical and subtropical regions of Africa, southern Asia, and northern Australasia in semi-arid zones. Henna is a tall shrub or small tree, 2–6 m high. It is glabrous, multibranched with spine tipped branchlets. Leaves are opposite, entire, glabrous, sub-sessile, elliptical, and broadly lanceolate (1.5–5.0 cm x 0.5–2 cm), acuminate, having depressed veins on the dorsal surface.
During the onset of precipitation intervals, the plant grows rapidly; putting out new shoots, then growth slows. The leaves gradually yellow and fall during prolonged dry or cool intervals. Henna flowers have four sepals and a 2 mm calyx tube with 3 mm spread lobes. Petals are obvate, white or red stamens inserted in pairs on the rim of the calyx tube. Ovary is four celled, style up to 5 mm long and erect. Fruits are small, brownish capsules, 4–8 mm in diameter, with 32–49 seeds per fruit, and open irregularly into four splits.[1] Lawsone content in leaves is negatively associated with the number of seeds in the fruits.[2]
# Cultivation and uses
Henna, Lawsonia inermis, produces a red-orange dye molecule, lawsone. This molecule has an affinity for bonding with protein, and thus has been used to dye skin, hair, fingernails, leather, silk and wool. Henna's indigenous zone is the tropical savannah and tropical arid zone, in latitudes between 15° and 25° N and S from Africa to the western Pacific rim, and produces highest dye content in temperatures between 35°C and 45°C. It does not thrive where minimum temperatures are below 11°C. Temperatures below 5°C will kill the henna plant. The dye molecule, lawsone, is primarily concentrated in the leaves, and is in the highest levels in the petioles of the leaf. Products sold as "black henna" or "neutral henna" are not made from henna, but may be derived from indigo (in the plant Indigofera tinctoria) or Cassia obovata, and may contain unlisted dyes and chemicals.[3]
Henna is commercially cultivated in western India, Pakistan, Morocco, Yemen, Iran, Sudan and Libya. Presently the Pali district of Rajasthan is the most heavily cultivated henna production area in India, with over 100 henna processors operating in Sojat City.
Though henna has been used for body art and hair dye since the Bronze Age, henna has had a recent renaissance in body art due to improvements in cultivation, processing, and the diasporas of people from traditional henna using regions. [4]
The word "henna" comes from the Arabic name Hina for Lawsonia inermis. In the Bible's Song of Songs and Song of Solomon, henna is referred to as Camphire. In the Indian subcontinent, there are many variant words such as Mehndi in North India, Pakistan and Bangladesh. In Arabic-speaking countries in North Africa and the Middle East the Arabic word is "hina".
In Telugu (India, Malaysia, USA), it is known as Gorintaaku. In Tamil (South India, Singapore, Malaysia, Sri Lanka) it is called "Marudhaani" and is used as ground fresh leaves rather than as dried powder. It is used in various festivals and celebrations and used by women and children. It is left on overnight and will last one month or more depending on the plant and how well it was ground and how long it is left on.
Henna has many traditional and commercial uses, the most common being as a dye for hair, skin and fingernails, as a dye and preservative for leather and cloth, and as an anti-fungal.[5] Henna was used as a hair dye in Indian court records around 400 CE,[6] in Rome during the Roman Empire, and in Spain during Convivienca.[7] It was listed in the medical texts of the Ebers Papyrus (16th c BCE Egypt)[8] and by Ibn Qayyim al-Jawziyya (14th c CE (Syria and Egypt) as a medicinal herb.[9] In Morocco, wool is dyed and ornamented with henna, as are drumheads and other leather goods. Henna will repel some insect pests and mildew.
The United States Food and Drug Administration has not approved henna for direct application to the skin. It is unconditionally approved as a hair dye, and can only be imported for that purpose.[10] Henna imported into the USA which appears to be for use as body art is subject to seizure, and at present it is illegal to use henna for body art in the U.S.,[11] though prosecution is rare. The fast black stains of “black henna” are not made with henna, but are from p-phenylenediamine. This can cause severe allergic reactions and permanent scarring. No henna can make a black stain on a torso in ½ hour. P-phenylenediamine can stain skin black quickly, but the FDA specifically forbids PPD to be used for that purpose.
# Preparation and application of paste
Henna body art is made by applying henna paste to the skin: the lawsone in the paste migrates into the outermost layer of the skin and makes a red-brown stain.
Whole, unbroken henna leaves will not stain the skin. Henna will not stain skin until the lawsone molecules are made available (released) from the henna leaf. Fresh henna leaves will stain the skin if they are smashed with a mildly acidic liquid. This will stain skin within moments, but it is difficult to form intricate patterns from coarse crushed leaves. Dried ground, sifted henna leaves are easily worked into a paste that can used to make intricate body art. Commercially available henna powder is made by drying the henna leaves and milling them to powder, then the powder is sifted. This powder is mixed with lemon juice, strong tea, or other mildly acidic liquids. Essential oils with high levels of "terps", monoterpene alcohols such as tea tree, eucalyptus, cajeput, or lavender will improve skin stain characteristics. The henna mix must rest for 6 to 12 hours so the leaf cellulose is dissolved, making the lawsone available to stain the skin. This is mixed to a toothpaste consistency and applied with a one of many traditional tools, including resist techniques, shading techniques, and thicker paste techniques, or the modern cellowrap cone.
Once applied to the skin, lawsone molecules gradually migrate from the henna paste into the outer layer of the skin. Though henna's lawsone will stain the skin within minutes, the longer the paste is left on the skin, the more lawsone will migrate. Henna paste will yield as much dye as the skin can easily absorb in less than eight hours. Henna tends to crack and fall off the skin during these hours, so it is often sealed down by dabbing a sugar/lemon mix over the dried paste, or simply adding some form of sugar to the paste. This also adds to the colour of the end result, increasing the intensity of the shade.
When the paste has fallen off the skin or been removed by scraping, the stain will be orange, but should darken over the following three days to a reddish brown. Soles and palms have the thickest layer of skin and so take up the most lawsone, and take it to the greatest depth, so that hands and feet will have the darkest and most long-lasting stains. Steaming or warming the henna pattern will darken the stain, either during the time the paste is still on the skin, or after the paste has been removed. Chlorinated water and soaps may spoil the darkening process: alkaline may hasten the darkening process. After the stain reaches its peak color it will appear to fade. The henna stain is not actually fading, the skin is exfoliating: the lower, less stained cells, rise to the surface, until all stained cells are shed.
# Chemistry and allergic reactions
Allergic reactions to natural henna are rare. The onset of a reaction to natural henna occurs within a few hours, symptoms being itching, shortness of breath, and/or tightness in the chest. Some people have an allergic reaction to an essential oil used to "terp" the mix, and others are allergic to lemon juice often used to mix henna.
Lawsone, the dye molecule in henna, can cause hemolytic oxidation in people who have G6PD deficiency, an inherited enzyme deficiency. A large application of henna to a child with G6PD deficiency (such as scalp, palms and soles) may cause severe hemolytic crisis and may be fatal [12]Ingestion of a henna by a person with G6PD deficiency can be fatal.
# Traditions of henna as body art
The different words for henna in ancient languages imply that henna had more than one point of discovery and origin, and different pathways of daily and ceremonial use.
Henna has been used to adorn young women’s bodies as part of social and holiday celebrations since the late Bronze Age in the eastern Mediterranean. The earliest text mentioning henna in the context of marriage and fertility celebrations comes from the Ugaritic legend of Baal and Anath [13], which has references to women marking themselves with henna in preparation to meet their husbands, and Anath adorning herself with henna to celebrate a victory over the enemies of Baal. Wall paintings excavated at Akrotiri (dating prior to the eruption of Thera in 1680 BCE) show women with markings consistent with henna on their nails, palms and soles, in a tableau consistent with the henna bridal description from Ugarit [14] Many statuettes of young women dating between 1500 and 500 BCE along the Mediterranean coastline have raised hands with markings consistent with henna. This early connection between young, fertile women and henna seems to be the origin of the Night of the Henna, which is now celebrated world-wide.
The Night of the Henna was celebrated by most groups in the areas where henna grew naturally: Jews, [15], Muslims[16], Hindus, and Zoroastrians, among others, all celebrated marriages by adorning the bride, and often the groom, with henna.
Across the henna-growing region, Purim [15], Eid[17], Diwali[18], Karva Chauth, Passover, Nawruwz, Mawlid, and most saints’ days were celebrated with some henna. Favorite horses, donkeys, and salukis had their hooves, paws, and tails hennaed. Battle victories, births, circumcision, birthdays, Zar, as well as weddings, usually included some henna as part of the celebration. When there was joy, there was henna, as long as henna was available. [19]
Henna was regarded as having “Barakah”, blessings, and was applied for luck as well as joy and beauty.[16] Brides typically had the most henna, and the most complex patterns, to support their greatest joy, and wishes for luck. Some bridal traditions were very complex, such as those in Yemen, where the Jewish bridal henna process took four or five days to complete, with multiple applications and resist work.
The fashion of "Bridal Mehndi" in Northern Libya and in North Indian diasporas is currently growing in complexity and elaboration, with new innovations in glitter, gilding, and fine-line work. Recent technological innovations in grinding, sifting, temperature control, and packaging henna, as well as government encouragement for henna cultivation, have improved dye content and artistic potential for henna.
Though traditional henna artists were Nai caste in India, and barbering castes in other countries, (socially low classes) talented contemporary henna artists can command high fees for their work. Women in countries where women are discouraged from working outside the home can find socially acceptable, lucrative work doing henna. Morocco, Mauritania[20], Yemen, Libya, Somalia, Sudan, as well as India and many other countries have thriving women’s henna businesses. These businesses are often open all night for Eids, Diwali and Karva Chauth, and many women may work as a team for a large wedding where hundreds of guests will be hennaed as well as the bride and groom.
# Health Effects
Pre-mixed henna body art pastes may have ingredients added to darken stain, or to alter stain color. The FDA considers these to be adulterants and therefore illegal for use on skin. Some pastes have been found to include: silver nitrate, carmine, pyrogallol, disperse orange dye, and chromium. These have been found to cause allergic reactions, chronic inflammatory reactions, or late-onset allergic reactions to hairdressing products and textile dyes.
- Medical report of heavy metals such as nickel, cobalt, chromium, lead and mercury found in henna tattoos [21]
- Allergies Associated with Body Piercing and Tattoos[22]
- OSHA on silver nitrate[23]
- CDC on silver nitrate[24]
# Black henna
“Black Henna” is a misnomer arising from imports of plant-based hair dyes into the West in the late 19th century. Partly fermented, dried indigo was called “black henna” because it could be used in combination with henna to dye hair black. This gave rise to the belief that there was such a thing as “black henna” which could dye skin black. Indigo will not dye skin black. Pictures of indigenous people with black body art (either alkalized henna or from some other source) also fed the belief that there was such a thing as “black henna.”
In the 1990s, henna artists in Africa, India, the Arabian Peninsula and the West began to experiment with para-phenylenediamine (PPD) based black hair dye, applying it as a thick paste as they would apply henna, in an effort to find something that would quickly make jet black temporary body art. PPD can cause severe allergic reactions, with blistering, intense itching, permanent scarring, and permanent chemical sensitivities[25] [26]. Estimates of allergic reactions range between 3% and 15%. Henna does not cause these injuries[27]. Henna boosted with PPD can cause life long health damage. [28]
Para-phenylenediamine is illegal for use on skin in western countries, though enforcement is lax. When used in hair dye, the PPD amount must be below 6%, and application instructions warn that the dye not touch the scalp and the dye must be quickly rinsed away. “Black henna” pastes have PPD percentages from 10% to 60%, and are left on the skin for half an hour.
Para-phenylenediamine “black henna” use is widespread, particularly in tourist areas. Because the blistering reaction appears 3 to 12 days after the application, most tourists have left and do not return to show how much damage the artist has done. This permits the artists to continue injuring others, unaware they are causing severe injuries. The high profit margins of ‘black henna” and the demand for body art that emulates “tribal tattoos” further encourage artists to ignore the dangers.
It is not difficult to recognize and avoid para-phenylenediamine “black henna”:
- if a paste stains torso skin black in less than ½ hour, it has PPD in it, and little or no henna.
- if the paste is mixed with peroxide, or if peroxide is wiped over the design to bring out the color, it has PPD in it, and little or no henna.
Anyone who has an itching and blistering reaction to a black body stain should go to a doctor, and report that they have had an application of para-phenylenediamine to their skin.
PPD sensitivity is life-long and once sensitized, the use of synthetic hair dye can be life threatening [29]. These injuries are not caused by henna, and a person can use henna as hair dye. | https://www.wikidoc.org/index.php/Henna | |
eda9e0ffe5042e6c9e8b0c865fa95d60c60bdb7c | wikidoc | Liver | Liver
# Overview
The liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, decomposition of red blood cells, plasma protein synthesis, and detoxification. This organ also is the largest gland in the human body. It lies below the diaphragm in the thoracic region of the abdomen. It produces bile, an alkaline compound which aids in digestion, via the emulsification of lipids. It also performs and regulates a wide variety of high-volume biochemical reactions requiring very specialized tissues.
Medical terms related to the liver often start in hepato- or hepatic from the Greek word for liver, hēpar (ήπαρ).
# Anatomy
The adult human liver normally weighs between 1.4 - 1.6 kilograms (3.1 - 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.
It is located on the right side of the upper abdomen below the diaphragm. The liver lies to the right of the stomach and overlies the gallbladder (which stores bile).
## Flow of blood
The splenic vein joins the inferior mesenteric vein, which then together join with the superior mesenteric vein to form the hepatic portal vein, bringing veneous blood from the spleen, pancreas, stomach, small intestine, and large intestine, so that the liver can process the nutrients and byproducts of food digestion.
The hepatic veins of the blood can be from other branches such as the superior mesenteric artery.
Both the portal venules & the hepatic arterioles enter approximately one million identical lobules acini, likened to and changes in the size of chylomicrons lipoproteins of dietary origin brought about by the quantity & types of food fats.
Approximately 60% to 80% of the blood flow to the liver is from the portal venous system, and 1/4 is from the hepatic artery.
## Flow of bile
The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts.
These eventually drain into the right and left hepatic ducts, which in turn merge to form the common hepatic duct. The cystic duct (from the gallbladder) joins with the common hepatic duct to form the common bile duct.
Bile can either drain directly into the duodenum via the common bile duct or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the duodenum together at the ampulla of Vater.
The branchings of the bile ducts resemble those of a tree, and indeed the term "biliary tree" is commonly used in this setting.
## Regeneration
The liver is among the few internal human organs capable of natural regeneration of lost tissue; as little as 25% of remaining liver can regenerate into a whole liver again.
This is predominantly due to the hepatocytes acting as unipotential stem cells (i.e. a single hepatocyte can divide into two hepatocyte daughter cells). There is also some evidence of bipotential stem cells, called ovalocyte(o´və-lo-sīt), which exist in the Canals of Hering. These cells can differentiate into either hepatocytes or cholangiocytes (cells that line the bile ducts).
## Traditional (Surface) anatomy
### Peritoneal ligaments
Apart from a patch where it connects to the diaphragm, the liver is covered entirely by visceral peritoneum, a thin, double-layered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.
These "ligaments" are in no way related to the true anatomic ligaments in joints, and have essentially no functional importance, but they are easily recognizable surface landmarks.
### Lobes
Traditional gross anatomy divided the liver into four lobes based on surface features.
The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.
If the liver flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior), and below this the quadrate lobe.
From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.
Each of the lobes is made up of lobules, a vein goes from the centre of each lobule which then joins to the hepatic vein to carry blood out from the liver.
On the surface of the lobules there are ducts, veins and arteries that carry fluids to and from them.
## Modern (Functional) anatomy
The central area where the common bile duct, hepatic portal vein, and hepatic artery enter the liver is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.
The functional lobes are separated by a plane joining the gallbladder fossa to the inferior vena cava. This separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres (the ligamentum teres becomes the falciform ligament) also separates the medial and lateral segments. The medial segment is what used to be called the quadrate lobe. In the widely used Couinaud or "French" system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches. The subsegments corresponding to the anatomical lobes are as follows:
- or lobe in the Caudate's case.
Each number in the list corresponds to one in the table.
- Caudate
- Superior subsegment of the lateral segment
- Inferior subsegment of the lateral segment
- Superior subsegment of the medial segment
Inferior subsegment of the medial segment
- Superior subsegment of the medial segment
- Inferior subsegment of the medial segment
- Inferior subsegment of the anterior segment
- Inferior subsegment of the posterior segment
- Superior subsegment of the posterior segment
- Superior subsegment of the anterior segment
# Physiology
The various functions of the liver are carried out by the liver cells or hepatocytes.
- The liver produces and excretes bile (a greenish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
- The liver performs several roles in carbohydrate metabolism:
Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
Glycogenesis (the formation of glycogen from glucose)
The breakdown of insulin and other hormones
The liver is responsible for the mainstay of protein metabolism.
- Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
- Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
- Glycogenesis (the formation of glycogen from glucose)
- The breakdown of insulin and other hormones
- The liver is responsible for the mainstay of protein metabolism.
- The liver also performs several roles in lipid metabolism:
Cholesterol synthesis
The production of triglycerides (fats).
- Cholesterol synthesis
- The production of triglycerides (fats).
- The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin.
- The liver breaks down haemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
- The liver breaks down toxic substances and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor.
- The liver converts ammonia to urea.
- The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin B12, iron, and copper.
- In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
- The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.
- The liver produces albumin, the major osmolar component of blood serum.
Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.
# Diseases of the liver
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.
- Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions.
- Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals.
- Haemochromatosis, a hereditary disease causing the accumulation of iron in the body, eventually leading to liver damage.
- Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the gastrointestinal tract).
- Wilson's disease, a hereditary disease which causes the body to retain copper.
- Primary sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in nature.
- Primary biliary cirrhosis, autoimmune disease of small bile ducts.
- Budd-Chiari syndrome, obstruction of the hepatic vein.
- Gilbert's syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the population.
- Glycogen storage disease type II,The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.
A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products.
# Liver transplantation
Human liver transplant was first performed by Thomas Starzl in USA and Roy Calne in Cambridge, England in 1963 and 1965 respectively.
Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.
Liver allografts for transplant usually come from non-living donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person's liver is removed and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.
More recently, adult-to-adult liver transplantation has been done using the donor's right hepatic lobe which amounts to 60% of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial as it entails performing a much larger operation on the donor, and indeed there have been at least 2 donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found. The risk of postoperative complications (and death) is far greater in right sided hepatectomy than left sided operations.
With the recent advances of non-invasive imaging, living liver donors usually have to undergo imaging examinations for liver anatomy to decide if the anatomy is feasible for donation. The evaluation is usually performed by multi-detector row computed tomography (MDCT) and magnetic resonence imaging (MRI). MDCT is good in vascular anatomy and volumetry. MRI is used for biliary tree anatomy. Donors with very unusual vascular anatomy, which makes them impossible for donation, could be screened out to avoid unnessary operation.
- MDCT image. Arterial anatomy contraindicated for liver donation.
- MDCT image. Portal venous anatomy contraindicated for liver donation.
- MDCT image. Beautiful 3D image created by MDCT can clearly visualize the liver, measure the liver volume, and plan the dissection plane to facilitate the liver transplantation procedure.
# Development
## Fetal blood supply
In the growing fetus, a major source of blood to the liver is the umbilical vein which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus, and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.
In the fetus, the liver develops throughout normal gestation, and does not perform the normal filtration of the infant liver. The liver does not perform digestive processes because the fetus does not consume meals directly, but receives nourishment from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, so initially the lymphocytes, called T-cells, are created from fetal liver stem cells. Once the fetus is delivered, the formation of blood stem cells in infants shifts to the red bone marrow.
After birth, the umbilical vein and ductus venosus are completely obliterated two to five days postpartum; the former becomes the ligamentum teres and the latter becomes the ligamentum venosum. In the disease state of cirrhosis and portal hypertension, the umbilical vein can open up again.
# Liver as food
Mammal and bird livers are commonly eaten as food. Liver can be baked, broiled, or fried (often served as liver and onions) or eaten raw (liver sashimi), but is perhaps most commonly made into a spread (examples including liver pâté, foie gras, Braunschweiger, chopped liver, and leverpostej) or sausage (liverwurst).
Both animal and fish livers are rich in iron and Vitamin A, and cod liver oil is commonly used as a dietary supplement. Very high doses of Vitamin A can be toxic; in 1913, Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned, the latter fatally, from eating husky liver. In the US, the USDA specifies 3000 μg per day as a tolerable upper limit, which amounts to about 50 g of raw pork liver or, as reported in a non scientific source, 3 g of polar-bear liver. However, acute vitamin A poisoning is not likely to result from liver consumption, since it is present in a less toxic form than in many dietary supplements.
# Cultural allusions
In Greek mythology, Prometheus was punished by the gods for revealing fire to humans by being chained to a rock where a vulture (or an eagle) would peck out his liver, which would regenerate overnight. Curiously, the liver is the only human internal organ that actually can regenerate itself to a significant extent; this characteristic may have already been known to the Greeks due to survived injuries in battle.
The Talmud (tractate Berakhot 61b) refers to the liver as the seat of anger, with the gallbladder counteracting this.
In Arabic and Persian language, the liver is used in figurative speech to refer to courage and strong feelings, or "their best," e.g. "This Mecca has thrown to you the pieces of its liver!"
The legend of Liver-Eating Johnson says that he would cut out and eat the liver of each man killed.
In the motion picture The Message, Hind bint Utbah is implied or portrayed eating the liver of Hamza ibn ‘Abd al-Muttalib during the Battle of Uhud.
Inuit will not eat the liver of polar bears (due to the fact a polar bear's liver contains so much Vitamin A as to be poisonous to humans) or seals
# Further reading
- Eugene R. Schiff, Michael F. Sorrell, Willis C. Maddrey, eds. Schiff's diseases of the liver, 9th ed. Philadelphia : Lippincott, Williams & Wilkins, 2003. ISBN 0-7817-3007-4
- Sheila Sherlock, James Dooley. Diseases of the liver and biliary system, 11th ed. Oxford, UK ; Malden, MA : Blackwell Science. 2002. ISBN 0-632-05582-0
- David Zakim, Thomas D. Boyer. eds. Hepatology: a textbook of liver disease, 4th ed. Philadelphia: Saunders. 2003. ISBN 0-7216-9051-3
- Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
- Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
- Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6. his Columbia University web site, "Diseases of the liver" | Liver
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
The liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, decomposition of red blood cells, plasma protein synthesis, and detoxification. This organ also is the largest gland in the human body. It lies below the diaphragm in the thoracic region of the abdomen.[1] It produces bile, an alkaline compound which aids in digestion, via the emulsification of lipids. It also performs and regulates a wide variety of high-volume biochemical reactions requiring very specialized tissues.
