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ad407ddecbbdb1788df3fc9baf1cfccd48ffee73 | wikidoc | FOSL1 | FOSL1
Fos-related antigen 1 (FRA1) is a protein that in humans is encoded by the FOSL1 gene.
# Function
The Fos gene family consists of 4 members: c-Fos, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.
# Interactions
FOSL1 has been shown to interact with USF1 (human gene) and C-jun. | FOSL1
Fos-related antigen 1 (FRA1) is a protein that in humans is encoded by the FOSL1 gene.[1][2]
# Function
The Fos gene family consists of 4 members: c-Fos, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[2]
# Interactions
FOSL1 has been shown to interact with USF1 (human gene)[3] and C-jun.[3] | https://www.wikidoc.org/index.php/FOSL1 | |
04dea19bcb982a7005f2c486e4ba426493b2099f | wikidoc | FOXA1 | FOXA1
Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.
# Function
FOXA1 is a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin as a pioneer factor. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.
# Marker in breast cancer
FOXA1 in breast cancer is highly correlated with ERα+, GATA3+, and PR+ protein expression as well as endocrine signaling. FOXA1 acts as a pioneer factor for ERa in ERα+ breast cancer, and its expression might identify ERα+ cancers that undergo rapid reprogramming of ERa signaling that is associated with poor outcomes and treatment resistance. Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of GATA3 in the mammary gland. Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such as androgen receptor antagonist treatment.
# Role in prostate cancer
Mutations in this gene have been recurrently seen in instances of prostate cancer. | FOXA1
Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.[1][2][3]
# Function
FOXA1 is a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin as a pioneer factor. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.[1]
# Marker in breast cancer
FOXA1 in breast cancer is highly correlated with ERα+, GATA3+, and PR+ protein expression as well as endocrine signaling. FOXA1 acts as a pioneer factor for ERa in ERα+ breast cancer, and its expression might identify ERα+ cancers that undergo rapid reprogramming of ERa signaling that is associated with poor outcomes and treatment resistance.[4] Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of GATA3 in the mammary gland.[5] Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such as androgen receptor antagonist treatment.[6][7]
# Role in prostate cancer
Mutations in this gene have been recurrently seen in instances of prostate cancer.[8] | https://www.wikidoc.org/index.php/FOXA1 | |
8cbda58bb22b95d7192731991876a5eb57666590 | wikidoc | FOXC2 | FOXC2
Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.
# Structure and function
The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size.
FOX transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of podocytes and maturation of the glomerular basement membrane. It is also involved in the early development of the heart.
An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin.
# Role in disease
Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form and problems with lymphatic remodelling. A number of mutations in the FOXC2 gene have been associated with Lymphedema–distichiasis syndrome, It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.
FOXC2 is also involved in cancer metastases. In particular, expression of FOXC2 is induced when epithelial cells undergo an epithelial-mesenchymal transition (EMT) and become mesenchymal looking cells. EMT can be induced by a number of genes including Snail, Twist, Goosecoid, and TGF-beta 1. Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic. Suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability. | FOXC2
Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene.[1][2] FOXC2 is a member of the fork head box (FOX) family of transcription factors.
# Structure and function
The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size.[2][3]
FOX transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of podocytes and maturation of the glomerular basement membrane. It is also involved in the early development of the heart.[4]
An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin.[5][6]
# Role in disease
Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form and problems with lymphatic remodelling. A number of mutations in the FOXC2 gene have been associated with Lymphedema–distichiasis syndrome,[7][8] It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.[8]
[9]
FOXC2 is also involved in cancer metastases. In particular, expression of FOXC2 is induced when epithelial cells undergo an epithelial-mesenchymal transition (EMT) and become mesenchymal looking cells. EMT can be induced by a number of genes including Snail, Twist, Goosecoid, and TGF-beta 1.[10] Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.[4] Suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability.[11] | https://www.wikidoc.org/index.php/FOXC2 | |
0cbaaa5f7351303919c6baedca3145e5743a1102 | wikidoc | FOXD3 | FOXD3
Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.
# Function
This gene belongs to the forkhead protein family of transcription factors which is characterized by a DNA-binding forkhead domain. FoxD3 functions as a transcriptional repressor and contains the C-terminal engrailed homology-1 motif (eh1), which provides an interactive surface with a transcriptional co-repressor Grg4 (Groucho-related gene-4).
## Stem cells
Multiple studies have suggested Foxd3 involvement in the transition from naive to primed pluripotent stem cells in embryo development. Previously, Foxd3 was demonstrated to be required in maintaining pluripotency in mouse embryonic stem cells. A recent finding further showed that Foxd3 is necessary as a repressor in the transition from ESC to epiblast-like cells (EpiLC). The study proposed that Foxd3 is associated with inactivation of important naive pluripotency genes by its modification of chromatin structures via recruiting histone demethylases and decreasing the number of activating factors. Another proposed mechanism on the other hand argued that Foxd3 begins nucleosome removal and induction to a "primed" pluripotent state by recruiting Brg1, a nucleosome remodeler, and then acts as a repressor of maximal activation of those enhancers by recruiting histone deacetylases, suggesting a complex mediating function in which enhancers are primed for some future controlled time-point rather than immediate expression. While there is no ambiguity that Foxd3 plays an important role regulating the transition from naive to primed pluripotency state, the two models show a different process. Attempts to reconcile the conclusions of the two studies have further suggested that Foxd3 functions as all of the above.
# Clinical significance
Mutations in this gene cause vitiligo. | FOXD3
Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.[1]
# Function
This gene belongs to the forkhead protein family of transcription factors which is characterized by a DNA-binding forkhead domain. FoxD3 functions as a transcriptional repressor and contains the C-terminal engrailed homology-1 motif (eh1), which provides an interactive surface with a transcriptional co-repressor Grg4 (Groucho-related gene-4).[2]
## Stem cells
Multiple studies have suggested Foxd3 involvement in the transition from naive to primed pluripotent stem cells in embryo development. Previously, Foxd3 was demonstrated to be required in maintaining pluripotency in mouse embryonic stem cells.[3] A recent finding further showed that Foxd3 is necessary as a repressor in the transition from ESC to epiblast-like cells (EpiLC).[4] The study proposed that Foxd3 is associated with inactivation of important naive pluripotency genes by its modification of chromatin structures via recruiting histone demethylases and decreasing the number of activating factors. Another proposed mechanism on the other hand argued that Foxd3 begins nucleosome removal and induction to a "primed" pluripotent state by recruiting Brg1, a nucleosome remodeler, and then acts as a repressor of maximal activation of those enhancers by recruiting histone deacetylases, suggesting a complex mediating function in which enhancers are primed for some future controlled time-point rather than immediate expression.[5] While there is no ambiguity that Foxd3 plays an important role regulating the transition from naive to primed pluripotency state, the two models show a different process. Attempts to reconcile the conclusions of the two studies have further suggested that Foxd3 functions as all of the above.[6]
# Clinical significance
Mutations in this gene cause vitiligo.[7] | https://www.wikidoc.org/index.php/FOXD3 | |
0f65fc31a1e3ec190da13d1d107cd2f3dae9d892 | wikidoc | FOXE1 | FOXE1
Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.
# Location
The FOXE1 gene is located on the long (q) arm of chromosome 9 at position 22
# Function
This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene functions as a thyroid transcription factor which likely plays a crucial role in thyroid morphogenesis.
# Clinical significance
Mutations in this gene cause Bamforth-Lazarus syndrome and are associated with congenital hypothyroidism and cleft palate with thyroid dysgenesis. The map localization of this gene suggests it may also be a candidate gene for squamous cell epithelioma and hereditary sensory neuropathy type I.
The region surrounding the FOXE1 gene has shown association in the pathogenesis of cleft lip and palate with genome-wide levels of significance in linkage analysis studies with additional fine-mapping and replication.
# Tissue localization
FOXE1 is expressed transiently in the developing thyroid and the anterior pituitary gland.
Avian FOXE1 is also expressed in developing feathers. | FOXE1
Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.[1][2][3]
# Location
The FOXE1 gene is located on the long (q) arm of chromosome 9 at position 22[4]
# Function
This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene functions as a thyroid transcription factor which likely plays a crucial role in thyroid morphogenesis.
# Clinical significance
Mutations in this gene cause Bamforth-Lazarus syndrome[5] and are associated with congenital hypothyroidism and cleft palate with thyroid dysgenesis. The map localization of this gene suggests it may also be a candidate gene for squamous cell epithelioma and hereditary sensory neuropathy type I.[3]
The region surrounding the FOXE1 gene has shown association in the pathogenesis of cleft lip and palate with genome-wide levels of significance in linkage analysis studies with additional fine-mapping and replication.[5]
# Tissue localization
FOXE1 is expressed transiently in the developing thyroid and the anterior pituitary gland.[6]
Avian FOXE1 is also expressed in developing feathers.[7] | https://www.wikidoc.org/index.php/FOXE1 | |
8c6a73fc5230755faf86efd8bc37f9a09c8260dc | wikidoc | FOXE3 | FOXE3
Forkhead box protein E3 (FOXE3) also known as forkhead-related transcription factor 8 (FREAC-8) is a protein that in humans is encoded by the FOXE3 gene located on the short arm of chromosome 1.
# Function
FOXE3 is a forkhead-box transcription factor which is involved in the proper formation of the ocular lens and is post-natally expressed in the lens epithelium.