Medical terms related to the liver often start in hepato- or hepatic from the Greek word for liver, hēpar (ήπαρ).[2]
# Anatomy
The adult human liver normally weighs between 1.4 - 1.6 kilograms (3.1 - 3.5 pounds),[3] and it is a soft, pinkish-brown "boomerang shaped" organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.
It is located on the right side of the upper abdomen below the diaphragm. The liver lies to the right of the stomach and overlies the gallbladder (which stores bile).
## Flow of blood
The splenic vein joins the inferior mesenteric vein, which then together join with the superior mesenteric vein to form the hepatic portal vein, bringing veneous blood from the spleen, pancreas, stomach, small intestine, and large intestine, so that the liver can process the nutrients and byproducts of food digestion.
The hepatic veins of the blood can be from other branches such as the superior mesenteric artery.
Both the portal venules & the hepatic arterioles enter approximately one million identical lobules acini, likened to and changes in the size of chylomicrons lipoproteins of dietary origin brought about by the quantity & types of food fats.
Approximately 60% to 80% of the blood flow to the liver is from the portal venous system, and 1/4 is from the hepatic artery.
## Flow of bile
The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts.
These eventually drain into the right and left hepatic ducts, which in turn merge to form the common hepatic duct. The cystic duct (from the gallbladder) joins with the common hepatic duct to form the common bile duct.
Bile can either drain directly into the duodenum via the common bile duct or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the duodenum together at the ampulla of Vater.
The branchings of the bile ducts resemble those of a tree, and indeed the term "biliary tree" is commonly used in this setting.
## Regeneration
The liver is among the few internal human organs capable of natural regeneration of lost tissue; as little as 25% of remaining liver can regenerate into a whole liver again.
This is predominantly due to the hepatocytes acting as unipotential stem cells (i.e. a single hepatocyte can divide into two hepatocyte daughter cells). There is also some evidence of bipotential stem cells, called ovalocyte(o´və-lo-sīt), which exist in the Canals of Hering. These cells can differentiate into either hepatocytes or cholangiocytes (cells that line the bile ducts).
## Traditional (Surface) anatomy
### Peritoneal ligaments
Apart from a patch where it connects to the diaphragm, the liver is covered entirely by visceral peritoneum, a thin, double-layered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.
These "ligaments" are in no way related to the true anatomic ligaments in joints, and have essentially no functional importance, but they are easily recognizable surface landmarks.
### Lobes
Traditional gross anatomy divided the liver into four lobes based on surface features.
The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.
If the liver flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior), and below this the quadrate lobe.
From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.
Each of the lobes is made up of lobules, a vein goes from the centre of each lobule which then joins to the hepatic vein to carry blood out from the liver.
On the surface of the lobules there are ducts, veins and arteries that carry fluids to and from them.
## Modern (Functional) anatomy
The central area where the common bile duct, hepatic portal vein, and hepatic artery enter the liver is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.
The functional lobes are separated by a plane joining the gallbladder fossa to the inferior vena cava. This separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres (the ligamentum teres becomes the falciform ligament) also separates the medial and lateral segments. The medial segment is what used to be called the quadrate lobe. In the widely used Couinaud or "French" system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches.[4][5] The subsegments corresponding to the anatomical lobes are as follows:
- or lobe in the Caudate's case.
Each number in the list corresponds to one in the table.
- Caudate
- Superior subsegment of the lateral segment
- Inferior subsegment of the lateral segment
- Superior subsegment of the medial segment
Inferior subsegment of the medial segment
- Superior subsegment of the medial segment
- Inferior subsegment of the medial segment
- Inferior subsegment of the anterior segment
- Inferior subsegment of the posterior segment
- Superior subsegment of the posterior segment
- Superior subsegment of the anterior segment
# Physiology
The various functions of the liver are carried out by the liver cells or hepatocytes.
- The liver produces and excretes bile (a greenish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
- The liver performs several roles in carbohydrate metabolism:
Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
Glycogenesis (the formation of glycogen from glucose)
The breakdown of insulin and other hormones
The liver is responsible for the mainstay of protein metabolism.
- Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
- Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
- Glycogenesis (the formation of glycogen from glucose)
- The breakdown of insulin and other hormones
- The liver is responsible for the mainstay of protein metabolism.
- The liver also performs several roles in lipid metabolism:
Cholesterol synthesis
The production of triglycerides (fats).
- Cholesterol synthesis
- The production of triglycerides (fats).
- The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin.
- The liver breaks down haemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
- The liver breaks down toxic substances and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor.
- The liver converts ammonia to urea.
- The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin B12, iron, and copper.
- In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
- The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.
- The liver produces albumin, the major osmolar component of blood serum.
Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.
# Diseases of the liver
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.
- Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions.
- Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals.
- Haemochromatosis, a hereditary disease causing the accumulation of iron in the body, eventually leading to liver damage.
- Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the gastrointestinal tract).
- Wilson's disease, a hereditary disease which causes the body to retain copper.
- Primary sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in nature.
- Primary biliary cirrhosis, autoimmune disease of small bile ducts.
- Budd-Chiari syndrome, obstruction of the hepatic vein.
- Gilbert's syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the population.
- Glycogen storage disease type II,The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.
A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products.
# Liver transplantation
Human liver transplant was first performed by Thomas Starzl in USA and Roy Calne in Cambridge, England in 1963 and 1965 respectively.
Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.
Liver allografts for transplant usually come from non-living donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person's liver is removed and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.
More recently, adult-to-adult liver transplantation has been done using the donor's right hepatic lobe which amounts to 60% of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial as it entails performing a much larger operation on the donor, and indeed there have been at least 2 donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found.[6] The risk of postoperative complications (and death) is far greater in right sided hepatectomy than left sided operations.
With the recent advances of non-invasive imaging, living liver donors usually have to undergo imaging examinations for liver anatomy to decide if the anatomy is feasible for donation. The evaluation is usually performed by multi-detector row computed tomography (MDCT) and magnetic resonence imaging (MRI). MDCT is good in vascular anatomy and volumetry. MRI is used for biliary tree anatomy. Donors with very unusual vascular anatomy, which makes them impossible for donation, could be screened out to avoid unnessary operation.
- MDCT image. Arterial anatomy contraindicated for liver donation.
- MDCT image. Portal venous anatomy contraindicated for liver donation.
- MDCT image. Beautiful 3D image created by MDCT can clearly visualize the liver, measure the liver volume, and plan the dissection plane to facilitate the liver transplantation procedure.
# Development
## Fetal blood supply
In the growing fetus, a major source of blood to the liver is the umbilical vein which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus, and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.
In the fetus, the liver develops throughout normal gestation, and does not perform the normal filtration of the infant liver. The liver does not perform digestive processes because the fetus does not consume meals directly, but receives nourishment from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, so initially the lymphocytes, called T-cells, are created from fetal liver stem cells. Once the fetus is delivered, the formation of blood stem cells in infants shifts to the red bone marrow.
After birth, the umbilical vein and ductus venosus are completely obliterated two to five days postpartum; the former becomes the ligamentum teres and the latter becomes the ligamentum venosum. In the disease state of cirrhosis and portal hypertension, the umbilical vein can open up again.
# Liver as food
Template:Nutritionalvalue
Mammal and bird livers are commonly eaten as food. Liver can be baked, broiled, or fried (often served as liver and onions) or eaten raw (liver sashimi), but is perhaps most commonly made into a spread (examples including liver pâté, foie gras, Braunschweiger, chopped liver, and leverpostej) or sausage (liverwurst).
Both animal and fish livers are rich in iron and Vitamin A, and cod liver oil is commonly used as a dietary supplement. Very high doses of Vitamin A can be toxic; in 1913, Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned, the latter fatally, from eating husky liver. In the US, the USDA specifies 3000 μg per day as a tolerable upper limit, which amounts to about 50 g of raw pork liver or, as reported in a non scientific source, 3 g of polar-bear liver.[7] However, acute vitamin A poisoning is not likely to result from liver consumption, since it is present in a less toxic form than in many dietary supplements.[8]
# Cultural allusions
In Greek mythology, Prometheus was punished by the gods for revealing fire to humans by being chained to a rock where a vulture (or an eagle) would peck out his liver, which would regenerate overnight. Curiously, the liver is the only human internal organ that actually can regenerate itself to a significant extent; this characteristic may have already been known to the Greeks due to survived injuries in battle.
The Talmud (tractate Berakhot 61b) refers to the liver as the seat of anger, with the gallbladder counteracting this.
In Arabic and Persian language, the liver is used in figurative speech to refer to courage and strong feelings, or "their best," e.g. "This Mecca has thrown to you the pieces of its liver!" [9]
The legend of Liver-Eating Johnson says that he would cut out and eat the liver of each man killed.
In the motion picture The Message, Hind bint Utbah is implied or portrayed eating the liver of Hamza ibn ‘Abd al-Muttalib during the Battle of Uhud.
Inuit will not eat the liver of polar bears (due to the fact a polar bear's liver contains so much Vitamin A as to be poisonous to humans) or seals [10]
# Further reading
- Eugene R. Schiff, Michael F. Sorrell, Willis C. Maddrey, eds. Schiff's diseases of the liver, 9th ed. Philadelphia : Lippincott, Williams & Wilkins, 2003. ISBN 0-7817-3007-4
- Sheila Sherlock, James Dooley. Diseases of the liver and biliary system, 11th ed. Oxford, UK ; Malden, MA : Blackwell Science. 2002. ISBN 0-632-05582-0
- David Zakim, Thomas D. Boyer. eds. Hepatology: a textbook of liver disease, 4th ed. Philadelphia: Saunders. 2003. ISBN 0-7216-9051-3
- Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
- Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
- Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6. his Columbia University web site, "Diseases of the liver" | https://www.wikidoc.org/index.php/Hepatic | |
384b8ce18c1d462850af4a0519ca3aef385a1645 | wikidoc | Her 3 | Her 3
This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized.
ErbB3 (Her-3) is a member of the epidermal growth factor receptor family of receptor tyrosine-kinases. However, despite the namesake of the protein family to which it belongs, ErbB3 does not have kinase activity. Rather, it is thought that ErbB3, when activated, becomes a substrate for dimerization and subsequent phosphorylation by ErbB1, ErbB2 and ErbB4.
Like many of the receptor tyrosine-kinases, ErbB3 is activated by extracellular ligand. Ligands known to bind to ErbB3 include heregulin. | Her 3
This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized.[1]
ErbB3 (Her-3) is a member of the epidermal growth factor receptor family of receptor tyrosine-kinases. However, despite the namesake of the protein family to which it belongs, ErbB3 does not have kinase activity. Rather, it is thought that ErbB3, when activated, becomes a substrate for dimerization and subsequent phosphorylation by ErbB1, ErbB2 and ErbB4.
Like many of the receptor tyrosine-kinases, ErbB3 is activated by extracellular ligand. Ligands known to bind to ErbB3 include heregulin. | https://www.wikidoc.org/index.php/Her_3 | |
bd7c01e47a5e6e8abb29118df0e2360713ed680f | wikidoc | Hilum | Hilum
# Overview
A hilum (formerly called a hilus) is a depression or pit at the part of an organ where structures such as blood vessels and nerves enter.
Medial depression for blood vessels and ureter to enter kidney chamber
The adjective form is "hilar", and the plural is "hila".
# Examples
- the hilum of kidney (admits the renal artery, vein, ureter, and nerves)
- splenic hilum
- hilum of lung | Hilum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A hilum (formerly called a hilus) is a depression or pit at the part of an organ where structures such as blood vessels and nerves enter.
Medial depression for blood vessels and ureter to enter kidney chamber
The adjective form is "hilar", and the plural is "hila".
# Examples
- the hilum of kidney (admits the renal artery, vein, ureter, and nerves)
- splenic hilum
- hilum of lung
# External links
- GPnotebook
- Template:EMedicineDictionary
- Template:Dorlands
de:Hilum
sv:Hilus
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hilar | |
df717c0debebd4d542618c64789dc6fc0b20f7a9 | wikidoc | HslVU | HslVU
The heat shock proteins hslV and hslU (also known as clpQ and clpY respectively) are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. The complex is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria.
# Genetics
Both proteins are encoded on the same operon within the bacterial genome. Unlike many eukaryotic proteasomes, which have several different peptide substrate specificities, hslV has a specificity similar to that of chymotrypsin; hence it is inhibited by proteasome inhibitors that specifically target the chymotrypsin site in eukaryotic proteasomes. Although the HslVU complex is stable on its own, some evidence suggests that the complex is formed in vivo in a substrate-induced manner due to a conformational change in the hslU-substrate complex that promotes hslV binding.
HslV and hslU genes have also been identified in some eukaryotes, although these also require the constitutively expressed proteasome for survival. These eukaryotic HslVU complexes assemble to apparently functional units, suggesting that these eukaryotes have both functional proteasomes and functional hslVU systems.
# Motifs in peptide unfolding
A four-amino acid sequence motif - GYVG, glycine-tyrosine-valine-glycine - conserved in hslU ATPases and located on the inner surface of the assembled pore dramatically accelerates the degradation of some proteins, and is required for the degradation of others. However, these motifs are not necessary for the degradation of short peptides and play no direct role in hydrolysis, suggesting that their major role is in unfolding the native state structure of the substrate and transferring the resulting disordered polypeptide chain to the hslV subunits for degradation. These motifs also influence the assembly of the complex. Translocation is also facilitated by the C-terminal tails of the HslU subunits, which form a gate closing off the proteolytic active sites in the central pore until a substrate has been bound and unfolded.
# Mechanism
The basic mechanism by which the hslVU complex undertakes proteolytic substrate degradation is essentially the same as that observed in the eukaryotic proteasome, catalyzed by active-site threonine residues. It is inhibited by enzyme inhibitors that covalently bind the threonine. Like the proteasome, hslU must bind ATP in a magnesium-dependent manner before substrate binding and unfolding can occur. | HslVU
The heat shock proteins hslV and hslU (also known as clpQ and clpY respectively[1]) are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. The complex is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria.[2]
# Genetics
Both proteins are encoded on the same operon within the bacterial genome. Unlike many eukaryotic proteasomes, which have several different peptide substrate specificities, hslV has a specificity similar to that of chymotrypsin; hence it is inhibited by proteasome inhibitors that specifically target the chymotrypsin site in eukaryotic proteasomes.[3] Although the HslVU complex is stable on its own, some evidence suggests that the complex is formed in vivo in a substrate-induced manner due to a conformational change in the hslU-substrate complex that promotes hslV binding.[4]
HslV and hslU genes have also been identified in some eukaryotes, although these also require the constitutively expressed proteasome for survival. These eukaryotic HslVU complexes assemble to apparently functional units, suggesting that these eukaryotes have both functional proteasomes and functional hslVU systems.[5]
# Motifs in peptide unfolding
A four-amino acid sequence motif - GYVG, glycine-tyrosine-valine-glycine - conserved in hslU ATPases and located on the inner surface of the assembled pore dramatically accelerates the degradation of some proteins, and is required for the degradation of others. However, these motifs are not necessary for the degradation of short peptides and play no direct role in hydrolysis, suggesting that their major role is in unfolding the native state structure of the substrate and transferring the resulting disordered polypeptide chain to the hslV subunits for degradation. These motifs also influence the assembly of the complex.[6] Translocation is also facilitated by the C-terminal tails of the HslU subunits, which form a gate closing off the proteolytic active sites in the central pore until a substrate has been bound and unfolded.[7]
# Mechanism
The basic mechanism by which the hslVU complex undertakes proteolytic substrate degradation is essentially the same as that observed in the eukaryotic proteasome, catalyzed by active-site threonine residues.[8] It is inhibited by enzyme inhibitors that covalently bind the threonine.[9] Like the proteasome, hslU must bind ATP in a magnesium-dependent manner before substrate binding and unfolding can occur.[10] | https://www.wikidoc.org/index.php/HslVU | |
2dd9938bce42d3e33ebd42ea2c2eec1760391227 | wikidoc | Hsp27 | Hsp27
Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.
Hsp27 is a chaperone of the sHsp (small heat shock protein) group among ubiquitin, α-crystallin, Hsp20 and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation. They also take part in signal transduction.
# Structure
sHsps have some structural features in common: Very characteristic is a homologous and highly conserved amino acid sequence, the so-called α-crystallin-domain at the C-terminus. These sequences consist of 80 to 100 residues with a homology between 20% and 60% and form β-sheets, which are important for the formation of stable dimers.
The N-terminus consists of a less conserved region, the so-called WD/EPF domain, followed by a short variable sequence with a rather conservative site near the C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.
This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. It is highly flexible and polar because of its negative charges. Probably it functions as a mediator of solubility for hydrophobic sHsps and it stabilizes the protein and protein/substrate complexes. This was shown by elimination of the C-terminal tail in Hsp27Δ182-205 and in Hsp25Δ18.
# Oligomerization
The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers, which exclusively have chaperone activity in vitro. Hsp27-oligomers probably consist of stable dimers, which are formed by two α-crystallin-domains of neighbouring monomers, which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii and wheat Hsp16.9. The stable dimers aggregate to tetramers and finally form unstable oligomers.
The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits. The oligomerization depends on the physiology of the cells, the phosphorylation status of Hsp27 and the exposure to stress. Stress induces an increase of expression (after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38 MAP kinase cascade by differentiating agents, mitogens, inflammatory cytokines such as TNFα and IL-1β, hydrogen peroxide and other oxidants, leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps. The phosphorylation plays an important role for the formation of oligomers in exponentially growing cells in vitro, but the oligomerization in tumor cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status. Furthermore, it was shown that HSP27 contains an Argpyrimidine modification.
In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity. Therefore it is clear, that a formation of large aggregates takes place under heat shock.
# Cellular localization
Hsp27 appears in many cell types, especially all types of muscle cells. It is located mainly in the cytosol, but also in the perinuclear region, endoplasmatic reticulum, and nucleus. It is overexpressed during different stages of cell differentiation and development. This suggests an essential role for Hsp27 in the differentiation of tissues.
An affinity of high expression levels of different phosphorylated Hsp27 species and muscle/neurodegenerative diseases and various cancers was observed. High expression levels possibly are in inverse relation with cell proliferation, metastasis, and resistance to chemotherapy. High levels of Hsp27 were also found in sera of breast cancer patients; therefore Hsp27 could be a potential diagnostic marker.
# Function
The main function of Hsp27 is to provide thermotolerance in vivo, cytoprotection, and support of cell survival under stress conditions. More specialized functions of Hsp27 are manifold and complex. In vitro it acts as an ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70-complex.
Hsp27 is also involved in the apoptotic signalling pathway. Hsp27 interacts with the outer mitochondrial membranes and interferes with the activation of cytochrome c/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9. The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1. Moreover, Hsp27 phosphorylation leads to the activation of TAK1 and TAK1-p38/ERK pro-survival signaling, thus opposing TNF-α-induced apoptosis.
A well documented function of Hsp27 is the interaction with actin and intermediate filaments. It prevents the formation of non-covalent filament/filament interactions of the intermediate filaments and protects actin filaments from fragmentation. It also preserves the focal contacts fixed at the cell membrane.
Another function of Hsp27 is the activation of the proteasome. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitinated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB pathway, that controls a lot of processes, such as cell growth and inflammatory and stress responses. The cytoprotective properties of Hsp27 result from its ability to modulate reactive oxygen species and to raise glutathione levels.
Probably Hsp27 – among other chaperones – is involved in the process of cell differentiation. Changes of Hsp27 levels were observed in Ehrlich ascite cells, embryonic stem cells, normal B-cells, B-lymphoma cells, osteoblasts, keratinocytes, neurons etc. The upregulation of Hsp27 correlates with the rate of phosphorylation and with an increase of large oligomers. It is possible that Hsp27 plays a crucial role in the termination of growth.
# Clinical significance
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporin, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development of some cancers, such as hepatocellular carcinoma, gastric cancers, colonic tumors, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. Notably, phosphorylated Hsp27 increases human prostate cancer (PCa) cell invasion, enhances cell proliferation, and suppresses Fas-induced apoptosis in human PCa cells. Unphosphorylated Hsp27 has been shown to act as an actin capping protein, preventing actin reorganization and, consequently, cell adhesion and motility. OGX-427, which targets HSP27 through an antisense mechanism, is currently undergoing testing in clinical trials.
Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation. As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials. Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge. Protein kinase C-mediated HSPB1 phosphorylation protects against ferroptosis, an iron-dependent form of non-apoptotic cell death, by reducing iron-mediated production of lipid reactive oxygen species. These novel data support the development of Hsp-targeting strategies and, specifically, anti-HSP27 agents for the treatment of ferroptosis-mediated cancer.
# Interactions
Hsp27 has been shown to interact with:
- ASK1,
- C2orf73,
- CRYAA,
- CRYAB,
- CRYBB2,
- HNRPD,
- HSPB8,
- MK2,
- TAK1, and
- TGFB1I1. | Hsp27
Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the HSPB1 gene.[1][2]
Hsp27 is a chaperone of the sHsp (small heat shock protein) group among ubiquitin, α-crystallin, Hsp20 and others. The common functions of sHsps are chaperone activity, thermotolerance, inhibition of apoptosis, regulation of cell development, and cell differentiation. They also take part in signal transduction.
# Structure
sHsps have some structural features in common: Very characteristic is a homologous and highly conserved amino acid sequence, the so-called α-crystallin-domain at the C-terminus. These sequences consist of 80 to 100 residues with a homology between 20% and 60% and form β-sheets, which are important for the formation of stable dimers.[3][4]
The N-terminus consists of a less conserved region, the so-called WD/EPF domain, followed by a short variable sequence with a rather conservative site near the C-terminus of this domain. The C-terminal part of the sHsps consists of the above mentioned α-crystallin domain, followed by a variable sequence with high motility and flexibility.[5]
This C-terminal tail appears in many mammalian sHsps (e.g. mouse Hsp25, αA-crystallin) and has no homology. It is highly flexible and polar because of its negative charges.[6] Probably it functions as a mediator of solubility for hydrophobic sHsps and it stabilizes the protein and protein/substrate complexes. This was shown by elimination of the C-terminal tail in Hsp27Δ182-205[7] and in Hsp25Δ18.[8]
# Oligomerization
The N-terminus with its WD/EPF-region is essential for the development of high molecular oligomers,[9][10] which exclusively have chaperone activity in vitro. Hsp27-oligomers probably consist of stable dimers, which are formed by two α-crystallin-domains of neighbouring monomers,[5] which was shown with the proteins MjHSP16.5 from Methanocaldococcus jannaschii[3] and wheat Hsp16.9.[4] The stable dimers aggregate to tetramers and finally form unstable oligomers.