# Development
Foxe3, also known as Forkhead Box E3, is a transcription factor that is responsible for the formation of the lens placode, a precursor to the lens of the eye, and the lens itself. Foxe3 controls multiple processes during development of the lens including, the expression of Cryaα which controls the solubility of the crystalline protein complex in the developing lens. Reduced solubility can lead to potential cataract formation due to crystallization of the lens. Foxe3 also controls the regulation of Prox1, which is responsible for cell cycle progression. As Foxe3 expression downregulates, Prox1 expression increases causing a reduction in cellular proliferation in the anterior lens. Foxe3 also regulates platelet-derived growth factor receptor-α (Pdgfrα) expression. This is responsible for lens fiber differentiation within the epithelium of certain parts of the lens. There are multiple defects associated with dysfunction of this gene with most being classified under the term anterior segment dysgenesis (ASD). For example, Peters anomaly is a rare disorder obtained during development characterized by adhesions due to malformations of the posterior corneal stroma, the absence of Descemet’s membrane and the corneal endothelium, and corneal opacities. This syndrome can be attributed to fetal alcohol syndrome and aneuploidy. Scientists have generated a knockout model for Foxe3 in mice and are testing the effects on the lenses of those animals. So far, it appears that Foxe3 is essential for normal lens development.
# Clinical significance
Mutations in the FOXE3 gene are associated with anterior segment mesenchymal dysgenesis.
Homozygous mutations in this gene have been associated with a number of ocular diseases such as congenital aphakia, sclerocornea, microphthalmia, and optic disc coloboma. There have also been reports of heterozygous mutations causing less severe ocular diseases such as anterior segment dysgenesis (sometimes referred to as anterior segment mesenchymal dysgenesis), and Peter's anomaly. | FOXE3
Forkhead box protein E3 (FOXE3) also known as forkhead-related transcription factor 8 (FREAC-8) is a protein that in humans is encoded by the FOXE3 gene located on the short arm of chromosome 1.[1]
# Function
FOXE3 is a forkhead-box transcription factor which is involved in the proper formation of the ocular lens and is post-natally expressed in the lens epithelium.
# Development
Foxe3, also known as Forkhead Box E3, is a transcription factor that is responsible for the formation of the lens placode, a precursor to the lens of the eye, and the lens itself. Foxe3 controls multiple processes during development of the lens including, the expression of Cryaα which controls the solubility of the crystalline protein complex in the developing lens. Reduced solubility can lead to potential cataract formation due to crystallization of the lens. Foxe3 also controls the regulation of Prox1, which is responsible for cell cycle progression. As Foxe3 expression downregulates, Prox1 expression increases causing a reduction in cellular proliferation in the anterior lens. Foxe3 also regulates platelet-derived growth factor receptor-α (Pdgfrα) expression. This is responsible for lens fiber differentiation within the epithelium of certain parts of the lens. There are multiple defects associated with dysfunction of this gene with most being classified under the term anterior segment dysgenesis (ASD). For example, Peters anomaly is a rare disorder obtained during development characterized by adhesions due to malformations of the posterior corneal stroma, the absence of Descemet’s membrane and the corneal endothelium, and corneal opacities. This syndrome can be attributed to fetal alcohol syndrome and aneuploidy.[2] Scientists have generated a knockout model for Foxe3 in mice and are testing the effects on the lenses of those animals. So far, it appears that Foxe3 is essential for normal lens development.[3]
# Clinical significance
Mutations in the FOXE3 gene are associated with anterior segment mesenchymal dysgenesis.[4]
Homozygous mutations in this gene have been associated with a number of ocular diseases such as congenital aphakia,[5][6] sclerocornea, microphthalmia, and optic disc coloboma.[7] There have also been reports of heterozygous mutations causing less severe ocular diseases such as anterior segment dysgenesis (sometimes referred to as anterior segment mesenchymal dysgenesis),[4] and Peter's anomaly.[8] | https://www.wikidoc.org/index.php/FOXE3 | |
68e5ebc66d6742f7e3e08a451d4bc1bd6faec1b8 | wikidoc | FOXG1 | FOXG1
Forkhead box protein G1 is a protein that in humans is encoded by the FOXG1 gene.
# Function
This gene belongs to the forkhead family of transcription factors that is characterized by a distinct forkhead domain. The complete function of this gene has not yet been determined; however, it has been shown to play a role in the development of the brain and telencephalon. Mutations of FOXG1 are the cause of FoxG1 Syndrome.
# FOXG1 syndrome
FoxG1 Syndrome is characterized by microcephaly and brain malformations. It affects most aspects of development and can cause seizures. FOXG1 syndrome is classified as an Autism Spectrum Disorder and was previously considered a variant of Rett syndrome.