The oligomerization of Hsp27 is a dynamic process: There is a balance between stable dimers respectively tetramers and instable oligomers (up to 800 kDa) consisting of 16 to 32 subunits and a high exchange rate of subunits.[10][11][12] The oligomerization depends on the physiology of the cells, the phosphorylation status of Hsp27 and the exposure to stress. Stress induces an increase of expression (after hours) and phosphorylation (after several minutes) of Hsp27. Stimulation of the p38 MAP kinase cascade by differentiating agents, mitogens, inflammatory cytokines such as TNFα and IL-1β, hydrogen peroxide and other oxidants,[13] leads to the activation of MAPKAP kinases 2 and 3 which directly phosphorylate mammalian sHsps.[12] The phosphorylation plays an important role for the formation of oligomers in exponentially growing cells in vitro, but the oligomerization in tumor cells growing in vivo or growing at confluence in vitro is dependent on cell-cell contact, but not on the phosphorylation status.[14] Furthermore, it was shown that HSP27 contains an Argpyrimidine modification.[15]
In all probability, the oligomerization status is connected with the chaperone activity: aggregates of large oligomers have high chaperone activity, whereas dimers have no chaperone activity.[5] Therefore it is clear, that a formation of large aggregates takes place under heat shock.[11]
# Cellular localization
Hsp27 appears in many cell types, especially all types of muscle cells. It is located mainly in the cytosol, but also in the perinuclear region, endoplasmatic reticulum, and nucleus. It is overexpressed during different stages of cell differentiation and development. This suggests an essential role for Hsp27 in the differentiation of tissues.
An affinity of high expression levels of different phosphorylated Hsp27 species and muscle/neurodegenerative diseases and various cancers was observed.[16] High expression levels possibly are in inverse relation with cell proliferation, metastasis, and resistance to chemotherapy.[17] High levels of Hsp27 were also found in sera of breast cancer patients;[18] therefore Hsp27 could be a potential diagnostic marker.
# Function
The main function of Hsp27 is to provide thermotolerance in vivo, cytoprotection, and support of cell survival under stress conditions. More specialized functions of Hsp27 are manifold and complex. In vitro it acts as an ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70-complex.
Hsp27 is also involved in the apoptotic signalling pathway. Hsp27 interacts with the outer mitochondrial membranes and interferes with the activation of cytochrome c/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9.[16] The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.[19] Moreover, Hsp27 phosphorylation leads to the activation of TAK1 and TAK1-p38/ERK pro-survival signaling, thus opposing TNF-α-induced apoptosis.[20]
A well documented function of Hsp27 is the interaction with actin and intermediate filaments. It prevents the formation of non-covalent filament/filament interactions of the intermediate filaments and protects actin filaments from fragmentation. It also preserves the focal contacts fixed at the cell membrane.[16]
Another function of Hsp27 is the activation of the proteasome. It speeds up the degradation of irreversibly denatured proteins and junkproteins by binding to ubiquitinated proteins and to the 26S proteasome. Hsp27 enhances the activation of the NF-κB pathway, that controls a lot of processes, such as cell growth and inflammatory and stress responses.[21] The cytoprotective properties of Hsp27 result from its ability to modulate reactive oxygen species and to raise glutathione levels.
Probably Hsp27 – among other chaperones – is involved in the process of cell differentiation.[22] Changes of Hsp27 levels were observed in Ehrlich ascite cells, embryonic stem cells, normal B-cells, B-lymphoma cells, osteoblasts, keratinocytes, neurons etc. The upregulation of Hsp27 correlates with the rate of phosphorylation and with an increase of large oligomers. It is possible that Hsp27 plays a crucial role in the termination of growth.
# Clinical significance
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporin, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development of some cancers, such as hepatocellular carcinoma, gastric cancers, colonic tumors, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers.[23] Notably, phosphorylated Hsp27 increases human prostate cancer (PCa) cell invasion, enhances cell proliferation, and suppresses Fas-induced apoptosis in human PCa cells. Unphosphorylated Hsp27 has been shown to act as an actin capping protein, preventing actin reorganization and, consequently, cell adhesion and motility. OGX-427, which targets HSP27 through an antisense mechanism, is currently undergoing testing in clinical trials.[24]
Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation.[25][23] As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials.[23] Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge.[25] Protein kinase C-mediated HSPB1 phosphorylation protects against ferroptosis, an iron-dependent form of non-apoptotic cell death, by reducing iron-mediated production of lipid reactive oxygen species. These novel data support the development of Hsp-targeting strategies and, specifically, anti-HSP27 agents for the treatment of ferroptosis-mediated cancer.[26]
# Interactions
Hsp27 has been shown to interact with:
- ASK1,[20]
- C2orf73,[27]
- CRYAA,[28]
- CRYAB,[28][29]
- CRYBB2,[28]
- HNRPD,[30]
- HSPB8,[31][32]
- MK2,[20]
- TAK1,[20] and
- TGFB1I1.[33] | https://www.wikidoc.org/index.php/Hsp27 | |
7d86ecbc207c59eaceae445d9a9b6aaf018f69c8 | wikidoc | Hymen | Hymen
# Overview
The hymen (also called maidenhead) is a fold of mucous membrane which surrounds or partially covers the external vaginal opening. Its name comes from the ancient greek for "hymenaeus," which means "vaginal-flap." It was also the name for the Greek god of marriage, later also the Greek god of membranes; "Hymenaios." A slang term is "cherry", as in "popping one's cherry" (losing one's virginity). It forms part of the vulva, or external genitalia. The most common formation of the hymen is crescentic or crescent-shaped, although several other formations are possible. After a woman gives birth she may be left with remnants of the hymen called carunculae myrtiformes or the hymen may be completely absent.
The hymen has no known anatomical function. In societies which value chastity, the greatest significance of the hymen is a traditional belief that an intact hymen indicates a state of intact virginity. However, it is not possible to confirm that a woman or post-pubescent girl is not a virgin by examining the hymen. A physician routinely checks the appearance of the hymen of baby girls at birth, and again during all future pelvic examinations. In cases of suspected rape or sexual abuse, a detailed examination of the hymen may be carried out; however, the condition of the hymen alone is often inconclusive or open to misinterpretation, especially if the patient has reached puberty.
# Types
There are several different formations of the hymen, some more common than others. In about 1 in 2000 females, the hymen fails to develop any opening at all: this is called an imperforate hymen and if it does not spontaneously resolve itself before puberty a physician will need to make a hole in the hymen to allow menstrual fluids to escape. A hymenotomy may also be required if the hymen is particularly thick or inelastic as it may interfere with sexual intercourse.
The shape of the hymen is easiest to observe in girls past infancy but before they reach puberty: at this time their hymen is thin and less likely to be redundant, that is to protrude or fold over on itself.
When describing the shape of a hymen, a clock face is used. The 12 o'clock position is below the urethra, and 6 o'clock is towards the anus, which is based on the patient lying on her back.
## Most common forms of the hymen
- crescent-shaped, crescentic, or posterior rim: no hymenal tissue at the 12 o'clock position; narrow band of tissue starts at 1 or 2 o'clock going clockwise, is at its widest around 6 o'clock, and tapers off at 10 or 11 o'clock
- annular, or circumferential: the hymen forms a ring around the vaginal opening; especially common in newborns
- redundant; sometimes sleeve-like: folds in on itself, which sometimes causes it to protrude; most common in infancy and at/following puberty due to estrogen levels; can be combined with other type such as "annular and redundant"
## Less common forms
- Fimbriated or denticular: an irregular edge to the hymenal orifice; more likely at an age when estrogen is present
- Septate: the hymen has one or more bands extending across the opening
- Cribriform, or microperforate: the hymen stretches completely across the vaginal opening, but is perforated with several holes
- Labial, or vertical: hymen has an opening from the 12 to the 6 o'clock positions and can look similar to a third set of vulvar lips
- Imperforate: hymen completely covers vaginal orifice; will require minor surgery if it has not corrected itself by puberty to allow menstrual fluids to escape
Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome.
- Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome.
The hymen is torn or stretched by penetrative sex, and more so when a woman gives birth vaginally.
- parous introitus refers to the vaginal opening which has had a baby pass through it and consequently has nothing left of its hymen but a fleshy irregular outline decorating its perimeter; these tags are called carunculae mytriformes
# Development of the hymen
During the early stages of fetal development there is no opening into the vagina at all. The thin layer of tissue that covers the vagina at this time usually divides to a certain extent prior to birth, forming the hymen. That layer was the Müllerian eminence before, and thus, the hymen is a remnant of that structure.
In newborn babies, who are still under the influence of the mother's hormones, the hymen is thick, pale pink, and redundant (folds in on itself and may protrude). For the first two to four years of life, the infant produces hormones which continue this effect.
By the time a girl reaches school-age, this hormonal influence has stopped and the hymen becomes thin, smooth, delicate and almost translucent. It is also very sensitive to touch; a physician who needed to swab the area would avoid the hymen and swab the outer vulval vestibule instead.
From puberty onwards the appearance of the hymen is affected once more by estrogen. It thickens and becomes pale pink, the opening is often fibriated or erratically shaped, and redundant: the hymen often appears rolled or sleeve-like.
There is a surgical procedure that can repair the hymen so that it is intact. The procedure, known as hymenoplasty, has become a popular procedure for some females.
# What might damage the hymen?
The hymen may be damaged by playing sports, using tampons, pelvic examinations or even straddle injuries.
Once a girl reaches puberty, the hymen tends to become quite elastic. It is not possible to determine whether a woman uses tampons or not by examining her hymen. Sexual intercourse is one of the most common ways to damage the hymen, although in one survey only 43% of women reported bleeding the first time they had sex; which means that in the other 57% of women the hymen likely stretched enough that it didn't tear.
It is rare to damage the hymen through accidental injury, such as falling on the top tube of a bicycle. Although such an accident may cause bleeding, this is usually due to damage to surrounding tissues such as the labia. It is unlikely that an accident would damage the hymen without injuring any other part of the vulva. Therefore, damage to the hymen alone, described as an accident, would be seen as a strong indicator of sexual assault.
# Debunking myths
- The condition of the hymen is not a reliable indicator of whether a woman past puberty has actually engaged in sexual intercourse.
- There is no such thing as "congenital absence of the hymen", i.e. it is a myth that girls are born without a hymen. However, a hymen can vary in size, and, as described above, be very hard to find, even if the person never had sex before.
- The hymen is not inside the vagina. It is part of the external genitalia.
As early as the late sixteenth century, Ambroise Paré and Andreas Laurentius asserted to have never seen the hymen and that it was "a primitive myth, unworthy of a civilized nation like France." In the sixteenth and seventeenth centuries, medical researchers have used the presence of the hymen, or lack thereof, as founding evidence of physical diseases such as "womb-fury". If not cured, womb-fury would, according to these early doctors, result in death. The cure, naturally enough, was marriage, since a woman could then go about having sexual intercourse on a "normal" schedule that would stop womb-fury from killing her.
# Revisionist perspectives
In late 2005, Monica Christiansson, former maternity ward nurse and Carola Eriksson, a PhD student at Umeå University announced that according to studies of medical literature and practical experience, the hymen should be considered a social and cultural myth, based on deeply rooted stereotypes of womens' roles in sexual relations with men. Christiansson and Eriksson support their claims by pointing out that there are no accurate medical descriptions of what a hymen actually consists of. Statistics presented by the two state that fewer than 30% of women who have gone through puberty and have consensual intercourse bleed the first time. Christiansson has expressed an opinion that the use of the term "hymen" should be discontinued and that it should be considered an integral part of the vaginal opening.
It is argued that since the hymen has been culturally constructed to be the sign of virginity, its existence plays into a political discourse that circulates around the body. By examining women's bodies for the existence of the hymen, researchers have used it to determine whether or not women are "virtuous." Sherry B. Ortner, professor at the University of Chicago, explains how "the hymen itself emerges physiologically with the development of sexual purity codes" as an element of patriarchy. In some cultures it was customary to examine a woman for her hymen before her marriage to see if she was truly fit to be married. If she was found with a broken hymen, or to have no hymen at all, often the male would not be obligated to marry her. Additionally, the hymen has been used to consistently create the image of women as physically bound to their sexuality, insofar as there's a specific membrane that needs "breaking" in order to have sex and enter into full womanhood, being sexually dependent on their men. | Hymen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The hymen (also called maidenhead)[1] is a fold of mucous membrane which surrounds or partially covers the external vaginal opening. Its name comes from the ancient greek for "hymenaeus," which means "vaginal-flap." It was also the name for the Greek god of marriage, later also the Greek god of membranes; "Hymenaios."[2][3] A slang term is "cherry", as in "popping one's cherry" (losing one's virginity). It forms part of the vulva, or external genitalia.[4][5] The most common formation of the hymen is crescentic or crescent-shaped, although several other formations are possible.[6] After a woman gives birth she may be left with remnants of the hymen called carunculae myrtiformes or the hymen may be completely absent.[7]
The hymen has no known anatomical function. In societies which value chastity, the greatest significance of the hymen is a traditional belief that an intact hymen indicates a state of intact virginity. However, it is not possible to confirm that a woman or post-pubescent girl is not a virgin by examining the hymen.[8] A physician routinely checks the appearance of the hymen of baby girls at birth, and again during all future pelvic examinations. In cases of suspected rape or sexual abuse, a detailed examination of the hymen may be carried out; however, the condition of the hymen alone is often inconclusive or open to misinterpretation, especially if the patient has reached puberty.[9]
# Types
There are several different formations of the hymen, some more common than others. In about 1 in 2000 females, the hymen fails to develop any opening at all:[10] this is called an imperforate hymen and if it does not spontaneously resolve itself before puberty a physician will need to make a hole in the hymen to allow menstrual fluids to escape.[11] A hymenotomy may also be required if the hymen is particularly thick or inelastic as it may interfere with sexual intercourse.
The shape of the hymen is easiest to observe in girls past infancy but before they reach puberty: at this time their hymen is thin and less likely to be redundant, that is to protrude or fold over on itself.[12]
When describing the shape of a hymen, a clock face is used. The 12 o'clock position is below the urethra, and 6 o'clock is towards the anus, which is based on the patient lying on her back.[13]
## Most common forms of the hymen
- crescent-shaped, crescentic, or posterior rim: no hymenal tissue at the 12 o'clock position; narrow band of tissue starts at 1 or 2 o'clock going clockwise, is at its widest around 6 o'clock, and tapers off at 10 or 11 o'clock
- annular, or circumferential: the hymen forms a ring around the vaginal opening; especially common in newborns[14]
- redundant; sometimes sleeve-like: folds in on itself, which sometimes causes it to protrude; most common in infancy and at/following puberty due to estrogen levels;[15] can be combined with other type such as "annular and redundant"
## Less common forms
- Fimbriated or denticular: an irregular edge to the hymenal orifice; more likely at an age when estrogen is present
- Septate: the hymen has one or more bands extending across the opening
- Cribriform, or microperforate: the hymen stretches completely across the vaginal opening, but is perforated with several holes
- Labial, or vertical: hymen has an opening from the 12 to the 6 o'clock positions and can look similar to a third set of vulvar lips
- Imperforate:[16] hymen completely covers vaginal orifice; will require minor surgery if it has not corrected itself by puberty to allow menstrual fluids to escape
Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome.
- Imperforated hymen must be differentiated from other diseases that cause latency in secondary sexual characteristics development (amenorrhea), such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, and Noonan's syndrome.
The hymen is torn or stretched by penetrative sex, and more so when a woman gives birth vaginally.
- parous introitus refers to the vaginal opening which has had a baby pass through it and consequently has nothing left of its hymen but a fleshy irregular outline decorating its perimeter; these tags are called carunculae mytriformes
# Development of the hymen
During the early stages of fetal development there is no opening into the vagina at all. The thin layer of tissue that covers the vagina at this time usually divides to a certain extent prior to birth, forming the hymen. That layer was the Müllerian eminence before[17], and thus, the hymen is a remnant of that structure.
In newborn babies, who are still under the influence of the mother's hormones, the hymen is thick, pale pink, and redundant (folds in on itself and may protrude). For the first two to four years of life, the infant produces hormones which continue this effect.[18]
By the time a girl reaches school-age, this hormonal influence has stopped and the hymen becomes thin, smooth, delicate and almost translucent. It is also very sensitive to touch; a physician who needed to swab the area would avoid the hymen and swab the outer vulval vestibule instead.[19]
From puberty onwards the appearance of the hymen is affected once more by estrogen. It thickens and becomes pale pink, the opening is often fibriated or erratically shaped, and redundant: the hymen often appears rolled or sleeve-like.[20]
There is a surgical procedure that can repair the hymen so that it is intact. The procedure, known as hymenoplasty, has become a popular procedure for some females.
# What might damage the hymen?
The hymen may be damaged by playing sports, using tampons, pelvic examinations or even straddle injuries.[21]
Once a girl reaches puberty, the hymen tends to become quite elastic. It is not possible to determine whether a woman uses tampons or not by examining her hymen. Sexual intercourse is one of the most common ways to damage the hymen, although in one survey only 43% of women reported bleeding the first time they had sex; which means that in the other 57% of women the hymen likely stretched enough that it didn't tear.
It is rare to damage the hymen through accidental injury, such as falling on the top tube of a bicycle. Although such an accident may cause bleeding, this is usually due to damage to surrounding tissues such as the labia.[22] It is unlikely that an accident would damage the hymen without injuring any other part of the vulva. Therefore, damage to the hymen alone, described as an accident, would be seen as a strong indicator of sexual assault.
# Debunking myths
- The condition of the hymen is not a reliable indicator of whether a woman past puberty has actually engaged in sexual intercourse.
- There is no such thing as "congenital absence of the hymen", i.e. it is a myth that girls are born without a hymen.[23] However, a hymen can vary in size, and, as described above, be very hard to find, even if the person never had sex before.
- The hymen is not inside the vagina. It is part of the external genitalia.
As early as the late sixteenth century, Ambroise Paré and Andreas Laurentius asserted to have never seen the hymen and that it was "a primitive myth, unworthy of a civilized nation like France." In the sixteenth and seventeenth centuries, medical researchers have used the presence of the hymen, or lack thereof, as founding evidence of physical diseases such as "womb-fury". If not cured, womb-fury would, according to these early doctors, result in death.[24] The cure, naturally enough, was marriage, since a woman could then go about having sexual intercourse on a "normal" schedule that would stop womb-fury from killing her.
# Revisionist perspectives
In late 2005, Monica Christiansson, former maternity ward nurse and Carola Eriksson, a PhD student at Umeå University announced that according to studies of medical literature and practical experience, the hymen should be considered a social and cultural myth, based on deeply rooted stereotypes of womens' roles in sexual relations with men. Christiansson and Eriksson support their claims by pointing out that there are no accurate medical descriptions of what a hymen actually consists of. Statistics presented by the two state that fewer than 30% of women who have gone through puberty and have consensual intercourse bleed the first time. Christiansson has expressed an opinion that the use of the term "hymen" should be discontinued and that it should be considered an integral part of the vaginal opening.[25]
It is argued that since the hymen has been culturally constructed to be the sign of virginity, its existence plays into a political discourse that circulates around the body. By examining women's bodies for the existence of the hymen, researchers have used it to determine whether or not women are "virtuous." Sherry B. Ortner, professor at the University of Chicago, explains how "the hymen itself emerges physiologically with the development of sexual purity codes" as an element of patriarchy.[26] In some cultures it was customary to examine a woman for her hymen before her marriage to see if she was truly fit to be married. If she was found with a broken hymen, or to have no hymen at all, often the male would not be obligated to marry her. Additionally, the hymen has been used to consistently create the image of women as physically bound to their sexuality, insofar as there's a specific membrane that needs "breaking" in order to have sex and enter into full womanhood, being sexually dependent on their men.[27] | https://www.wikidoc.org/index.php/Hymen | |
6b0416710b697c26bb88f3969791e5cd04396735 | wikidoc | Hyrax | Hyrax
A hyrax (from Greek Template:Polytonic 'shrewmouse'; Afrikaans: klipdassie, from Dutch: klipdas 'rockbadger') is any of four species of fairly small, thickset, herbivorous mammals in the order Hyracoidea. They live in Africa and the Middle East.
Hyraxes are well-furred rotund creatures with a mere stump for a tail. They are about the size of a Corgi; most measure between about 30 and 70 cm long and weigh between 2 and 5 kg. From a distance, a hyrax could be mistaken for a very well-fed rabbit or guinea pig.
# Characteristics
Hyraxes retain a number of early mammal characteristics; in particular they have poorly developed internal temperature regulation (which they deal with by huddling together for warmth, and by basking in the sun like reptiles). Unlike other browsing and grazing animals, they do not use the incisors at the front of the jaw for slicing off leaves and grass, and use the molar teeth at the side of the jaw instead. The incisors are nonetheless large, and grow continuously through life, in a similar manner to those of rodents. There is a short diastema between the incisors and the cheek teeth. The dental formula for hyraxes is:Template:Dentition2
Unlike the even-toed ungulates and some of the macropods, hyraxes do not chew cud to help extract nutrients from coarse, low-grade leaves and grasses. They do, however, have complex, multi-chambered stomachs which allow symbiotic bacteria to break down tough plant materials, and their overall ability to digest fibre is similar to that of the ungulates.
Hyraxes inhabit rocky terrain across sub-Saharan Africa. Their feet have rubbery pads with numerous sweat glands, which help the animal maintain its grip when moving fast up steep rocky surfaces. They also have efficient kidneys, retaining water so that they can survive in arid environments.
Female hyraxes give birth to up to four young after a gestation period of between seven and eight months, depending on the species. The young are weaned at one to five months of age, and reach sexual maturity at sixteen to seventeen months.
Hyraxes live in small family groups, dominated by a single male who aggressively defends the territory from rivals. Where there is abundant living space, the male may dominate multiple groups of females, each with their own range. The remaining males live solitary lives, often on the periphery of areas controlled by larger males, and mate only with younger females
# Historical accounts
Early Phoenician navigators mistook the rabbits of the Iberian Peninsula for hyraxes (Hebrew Shaphan); hence they named it I-Shapan-im, meaning "land of the hyraxes", which possibly became the Latin word "Hispania", the root of Spain's modern Spanish name España and the English name Spain.
The word "rabbit, or "hare" was used instead of "hyrax" many times in some earlier English Bible translations. European translators of those times had no knowledge of the hyrax (Hebrew שָּׁפָן Shaphan), and therefore no name for them. There are references to hyraxes in the Old Testament which describe hyraxes and rabbits as cud-chewing animals, but the Hebrew phrase means literally, "raising up what has been swallowed." and they are not true cud chewers in the modern sense of the term, but rather coprophages. After eating, they ferment and partially digest their food; their cecum plays a similar role in this process to a cow's rumen. After passing this partially-digested food, they re-ingest it and complete the digestive process. Once digestion is complete, they pass feces of a different texture which they do not re-ingest.