# Interactions
FOXG1 has been shown to interact with JARID1B. | FOXG1
Forkhead box protein G1 is a protein that in humans is encoded by the FOXG1 gene.[1][2][3]
# Function
This gene belongs to the forkhead family of transcription factors that is characterized by a distinct forkhead domain. The complete function of this gene has not yet been determined; however, it has been shown to play a role in the development of the brain and telencephalon. Mutations of FOXG1 are the cause of FoxG1 Syndrome[4].
# FOXG1 syndrome
FoxG1 Syndrome is characterized by microcephaly and brain malformations. It affects most aspects of development and can cause seizures. FOXG1 syndrome is classified as an Autism Spectrum Disorder and was previously considered a variant of Rett syndrome.[5][6]
# Interactions
FOXG1 has been shown to interact with JARID1B.[7] | https://www.wikidoc.org/index.php/FOXG1 | |
7b6610d9b1375722804f3d1ae615ec0470691129 | wikidoc | FOXH1 | FOXH1
Forkhead box protein H1 is a protein that in humans is encoded by the FOXH1 gene.
# Function
FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT.
# Interactions
FOXH1 has been shown to interact with DRAP1 and Mothers against decapentaplegic homolog 2. | FOXH1
Forkhead box protein H1 is a protein that in humans is encoded by the FOXH1 gene.[1][2]
# Function
FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT.[2]
# Interactions
FOXH1 has been shown to interact with DRAP1[3] and Mothers against decapentaplegic homolog 2.[4][5][6][7][8] | https://www.wikidoc.org/index.php/FOXH1 | |
3fddc3406244e8b8c55a387b4adb8ea343de5475 | wikidoc | FOXJ1 | FOXJ1
Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the lung, choroid plexus, reproductive track, embryonic kidney and pre-somite embryo stage.
# Gene Location
The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1.
# Structure
FOXJ1 has a conserved 100 amino acid long DNA binding domain.
# Function
This gene encodes a member of the forkhead family of transcription factors. Similar genes in zebra fish and mouse have been shown to regulate the transcription of genes that control the production of motile cilia. The mouse ortholog also functions in the determination of left-right asymmetry.
## Ciliogenesis
Primary ciliogenesis is FOXJ1 dependent and this transcription factor is required for motile ciliated cell differentiation. The onset of FOXJ1 expression is indicative of cells fated to become motile cilliated cells. Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth. The protein p73 a member of the p53 protein family directly regulates FOXJ1 and is a requirement for ciliated cell formation. The ten thousand base pair long transcription start site of FOXJ1 features three sequence specific binding sites for p73.
## Immune system
In mammalian cells FOXJ1 has been shown to suppress NFκB a key regulator in the immune response and also inhibits the humoral response in B-Cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.
## Development
FOXJ1 is expressed at various points during embryonic development in relation to teeth germination, enamel, oral and tongue epithelium formation, and formation of sub-mandibular salivary glands and hair follicles. Absence of FOXJ1 expression decreases calpastatin, an inhibitor of the protease calpain. Calpain dysregulation affects basal body anchoring to the apical cytoskeleton affecting axeonemal formation. Expression of FOXJ1 is inhibited by IL-13.
# Clinical significance
Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis.
Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action.
## Breast cancer
Studies into human breast tissue lines and primary breast tumors have observed that the gene FOXJ1 are aberrantly hypermethylated in primary tumors. This hypermethylation serves to silence production of the FOXJ1 protein and has been proposed as a potentially important event in tumor formation.
## Clear renal cell carcinoma
FOXJ1 expression has been shown to be elevated in clear cell renal carcinoma patients and indicative of tumor stage, histological grade and tumor size. High expression of FOXJ1 in CRCC patients was associated with poor prognosis. There is potential for FOXJ1 to act as an oncogene marker for CRCC patients and has value as a therapeutic target.