# Evolution
Hyraxes are sometimes described as being the closest living relative to the elephant. This is because they may share an ancestor in the distant past when hyraxes were larger and more diverse. However, the details of their relationship remain open to debate.
All modern hyraxes are members of the family Procaviidae (the only living family within the Hyracoidea) and are found only in Africa and the Middle East. In the past, however, hyraxes were more diverse and widespread. The order first appears in the fossil record over 40 million years ago, and for many millions of years hyraxes were the primary terrestrial herbivore in Africa, just as odd-toed ungulates were in the Americas. There were many different species, the largest of them about the weight of a small horse, the smallest the size of a mouse. During the Miocene, however, competition from the newly-developed bovids—very efficient grazers and browsers—pushed the hyraxes out of the prime territory and into marginal niches. Nevertheless, the order remained widespread, diverse and successful as late as the end of the Pliocene (about two million years ago) with representatives throughout most of Africa, Europe and Asia.
The descendants of the giant hyracoids evolved in different ways. Some became smaller, and gave rise to the modern hyrax family. Others appear to have taken to the water (perhaps like the modern capybara), and ultimately gave rise to the elephant family, and perhaps also the Sirenians (dugongs and manatees). DNA evidence supports this hypothesis, and the small modern hyraxes share numerous features with elephants, such as toenails, excellent hearing, sensitive pads on their feet, small tusks, good memory, high brain functions compared to other similar mammals, and the shape of some of their bones.
Not all scientists support the proposal that hyraxes are the closest living relative of the elephant. Recent morphological and molecular based classifications reveal the Sirenians to be the closest living relatives of elephants, while hyraxes are closely related but form an outgroup to the assemblage of elephants, sirenians, and extinct orders like Embrithopoda and Desmostylia..
## List of extinct species
- Pliohyracidae
Geniohyinae
Seggeurius
Geniohyus
Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
Titanohyracinae
Antilohyrax
Titanohyrax
Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Geniohyinae
Seggeurius
Geniohyus
- Seggeurius
- Geniohyus
- Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
- Microhyrax
- Meroehyrax
- Selenohyrax
- Bunohyrax
- Pachyhyrax
- Megalohyrax
- Saghatherium
- Thyrohyrax
- Titanohyracinae
Antilohyrax
Titanohyrax
- Antilohyrax
- Titanohyrax
- Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Sogdohyrax
- Kvabebihyrax
- Prohyrax
- Parapliohyrax
- Pliohyrax
- Postschizotherium
- Procaviidae
Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Gigantohyrax
- Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procavia antigua
- Procavia transvaalensis
# Living species
Scientists have recently reduced the number of distinct species of hyrax recognized. As recently as 1995 there were eleven or more recognized species; only four are recognized today. The remaining species are regarded as subspecies of the remaining four. There are over 50 recognized subspecies and species, many of which are considered highly endangered.
- ORDER HYRACOIDEA
Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
- Southern Tree Hyrax, Dendrohyrax arboreus
- Western Tree Hyrax, Dendrohyrax dorsalis
- Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Genus Procavia
Cape Hyrax, Procavia capensis
- Cape Hyrax, Procavia capensis | Hyrax
A hyrax (from Greek Template:Polytonic 'shrewmouse'; Afrikaans: klipdassie, from Dutch: klipdas 'rockbadger') is any of four species of fairly small, thickset, herbivorous mammals in the order Hyracoidea. They live in Africa and the Middle East.
Hyraxes are well-furred rotund creatures with a mere stump for a tail. They are about the size of a Corgi; most measure between about 30 and 70 cm long and weigh between 2 and 5 kg. From a distance, a hyrax could be mistaken for a very well-fed rabbit or guinea pig.
# Characteristics
Hyraxes retain a number of early mammal characteristics; in particular they have poorly developed internal temperature regulation (which they deal with by huddling together for warmth, and by basking in the sun like reptiles). Unlike other browsing and grazing animals, they do not use the incisors at the front of the jaw for slicing off leaves and grass, and use the molar teeth at the side of the jaw instead. The incisors are nonetheless large, and grow continuously through life, in a similar manner to those of rodents. There is a short diastema between the incisors and the cheek teeth. The dental formula for hyraxes is:Template:Dentition2
Unlike the even-toed ungulates and some of the macropods, hyraxes do not chew cud to help extract nutrients from coarse, low-grade leaves and grasses. They do, however, have complex, multi-chambered stomachs which allow symbiotic bacteria to break down tough plant materials, and their overall ability to digest fibre is similar to that of the ungulates.
Hyraxes inhabit rocky terrain across sub-Saharan Africa. Their feet have rubbery pads with numerous sweat glands, which help the animal maintain its grip when moving fast up steep rocky surfaces. They also have efficient kidneys, retaining water so that they can survive in arid environments.
Female hyraxes give birth to up to four young after a gestation period of between seven and eight months, depending on the species. The young are weaned at one to five months of age, and reach sexual maturity at sixteen to seventeen months.
Hyraxes live in small family groups, dominated by a single male who aggressively defends the territory from rivals. Where there is abundant living space, the male may dominate multiple groups of females, each with their own range. The remaining males live solitary lives, often on the periphery of areas controlled by larger males, and mate only with younger females[1]
.
# Historical accounts
Early Phoenician navigators mistook the rabbits of the Iberian Peninsula for hyraxes (Hebrew Shaphan); hence they named it I-Shapan-im, meaning "land of the hyraxes", which possibly became the Latin word "Hispania", the root of Spain's modern Spanish name España and the English name Spain.[citation needed]
The word "rabbit, or "hare" was used instead of "hyrax" many times in some earlier English Bible translations. European translators of those times had no knowledge of the hyrax (Hebrew שָּׁפָן Shaphan[2]), and therefore no name for them. There are references to hyraxes in the Old Testament[3] which describe hyraxes and rabbits as cud-chewing animals, but the Hebrew phrase means literally, "raising up what has been swallowed."[4] and they are not true cud chewers in the modern sense of the term, but rather coprophages. After eating, they ferment and partially digest their food; their cecum plays a similar role in this process to a cow's rumen. After passing this partially-digested food, they re-ingest it and complete the digestive process. Once digestion is complete, they pass feces of a different texture which they do not re-ingest.
# Evolution
Hyraxes are sometimes described as being the closest living relative to the elephant. This is because they may share an ancestor in the distant past when hyraxes were larger and more diverse. However, the details of their relationship remain open to debate.
All modern hyraxes are members of the family Procaviidae (the only living family within the Hyracoidea) and are found only in Africa and the Middle East. In the past, however, hyraxes were more diverse and widespread. The order first appears in the fossil record over 40 million years ago, and for many millions of years hyraxes were the primary terrestrial herbivore in Africa, just as odd-toed ungulates were in the Americas. There were many different species, the largest of them about the weight of a small horse, the smallest the size of a mouse. During the Miocene, however, competition from the newly-developed bovids—very efficient grazers and browsers—pushed the hyraxes out of the prime territory and into marginal niches. Nevertheless, the order remained widespread, diverse and successful as late as the end of the Pliocene (about two million years ago) with representatives throughout most of Africa, Europe and Asia.
The descendants of the giant hyracoids evolved in different ways. Some became smaller, and gave rise to the modern hyrax family. Others appear to have taken to the water (perhaps like the modern capybara), and ultimately gave rise to the elephant family, and perhaps also the Sirenians (dugongs and manatees). DNA evidence supports this hypothesis, and the small modern hyraxes share numerous features with elephants, such as toenails, excellent hearing, sensitive pads on their feet, small tusks, good memory, high brain functions compared to other similar mammals, and the shape of some of their bones.[5]
Not all scientists support the proposal that hyraxes are the closest living relative of the elephant. Recent morphological and molecular based classifications reveal the Sirenians to be the closest living relatives of elephants, while hyraxes are closely related but form an outgroup to the assemblage of elephants, sirenians, and extinct orders like Embrithopoda and Desmostylia.[6].
## List of extinct species
- Pliohyracidae
Geniohyinae
Seggeurius
Geniohyus
Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
Titanohyracinae
Antilohyrax
Titanohyrax
Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Geniohyinae
Seggeurius
Geniohyus
- Seggeurius
- Geniohyus
- Saghatheriinae
Microhyrax
Meroehyrax
Selenohyrax
Bunohyrax
Pachyhyrax
Megalohyrax
Saghatherium
Thyrohyrax
- Microhyrax
- Meroehyrax
- Selenohyrax
- Bunohyrax
- Pachyhyrax
- Megalohyrax
- Saghatherium
- Thyrohyrax
- Titanohyracinae
Antilohyrax
Titanohyrax
- Antilohyrax
- Titanohyrax
- Pliohyracinae
Sogdohyrax
Kvabebihyrax
Prohyrax
Parapliohyrax
Pliohyrax
Postschizotherium
- Sogdohyrax
- Kvabebihyrax
- Prohyrax
- Parapliohyrax
- Pliohyrax
- Postschizotherium
- Procaviidae
Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procaviinae
Gigantohyrax
Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Gigantohyrax
- Procavia (Cape Hyrax)
Procavia antigua
Procavia transvaalensis
- Procavia antigua
- Procavia transvaalensis
# Living species
Scientists have recently reduced the number of distinct species of hyrax recognized. As recently as 1995 there were eleven or more recognized species; only four are recognized today. The remaining species are regarded as subspecies of the remaining four. There are over 50 recognized subspecies and species, many of which are considered highly endangered.[7]
- ORDER HYRACOIDEA
Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Family Procaviidae
Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
Genus Procavia
Cape Hyrax, Procavia capensis
- Genus Dendrohyrax
Southern Tree Hyrax, Dendrohyrax arboreus
Western Tree Hyrax, Dendrohyrax dorsalis
- Southern Tree Hyrax, Dendrohyrax arboreus
- Western Tree Hyrax, Dendrohyrax dorsalis
- Genus Heterohyrax
Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Yellow-spotted Rock Hyrax, Heterohyrax brucei
- Genus Procavia
Cape Hyrax, Procavia capensis
- Cape Hyrax, Procavia capensis | https://www.wikidoc.org/index.php/Hyrax | |
6d9d109cc87de9faa60a7a0c21a0e4fe0a6fc76b | wikidoc | ICAM2 | ICAM2
Intercellular adhesion molecule 2 (ICAM2), also known as CD102 (Cluster of Differentiation 102), is a human gene, and the protein resulting from it.
# Protein structure
The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2–9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein.
# Protein functions
ICAM-2 molecules regulate spermatid adhesion on Sertoli cell on the apical side of the blood-testis barrier (towards the lumen), thus playing a major role in spermatogenesis.
This protein may also play a role in lymphocyte recirculation by blocking LFA-1-dependent cell adhesion. It mediates adhesive interactions important for antigen-specific immune response, NK-cell mediated clearance, lymphocyte recirculation, and other cellular interactions important for immune response and surveillance.
# Interactions
ICAM2 has been shown to interact with EZR. | ICAM2
Intercellular adhesion molecule 2 (ICAM2), also known as CD102 (Cluster of Differentiation 102), is a human gene, and the protein resulting from it.
# Protein structure
The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2–9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein.
# Protein functions
ICAM-2 molecules regulate spermatid adhesion on Sertoli cell on the apical side of the blood-testis barrier (towards the lumen), thus playing a major role in spermatogenesis.[1]
This protein may also play a role in lymphocyte recirculation by blocking LFA-1-dependent cell adhesion. It mediates adhesive interactions important for antigen-specific immune response, NK-cell mediated clearance, lymphocyte recirculation, and other cellular interactions important for immune response and surveillance.[2]
# Interactions
ICAM2 has been shown to interact with EZR.[3] | https://www.wikidoc.org/index.php/ICAM2 | |
de36baece494de1e44349de7c876a548e6b0169d | wikidoc | ICAM4 | ICAM4
The LW blood system was first described by Landsteiner and Wiener in 1940. It was often confused with the Rh system, not becoming a separate antigen system until 1982. The LW and RhD antigens are genetically independent though they are phenotypically related and the LW antigen is expressed more strongly on RhD positive cells than on RhD negative cells. In most populations, the antithetical LW antigens, LWa and LWb are present as very high and very low frequency, respectively.
# Genomics
The LW locus is located on the short arm of chromosome 19 (19p13.3).
# Molecular biology
LW antigens reside on a 40- to 42-kiloDalton red cell membrane glycoprotein named CD242. The LW glycoprotein has recently been renamed ICAM-4 due to its similarity to intercellular adhesion molecule, although exactly which integrins bind to ICAM-4 is subject to controversy.
The function of ICAM-4 is not fully understood but appears to be restricted to erythroid cells. During in vitro erythropoesis, LW appears at either the erythroid colony forming stage or later at the proerythroblast stage. A vital part of erythropoesis is the clustering of erythroblasts around bone marrow macrophages to form erythroblastic islands. The erythroblast is then able to remove its nucleus, which is in turn ingested and broken down by the macrophages, to become a mature erythrocyte. During this process ICAM-4 binds to VLA-4, an erythroblast binding site, on adjacent erythroblasts and to αv integrins on macrophages to help stabilise the erythroblastic islands. The binding of red cells to macrophages in the spleen by ICAM-4 could also play a part in the removal of senescent red cells.
Despite the functional aspects of ICAM-4, its apparent absence in LW(a-b-) and Rhnull phenotypes does not appear to lead to any obvious pathological effects. ICAM-4 expression is elevated on sickle red cells and its binding to αv integrins on the endothelial cells may cause the pain associated with sickle cell crises.
Auto anti-LW is not uncommon as an autoantibody but usually presents with transient suppression of the LW antigen in genetically LW+ individuals, and so appears to be an alloantibody. True alloanti-LW is a very rare occurrence, with only two known examples of alloanti-LWab, produced by patients with an LW(a-b-) phenotype. Anti-LW can be present as a clinically insignificant autoantibody and not be associated with increased red cell destruction. Anti-LW has also been associated with cases of warm type autoimmune haemolytic anaemia; Philip Levine suggested that it was the most common antibody in cases of AIHA with a positive Coombs test.
# Transfusion medicine
Haemolytic disease of the newborn (HDFN) due to alloanti-LW is described as mild and very rare, even the very potent anti-LWab of one known patient caused minimal evidence of HDFN in her three pregnancies. To date auto anti-LW has only been implicated as the cause of one case of HDFN. | ICAM4
The LW blood system was first described by Landsteiner and Wiener in 1940.[1] It was often confused with the Rh system, not becoming a separate antigen system until 1982. The LW and RhD antigens are genetically independent though they are phenotypically related and the LW antigen is expressed more strongly on RhD positive cells than on RhD negative cells. In most populations, the antithetical LW antigens, LWa and LWb are present as very high and very low frequency, respectively.[1][2][3]
# Genomics
The LW locus is located on the short arm of chromosome 19 (19p13.3).[1]
# Molecular biology
LW antigens reside on a 40- to 42-kiloDalton red cell membrane glycoprotein named CD242.[2] The LW glycoprotein has recently been renamed ICAM-4 due to its similarity to intercellular adhesion molecule, although exactly which integrins bind to ICAM-4 is subject to controversy.
The function of ICAM-4 is not fully understood but appears to be restricted to erythroid cells. During in vitro erythropoesis, LW appears at either the erythroid colony forming stage or later at the proerythroblast stage. A vital part of erythropoesis is the clustering of erythroblasts around bone marrow macrophages to form erythroblastic islands. The erythroblast is then able to remove its nucleus, which is in turn ingested and broken down by the macrophages, to become a mature erythrocyte. During this process ICAM-4 binds to VLA-4, an erythroblast binding site, on adjacent erythroblasts and to αv integrins on macrophages to help stabilise the erythroblastic islands. The binding of red cells to macrophages in the spleen by ICAM-4 could also play a part in the removal of senescent red cells.[1][2][3]
Despite the functional aspects of ICAM-4, its apparent absence in LW(a-b-) and Rhnull phenotypes does not appear to lead to any obvious pathological effects. ICAM-4 expression is elevated on sickle red cells and its binding to αv integrins on the endothelial cells may cause the pain associated with sickle cell crises.[1][2]
Auto anti-LW is not uncommon as an autoantibody but usually presents with transient suppression of the LW antigen in genetically LW+ individuals, and so appears to be an alloantibody. True alloanti-LW is a very rare occurrence, with only two known examples of alloanti-LWab, produced by patients with an LW(a-b-) phenotype. Anti-LW can be present as a clinically insignificant autoantibody and not be associated with increased red cell destruction. Anti-LW has also been associated with cases of warm type autoimmune haemolytic anaemia; Philip Levine suggested that it was the most common antibody in cases of AIHA with a positive Coombs test.[1][4][5]
# Transfusion medicine
Haemolytic disease of the newborn (HDFN) due to alloanti-LW is described as mild and very rare, even the very potent anti-LWab of one known patient caused minimal evidence of HDFN in her three pregnancies.[6] To date auto anti-LW has only been implicated as the cause of one case of HDFN.[7] | https://www.wikidoc.org/index.php/ICAM4 | |
1cc1adb0c365694142436c84e7e7c7066435a43d | wikidoc | IDH3A | IDH3A
Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase.
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G. The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points. Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types. Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme’s allosteric regulation by ADP and NAD. Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits. Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding. Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction. Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism. This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2. IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH. This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle. Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.
# Clinical Significance
IDH3α expression has been linked to cancer, with high basal expression in multiple cancer cell lines and increased expression indicative of poorer prognosis in cancer patients. IDH3α is proposed to promote tumor growth as a regulator of α-KG, which subsequently regulates HIF-1. HIF-1 is largely known for shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis in cancer cells (the Warburg effect). Moreover, IDH3α activity leads to angiogenesis and metabolic reprogramming to provide the necessary nutrients for continuous cell growth. Meanwhile, silencing IDH3α is observed to obstruct tumor growth. Thus, IDH3α may prove to be a promising therapeutic target in treating cancer.
IDH3α is also implicated in psychiatric disorders. In particular, IDH3α expression in the cerebellum is observed to be significantly lower for bipolar disorder, major depressive disorder, and schizophrenia. The abnormal IDH3α levels may disrupt mitochondrial function and contribute to the pathogenesis of these disorders. | IDH3A
Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.[1][2]
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. [provided by RefSeq, Jul 2008][2]
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[3] The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points.[4][5][6] Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types.[5][6][7][8] Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme’s allosteric regulation by ADP and NAD.[7] Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits.[5][7] Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding.[5] Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction.[6][7] Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.[5][6]
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism.[1][4][5][6][7] This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2.[4][5] IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH.[5][6] This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle.[1][9] Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.[1][5][6]
# Clinical Significance
IDH3α expression has been linked to cancer, with high basal expression in multiple cancer cell lines and increased expression indicative of poorer prognosis in cancer patients. IDH3α is proposed to promote tumor growth as a regulator of α-KG, which subsequently regulates HIF-1. HIF-1 is largely known for shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis in cancer cells (the Warburg effect). Moreover, IDH3α activity leads to angiogenesis and metabolic reprogramming to provide the necessary nutrients for continuous cell growth. Meanwhile, silencing IDH3α is observed to obstruct tumor growth. Thus, IDH3α may prove to be a promising therapeutic target in treating cancer.[4]
IDH3α is also implicated in psychiatric disorders. In particular, IDH3α expression in the cerebellum is observed to be significantly lower for bipolar disorder, major depressive disorder, and schizophrenia. The abnormal IDH3α levels may disrupt mitochondrial function and contribute to the pathogenesis of these disorders.[9] | https://www.wikidoc.org/index.php/IDH3A | |
a7fe4c61bdc3566e5ea914838915a84e8028eed2 | wikidoc | IDH3B | IDH3B
Isocitrate dehydrogenase subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene.
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the beta subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene.
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G. The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points. Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types. Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme’s allosteric regulation by ADP and NAD. Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits. Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding. Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction. Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.
## Isoforms
The IDH3B gene contains 12 exons and encodes two alternatively spliced isoforms: IDH3β1 (349 residues) and IDH3β2 (354 residues). These isoforms are tissue-specific and possess optimal pHs matching those of their target tissues. IDH3β1, with an optimal pH of 8.0, is expressed in brain and kidney, whereas IDH3β2, with an optimal pH of 7.6, is expressed in heart and skeletal muscle.
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism. This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2. IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH. This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle. Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.
# Clinical Significance
Homozygous loss-of-function mutations of the IDH3B gene has been linked to retinitis pigmentosa, the neurodegeneration of rods and cones in the retina resulting in blindness.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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} | IDH3B
Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene.[1][2]
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the beta subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008][2]
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[3] The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points.[4][5][6] Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types.[5][6][7][8] Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme’s allosteric regulation by ADP and NAD.[7] Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits.[5][7] Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding.[5] Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction.[6][7] Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.[5][6]
## Isoforms
The IDH3B gene contains 12 exons and encodes two alternatively spliced isoforms: IDH3β1 (349 residues) and IDH3β2 (354 residues).[9][10] These isoforms are tissue-specific and possess optimal pHs matching those of their target tissues. IDH3β1, with an optimal pH of 8.0, is expressed in brain and kidney, whereas IDH3β2, with an optimal pH of 7.6, is expressed in heart and skeletal muscle.[10]
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism.[4][5][6][7][11] This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2.[4][5] IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH.[5][6] This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle.[11][12] Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.[5][6][11]
# Clinical Significance
Homozygous loss-of-function mutations of the IDH3B gene has been linked to retinitis pigmentosa, the neurodegeneration of rods and cones in the retina resulting in blindness.[8][9][13]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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} | https://www.wikidoc.org/index.php/IDH3B | |
7524bd92b9efd8a65ebaec36d3b56344128e3927 | wikidoc | IDH3G | IDH3G
Isocitrate dehydrogenase subunit gamma, mitochondrial is an enzyme that in humans is encoded by the IDH3G gene.
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined.
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G. The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points. Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types. Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme's allosteric regulation by ADP and NAD. Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits. Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding. Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction. Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism. This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2. IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH. This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle. Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.