## Axenfeld-Rieger Syndrome
Axenfeld-Rieger syndrome patients have a point mutation in PITX2 a regulatory protein of the FOXJ1 gene. PITX2 alongside LEF-1 and β-Catenin regulate FOXJ1. FOXJ1 in turn interacts with PITX2 to form a positive feedback mechanism. In the PITX2 point mutant whilst able to bind with FOXJ1 lacks the ability to activate the FOXJ1 promoter, this results in improper oro-facial morphogenesis a factor in ARS. | FOXJ1
Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene.[1] It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis.[2] FOXJ1 is expressed in ciliated cells of the lung,[3] choroid plexus,[4] reproductive track,[5] embryonic kidney and pre-somite embryo stage.[6]
# Gene Location
The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1.[7]
# Structure
FOXJ1 has a conserved 100 amino acid long DNA binding domain.[8]
# Function
This gene encodes a member of the forkhead family of transcription factors. Similar genes in zebra fish and mouse have been shown to regulate the transcription of genes that control the production of motile cilia. The mouse ortholog also functions in the determination of left-right asymmetry.[1]
## Ciliogenesis
Primary ciliogenesis is FOXJ1 dependent and this transcription factor is required for motile ciliated cell differentiation. The onset of FOXJ1 expression is indicative of cells fated to become motile cilliated cells.[9] Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth.[10] The protein p73 a member of the p53 protein family directly regulates FOXJ1 and is a requirement for ciliated cell formation. The ten thousand base pair long transcription start site of FOXJ1 features three sequence specific binding sites for p73.[11]
## Immune system
In mammalian cells FOXJ1 has been shown to suppress NFκB a key regulator in the immune response[12] and also inhibits the humoral response in B-Cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.[13]
## Development
FOXJ1 is expressed at various points during embryonic development in relation to teeth germination, enamel, oral and tongue epithelium formation, and formation of sub-mandibular salivary glands and hair follicles.[14] Absence of FOXJ1 expression decreases calpastatin, an inhibitor of the protease calpain. Calpain dysregulation affects basal body anchoring to the apical cytoskeleton affecting axeonemal formation.[15] Expression of FOXJ1 is inhibited by IL-13.[16]
# Clinical significance
Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis.[1]
Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action.[17]
## Breast cancer
Studies into human breast tissue lines and primary breast tumors have observed that the gene FOXJ1 are aberrantly hypermethylated in primary tumors. This hypermethylation serves to silence production of the FOXJ1 protein and has been proposed as a potentially important event in tumor formation.[18]
## Clear renal cell carcinoma
FOXJ1 expression has been shown to be elevated in clear cell renal carcinoma patients and indicative of tumor stage, histological grade and tumor size. High expression of FOXJ1 in CRCC patients was associated with poor prognosis. There is potential for FOXJ1 to act as an oncogene marker for CRCC patients and has value as a therapeutic target.[19]
## Axenfeld-Rieger Syndrome
Axenfeld-Rieger syndrome patients have a point mutation in PITX2 a regulatory protein of the FOXJ1 gene. PITX2 alongside LEF-1 and β-Catenin regulate FOXJ1. FOXJ1 in turn interacts with PITX2 to form a positive feedback mechanism. In the PITX2 point mutant whilst able to bind with FOXJ1 lacks the ability to activate the FOXJ1 promoter, this results in improper oro-facial morphogenesis a factor in ARS.[20] | https://www.wikidoc.org/index.php/FOXJ1 | |
57fdaf1e5e6878063ec830ae6e7f595f20e3c473 | wikidoc | FOXM1 | FOXM1
Forkhead box protein M1 is a protein that in humans is encoded by the FOXM1 gene. The protein encoded by this gene is a member of the FOX family of transcription factors. Its potential as a target for future cancer treatments led to it being designated the 2010 Molecule of the Year.
# Function
FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases. FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid cardiomyocytes and hepatocytes, highlighting the role of FOXM1 in mitotic division. More recently a study using transgenic/knockout mouse embryonic fibroblasts and human osteosarcoma cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as Plk1, cyclin B2, Nek2 and CENPF, and plays an important role in maintenance of chromosomal segregation and genomic stability.
# Cancer link
FOXM1 gene is now known as a human proto-oncogene. Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide. FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver, breast, lung, prostate, cervix of uterus, colon, pancreas, and brain.
# Isoforms
There are three FOXM1 isoforms, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional repressor whereas the remaining isoforms (B and C) are both transcriptional activators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.
# Mechanism of oncogenesis
The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.
FOXM1 overexpression is involved in early events of carcinogenesis in head and neck squamous cell carcinoma. It has been shown that nicotine exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation.
# Role in stem cell fate
A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.
# Role in epigenome regulations
Given the role in progenitor/stem cells expansion, FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome. A number of new epigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to represent epigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.
# Interactions
FOXM1 has been shown to interact with Cdh1. | FOXM1
Forkhead box protein M1 is a protein that in humans is encoded by the FOXM1 gene.[1][2] The protein encoded by this gene is a member of the FOX family of transcription factors.[1][3] Its potential as a target for future cancer treatments led to it being designated the 2010 Molecule of the Year.[4]
# Function
FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases.[5] FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid cardiomyocytes and hepatocytes, highlighting the role of FOXM1 in mitotic division. More recently a study using transgenic/knockout mouse embryonic fibroblasts and human osteosarcoma cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as Plk1, cyclin B2, Nek2 and CENPF, and plays an important role in maintenance of chromosomal segregation and genomic stability.[6]
# Cancer link
FOXM1 gene is now known as a human proto-oncogene.[7] Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide.[8] FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver,[9] breast,[10] lung,[11] prostate,[12] cervix of uterus,[13] colon,[14] pancreas,[15] and brain.[16]
# Isoforms
There are three FOXM1 isoforms, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional repressor whereas the remaining isoforms (B and C) are both transcriptional activators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.[5]
# Mechanism of oncogenesis
The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.[17]
FOXM1 overexpression is involved in early events of carcinogenesis in head and neck squamous cell carcinoma. It has been shown that nicotine exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation.[18]
# Role in stem cell fate
A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.[19]
# Role in epigenome regulations
Given the role in progenitor/stem cells expansion,[19] FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome. A number of new epigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to represent epigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.[20]
# Interactions
FOXM1 has been shown to interact with Cdh1.[21] | https://www.wikidoc.org/index.php/FOXM1 | |
b7b42bfc04c9da890ba1ec72fd467864679c8839 | wikidoc | FOXO1 | FOXO1
Forkhead box protein O1 (FOXO1) also known as forkhead in rhabdomyosarcoma is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.
# Function
## Adipogenesis
FOXO1 negatively regulates adipogenesis. Presently, the exact mechanism by which this is accomplished is not entirely understood. In the currently accepted model, FOXO1 negatively regulates adipogenesis by binding to the promoter sites of PPARG and preventing its transcription. Rising levels of PPARG are required to initiate adipogenesis; by preventing its transcription, FOXO1 is preventing the onset of adipogenesis. During stimulation by insulin, FOXO1 is excluded from the nucleus and is subsequently unable to prevent transcription of PPARG and inhibit adipogenesis. However, there is substantial evidence to suggest that there are other factors that mediate the interaction between FOXO1 and the PPARG promoter, and that inhibition of adipogenesis is not entirely dependent on FOXO1 preventing transcription of PPARG. The failure to commit to adipogenesis is primarily due to active FOXO1 arresting the cell in G0/G1 through activation of yet unknown downstream targets, with a putative target being SOD2.
FOXO1 belongs to the forkhead family of transcription factors that are characterized by a distinct fork head domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. FOXO1 is essential for the maintenance of human ESC pluripotency. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. In hepatic cells this transcription factor seems to increase the expression of PEPCK and glycogen-6-phosphatase (the same enzymes that are blocked via the metformin/AMPK/SHP pathway). Blocking this transcription factor offers an opportunity for novel therapies for diabetes mellitus. In pancreatic alpha-cells FOXO1 is important in regulating prepro-glucagon expression. In pancreatic beta cells FOXO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass.
## Gluconeogenesis and glycogenolysis
When the level of blood glucose is high, the pancreas releases insulin into the bloodstream. Insulin then causes the activation of PI3K, which subsequently phosphorylates Akt. Akt then phosphorylates FOXO1, causing nuclear exclusion. This phosphorylated FOXO1 is then ubiquitinated and degraded by the proteosome. The phosphorylation of FOXO1 is irreversible; this prolongs insulin's inhibitory effect on glucose metabolism and hepatic glucose production. Transcription of glucose 6-phosphatase subsequently decreases, which consequently decreases the rates of gluconeogenesis and glycogenolysis. FOXO1 also activates transcription of phosphoenolpyruvate carboxykinase, which is required for gluconeogenesis. The activity of FOXO1 is also regulated through CBP induced acetylation on Lys-242, Lys-245, and Lys-262. These lysine residues are located within the DNA-binding domain; acetylation inhibits the ability of FOXO1 to interact with the glucose-6 phosphatase promoter by decreasing the stability of the FOXO1-DNA complex. Additionally, this acetylation increases the rate of phosphorylation on Ser-253 by Akt. Mutating Ser-253 to Ala-253 makes FOXO1 constitutionally active. SIRT1 reverses this acetylation process; however, the exact mechanism by which SIRT1 deacetylates FOXO1 is still under investigation; presently, acetylation is thought to mitigate the transcriptional activity of FOXO1 and thereby provide an additional level of metabolic regulation that is independent of the insulin/PI3K pathway.
## Apoptosis
FOXO1 may play an important role in apoptosis because it is phosphorylated and inhibited by AKT. When FOXO1 over expressed in human LNCaP prostate cancer cells, it caused apoptosis in these cancer cells. Also, It is detected that FOXO1 regulateTNF-related apoptosis-inducing ligand (TRAIL), which cause FOXO1-induced apoptosis in the human prostate cancer cell line LAPC4 when FOXO1 adenovirus-mediated overexpression was used. FOXO1 upregulate Fas ligand (FasL) transcriptionally that result in promotes apoptotic cell death. Additionally, FOXO1 trans-activate Bim protein, which a member of the Bcl-2 family that promotes apoptosis and plays a role in the intrinsic mitochondrial apoptotic pathway. Further, it was revealed that DNA damage-induced cell death in p53-deficient and p53-proficient cells reduced when human FOXO1 silenced by siRNA.