# Clinical Significance
The IDH3G gene may be involved in drug resistance in gastric cancer.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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} | IDH3G
Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial is an enzyme that in humans is encoded by the IDH3G gene.[1][2]
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008][2]
# Structure
IDH3 is one of three isocitrate dehydrogenase isozymes, the other two being IDH1 and IDH2, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[3] The genes IDH3A, IDH3B, and IDH3G encode subunits of IDH3, which is a heterotetramer composed of two 37-kDa α subunits (IDH3α), one 39-kDa β subunit (IDH3β), and one 39-kDa γ subunit (IDH3γ), each with distinct isoelectric points.[4][5][6] Alignment of their amino acid sequences reveals ~40% identity between IDH3α and IDH3β, ~42% identity between IDH3α and IDH3γ, and an even closer identity of 53% between IDH3β and IDH3γ, for an overall 34% identity and 23% similarity across all three subunit types.[5][6][7][8] Notably, Arg88 in IDH3α is essential for IDH3 catalytic activity, whereas the equivalent Arg99 in IDH3β and Arg97 in IDH3γ are largely involved in the enzyme's allosteric regulation by ADP and NAD.[7] Thus, it is possible that these subunits arose from gene duplication of a common ancestral gene, and the original catalytic Arg residue were adapted to allosteric functions in the β- and γ-subunits.[5][7] Likewise, Asp181 in IDH3α is essential for catalysis, while the equivalent Asp192 in IDH3β and Asp190 in IDH3γ enhance NAD- and Mn2+-binding.[5] Since the oxidative decarboxylation catalyzed by IDH3 requires binding of NAD, Mn2+, and the substrate isocitrate, all three subunits participate in the catalytic reaction.[6][7] Moreover, studies of the enzyme in pig heart reveal that the αβ and αγ dimers constitute two binding sites for each of its ligands, including isocitrate, Mn2+, and NAD, in one IDH3 tetramer.[5][6]
# Function
As an isocitrate dehydrogenase, IDH3 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) and CO2 as part of the TCA cycle in glucose metabolism.[4][5][6][7][9] This step also allows for the concomitant reduction of NAD+ to NADH, which is then used to generate ATP through the electron transport chain. Notably, IDH3 relies on NAD+ as its electron acceptor, as opposed to NADP+ like IDH1 and IDH2.[4][5] IDH3 activity is regulated by the energy needs of the cell: when the cell requires energy, IDH3 is activated by ADP; and when energy is no longer required, IDH3 is inhibited by ATP and NADH.[5][6] This allosteric regulation allows IDH3 to function as a rate-limiting step in the TCA cycle.[9][10] Within cells, IDH3 and its subunits have been observed to localize to the mitochondria.[5][6][9]
# Clinical Significance
The IDH3G gene may be involved in drug resistance in gastric cancer.[11]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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} | https://www.wikidoc.org/index.php/IDH3G | |
7eb00e537511e548b7646a371044b54eb9ca2bca | wikidoc | IFFO1 | IFFO1
Intermediate filament family orphan 1 is a protein that in humans is encoded by the IFFO1 gene. IFFO1 has uncharacterized function and a weight of 61.98 kDa. IFFO1 proteins play an important role in the cytoskeleton and the nuclear envelope of most eukaryotic cell types.
# Gene
IFFO in human is located on the minus strand at Chromosome 12p13.3. The protein contains 17,709 nucleotide bases that encodes for 570 amino acids. The basal isoelectric point is 4.83. IFFO1 contains a highly conserved filament domain that spans 299 amino acids from amino residue 230 to 529. This region has been identified as pfam00038 conserved protein domain family. Due to alternative splicing, there are 7 isoforms of IFFO1 in humans with 10 typical coding exons.
## Aliases
IFFO1 is also called Intermediate Filament Family Orphan Isoform X1, Intermediate Filament Family Orphan, HOM-TES-103, Intermediate Filament-Like MGC: 2625, and Tumor Antigen HOM-TES-10.
# Homology
## Orthologs
The gene is found to be highly conserved. The most distant orthologs are found in fish and sharks (cartilaginous fishes) such as Callorhinchus milii. Very low percentages of sequence coverage and identity of the gene's orthologs in fungi and invertebrates suggest that the gene was lost in those organisms. Therefore, it is highly probable that IFFO1 originated in vertebrates.
## Paralogs
One paralog named IFFO2 has been found in humans. The paralog is found to have 99% similarity and 99% coverage when compared to IFFO1. The paralogous sequence is highly conserved, all the way back to fish and amphibians.
## Evolution
Multiple sequence alignments indicated that the Proline-Rich region from amino residues 39 to 61 near the 5' end of the sequence is highly conserved in both close and distant orthologs. In addition, the filament region near the 3' end of the sequence is also highly conserved. Of the 42 conserved amino acid residues found within the IFFO1 sequence, 33 of them are found in the filament region.
When compared to fibrinogen and Cytochrome C (CYCS), IFFO1 is evolving at a moderate rate. The evolutionary history of fibrinogen demonstrates that it is a fast evolving gene, while cytochrome C has been found to be a slow evolving gene. With the most distant ortholog found to be in the Australian ghostshark, IFFO1 gene duplication took place in fish, which diverged from humans 462.5 million years ago.
# Protein
## Structure
The predicted secondary structure of the protein consists mostly of alpha helices (47.19%) and random coils (44.74%). The building block of intermediate filaments are elongated coiled-coil dimer consisting of four consecutive alpha-helical segments.
Structurally, it is most similar to 1GK4, which is chain A of the human vimentin coil 2b fragment (Cys2). Vimentin is a class-II intermediate filament that is found in various non-epithelial cells, especially mesenchymal cells. The vimentin protein is also responsible for maintaining cell shape, integrity of the cytoplasm, and stabilizing cytoskeletal interactions. Its 1A subunit, most similar to IFFO1 protein, forms a single, amphipatic alpha-helix that's compatible with a coiled-coil geometry. It is speculated that this chain is involved in specific dimer-dimer interactions during intermediate filament assembly. A "YRKLLEGEE" domain on the C-terminus is found to be important for the formation of authentic tetrameric complexes and also for the control of filament width during assembly.
## Expression
Based on experimental data on normal tissues in the human body, IFFO1 gene is highly expressed in the cerebellum, cerebral cortex, and especially in the spleen. Medium expression is seen in several areas such as the adrenal gland, colon, lymph nodes, thymus, and ovary. The tissue areas that had the relatively low expression includes CD4 and CD8 T-cells, epidymal cells, the heart, and the stomach. Extremely low levels of expression were observed in tissues obtained from fetus, kidney, testis, thyroid, and especially in the salivary gland. However, the gene has been found to be highly expressed in chondrosarcoma. Chondrosarcoma is the cancer of the cells that generate collagen. Therefore, there seems to be an association between IFFO1's filamentous characteristic and chondrosarcoma.
## Post-translational modifications
One nuclear export signal is predicted to be located at Leucine 141. The IFFO1 protein is predicted to have one 11-amino acid long nuclear localization signal at 373. Based on evidence, the protein is predicted to have high nuclear discrimination. One negative charge acidic cluster was found from amino residue 435 to 447. One repetitive sequence PAPLSPAGP appears twice at 40 to 48 and then again from 159 to 166. This proline-rich region is found to be highly conserved. One long amino acid multiplets of 5 prolines is found at 549.
4 ubiquitination sites are found on Four different Lysine residues. They can be found at Lys78, Lys103, Lys113, Lys339. Experimentally, there was evidence of 43 phosphorylation sites located on 31 serines, 7 threonines, and 5 tyrosines. Furthermore, the evidence has shown with high confidence that Ser533 is a phosphorylation site specifically for protein kinase C. The phosphorylation site at Ser162 also acts as a )-glycosylated site. This type of glycosylation functions to have proteins fold properly, stabilizes the protein, and plays a role in cell-cell adhesion. 4 sumolyated amino acids were found at Leu249, Leu293, Leu298, and Leu325. Sumolation have several effects including interfering with the interaction between the protein’s target and its partner or provide a binding site for an interacting partner, causing conformational changes of the modified target, and facilitating or antagonizing ubiquitinization. 5 glycation sites were predicted to be at Lys78, Lys256, Lys305, Lys380, and Lys478. End productions of glycation are involved in protein conformation changes, loss of function, and irreversible crosslinking.
## Interactions
Evidence from two-hybrid screening exists for four protein interactions with IFFO1.
- ACAP1 (ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 1): GTPase-activating proteins for ADP ribosylation factor 6 needed for clathrin-dependent export of proteins from recycling endosome to the trans-golgi network and the cell surface
- RNF183 (Ring Finger Protein 183): ring finger binding protein of zinc finger that may be involved in the ubiquitination pathways
- GFI1B (Growth Factor-Independent 1B): transcription factor that plays an important role in the development and differentiation of erythroid and megakaryocytic lineages
- XRCC4: work with DNA ligase IV and DNA-dependent protein kinase in DNA repair of double-stranded breaks by non-homologous end joining
Another protein interaction with ubiquitin C was found from affinity capture-MS assay.
# Clinical relevance
The IFFO1 gene has not been found to be associated with any particular diseases. | IFFO1
Intermediate filament family orphan 1 is a protein that in humans is encoded by the IFFO1 gene. IFFO1 has uncharacterized function and a weight of 61.98 kDa.[1] IFFO1 proteins play an important role in the cytoskeleton and the nuclear envelope of most eukaryotic cell types.[2]
# Gene
IFFO in human is located on the minus strand at Chromosome 12p13.3. The protein contains 17,709 nucleotide bases that encodes for 570 amino acids. The basal isoelectric point is 4.83.[3] IFFO1 contains a highly conserved filament domain that spans 299 amino acids from amino residue 230 to 529.[4] This region has been identified as pfam00038 conserved protein domain family.[5] Due to alternative splicing, there are 7 isoforms of IFFO1 in humans with 10 typical coding exons.
## Aliases
IFFO1 is also called Intermediate Filament Family Orphan Isoform X1, Intermediate Filament Family Orphan, HOM-TES-103, Intermediate Filament-Like MGC: 2625, and Tumor Antigen HOM-TES-10.[6]
# Homology
## Orthologs
The gene is found to be highly conserved. The most distant orthologs are found in fish and sharks (cartilaginous fishes) such as Callorhinchus milii.[7] Very low percentages of sequence coverage and identity of the gene's orthologs in fungi and invertebrates suggest that the gene was lost in those organisms.[8] Therefore, it is highly probable that IFFO1 originated in vertebrates.
## Paralogs
One paralog named IFFO2 has been found in humans. The paralog is found to have 99% similarity and 99% coverage when compared to IFFO1. The paralogous sequence is highly conserved, all the way back to fish and amphibians.
## Evolution
Multiple sequence alignments indicated that the Proline-Rich region from amino residues 39 to 61 near the 5' end of the sequence is highly conserved in both close and distant orthologs.[9] In addition, the filament region near the 3' end of the sequence is also highly conserved. Of the 42 conserved amino acid residues found within the IFFO1 sequence, 33 of them are found in the filament region.
When compared to fibrinogen and Cytochrome C (CYCS), IFFO1 is evolving at a moderate rate. The evolutionary history of fibrinogen demonstrates that it is a fast evolving gene, while cytochrome C has been found to be a slow evolving gene. With the most distant ortholog found to be in the Australian ghostshark, IFFO1 gene duplication took place in fish, which diverged from humans 462.5 million years ago.[10]
# Protein
## Structure
The predicted secondary structure of the protein consists mostly of alpha helices (47.19%) and random coils (44.74%). The building block of intermediate filaments are elongated coiled-coil dimer consisting of four consecutive alpha-helical segments.[11]
Structurally, it is most similar to 1GK4, which is chain A of the human vimentin coil 2b fragment (Cys2).[12] Vimentin is a class-II intermediate filament that is found in various non-epithelial cells, especially mesenchymal cells.[13] The vimentin protein is also responsible for maintaining cell shape, integrity of the cytoplasm, and stabilizing cytoskeletal interactions.[14] Its 1A subunit, most similar to IFFO1 protein, forms a single, amphipatic alpha-helix that's compatible with a coiled-coil geometry. It is speculated that this chain is involved in specific dimer-dimer interactions during intermediate filament assembly. A "YRKLLEGEE" domain on the C-terminus is found to be important for the formation of authentic tetrameric complexes and also for the control of filament width during assembly.[15]
## Expression
Based on experimental data on normal tissues in the human body, IFFO1 gene is highly expressed in the cerebellum, cerebral cortex, and especially in the spleen. Medium expression is seen in several areas such as the adrenal gland, colon, lymph nodes, thymus, and ovary. The tissue areas that had the relatively low expression includes CD4 and CD8 T-cells, epidymal cells, the heart, and the stomach. Extremely low levels of expression were observed in tissues obtained from fetus, kidney, testis, thyroid, and especially in the salivary gland. However, the gene has been found to be highly expressed in chondrosarcoma.[16] Chondrosarcoma is the cancer of the cells that generate collagen. Therefore, there seems to be an association between IFFO1's filamentous characteristic and chondrosarcoma.
## Post-translational modifications
One nuclear export signal is predicted to be located at Leucine 141.[17] The IFFO1 protein is predicted to have one 11-amino acid long nuclear localization signal at 373.[18] Based on evidence, the protein is predicted to have high nuclear discrimination.[19] One negative charge acidic cluster was found from amino residue 435 to 447. One repetitive sequence PAPLSPAGP appears twice at 40 to 48 and then again from 159 to 166. This proline-rich region is found to be highly conserved. One long amino acid multiplets of 5 prolines is found at 549.
4 ubiquitination sites are found on Four different Lysine residues. They can be found at Lys78, Lys103, Lys113, Lys339.[20] Experimentally, there was evidence of 43 phosphorylation sites located on 31 serines, 7 threonines, and 5 tyrosines.[21] Furthermore, the evidence has shown with high confidence that Ser533 is a phosphorylation site specifically for protein kinase C. The phosphorylation site at Ser162 also acts as a )-glycosylated site. This type of glycosylation functions to have proteins fold properly, stabilizes the protein, and plays a role in cell-cell adhesion.[22] 4 sumolyated amino acids were found at Leu249, Leu293, Leu298, and Leu325.[23] Sumolation have several effects including interfering with the interaction between the protein’s target and its partner or provide a binding site for an interacting partner, causing conformational changes of the modified target, and facilitating or antagonizing ubiquitinization.[24] 5 glycation sites were predicted to be at Lys78, Lys256, Lys305, Lys380, and Lys478. End productions of glycation are involved in protein conformation changes, loss of function, and irreversible crosslinking.[25]
## Interactions
Evidence from two-hybrid screening exists for four protein interactions with IFFO1.[26]
- ACAP1 (ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 1):[27] GTPase-activating proteins for ADP ribosylation factor 6 needed for clathrin-dependent export of proteins from recycling endosome to the trans-golgi network and the cell surface [28]
- RNF183 (Ring Finger Protein 183):[29] ring finger binding protein of zinc finger that may be involved in the ubiquitination pathways
- GFI1B (Growth Factor-Independent 1B):[30] transcription factor that plays an important role in the development and differentiation of erythroid and megakaryocytic lineages[31]
- XRCC4:[32] work with DNA ligase IV and DNA-dependent protein kinase in DNA repair of double-stranded breaks by non-homologous end joining
Another protein interaction with ubiquitin C was found from affinity capture-MS assay.[33]
# Clinical relevance
The IFFO1 gene has not been found to be associated with any particular diseases. | https://www.wikidoc.org/index.php/IFFO1 | |
0984cc0b0837717cff5f710ef2050f6c041a2015 | wikidoc | IFNA2 | IFNA2
Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.
# Protein family
Human interferon alpha-2 (IFNα2) is a cytokine belonging to the family of type I IFNs. IFNα2 is a protein secreted by cells infected by a virus and acting on other cells to inhibit viral infection. The first description of IFNs as a cellular agent interfering with viral replication was made by Alick Isaacs and Jean Lindenmann in 1957. The history of this finding was recently reviewed. There are 3 types of IFNs: Interferon type I, Interferon type II and Interferon type III. The type II IFN, also called IFNγ, is produced by specific cells of the immune system. Unlike type I and type III IFNs, IFNγ has only a modest role in directly restricting viral infections. Type I and type III IFNs act similarly. However, the action of type III IFNs, also known as IFNλ, is limited to epithelial cells while type I IFNs act on all body's cells.
Type I IFNs form a family of several proteins: in humans, there are 13 α subtypes, 1 β subtype, 1 ω subtype and other less studied subtypes (κ and ε). IFNα2 was the first subtype to be characterized in the early eighties. As a result, IFNα2 was widely used in basic research to elucidate biological activities, structure and mechanism of action of type I IFNs. IFNα2 was also the first IFN to be produced by the pharmaceutical industry for use as a drug. Thereby, IFNα2 is the best known type I IFN subtype. The properties of IFNα2 are widely shared by the other type I IFNs, although subtle differences exist.
# Gene and protein
The gene encoding IFNα2, the IFNA2 gene, is clustered with all other type I IFN genes on chromosome 9 and as all type I IFN genes, it is devoid of intron. The open reading frame (coding sequence) of IFNA2 codes for a pre-protein of 188 amino acids with a 23 amino acid signal peptide allowing secretion of the mature protein. The mature protein is made of 165 amino acids, one less than the other human IFNα subtypes. The secondary structure of IFNα2 consists of five α-helices: A to E, from the N-terminal to the C-terminal end. Helices A, B, C and E are organized as a bundle with a long loop between the helices A and B (the A-B loop) and two disulfide bonds which connect helix E to the A-B loop and helix C to the N-terminal end. Several variants, or allelic variants, have been identified in the human population. Among them, IFNα2a and IFNα2b are better known by their commercial name, Roferon-A® and Intron A®, respectively.
Upstream of the coding sequence is the promoter region that contains sequences that regulate the transcription of the IFNA2 gene into a messenger RNA (mRNA).
# Synthesis
When a cell is infected by a virus, some components of the virus, mainly viral nucleic acids, are recognized by specialized cellular molecules such as RIG-I, MDA5 and some toll-like receptors (TLR). This recognition induces the activation of specific serine kinases, enzymes which activate by phosphorylation the IFN regulatory factors (IRF), IRF3 and IRF7. IRF3 and IRF7 are themselves transcription factors that translocate into the nucleus and activate the transcription of type I IFNs genes and thereby initiate the process leading to the secretion of IFN by the infected cells. The "danger" signals carried by viruses were the first IFN inducers described but it is now known that non-viral "danger" signals, such as some types of dead cells, can stimulate the synthesis of type I IFNs.
# Mechanism of action
Induced IFNα2 is secreted by the infected cells and acts locally as well as systemically on cells expressing a specific cell surface receptor able to bind type I IFNs. The type I IFN receptor (IFNAR) is composed of two subunits, IFNAR 1 and IFNAR 2, which are expressed by all body’s cells. After binding to its receptor, type I IFNs activate multiple cellular factors that transduce the signal from the cell surface into the nucleus. The main signaling pathway activated by type I IFNs consists of a series of events:
- phosphorylation and activation of two enzymes of the Janus kinases or JAK family, TYK2 which is associated with IFNAR1 and JAK1 associated to IFNAR2;
- phosphorylation by the activated JAK kinases of key transcription factors, namely STAT1 and STAT2, members of the family Signal Transducer and Activator of Transcription (STAT protein);
- phosphorylated STAT1 and STAT2 bind IRF9 forming a complex named "IFN-Stimulated Gene Factor 3" (ISGF3). This complex translocates in the nucleus and initiates the transcription of the IFN-stimulated genes (ISGs).
ISGs encode proteins that modulate cellular functions. Following viral infection, many ISGs lead to the inhibition of the viral spread. Several ISGs inhibit viral replication in the infected cells. Other ISGs protect neighbouring uninfected cells from being infected by inhibiting viral entry. Several hundreds of ISGs are known to be activated by type I IFNs and are listed in a searchable database named interferome (/).
# Function
The broad spectrum of ISGs explains the wide range of biological activity of type I IFNs. In addition to their antiviral activity, type I IFNs also inhibit the proliferation of cells and regulate the activation of the immune system.
Type I IFNs exert potent antitumor activity by several mechanisms such as:
- inhibition of the proliferation of cancer cells
- activation of the immune system which can eliminate tumor cells
- increasing the antitumor activity of other antitumoral agents (radiotherapy, chemotherapy, targeted therapies)
Type I IFNs can have detrimental effects during viral and non-viral infections (bacterial, parasitic, fungal). This is due in part by the ability of type I IFNs to polarize the immune system towards a specific type of response in order to interfere with virus infections.
When improperly regulated, IFN production or IFN-induced signalling can result in autoimmune diseases, such as systemic lupus erythematosus.
# Clinical significance
If given orally, IFNα2 is degraded by digestive enzymes and is no longer active. Thus, IFNα2 is mainly administrated by injection essentially subcutaneous or intramuscular. Once in the blood, IFNα2 is rapidly eliminated by the kidney. Due to the short life of IFNα2 in the organism, several injections per week are required. Peginterferon alpha-2a and Peginterferon alpha-2b (polyethylene glycol linked to IFNα2) are long-lasting IFNα2 formulations, which enable a single injection per week.
Recombinant IFNα2 (α2a and α2b) has demonstrated efficiency in the treatment of patients diagnosed with some viral infections (such as chronic viral hepatitis B and hepatitis C) or some kinds of cancer (melanoma, renal cell carcinoma and various hematological malignancies). Yet, patients on therapy with IFNα2 suffer from adverse effects which often require to reduce or even stop the treatment. These adverse effects include flu-like symptoms such as chills, fever, joint and muscle pain, depression with suicidal ideation, and a reduction in the number of blood cells. Thereby, IFNα2 has been progressively replaced by better tolerated drugs, such as antiviral agents or targeted antitumor therapies. Chronic viral hepatitis C is the main indication for which IFNα2 remains widely used. Nevertheless, there is increasing evidence that endogenous type I IFNs plays a role in the induction of an immune antiviral response and that they can enhance the antitumor activity of chemotherapies, radiotherapies and some targeted therapies. Therefore, an important future goal for scientists is to modify IFNα2 in order to obtain an active molecule to be used in the clinic that does not exert adverse effects. | IFNA2
Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.[1]
# Protein family
Human interferon alpha-2 (IFNα2) is a cytokine belonging to the family of type I IFNs. IFNα2 is a protein secreted by cells infected by a virus and acting on other cells to inhibit viral infection. The first description of IFNs as a cellular agent interfering with viral replication was made by Alick Isaacs and Jean Lindenmann in 1957. The history of this finding was recently reviewed.[2] There are 3 types of IFNs: Interferon type I, Interferon type II and Interferon type III. The type II IFN, also called IFNγ, is produced by specific cells of the immune system. Unlike type I and type III IFNs, IFNγ has only a modest role in directly restricting viral infections. Type I and type III IFNs act similarly. However, the action of type III IFNs, also known as IFNλ, is limited to epithelial cells while type I IFNs act on all body's cells.
Type I IFNs form a family of several proteins: in humans, there are 13 α subtypes, 1 β subtype, 1 ω subtype and other less studied subtypes (κ and ε).[3] IFNα2 was the first subtype to be characterized in the early eighties. As a result, IFNα2 was widely used in basic research to elucidate biological activities, structure and mechanism of action of type I IFNs. IFNα2 was also the first IFN to be produced by the pharmaceutical industry for use as a drug. Thereby, IFNα2 is the best known type I IFN subtype. The properties of IFNα2 are widely shared by the other type I IFNs, although subtle differences exist.
# Gene and protein
The gene encoding IFNα2, the IFNA2 gene, is clustered with all other type I IFN genes on chromosome 9 [4] and as all type I IFN genes, it is devoid of intron.[5] The open reading frame (coding sequence) of IFNA2 codes for a pre-protein of 188 amino acids with a 23 amino acid signal peptide allowing secretion of the mature protein. The mature protein is made of 165 amino acids, one less than the other human IFNα subtypes. The secondary structure of IFNα2 consists of five α-helices: A to E, from the N-terminal to the C-terminal end. Helices A, B, C and E are organized as a bundle with a long loop between the helices A and B (the A-B loop) and two disulfide bonds which connect helix E to the A-B loop and helix C to the N-terminal end.[6][7] Several variants, or allelic variants, have been identified in the human population.[8] Among them, IFNα2a and IFNα2b are better known by their commercial name, Roferon-A® and Intron A®, respectively.
Upstream of the coding sequence is the promoter region that contains sequences that regulate the transcription of the IFNA2 gene into a messenger RNA (mRNA).[9][10]
# Synthesis
When a cell is infected by a virus, some components of the virus, mainly viral nucleic acids, are recognized by specialized cellular molecules such as RIG-I, MDA5 and some toll-like receptors (TLR).[11] This recognition induces the activation of specific serine kinases, enzymes which activate by phosphorylation the IFN regulatory factors (IRF), IRF3 and IRF7. IRF3 and IRF7 are themselves transcription factors that translocate into the nucleus and activate the transcription of type I IFNs genes and thereby initiate the process leading to the secretion of IFN by the infected cells. The "danger" signals carried by viruses were the first IFN inducers described but it is now known that non-viral "danger" signals, such as some types of dead cells, can stimulate the synthesis of type I IFNs.
# Mechanism of action
Induced IFNα2 is secreted by the infected cells and acts locally as well as systemically on cells expressing a specific cell surface receptor able to bind type I IFNs. The type I IFN receptor (IFNAR) is composed of two subunits, IFNAR 1 and IFNAR 2, which are expressed by all body’s cells. After binding to its receptor,[12] type I IFNs activate multiple cellular factors that transduce the signal from the cell surface into the nucleus.[13] The main signaling pathway activated by type I IFNs consists of a series of events:[14]
- phosphorylation and activation of two enzymes of the Janus kinases or JAK family, TYK2 which is associated with IFNAR1 and JAK1 associated to IFNAR2;
- phosphorylation by the activated JAK kinases of key transcription factors, namely STAT1 and STAT2, members of the family Signal Transducer and Activator of Transcription (STAT protein);
- phosphorylated STAT1 and STAT2 bind IRF9 forming a complex named "IFN-Stimulated Gene Factor 3" (ISGF3). This complex translocates in the nucleus and initiates the transcription of the IFN-stimulated genes (ISGs).
ISGs encode proteins that modulate cellular functions. Following viral infection, many ISGs lead to the inhibition of the viral spread.[11] Several ISGs inhibit viral replication in the infected cells. Other ISGs protect neighbouring uninfected cells from being infected by inhibiting viral entry. Several hundreds of ISGs are known to be activated by type I IFNs [15] and are listed in a searchable database named interferome (http://www.interferome.org/).
# Function
The broad spectrum of ISGs explains the wide range of biological activity of type I IFNs.[11][16][17][18][19] In addition to their antiviral activity, type I IFNs also inhibit the proliferation of cells and regulate the activation of the immune system.
Type I IFNs exert potent antitumor activity by several mechanisms such as:
- inhibition of the proliferation of cancer cells
- activation of the immune system which can eliminate tumor cells [20][21]
- increasing the antitumor activity of other antitumoral agents (radiotherapy, chemotherapy, targeted therapies) [22][23][24]
Type I IFNs can have detrimental effects during viral and non-viral infections (bacterial, parasitic, fungal). This is due in part by the ability of type I IFNs to polarize the immune system towards a specific type of response in order to interfere with virus infections.
When improperly regulated, IFN production or IFN-induced signalling can result in autoimmune diseases, such as systemic lupus erythematosus.[25]
# Clinical significance
If given orally, IFNα2 is degraded by digestive enzymes and is no longer active. Thus, IFNα2 is mainly administrated by injection essentially subcutaneous or intramuscular. Once in the blood, IFNα2 is rapidly eliminated by the kidney. Due to the short life of IFNα2 in the organism, several injections per week are required. Peginterferon alpha-2a and Peginterferon alpha-2b (polyethylene glycol linked to IFNα2) are long-lasting IFNα2 formulations, which enable a single injection per week.
Recombinant IFNα2 (α2a and α2b) has demonstrated efficiency in the treatment of patients diagnosed with some viral infections (such as chronic viral hepatitis B and hepatitis C) or some kinds of cancer (melanoma, renal cell carcinoma and various hematological malignancies).[26] Yet, patients on therapy with IFNα2 suffer from adverse effects which often require to reduce or even stop the treatment.[27] These adverse effects include flu-like symptoms such as chills, fever, joint and muscle pain, depression with suicidal ideation, and a reduction in the number of blood cells. Thereby, IFNα2 has been progressively replaced by better tolerated drugs, such as antiviral agents or targeted antitumor therapies. Chronic viral hepatitis C is the main indication for which IFNα2 remains widely used.[26] Nevertheless, there is increasing evidence that endogenous type I IFNs plays a role in the induction of an immune antiviral response and that they can enhance the antitumor activity of chemotherapies, radiotherapies and some targeted therapies.[22][23][24] Therefore, an important future goal for scientists is to modify IFNα2 in order to obtain an active molecule to be used in the clinic that does not exert adverse effects.[28] | https://www.wikidoc.org/index.php/IFNA2 | |
52d778a99328c0945095dacc21f559cb4fc9a667 | wikidoc | IFRD1 | IFRD1
Interferon-related developmental regulator 1 is a protein that in humans is encoded by the IFRD1 gene. The gene is expressed mostly in neutrophils, skeletal and cardiac muscle, brain, pancreas.
The rat and the mouse homolog genes of interferon-related developmental regulator 1 gene (and their proteins) are also known with the name PC4 and Tis21, respectively.
IFRD1 is member of a gene family that comprises a second gene, IFRD2, also known as SKmc15.
# Clinical significance
IFRD1 has been identified as a modifier gene for cystic fibrosis lung disease. In humans, neutrophil effector function is dependent on the type of IRFD1 polymorphism present in the individual. Human and mouse data both indicate that IFRD1 has a sizable impact on cystic fibrosis pathogenesis by regulating neutrophil effector function.
# Inducer of muscle regeneration
IFRD1(also known as PC4 or Tis7, see above) participates to the process of skeletal muscle cell differentiation. In fact, inhibition of IFRD1 function in C2C12 myoblasts, by antisense IFRD1 cDNA transfection or microinjection of anti-IFRD1 antibodies, prevents their morphological and biochemical differentiation by inhibiting the expression of MyoD and myogenin, key master genes of muscle development. A role for IFRD1 in muscle differentiation has been observed also in vivo. Muscles from mice lacking IFRD1 display decreased protein and mRNA levels of MyoD, and myogenin, and after muscle crash damage in young mice there was a delay in regeneration.
Recently it has been shown that upregulation of IFRD1 in vivo in injured muscle potentiates muscle regeneration by increasing the production of staminal muscle cells (satellite cells). The underlying molecular mechanism lies in the ability of IFRD1 to cooperate with MyoD at inducing the transcriptional activity of MEF2C. This relies on the ability of IFRD1 to bind selectively MEF2C, thus inhibiting its interaction with HDAC4. Therefore, IFRD1 appears to act as a positive cofactor of MyoD. More recently it has been shown that IFRD1 potentiates muscle regeneration by a second mechanism that potentiates MyoD, i.e., by repressing the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation. IFRD1 represses the activity of NF-κB p65 by enhancing the HDAC-mediated deacetylation of the p65 subunit, by favoring the recruitment of HDAC3 to p65. In fact IFRD1 forms trimolecular complexes with p65 and HDAC3.
Thus, IFRD1 can induce muscle regeneration acting as a pivotal regulator of the MyoD pathway through multiple mechanisms.
Given the dramatic decrease of myogenic cells occurring in muscle degenerative pathologies such as Duchenne dystrophy, the ability of IFRD1 to potentiate the regenerative process suggests that IFRD1 might be a therapeutic target.
# Interactions
IFRD1 has been shown to interact with several proteins in the SIN3 complex including SIN3B, SAP30, NCOR1, and HDAC1. Moreover, IFRD1 protein binds MyoD, MEF2C, HDAC4, HDAC3 and the p65 subunit of NF-κB, forming trimolecular complexes with HDAC3 and p65 NF-κB proteins. IFRD1 protein also forms homodimers. | IFRD1
Interferon-related developmental regulator 1 is a protein that in humans is encoded by the IFRD1 gene.[1][2] The gene is expressed mostly in neutrophils, skeletal and cardiac muscle, brain, pancreas.[1][2]
The rat and the mouse homolog genes of interferon-related developmental regulator 1 gene (and their proteins) are also known with the name PC4 [3] and Tis21, respectively.
IFRD1 is member of a gene family that comprises a second gene, IFRD2, also known as SKmc15.[1][2]
# Clinical significance
IFRD1 has been identified as a modifier gene for cystic fibrosis lung disease. In humans, neutrophil effector function is dependent on the type of IRFD1 polymorphism present in the individual. Human and mouse data both indicate that IFRD1 has a sizable impact on cystic fibrosis pathogenesis by regulating neutrophil effector function. [4]
# Inducer of muscle regeneration
IFRD1(also known as PC4 or Tis7, see above) participates to the process of skeletal muscle cell differentiation. In fact, inhibition of IFRD1 function in C2C12 myoblasts, by antisense IFRD1 cDNA transfection or microinjection of anti-IFRD1 antibodies, prevents their morphological and biochemical differentiation by inhibiting the expression of MyoD and myogenin, key master genes of muscle development.[5] A role for IFRD1 in muscle differentiation has been observed also in vivo. Muscles from mice lacking IFRD1 display decreased protein and mRNA levels of MyoD, and myogenin, and after muscle crash damage in young mice there was a delay in regeneration.[6]
Recently it has been shown that upregulation of IFRD1 in vivo in injured muscle potentiates muscle regeneration by increasing the production of staminal muscle cells (satellite cells).[7] The underlying molecular mechanism lies in the ability of IFRD1 to cooperate with MyoD at inducing the transcriptional activity of MEF2C. This relies on the ability of IFRD1 to bind selectively MEF2C, thus inhibiting its interaction with HDAC4.[7][8] Therefore, IFRD1 appears to act as a positive cofactor of MyoD.[7][8] More recently it has been shown that IFRD1 potentiates muscle regeneration by a second mechanism that potentiates MyoD, i.e., by repressing the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation. IFRD1 represses the activity of NF-κB p65 by enhancing the HDAC-mediated deacetylation of the p65 subunit, by favoring the recruitment of HDAC3 to p65. In fact IFRD1 forms trimolecular complexes with p65 and HDAC3.[7]
Thus, IFRD1 can induce muscle regeneration acting as a pivotal regulator of the MyoD pathway through multiple mechanisms.
Given the dramatic decrease of myogenic cells occurring in muscle degenerative pathologies such as Duchenne dystrophy, the ability of IFRD1 to potentiate the regenerative process suggests that IFRD1 might be a therapeutic target.
# Interactions
IFRD1 has been shown to interact with several proteins in the SIN3 complex including SIN3B, SAP30, NCOR1, and HDAC1.[9] Moreover, IFRD1 protein binds MyoD, MEF2C, HDAC4, HDAC3 and the p65 subunit of NF-κB, forming trimolecular complexes with HDAC3 and p65 NF-κB proteins.[7][8] IFRD1 protein also forms homodimers.[8] | https://www.wikidoc.org/index.php/IFRD1 | |
2b833bbfdc7d8bfd663a650c316f5914a992ac66 | wikidoc | IFT20 | IFT20
Intraflagellar transport protein 20 homolog is a protein that in humans is encoded by the IFT20 gene. The gene is composed of 6 exons and is
located on human chromosome 17p11.1. This gene is expressed in human brain, lung, kidney and pancreas, and lower expression were also detected in human placenta, liver, thymus, prostate and testis.
Intraflagellar transport (IFT), in which molecular motors and IFT particle proteins participate, is very important in assembling and maintaining many cilia/flagella, such as the motile cilia that drive the swimming of cells and embryos, the nodal cilia that generate left-right asymmetry in vertebrate embryos, and the sensory cilia that detect sensory stimuli in some animals. IFT20 subunit of the particle is localized to the Golgi complex in addition to the basal body and cilia where all previous IFT particle proteins had been found. In living cells, fluorescently tagged IFT20 is highly dynamic and moves between the Golgi complex and the cilium as well as along ciliary microtubules. IFT20 has been shown to interact with SPEF2 in the testis, and plays a role in sperm motility. | IFT20
Intraflagellar transport protein 20 homolog is a protein that in humans is encoded by the IFT20 gene.[1] The gene is composed of 6 exons and is
located on human chromosome 17p11.1. This gene is expressed in human brain, lung, kidney and pancreas, and lower expression were also detected in human placenta, liver, thymus, prostate and testis.[2]
Intraflagellar transport (IFT), in which molecular motors and IFT particle proteins participate, is very important in assembling and maintaining many cilia/flagella, such as the motile cilia that drive the swimming of cells and embryos, the nodal cilia that generate left-right asymmetry in vertebrate embryos, and the sensory cilia that detect sensory stimuli in some animals.[2] IFT20 subunit of the particle is localized to the Golgi complex in addition to the basal body and cilia where all previous IFT particle proteins had been found. In living cells, fluorescently tagged IFT20 is highly dynamic and moves between the Golgi complex and the cilium as well as along ciliary microtubules.[3] IFT20 has been shown to interact with SPEF2 in the testis, and plays a role in sperm motility.[4] | https://www.wikidoc.org/index.php/IFT20 | |
2dd5b5e75e6cd53374e8a28840849c199eff8eaf | wikidoc | IFT80 | IFT80
Intraflagellar transport protein 80 homolog (IFT80), also known as WD repeat-containing protein 56, is a protein that in humans is encoded by the IFT80 gene.
# Function
IFT80 is part of the intraflagellar transport complex B and is necessary for the function of motile and sensory cilia.
# Clinical significance
Mutations in the IFT80 gene are associated with asphyxiating thoracic dysplasia. | IFT80
Intraflagellar transport protein 80 homolog (IFT80), also known as WD repeat-containing protein 56, is a protein that in humans is encoded by the IFT80 gene.[1][2]
# Function
IFT80 is part of the intraflagellar transport complex B and is necessary for the function of motile and sensory cilia.[1]
# Clinical significance
Mutations in the IFT80 gene are associated with asphyxiating thoracic dysplasia.[2] | https://www.wikidoc.org/index.php/IFT80 | |
99fc7f68d193e03fc16fd2753af781df43dab399 | wikidoc | IGBP1 | IGBP1
Immunoglobulin-binding protein 1 is a protein that in humans is encoded by the IGBP1 gene.
# Function
The proliferation and differentiation of B cells is dependent upon a B-cell antigen receptor (BCR) complex. Binding of antigens to specific B-cell receptors results in a tyrosine phosphorylation reaction through the BCR complex and leads to multiple signal transduction pathways.
# Interactions
IGBP1 has been shown to interact with PPP4C, PPP6C and PPP2CA. | IGBP1
Immunoglobulin-binding protein 1 is a protein that in humans is encoded by the IGBP1 gene.[1][2]
# Function
The proliferation and differentiation of B cells is dependent upon a B-cell antigen receptor (BCR) complex. Binding of antigens to specific B-cell receptors results in a tyrosine phosphorylation reaction through the BCR complex and leads to multiple signal transduction pathways.[2]
# Interactions
IGBP1 has been shown to interact with PPP4C,[3][4][5] PPP6C[4][5] and PPP2CA.[4][5][6][7] | https://www.wikidoc.org/index.php/IGBP1 | |
f73a0469973dac790ea917c63b97035a0ae3e8c9 | wikidoc | IGSF1 | IGSF1
Immunoglobulin superfamily, member 1 is a plasma membrane glycoprotein encoded by the IGSF1 gene, which maps to the X chromosome in humans and other mammalian species.
# Function
IGSF1's function in normal cells is unresolved. The protein is a member of the immunoglobulin (Ig) superfamily. It was predicted to contain 12 Ig loops, a transmembrane domain, and a short cytoplasmic tail. However, during translation of the protein, it is cleaved into amino- and carboxy-terminal domains (NTD and CTD, respectively). Only the CTD is trafficked to the plasma membrane. The NTD is trapped within the endoplasmic reticulum (ER). Pathogenic mutations in the IGSF1 gene block the transport of the CTD to the plasma membrane.
# Clinical Relevance
Mutations in IGSF1 cause a condition called IGSF1 deficiency syndrome or central hypothyroidism/testicular enlargement (CHTE). The condition, which affects an estimated 1:100,000 people, is more common in males than females. Most affected males are discovered through neonatal screening for hypothyroidism. The extent of hypothyroidism is variable, but most male cases require treatment with thyroid hormone replacement. Males with IGSF1 deficiency exhibit enlarged testicles (also known as macroorchidism) and a delay in the development of secondary sexual characteristics. Post-pubertally, there is no evidence of impaired fertility in these men.
The IGSF1 gene is also active in the brain and in the developing liver. It can also become reactivated in liver cancer (hepatocellular carcinoma).
# Animal Model
Mice lacking a functional Igsf1 gene similarly exhibit hypothyroidism of central origin. The IGSF1 gene is particularly active in the pituitary gland. The pituitary synthesizes and secretes thyroid-stimulating hormone (TSH). TSH, in turn, stimulates production of the thyroid hormones, thyroxine and triiodothyronine, by the thyroid gland. TSH secretion is controlled by thyrotropin-releasing hormone (TRH), which is released by neurons in the hypothalamus of the brain. In Igsf1 deficient mice, the receptor for TRH is downregulated in the pituitary. This decrease could explain, at least in part, the central hypothyroidism observed in both humans and mice with IGSF1 deficiency. How the loss of IGSF1 causes a decrease in TRH receptors is presently unknown. | IGSF1
Immunoglobulin superfamily, member 1[1] is a plasma membrane glycoprotein encoded by the IGSF1 gene,[2][3][4] which maps to the X chromosome in humans and other mammalian species.
# Function
IGSF1's function in normal cells is unresolved. The protein is a member of the immunoglobulin (Ig) superfamily. It was predicted to contain 12 Ig loops, a transmembrane domain, and a short cytoplasmic tail. However, during translation of the protein, it is cleaved into amino- and carboxy-terminal domains (NTD and CTD, respectively).[5] Only the CTD is trafficked to the plasma membrane. The NTD is trapped within the endoplasmic reticulum (ER). Pathogenic mutations in the IGSF1 gene block the transport of the CTD to the plasma membrane.
# Clinical Relevance
Mutations in IGSF1 cause a condition called IGSF1 deficiency syndrome[6] or central hypothyroidism/testicular enlargement (CHTE[7]). The condition, which affects an estimated 1:100,000 people,[8] is more common in males than females. Most affected males are discovered through neonatal screening for hypothyroidism. The extent of hypothyroidism is variable, but most male cases require treatment with thyroid hormone replacement. Males with IGSF1 deficiency exhibit enlarged testicles (also known as macroorchidism) and a delay in the development of secondary sexual characteristics. Post-pubertally, there is no evidence of impaired fertility in these men.
The IGSF1 gene is also active in the brain and in the developing liver. It can also become reactivated in liver cancer (hepatocellular carcinoma).[9]
# Animal Model
Mice lacking a functional Igsf1 gene similarly exhibit hypothyroidism of central origin.[6] The IGSF1 gene is particularly active in the pituitary gland. The pituitary synthesizes and secretes thyroid-stimulating hormone (TSH). TSH, in turn, stimulates production of the thyroid hormones, thyroxine and triiodothyronine, by the thyroid gland. TSH secretion is controlled by thyrotropin-releasing hormone (TRH), which is released by neurons in the hypothalamus of the brain. In Igsf1 deficient mice, the receptor for TRH is downregulated in the pituitary.[6] This decrease could explain, at least in part, the central hypothyroidism observed in both humans and mice with IGSF1 deficiency. How the loss of IGSF1 causes a decrease in TRH receptors is presently unknown. | https://www.wikidoc.org/index.php/IGSF1 | |
3c2adb77a696f753106118996d7bdda9158a9e0f | wikidoc | IKBKE | IKBKE
Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the IKBKE gene.
# Interactions
IKBKE has been shown to interact with TANK.
# Function
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD (TANK-binding kinase 1-binding protein 1) can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (gamma-activation factor) (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, which leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.
# Clinical significance
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer. | IKBKE
Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the IKBKE gene.[1][2][3]
# Interactions
IKBKE has been shown to interact with TANK.[4]
# Function
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD (TANK-binding kinase 1-binding protein 1) can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (gamma-activation factor) (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, which leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.[5]
# Clinical significance
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[6] | https://www.wikidoc.org/index.php/IKBKE | |
c4f4511e5a98dd840b1176a218583c28a594d319 | wikidoc | IKBKG | IKBKG
NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the IKBKG gene. NEMO is a subunit of the IκB kinase complex that activates NF-κB. The human gene for IKBKG is located on chromosome Xq28. Multiple transcript variants encoding different isoforms have been found for this gene.
# Function
NEMO (IKK-γ) is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, which activates NF-κB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways.
# Clinical significance
Mutations in the IKBKG gene results in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies.
Incontinentia Pigmenti (IP) is an X-linked dominant disease caused by a mutation in the IKBKG gene. Since IKBKG helps activate NF-κB, which protects cells against TNF-alpha induced apoptosis, a lack of IKBKG (and hence a lack of active NF-κB) makes cells more prone to apoptosis.
Moreover, NEMO has been shown to play a role in preeclampsia and may offer insights into the genetic etiology of this condition. An increased level of NEMO gene expression was found in the blood of pregnant women with preeclampsia and their children. However, a decrease of the mRNA levels of total NEMO and the transcripts 1A, 1B, and 1C in placentas derived from preeclamptic women may be the main reason for intensified apoptosis. Sanger sequencing has indicated two distinct variations in the 3’ UTR region of the NEMO gene in preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T). The occurrence of a maternal TT genotype and either a TT genotype in the daughter or T allele in the son increases the risk of preeclampsia by 2.59 fold. The configuration of those maternal and fetal genotypes (TT mother/TT daughter or TT mother/T son) is also associated with the level of NEMO gene expression.
NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG. It mostly affects males and has a highly variable set of symptoms and prognoses.