## Cell Cycle Regulation
FOXO1 activation plays a role in cell cycle progression regulation. The transcription and half- life of cyclin-dependent kinase inhibitor p27KIP1 rises when FOXO1 is active. A study detects that FOXO1 regulates the nuclear localization of p27KIP1 in porcine granulosa cells and impacts cell cycle progression. Furthermore, FOXO1-mediated cell cycle arrest is linked with cyclin D1 and cyclin D2 suppression in mammals. It was detected that human FOXO1 is linked with the cyclin D1 promoter using chromatin immunoprecipitation assays (ChIP assays). H215R is a human FOXO1 mutant, which cannot bind to the canonical FRE to induce expression of p27KIP1, repress cyclin D1 and cyclin D2 promoter activity and encourages cell cycle arrest at cyclin G1 (CCNG1). As a result of that, activation of FOXO1 prevents the cell-division cycle at cyclin G1 (CCNG1) out of one of two ways stimulating or suppressing gene transcription.
# Mechanism of action
In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production. However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.
# Regulation
There are three processes, namely acetylation, phosphorylation, and ubiquitination that are responsible for regulation of the activity of forkhead box O1 (FOXO1).
## Phosphorylation
Phosphorylation of the FOXO1 protein is a result of the activation of the PI3K /AKT pathway. Serum and glucocorticoid-inducible kinase SGK can also phosphorylate and inactivate FOXO1 transcription factor. FOXO1 translocate from the nucleus to cytoplasm and inactivate through phosphorylation at well-defined sites by AKT/SGK1 protein kinases. FOXO1 transcription factor can phosphorylate directly by AKT/SGK1 on three sites T24, S256 and S319. Additionally, FOXO1 loses its interactions with DNA when phosphorylated by AKT/SGK1 because S256, which is one of the three AKT/SGK sites, changes the DNA-binding domain charge from a positive charge to a negative charge.
Insulin signaling substrates 1 and 2 of the insulin-signaling cascade also regulate FOXO1 through phosphorylation by AKT. AKT, which is referred to as protein kinase B, phosphorylates FOXO1 and accumulates in the cytosol.
Casein kinase 1, a growth factor-activated protein kinase, also phosphorylates and potentiates FOXO1 and translocates FOXO1 to the cytoplasm.
# Research
Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of type 2 diabetes. In the insulin-resistant murine model, there is increased hepatic glucose production due to a loss in insulin sensitivity; the rates of hepatic gluconeogenesis and glycogenolysis are increased when compared to normal mice; this is presumably due to un-regulated FOXO1. When the same experiment was repeated with haploinsufficient FOXO1, insulin sensitivity was partially restored, and hepatic glucose production subsequently decreased. Similarly, in mice fed with a high fat diet (HFD), there is increased insulin resistance in skeletal and liver cells. However, when haploinsufficient FOXO1 mice were treated with the same HFD, there was a notable decrease in insulin resistance in both skeletal and liver cells. This effect was significantly augmented by the simultaneous administration of rosiglitazone, which is a commonly prescribed anti-diabetic drug. These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes.
In HFD-fed mice, the combination of FOXO1 and Notch-1 haploinsufficiency was more effective at restoring insulin sensitivity than FOXO1 haploinsufficiency alone.
Insulin-producing cells could be generated through the inhibition of FOXO1 in intestinal organoids generated from intestinal stem cells isolated from adult tissue.
# Clinical significance
- Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma.
- In Gluconeogenesis, FOXO1 gene regulates the glucose levels due to the low output of hepatic glucose. In mice, it cuts fasting blood glucose levels by inhibiting formulation of the gluconeogenic genes.
- FOXO1 plays a role in the protection of cells from oxidative stress. It seems to promote cell death when oxidative stress is high in tissues that are involved in diabetic complications. In such situations, it has a destructive role instead of a protective role.
- FOXO1 helps in wound healing in mice through coordination of response of keratinocytes and functions in keratinocytes to bring down oxidative stress. Wound healing is a very complicated biological process and studies have indicated that FOXO1 transcription factor helps in orchestrating events that enhance the healing process in keratinocytes. Localization of FOXO1 nuclear increased four times in wound-healing keratinocytes. It encourages the migration of the keratinocytes through upregulating the growth factor.
- In the Innate Immune system, FOXO1 has been proved to enhance inflammation through increasing formulation of several proinflammatory genes. It mediates formulation of proinflammatory cytokines in response to high glucose levels, TNF and LPS stimulation.