# As a drug target
A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of NF-κB. NBD is a peptide that acts by binding to regulatory subunit NEMO (IKK-γ) thereby preventing it from binding subunits IKK-α and IKK-β and activating the IKK complex. In the absence of regulatory subunit IKK-γ the IKK complex is inactive, preventing the downstream signal transduction cascade leading to NF-κB activation. Binding of IKK-γ to IKK-α and IKK-β subunits activates the IKK complex leading to phosphorylation of IκB kinase, IκBα, and release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive genes. In the presence of the NBD peptide, the IKK complex remains inactive and IκBα sequesters NF-κB dimers in the cytoplasm inhibiting transcription of NF-κB responsive genes. While NF-κB inhibitory drugs have previously been attractive to disease such as chronic inflammation and diabetes, specific cancers have been shown to have constitutive NF-κB activity. Advanced B-cell lymphoma (ABC), a subtype of Diffuse large B-cell lymphoma (DLBCL) has been shown to have fundamental and upregulated NF-κB activity. ABC lymphoma also has the lowest survival rate compared to DLBCL subtypes, Germinal Center B-cell-like and Undefined Type 3 lymphoma, highlighting the great clinical need to define targets for cancer therapy. Notably, the NBD peptide targets the inflammation induced NF-κB activation pathway sparing the protective functions of basal NF-κB activity allowing for greater therapeutic value and fewer undesired side effects.
The NBD peptide was designed by identifying the amino acid binding sequence on IKK-α and IKK-β to which NEMO binds. A small region on the carboxyl terminus of IKK-α (L738-L743) and IKK-β (L737-L742) is essential for a stable interaction with NEMO and for the assembly of the active IKK complex. Henceforth this region is called the NEMO binding domain (NBD). The NBD peptide consists of the region from T735 to E745 of the IKK-β subunit fused with a sequence derived from the Antennapedia homeodomain that mediates membrane translocation. Furthermore, wild type NBD peptide has been shown to dose-dependently inhibit interaction of IKKB with NEMO compared to mutant controls. Additionally, NF-κB activation was suppressed in HeLa cells after incubation with NBD wild type peptides. Moreover, to better understand the potential efficacy of the NBD peptide in suppressing inflammation, NBD peptide was tested on collagen induced rheumatoid arthritis mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the pathology of rheumatoid arthritis. Mice injected with wild-type NBD peptide showed only slightly visual signs of paw and joint swelling whereas mice injected with PBS or mutant NBD control peptides developed severe joint inflammation. Additionally, analysis of the number of osteoclasts present in the joints of rheumatoid arthritic showed to be more prevalent in mice treated with PBS or the mutant NBD peptide compared to the NBD wild type peptide. Markedly, throughout the mouse model studies neither toxicity or lethality nor damage to kidneys or livers, was observed.
Despite the potential for NBD peptide as a viable NF- κB inhibitory drug, disadvantages arise because of its peptide form. Peptides as drugs lack membrane permeability, are poorly orally viable, and generally have lower metabolic stability than small molecule drugs. Therefore, the NBD peptide is unable to be an orally available compound and must be administered either intravenously or via intraperitoneal injection.
# Interactions
IKBKG has been shown to interact with:
- BCL10,
- CDC37,
- CHUK and
- IKK2,
- IRAK1,
- NCOA3,
- PPM1B,
- TANK,
- TNFAIP3,
- TRAF3IP2, and
- TRAF6. | IKBKG
NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the IKBKG gene. NEMO is a subunit of the IκB kinase complex that activates NF-κB.[1] The human gene for IKBKG is located on chromosome Xq28.[2] Multiple transcript variants encoding different isoforms have been found for this gene.
# Function
NEMO (IKK-γ) is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, which activates NF-κB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways.
# Clinical significance
Mutations in the IKBKG gene results in incontinentia pigmenti,[3] hypohidrotic ectodermal dysplasia,[4] and several other types of immunodeficiencies.
Incontinentia Pigmenti (IP) is an X-linked dominant disease caused by a mutation in the IKBKG gene. Since IKBKG helps activate NF-κB, which protects cells against TNF-alpha induced apoptosis, a lack of IKBKG (and hence a lack of active NF-κB) makes cells more prone to apoptosis.
Moreover, NEMO has been shown to play a role in preeclampsia and may offer insights into the genetic etiology of this condition. An increased level of NEMO gene expression was found in the blood of pregnant women with preeclampsia and their children.[5] However, a decrease of the mRNA levels of total NEMO and the transcripts 1A, 1B, and 1C in placentas derived from preeclamptic women may be the main reason for intensified apoptosis.[5] Sanger sequencing has indicated two distinct variations in the 3’ UTR region of the NEMO gene in preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T).[6] The occurrence of a maternal TT genotype and either a TT genotype in the daughter or T allele in the son increases the risk of preeclampsia by 2.59 fold. The configuration of those maternal and fetal genotypes (TT mother/TT daughter or TT mother/T son) is also associated with the level of NEMO gene expression.[6]
NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG. It mostly affects males and has a highly variable set of symptoms and prognoses.[7]
# As a drug target
A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of NF-κB.[8] NBD is a peptide that acts by binding to regulatory subunit NEMO (IKK-γ) thereby preventing it from binding subunits IKK-α and IKK-β and activating the IKK complex. In the absence of regulatory subunit IKK-γ the IKK complex is inactive, preventing the downstream signal transduction cascade leading to NF-κB activation. Binding of IKK-γ to IKK-α and IKK-β subunits activates the IKK complex leading to phosphorylation of IκB kinase, IκBα, and release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive genes. In the presence of the NBD peptide, the IKK complex remains inactive and IκBα sequesters NF-κB dimers in the cytoplasm inhibiting transcription of NF-κB responsive genes. While NF-κB inhibitory drugs have previously been attractive to disease such as chronic inflammation and diabetes, specific cancers have been shown to have constitutive NF-κB activity.[9] Advanced B-cell lymphoma (ABC), a subtype of Diffuse large B-cell lymphoma (DLBCL) has been shown to have fundamental and upregulated NF-κB activity.[9] ABC lymphoma also has the lowest survival rate compared to DLBCL subtypes, Germinal Center B-cell-like and Undefined Type 3 lymphoma, highlighting the great clinical need to define targets for cancer therapy.[9] Notably, the NBD peptide targets the inflammation induced NF-κB activation pathway sparing the protective functions of basal NF-κB activity allowing for greater therapeutic value and fewer undesired side effects.
The NBD peptide was designed by identifying the amino acid binding sequence on IKK-α and IKK-β to which NEMO binds.[8] A small region on the carboxyl terminus of IKK-α (L738-L743) and IKK-β (L737-L742) is essential for a stable interaction with NEMO and for the assembly of the active IKK complex. Henceforth this region is called the NEMO binding domain (NBD). The NBD peptide consists of the region from T735 to E745 of the IKK-β subunit fused with a sequence derived from the Antennapedia homeodomain that mediates membrane translocation. Furthermore, wild type NBD peptide has been shown to dose-dependently inhibit interaction of IKKB with NEMO compared to mutant controls.[8] Additionally, NF-κB activation was suppressed in HeLa cells after incubation with NBD wild type peptides.[8] Moreover, to better understand the potential efficacy of the NBD peptide in suppressing inflammation, NBD peptide was tested on collagen induced rheumatoid arthritis mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the pathology of rheumatoid arthritis. Mice injected with wild-type NBD peptide showed only slightly visual signs of paw and joint swelling whereas mice injected with PBS or mutant NBD control peptides developed severe joint inflammation.[10] Additionally, analysis of the number of osteoclasts present in the joints of rheumatoid arthritic showed to be more prevalent in mice treated with PBS or the mutant NBD peptide compared to the NBD wild type peptide.[10] Markedly, throughout the mouse model studies neither toxicity or lethality nor damage to kidneys or livers, was observed.
Despite the potential for NBD peptide as a viable NF- κB inhibitory drug, disadvantages arise because of its peptide form. Peptides as drugs lack membrane permeability, are poorly orally viable, and generally have lower metabolic stability than small molecule drugs.[11] Therefore, the NBD peptide is unable to be an orally available compound and must be administered either intravenously or via intraperitoneal injection.
# Interactions
IKBKG has been shown to interact with:
- BCL10,[12]
- CDC37,[13][14]
- CHUK[14][15][16][17] and
- IKK2,[14][16][17][18][19]
- IRAK1,[20][21]
- NCOA3,[19]
- PPM1B,[22]
- TANK,[18]
- TNFAIP3,[23]
- TRAF3IP2,[24][25] and
- TRAF6.[21][26] | https://www.wikidoc.org/index.php/IKBKG | |
3f332051599e43633b0048201051108ba2f333a0 | wikidoc | IKZF3 | IKZF3
Zinc finger protein Aiolos also known as Ikaros family zinc finger protein 3 is a protein that in humans is encoded by the IKZF3 gene.
# Function
This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This gene product is a transcription factor that is important in the regulation of B lymphocyte proliferation and differentiation. Both Ikaros and Aiolos can participate in chromatin remodeling. Regulation of gene expression in B lymphocytes by Aiolos is complex as it appears to require the sequential formation of Ikaros homodimers, Ikaros/Aiolos heterodimers, and Aiolos homodimers. At least six alternative transcripts encoding different isoforms have been described.
# Interactions
IKZF3 has been shown to interact with BCL2-like 1 and HRAS. | IKZF3
Zinc finger protein Aiolos also known as Ikaros family zinc finger protein 3 is a protein that in humans is encoded by the IKZF3 gene.[1][2][3]
# Function
This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This gene product is a transcription factor that is important in the regulation of B lymphocyte proliferation and differentiation. Both Ikaros and Aiolos can participate in chromatin remodeling. Regulation of gene expression in B lymphocytes by Aiolos is complex as it appears to require the sequential formation of Ikaros homodimers, Ikaros/Aiolos heterodimers, and Aiolos homodimers. At least six alternative transcripts encoding different isoforms have been described.[3]
# Interactions
IKZF3 has been shown to interact with BCL2-like 1[4] and HRAS.[5] | https://www.wikidoc.org/index.php/IKZF3 | |
edf4dca7ddbf90ab9864667fb88cd1302051b2c8 | wikidoc | IL17A | IL17A
Interleukin-17A is a protein that in humans is encoded by the IL17A gene.
# Function
The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).
# Discovery
IL-17A, often referred to as IL-17, was originally discovered at transcriptional level by Rouvier et al. in 1993 from a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma. Human and mouse IL-17A were cloned a few years later by Yao and Kennedy. Lymphocytes including CD4+, CD8+, gamma-delta T (γδ-T), invariant NKT and innate lymphoid cells (ILCs) are primary sources of IL-17A. Non-T cells, such as neutrophils, have also been reported to produce IL-17A under certain circumstances. IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and the differentiation of Th17 cells requires STAT3 and RORC.
IL-17A receptor A (IL-17RA) was first isolated and cloned from mouse EL4 thymoma cells and the bioactivity of IL-17A was confirmed by stimulating the transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblasts. IL-17RA pairs with IL-17RC to allow binding and signaling of IL-17A and IL-17F.
# Clinical significance
High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis.
## Autoimmune diseases
Multiple sclerosis (MS) is a neurological disease caused by immune cells, which attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This disease and its animal model experimental autoimmune encephalomyelitis (EAE) have historically been associated with the discovery of Th17 cells. However, elevated expression of IL-17A in multiple sclerosis (MS) lesions as well as peripheral blood has been documented before the identification of Th17 cells. Human TH17 cells have been shown to efficiently transmigrate across the blood-brain barrier in multiple sclerosis lesions, promoting central nervous system inflammation.
Psoriasis is an auto-inflammatory skin disease characterized by circumscribed, crimson red, silver-scaled, plaque-like inflammatory lesions. Initially, psoriasis was considered to be a Th1-mediated disease since elevated levels of IFN-γ, TNF-α, and IL-12 was found in the serum and lesions of psoriasis patients. However, the finding of IL-17-producing cells as well as IL17A transcripts in the lesions of psoriatic patients suggested that Th17 cells may synergize with Th1 cells in driving the pathology in psoriasis. The levels of IL-17A in the synovium correlate with tissue damage, whereas levels of IFN-γ correlate with protection. Direct clinical significance of IL-17A in RA comes from recent clinical trials which found that two anti-IL-17A antibodies, namely Secukinumab and Ixekizumab significantly benefit these patients.
Th17 cells is also strongly associated rheumatoid arthritis (RA), a chronic disorder with symptoms include chronic joint inflammation, autoantibody production, which lead to the destruction of cartilage and bone.
Th17 cells and IL-17 have also been linked to Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD) in man. Th17 cells infiltrate massively to the inflamed tissue of IBD patients and both in vitro and in vivo studies have shown that Th17-related cytokines may initiate and amplify multiple pro-inflammatory pathways. Elevated IL-17A levels in IBD have been reported by several groups. Nonetheless, Th17 signature cytokines, such as IL-17A and IL-22, may target gut epithelial cells and promote the activation of regulatory pathways and confer protection in the gastrointestinal tract. To this end, recent clinical trials targeting IL-17A in IBD were negative and actually showed increased adverse events in the treatment arm. This data raised the question regarding the role of IL-17A in IBD pathogenesis and suggested that the elevated IL-17A might be beneficial for IBD patients.
Systemic lupus erythematosus, commonly referred as SLE or lupus, is a complex immune disorder affects the skin, joints, kidneys, and brain. Although the exact cause of lupus is not fully known, it has been reported that IL-17 and Th17 cells are involved in disease pathogenesis. It has been reported that serum IL-17 levels are also elevated in SLE patients compared to controls and the Th17 pathway has been shown to drive autoimmune responses in pre-clinical mouse models of lupus. More importantly, IL-17 and IL-17 producing cells are also been detected in kidney tissue and skin biopsies from SLE patients.
## Lung diseases
Elevated levels of IL-17A have been found in the sputum and in bronchoalveolar lavage fluid of patients with asthma and a positive correlation between IL-17A production and asthma severity has been established. In murine models, treatment with dexamethasone inhibits the release of Th2-related cytokines but does not affect IL-17A production. Furthermore, Th17 cell-mediated airway inflammation and airway hyperresponsiveness are steroid resistant, indicating a potential role for Th17 cells in steroid-resistant asthma. However, a recent trial using anti-IL-17RA did not show efficacy in subjects with asthma.
Recent studies have suggested the involvement of immunological mechanisms in COPD. An increase in Th17 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects, and inverse correlations were found between Th17 cells with lung function. Gene expression profiling of bronchial brushings obtained from COPD patients also linked lung function to several Th17 signature genes such as SAA1, SAA2, SLC26A4 and LCN2. Animal studies have shown that cigarette smoke promotes pathogenic Th17 differentiation and induces emphysema, while blocking IL-17A using neutralizing antibody significantly decreased neutrophil recruitment and the pathological score of airway inflammation in tobacco-smoke-exposed mice.
## Host defense
In host defense, IL-17A has been shown to be mostly beneficial against infection caused by extracellular bacteria and fungi.
The primary function of Th17 cells appears to be control of the gut microbiota as well as the clearance of extracellular bacteria and fungi. IL-17A and IL-17 receptor signaling has been shown to be play a protective role in host defenses against many bacterial and fungal pathogens including Klebsiella pneumoniae, Mycoplasma pneumonia, Candida albicans, Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis. However, IL-17A seems to be detrimental in viral infection such as influenza through promoting neutrophilic inflammation.
The requirements of IL-17A and IL-17 receptor signaling in host defense were well documented and appreciated before the identification of Th17 cells as an independent T helper cell lineage. In experimental pneumonia models, IL-17A or IL-17RA knock mice have increased susceptibility to various Gram-negative bacteria, such as Klebsiella pneumoniae and Mycoplasma pneumonia. In contrast, data suggest that IL-23 and IL-17A are not required for protection against primary infection by the intracellular bacteria Mycobacterium tuberculosis. Both the IL-17RA knock out mice and the IL-23p19 knock out mice cleared primary infection with M. tuberculosis. However, IL-17A is required for protection against primary infection with a different intracellular bacteria, Francisella tularensis.
Mouse model studies using the IL-17RA knock out mice and the IL-17A knock out mice with the murine adapted influenza strain (PR8) as well as the 2009 pandemic H1N1 stain both support that IL-17A plays a detrimental role in mediating the acute lung injury.
The role of adaptive immune responses mediated by antigen specific Th17 has been investigated more recently. Antigen specific Th17 cells were also shown to recognize conserved protein antigens among different K. pneumoniae strains and provide broad-spectrum serotype-independent protection. Antigen specific CD4 T cells also limit nasopharyngeal colonization of S. pneumoniae in mouse models. Furthermore, immunization with pneumococcal whole cell antigen and several derivatives provided IL-17-mediated, but not antibody dependent, protection against S. pneumoniae challenge. In fungal infection, it has been shown an IL-17 producing clone with a TCR specific for calnexin from Blastomyces dermatitidis confers protection with evolutionary related fungal species including Histoplasma spp.
## Cancer
In tumorigenesis, IL-17A has been shown to recruit myeloid derived suppressor cells (MDSCs) to dampen anti-tumor immunity. IL-17A can also enhance tumor growth in vivo through the induction of IL-6, which in turn activates oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) and upregulates pro-survival and pro-angiogenic genes in tumors. The exact role of IL-17A in angiogenesis has yet to be determined and current data suggest that IL-17A can promote or suppress tumor development. IL-17A seemed to facilitate development of colorectal carcinoma by fostering angiogenesis via promote VEGF production from cancer cells and it has been show that IL-17A also mediates tumor resistance to anti-VEGF therapy through the recruitment of MDSCs.
However IL-17A KO mice were more susceptible to developing metastatic lung melanoma, suggesting that IL-17A can possibly promote the production of the potent antitumor cytokine IFN-γ, produced by cytotoxic T cells. Indeed, data from ovarian cancer suggest that Th17 cells are positively correlated with NK cell–mediated immunity and anti-tumor CD8 responses.
# As a drug target
The discovery of the key roles of IL-17A and IL-17A producing cells in inflammation, autoimmune diseases and host defense has led to the experimental targeting of the IL-17A pathway in animal models of diseases as well as in clinical trials in humans. Targeting IL-17A has been proven to be a good approach as anti-IL-17A is FDA approved for the treatment of psoriasis in 2015.
Secukinumab (anti-IL-17A) has been evaluated in psoriasis and the first report showing Secukinumab is effective when compared with placebo was published in 2010. In 2015, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved anti-IL-17 for the treatment of psoriasis.
Other than the monoclonal antibodies, highly specific and potent inhibitors targeting Th17 specific transcription factor RORγt have been identified and found to be highly effective.
Vitamin D, a potent immunomodulator, has also been shown to suppress Th17 cell differentiation and function by several research groups.
The active form of vitamin D has been found to 'severely impair' production of the IL17 and IL-17F cytokines by Th17 cells. | IL17A
Interleukin-17A is a protein that in humans is encoded by the IL17A gene.[1][2]
# Function
The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).
# Discovery
IL-17A, often referred to as IL-17, was originally discovered at transcriptional level by Rouvier et al. in 1993 from a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma.[1] Human and mouse IL-17A were cloned a few years later by Yao[3] and Kennedy.[4] Lymphocytes including CD4+, CD8+, gamma-delta T (γδ-T), invariant NKT and innate lymphoid cells (ILCs) are primary sources of IL-17A.[5] Non-T cells, such as neutrophils, have also been reported to produce IL-17A under certain circumstances.[6] IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and the differentiation of Th17 cells requires STAT3[7] and RORC.[8]
IL-17A receptor A (IL-17RA) was first isolated and cloned from mouse EL4 thymoma cells and the bioactivity of IL-17A was confirmed by stimulating the transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblasts.[9] IL-17RA pairs with IL-17RC to allow binding and signaling of IL-17A and IL-17F.[10]
# Clinical significance
High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis.[2]
## Autoimmune diseases
Multiple sclerosis (MS) is a neurological disease caused by immune cells, which attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This disease and its animal model experimental autoimmune encephalomyelitis (EAE) have historically been associated with the discovery of Th17 cells.[11][12] However, elevated expression of IL-17A in multiple sclerosis (MS) lesions as well as peripheral blood has been documented before the identification of Th17 cells.[13][14] Human TH17 cells have been shown to efficiently transmigrate across the blood-brain barrier in multiple sclerosis lesions, promoting central nervous system inflammation.[15]
Psoriasis is an auto-inflammatory skin disease characterized by circumscribed, crimson red, silver-scaled, plaque-like inflammatory lesions. Initially, psoriasis was considered to be a Th1-mediated disease since elevated levels of IFN-γ, TNF-α, and IL-12 was found in the serum and lesions of psoriasis patients.[16] However, the finding of IL-17-producing cells as well as IL17A transcripts in the lesions of psoriatic patients suggested that Th17 cells may synergize with Th1 cells in driving the pathology in psoriasis.[17][18] The levels of IL-17A in the synovium correlate with tissue damage, whereas levels of IFN-γ correlate with protection.[19] Direct clinical significance of IL-17A in RA comes from recent clinical trials which found that two anti-IL-17A antibodies, namely Secukinumab and Ixekizumab significantly benefit these patients.[20][21]
Th17 cells is also strongly associated rheumatoid arthritis (RA), a chronic disorder with symptoms include chronic joint inflammation, autoantibody production, which lead to the destruction of cartilage and bone.[22]
Th17 cells and IL-17 have also been linked to Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD) in man. Th17 cells infiltrate massively to the inflamed tissue of IBD patients and both in vitro and in vivo studies have shown that Th17-related cytokines may initiate and amplify multiple pro-inflammatory pathways.[23] Elevated IL-17A levels in IBD have been reported by several groups.[24][25] Nonetheless, Th17 signature cytokines, such as IL-17A and IL-22, may target gut epithelial cells and promote the activation of regulatory pathways and confer protection in the gastrointestinal tract.[26][27] To this end, recent clinical trials targeting IL-17A in IBD were negative and actually showed increased adverse events in the treatment arm.[28] This data raised the question regarding the role of IL-17A in IBD pathogenesis and suggested that the elevated IL-17A might be beneficial for IBD patients.
Systemic lupus erythematosus, commonly referred as SLE or lupus, is a complex immune disorder affects the skin, joints, kidneys, and brain. Although the exact cause of lupus is not fully known, it has been reported that IL-17 and Th17 cells are involved in disease pathogenesis.[29] It has been reported that serum IL-17 levels are also elevated in SLE patients compared to controls[30][31] and the Th17 pathway has been shown to drive autoimmune responses in pre-clinical mouse models of lupus.[32][33] More importantly, IL-17 and IL-17 producing cells are also been detected in kidney tissue and skin biopsies from SLE patients.[34][35][36]
## Lung diseases
Elevated levels of IL-17A have been found in the sputum and in bronchoalveolar lavage fluid of patients with asthma[37] and a positive correlation between IL-17A production and asthma severity has been established.[38] In murine models, treatment with dexamethasone inhibits the release of Th2-related cytokines but does not affect IL-17A production.[39] Furthermore, Th17 cell-mediated airway inflammation and airway hyperresponsiveness are steroid resistant, indicating a potential role for Th17 cells in steroid-resistant asthma.[39] However, a recent trial using anti-IL-17RA did not show efficacy in subjects with asthma.[40]
Recent studies have suggested the involvement of immunological mechanisms in COPD.[41] An increase in Th17 cells was observed in patients with COPD compared with current smokers without COPD and healthy subjects, and inverse correlations were found between Th17 cells with lung function.[42] Gene expression profiling of bronchial brushings obtained from COPD patients also linked lung function to several Th17 signature genes such as SAA1, SAA2, SLC26A4 and LCN2.[43] Animal studies have shown that cigarette smoke promotes pathogenic Th17 differentiation and induces emphysema,[44] while blocking IL-17A using neutralizing antibody significantly decreased neutrophil recruitment and the pathological score of airway inflammation in tobacco-smoke-exposed mice.[44][45]
## Host defense
In host defense, IL-17A has been shown to be mostly beneficial against infection caused by extracellular bacteria and fungi.[46]
The primary function of Th17 cells appears to be control of the gut microbiota[47][48] as well as the clearance of extracellular bacteria and fungi. IL-17A and IL-17 receptor signaling has been shown to be play a protective role in host defenses against many bacterial and fungal pathogens including Klebsiella pneumoniae, Mycoplasma pneumonia, Candida albicans, Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis.[49] However, IL-17A seems to be detrimental in viral infection such as influenza through promoting neutrophilic inflammation.[50]
The requirements of IL-17A and IL-17 receptor signaling in host defense were well documented and appreciated before the identification of Th17 cells as an independent T helper cell lineage. In experimental pneumonia models, IL-17A or IL-17RA knock mice have increased susceptibility to various Gram-negative bacteria, such as Klebsiella pneumoniae[51] and Mycoplasma pneumonia.[52] In contrast, data suggest that IL-23 and IL-17A are not required for protection against primary infection by the intracellular bacteria Mycobacterium tuberculosis. Both the IL-17RA knock out mice and the IL-23p19 knock out mice cleared primary infection with M. tuberculosis.[53][54] However, IL-17A is required for protection against primary infection with a different intracellular bacteria, Francisella tularensis.[55]
Mouse model studies using the IL-17RA knock out mice and the IL-17A knock out mice with the murine adapted influenza strain (PR8)[50] as well as the 2009 pandemic H1N1 stain [93] both support that IL-17A plays a detrimental role in mediating the acute lung injury.[56]
The role of adaptive immune responses mediated by antigen specific Th17 has been investigated more recently. Antigen specific Th17 cells were also shown to recognize conserved protein antigens among different K. pneumoniae strains and provide broad-spectrum serotype-independent protection.[57] Antigen specific CD4 T cells also limit nasopharyngeal colonization of S. pneumoniae in mouse models.[58] Furthermore, immunization with pneumococcal whole cell antigen and several derivatives provided IL-17-mediated, but not antibody dependent, protection against S. pneumoniae challenge.[59][60] In fungal infection, it has been shown an IL-17 producing clone with a TCR specific for calnexin from Blastomyces dermatitidis confers protection with evolutionary related fungal species including Histoplasma spp.[61]
## Cancer
In tumorigenesis, IL-17A has been shown to recruit myeloid derived suppressor cells (MDSCs) to dampen anti-tumor immunity.[62][63] IL-17A can also enhance tumor growth in vivo through the induction of IL-6, which in turn activates oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) and upregulates pro-survival and pro-angiogenic genes in tumors.[64] The exact role of IL-17A in angiogenesis has yet to be determined and current data suggest that IL-17A can promote or suppress tumor development.[65] IL-17A seemed to facilitate development of colorectal carcinoma by fostering angiogenesis via promote VEGF production from cancer cells[66] and it has been show that IL-17A also mediates tumor resistance to anti-VEGF therapy through the recruitment of MDSCs.[67]
However IL-17A KO mice were more susceptible to developing metastatic lung melanoma,[68] suggesting that IL-17A can possibly promote the production of the potent antitumor cytokine IFN-γ, produced by cytotoxic T cells. Indeed, data from ovarian cancer suggest that Th17 cells are positively correlated with NK cell–mediated immunity and anti-tumor CD8 responses.[69]
# As a drug target
The discovery of the key roles of IL-17A and IL-17A producing cells in inflammation, autoimmune diseases and host defense has led to the experimental targeting of the IL-17A pathway in animal models of diseases as well as in clinical trials in humans. Targeting IL-17A has been proven to be a good approach as anti-IL-17A is FDA approved for the treatment of psoriasis in 2015.[70]
Secukinumab (anti-IL-17A) has been evaluated in psoriasis and the first report showing Secukinumab is effective when compared with placebo was published in 2010.[71] In 2015, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved anti-IL-17 for the treatment of psoriasis.[72]
Other than the monoclonal antibodies, highly specific and potent inhibitors targeting Th17 specific transcription factor RORγt have been identified and found to be highly effective.[73]
Vitamin D, a potent immunomodulator, has also been shown to suppress Th17 cell differentiation and function by several research groups.[74]
The active form of vitamin D has been found to 'severely impair'[75] production of the IL17 and IL-17F cytokines by Th17 cells. | https://www.wikidoc.org/index.php/IL17A | |
6c51adff7a404ec879c139410d3d374afe5e1635 | wikidoc | IL2RA | IL2RA
Interleukin-2 receptor alpha chain (also called CD25) is a protein that in humans is encoded by the IL2RA gene.
The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolysis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is currently unknown.
# Description
It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes. Though IL2RA has been used as a marker to identify CD4+FoxP3+ regulatory T cells in mice, it has been found that a large proportion of resting memory T cells constitutively express IL2RA in humans.
IL2RA is expressed in most B-cell neoplasms, some acute nonlymphocytic leukemias, neuroblastomas, mastocytosis and tumor infiltrating lymphocytes. It functions as the receptor for HTLV-1 and is consequently expressed on neoplastic cells in adult T cell lymphoma/leukemia. Its soluble form, called sIL-2R may be elevated in these diseases and is occasionally used to track disease progression.
# Clinical significance
## Chagas disease
Infection by the protozoan Trypanosoma cruzi causes Chagas disease, characterized by a reduction in the amount of IL2RA expressed on the surface of immune cells. This leads to chronic immune suppression, becoming increasingly severe over the course of many years and ultimately resulting in death if left untreated.
## Multiple sclerosis
The multiple sclerosis drug daclizumab binds to and blocks IL2RA.
Sarcoidosis
IL2RA has been shown to be elevated in Sarcoidosis with a sensitivity of 88% and specificity of 85%. | IL2RA
Interleukin-2 receptor alpha chain (also called CD25) is a protein that in humans is encoded by the IL2RA gene.[1]
The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolysis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is currently unknown.[2]
# Description
It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes. Though IL2RA has been used as a marker to identify CD4+FoxP3+ regulatory T cells in mice, it has been found that a large proportion of resting memory T cells constitutively express IL2RA in humans.[3]
IL2RA is expressed in most B-cell neoplasms, some acute nonlymphocytic leukemias, neuroblastomas, mastocytosis and tumor infiltrating lymphocytes. It functions as the receptor for HTLV-1 and is consequently expressed on neoplastic cells in adult T cell lymphoma/leukemia. Its soluble form, called sIL-2R may be elevated in these diseases and is occasionally used to track disease progression.
# Clinical significance
## Chagas disease
Infection by the protozoan Trypanosoma cruzi causes Chagas disease, characterized by a reduction in the amount of IL2RA expressed on the surface of immune cells. This leads to chronic immune suppression, becoming increasingly severe over the course of many years and ultimately resulting in death if left untreated.
## Multiple sclerosis
The multiple sclerosis drug daclizumab binds to and blocks IL2RA.[4]
Sarcoidosis
IL2RA has been shown to be elevated in Sarcoidosis with a sensitivity of 88% and specificity of 85%. | https://www.wikidoc.org/index.php/IL2RA | |
c3a9f29098fccd42fc5c25710046681958db344d | wikidoc | IL2RB | IL2RB
Interleukin-2 receptor subunit beta is a protein that in humans is encoded by the IL2RB gene. Also known as CD122; IL15RB; P70-75.
# Function
The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 forms with respect to ability to bind interleukin 2. The low affinity form is a monomer of the alpha subunit (also called CD25) and is not involved in signal transduction. The intermediate affinity form consists of a gamma/beta subunit heterodimer, while the high affinity form consists of an alpha/beta/gamma subunit heterotrimer. Both the intermediate and high affinity forms of the receptor are involved in receptor-mediated endocytosis and transduction of mitogenic signals from interleukin 2. The protein encoded by this gene represents the beta subunit and is a type I membrane protein.
This protein also forms one of the three subunits of the IL-15 receptor.
Activation of the receptor increases proliferation of CD8+ effector T cells.
# Interactions
IL2RB has been shown to interact with:
- CISH,
- HGS,
- Janus kinase 1, and
- SHC1. | IL2RB
Interleukin-2 receptor subunit beta is a protein that in humans is encoded by the IL2RB gene.[1] Also known as CD122; IL15RB; P70-75.[1]
# Function
The interleukin 2 receptor, which is involved in T cell-mediated immune responses, is present in 3 forms with respect to ability to bind interleukin 2. The low affinity form is a monomer of the alpha subunit (also called CD25) and is not involved in signal transduction. The intermediate affinity form consists of a gamma/beta subunit heterodimer, while the high affinity form consists of an alpha/beta/gamma subunit heterotrimer. Both the intermediate and high affinity forms of the receptor are involved in receptor-mediated endocytosis and transduction of mitogenic signals from interleukin 2. The protein encoded by this gene represents the beta subunit and is a type I membrane protein.[1]
This protein also forms one of the three subunits of the IL-15 receptor.
Activation of the receptor increases proliferation of CD8+ effector T cells.[2]
# Interactions
IL2RB has been shown to interact with:
- CISH,[3]
- HGS,[4]
- Janus kinase 1,[5][6][7][8][9] and
- SHC1.[10][11] | https://www.wikidoc.org/index.php/IL2RB | |
63d62f3f434a85e28300e283ecf7cc3582e49834 | wikidoc | IMViC | IMViC
The IMViC tests are a group of individual tests used in microbiology lab testing to identify an organism.
These four tests include:
- Indole production
- Methyl Red test
- Voges-Proskauer test
- Citrate Production
These IMViC tests are useful for differentiating the the family Enterobacteriaceae, especially when used alongside the Urease test.
Except for the lowercase “i”, which is added for ease of pronunciation, each of the letters in “IMViC” stands for one of these tests. “I” is for indole; “M” is for methyl red; “V” is for Voges-Proskauer, and “C” is for citrate. | IMViC
The IMViC tests are a group of individual tests used in microbiology lab testing to identify an organism.
These four tests include:
- Indole production
- Methyl Red test
- Voges-Proskauer test
- Citrate Production
These IMViC tests are useful for differentiating the the family Enterobacteriaceae, especially when used alongside the Urease test.
Except for the lowercase “i”, which is added for ease of pronunciation, each of the letters in “IMViC” stands for one of these tests. “I” is for indole; “M” is for methyl red; “V” is for Voges-Proskauer, and “C” is for citrate.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/IMViC | |
0ae8920039e67edf8f9f8138588905cb6f943d4d | wikidoc | INAVA | INAVA
INAVA, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the INAVA gene. Less common gene aliases include FLJ10901 and MGC125608.
# Gene
## Location
In humans, INAVA is located on the long arm of chromosome 1 at locus 1q32.1. It spans from 200,891,499 to 200,915,736 (24.238 kb) on the plus strand.
## Gene neighborhood
INAVA is flanked by G protein-coupled receptor 25 (upstream) and maestro heat-like repeat family member 3 (MROH3P), a predicted downstream pseudogene. Ribosomal protein L34 pseudogene 6 (RPL34P6) is further upstream and kinesin family member 21B is further downstream.
## Promoter
There are seven predicted promoters for INAVA, and experimental evidence suggests that isoform 1 and 2, the most common isoforms, are transcribed using different promoters. MatInspector, a tool available through Genomatix, was used to predict transcription factor binding sites within potential promoter regions. The transcription factors that are predicted to target the anticipated promoter for isoform 1 are expressed in a range of tissues. The most common tissues of expression are the urogenital system, nervous system and bone marrow. This coincides with expression data for the INAVA protein, which is highly expressed in the kidney and bone marrow. A diagram of the predicted promoter region, with highlighted transcription factor binding sites, is shown to the right. The factors that are predicted to bind to the promoter region of isoform 2 differ, and twelve of the top twenty predicted factors are expressed in blood cells and/or tissues of the cardiovascular system.
## Expression
C1orf106 is expressed in a wide range of tissues. Expression data from GEO profiles is shown below. The sites of highest expression, are listed in the table.
Expression is moderate in the placenta, prostate, testis, lung, salivary glands and dendritic cells. It is low in the brain, most immune cells, the adrenal gland, uterus, heart and adipocytes. Expression data, from various experiments, found on GEO profiles suggests that INAVA expression is up-regulated in several cancers including: lung, ovarian, colorectal and breast.
# mRNA
## Isoforms
Nine putative isoforms are produced from the INAVA gene, seven of which are predicted to encode proteins. Isoform 1 and 2, shown below, are the most common isoforms.
Isoform 1, which is the longest, is accepted as the canonical isoform. It contains ten exons, which encode a protein that is 677 amino acids long, depending on the source. Some sources report that the protein is only 663 amino acids due to the use of a start codon that is forty-two nucleotides downstream. According to NCBI, this isoform has only been predicted computationally. This may be because the Kozak sequence surrounding the downstream start codon is more similar to the consensus Kozak sequence as shown in the table below. Softberry was used to obtain the sequence of the predicted isoform. Isoform 2 is shorter due to a truncated N-terminus. Both isoforms have an alternative polyadenylation site.
## miRNA regulation
miRNA-24 was identified as a microRNA that could potentially target INAVA mRNA.
The binding site, which is located in the 5' untranslated region is shown.
# Protein
## General properties
Isoform 1, diagramed below, contains a DUF3338 domain, two low complexity regions and a proline rich region. The protein is arginine and proline rich, and has a lower than average amount of asparagine and hydrophobic amino acids, specifically phenylalanine and isoleucine. The isoelectric point is 9.58, and the molecular weight of the unmodified protein is 72.9 kdal. The protein is not predicted to have an N-terminal signal peptide, but there are predicted nuclear localization signals (NLS) and a leucine rich nuclear export signal.
## Modifications
INAVA is predicted to be highly phosphorylated. Phosphoylation sites predicted by PROSITE are shown in the table below. NETPhos predictions are illustrated in the diagram. Each line points to a predicted phosphorylation site, and connects to a letter which represents either serine (S), threonine (T) or tyrosine (Y).
## Structure
Coiled-coils are predicted to span from residue 130-160 and 200-260. The secondary composition was predicted to be about 60% random coils, 30% alpha helices and 10% beta sheets.
## Interactions
The proteins with which the INAVA protein interacts are not well characterized. Text mining evidence suggests INAVA may interact with the following proteins: DNAJC5G, SLC7A13, PIEZO2, MUC19. Experimental evidence, from a yeast two hybrid screen, suggests the INAVA protein interacts with 14-3-3 protein sigma, which is an adaptor protein.
## Homology
INAVA is well conserved in vertebrates as shown in the table below. Sequences were retrieved from BLAST and BLAT.
A graph of the sequence identity versus the time since divergence for the asteriked entries is shown below. The colors correspond to degree of relatedness (green = closely related, purple = distantly related).
## Paralogs
Proteins that are considered to be INAVA paralogs are not consistent between databases. A multiple sequence alignment (MSA) of potentially paralogous proteins was made to determine the likelihood of a truly paralogous relationship. The sequences were retrieved from a BLAST search in humans with the C1orf106 protein. The MSA suggests the proteins share a homologous domain, DUF3338, which is found in eukaryotes. A portion of the multiple sequence alignment is shown below. Apart from the DUF domain (boxed in green), there was little conservation. The DUF3338 domain does not have any extraordinary physical properties, however, one notable finding is that each of the proteins in the MSA is predicted to have two nuclear localization signals. The proteins in the MSA are all predicted to localize to the nucleus. A comparison of the physical properties of the proteins was also conducted using SAPS and is shown in the table.
# Clinical significance
A total of 556 single nucleotide polymorphisms (SNPs) have been identified in the gene region of INAVA, 96 of which are associated with a clinical source. Rivas et al. identified four SNPs, shown in the table below, that may be associated with inflammatory bowel disease and Crohn's disease. According to GeneCards, other disease associations may include multiple sclerosis and ulcerative colitis.
# Model organisms
Model organisms have been used in the study of INAVA function. A conditional knockout mouse line called 5730559C18Riktm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | INAVA
INAVA, sometimes referred to as hypothetical protein LOC55765, is a protein of unknown function that in humans is encoded by the INAVA gene.[1] Less common gene aliases include FLJ10901 and MGC125608.
# Gene
## Location
In humans, INAVA is located on the long arm of chromosome 1 at locus 1q32.1. It spans from 200,891,499 to 200,915,736 (24.238 kb) on the plus strand.[1]
## Gene neighborhood
INAVA is flanked by G protein-coupled receptor 25 (upstream) and maestro heat-like repeat family member 3 (MROH3P), a predicted downstream pseudogene. Ribosomal protein L34 pseudogene 6 (RPL34P6) is further upstream and kinesin family member 21B is further downstream.[1]
## Promoter
There are seven predicted promoters for INAVA, and experimental evidence suggests that isoform 1 and 2, the most common isoforms, are transcribed using different promoters.[2] MatInspector, a tool available through Genomatix, was used to predict transcription factor binding sites within potential promoter regions. The transcription factors that are predicted to target the anticipated promoter for isoform 1 are expressed in a range of tissues. The most common tissues of expression are the urogenital system, nervous system and bone marrow. This coincides with expression data for the INAVA protein, which is highly expressed in the kidney and bone marrow.[3] A diagram of the predicted promoter region, with highlighted transcription factor binding sites, is shown to the right. The factors that are predicted to bind to the promoter region of isoform 2 differ, and twelve of the top twenty predicted factors are expressed in blood cells and/or tissues of the cardiovascular system.
## Expression
C1orf106 is expressed in a wide range of tissues. Expression data from GEO profiles is shown below. The sites of highest expression, are listed in the table.
Expression is moderate in the placenta, prostate, testis, lung, salivary glands and dendritic cells. It is low in the brain, most immune cells, the adrenal gland, uterus, heart and adipocytes.[3] Expression data, from various experiments, found on GEO profiles suggests that INAVA expression is up-regulated in several cancers including: lung, ovarian, colorectal and breast.
# mRNA
## Isoforms
Nine putative isoforms are produced from the INAVA gene, seven of which are predicted to encode proteins.[4] Isoform 1 and 2, shown below, are the most common isoforms.
Isoform 1, which is the longest, is accepted as the canonical isoform. It contains ten exons, which encode a protein that is 677 amino acids long, depending on the source. Some sources report that the protein is only 663 amino acids due to the use of a start codon that is forty-two nucleotides downstream. According to NCBI, this isoform has only been predicted computationally.[1] This may be because the Kozak sequence surrounding the downstream start codon is more similar to the consensus Kozak sequence as shown in the table below. Softberry was used to obtain the sequence of the predicted isoform.[5] Isoform 2 is shorter due to a truncated N-terminus. Both isoforms have an alternative polyadenylation site.[4]
## miRNA regulation
miRNA-24 was identified as a microRNA that could potentially target INAVA mRNA.[6]
The binding site, which is located in the 5' untranslated region is shown.
# Protein
## General properties
Isoform 1, diagramed below, contains a DUF3338 domain, two low complexity regions and a proline rich region. The protein is arginine and proline rich, and has a lower than average amount of asparagine and hydrophobic amino acids, specifically phenylalanine and isoleucine.[7] The isoelectric point is 9.58, and the molecular weight of the unmodified protein is 72.9 kdal.[8] The protein is not predicted to have an N-terminal signal peptide, but there are predicted nuclear localization signals (NLS) and a leucine rich nuclear export signal.[9][10][11]
## Modifications
INAVA is predicted to be highly phosphorylated.[12][13] Phosphoylation sites predicted by PROSITE are shown in the table below. NETPhos predictions are illustrated in the diagram. Each line points to a predicted phosphorylation site, and connects to a letter which represents either serine (S), threonine (T) or tyrosine (Y).
## Structure
Coiled-coils are predicted to span from residue 130-160 and 200-260.[14] The secondary composition was predicted to be about 60% random coils, 30% alpha helices and 10% beta sheets.[15]
## Interactions
The proteins with which the INAVA protein interacts are not well characterized. Text mining evidence suggests INAVA may interact with the following proteins: DNAJC5G, SLC7A13, PIEZO2, MUC19.[16] Experimental evidence, from a yeast two hybrid screen, suggests the INAVA protein interacts with 14-3-3 protein sigma, which is an adaptor protein.[17]
## Homology
INAVA is well conserved in vertebrates as shown in the table below. Sequences were retrieved from BLAST[18] and BLAT.[19]
A graph of the sequence identity versus the time since divergence for the asteriked entries is shown below. The colors correspond to degree of relatedness (green = closely related, purple = distantly related).
## Paralogs
Proteins that are considered to be INAVA paralogs are not consistent between databases. A multiple sequence alignment (MSA) of potentially paralogous proteins was made to determine the likelihood of a truly paralogous relationship.[20] The sequences were retrieved from a BLAST search in humans with the C1orf106 protein. The MSA suggests the proteins share a homologous domain, DUF3338, which is found in eukaryotes. A portion of the multiple sequence alignment is shown below. Apart from the DUF domain (boxed in green), there was little conservation. The DUF3338 domain does not have any extraordinary physical properties, however, one notable finding is that each of the proteins in the MSA is predicted to have two nuclear localization signals. The proteins in the MSA are all predicted to localize to the nucleus.[9] A comparison of the physical properties of the proteins was also conducted using SAPS and is shown in the table.[7]
# Clinical significance
A total of 556 single nucleotide polymorphisms (SNPs) have been identified in the gene region of INAVA, 96 of which are associated with a clinical source.[21] Rivas et al.[22] identified four SNPs, shown in the table below, that may be associated with inflammatory bowel disease and Crohn's disease. According to GeneCards, other disease associations may include multiple sclerosis and ulcerative colitis.[23]
# Model organisms
Model organisms have been used in the study of INAVA function. A conditional knockout mouse line called 5730559C18Riktm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[24] Male and female animals underwent a standardized phenotypic screen[25] to determine the effects of deletion.[26][27][28][29] Additional screens performed: - In-depth immunological phenotyping[30] - in-depth bone and cartilage phenotyping[31] | https://www.wikidoc.org/index.php/INAVA |
Subsets and Splits