- In Adaptive Immunity system, FOXO1 regulates the return of peripheral B cells by upregulation of L-section and controls class-switch recombination of peripheral B cells and in T cells it enhances survival of CD8 memory.
- In Carcinogenesis, FOXO1 plays a role of a tumor suppressor and its inactivation has been documented in many kinds of human cancer. It suppresses survival of tumor cells by inducing apoptosis in prostate cancer cells and glioma cells by upregulating the proapoptotic factors. Increased activation of FOXO1 may inhibit the metastasis of the prostate cancer cells to other organs by suppressing the migration and invasion or suppressing the Runt-domain containing Runx2 transcriptional activity.
# Interactions
FOXO1 has been shown to interact with:
- androgen receptor,
- estrogen receptor alpha,
- CREB-binding protein, and
- tuberous sclerosis protein 2. | FOXO1
Forkhead box protein O1 (FOXO1) also known as forkhead in rhabdomyosarcoma is a protein that in humans is encoded by the FOXO1 gene.[1] FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis.[2] It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.[3]
# Function
## Adipogenesis
FOXO1 negatively regulates adipogenesis.[4] Presently, the exact mechanism by which this is accomplished is not entirely understood. In the currently accepted model, FOXO1 negatively regulates adipogenesis by binding to the promoter sites of PPARG and preventing its transcription. Rising levels of PPARG are required to initiate adipogenesis; by preventing its transcription, FOXO1 is preventing the onset of adipogenesis. During stimulation by insulin, FOXO1 is excluded from the nucleus and is subsequently unable to prevent transcription of PPARG and inhibit adipogenesis.[5] However, there is substantial evidence to suggest that there are other factors that mediate the interaction between FOXO1 and the PPARG promoter, and that inhibition of adipogenesis is not entirely dependent on FOXO1 preventing transcription of PPARG.[6] The failure to commit to adipogenesis is primarily due to active FOXO1 arresting the cell in G0/G1 through activation of yet unknown downstream targets, with a putative target being SOD2.[7]
FOXO1 belongs to the forkhead family of transcription factors that are characterized by a distinct fork head domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation.[8] FOXO1 is essential for the maintenance of human ESC pluripotency. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters.[9] In hepatic cells this transcription factor seems to increase the expression of PEPCK and glycogen-6-phosphatase (the same enzymes that are blocked via the metformin/AMPK/SHP pathway). Blocking this transcription factor offers an opportunity for novel therapies for diabetes mellitus.[10] In pancreatic alpha-cells FOXO1 is important in regulating prepro-glucagon expression.[11] In pancreatic beta cells FOXO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass.[12]
## Gluconeogenesis and glycogenolysis
When the level of blood glucose is high, the pancreas releases insulin into the bloodstream. Insulin then causes the activation of PI3K, which subsequently phosphorylates Akt. Akt then phosphorylates FOXO1, causing nuclear exclusion. This phosphorylated FOXO1 is then ubiquitinated and degraded by the proteosome.[13] The phosphorylation of FOXO1 is irreversible; this prolongs insulin's inhibitory effect on glucose metabolism and hepatic glucose production. Transcription of glucose 6-phosphatase subsequently decreases, which consequently decreases the rates of gluconeogenesis and glycogenolysis.[14] FOXO1 also activates transcription of phosphoenolpyruvate carboxykinase, which is required for gluconeogenesis.[15] The activity of FOXO1 is also regulated through CBP induced acetylation[16] on Lys-242, Lys-245, and Lys-262. These lysine residues are located within the DNA-binding domain; acetylation inhibits the ability of FOXO1 to interact with the glucose-6 phosphatase promoter by decreasing the stability of the FOXO1-DNA complex. Additionally, this acetylation increases the rate of phosphorylation on Ser-253 by Akt. Mutating Ser-253 to Ala-253 makes FOXO1 constitutionally active. SIRT1 reverses this acetylation process; however, the exact mechanism by which SIRT1 deacetylates FOXO1 is still under investigation; presently, acetylation is thought to mitigate the transcriptional activity of FOXO1 and thereby provide an additional level of metabolic regulation that is independent of the insulin/PI3K pathway.[17]
## Apoptosis
FOXO1 may play an important role in apoptosis because it is phosphorylated and inhibited by AKT.[18] When FOXO1 over expressed in human LNCaP prostate cancer cells, it caused apoptosis in these cancer cells.[18] Also, It is detected that FOXO1 regulateTNF-related apoptosis-inducing ligand (TRAIL), which cause FOXO1-induced apoptosis in the human prostate cancer cell line LAPC4 when FOXO1 adenovirus-mediated overexpression was used.[18] FOXO1 upregulate Fas ligand (FasL) transcriptionally that result in promotes apoptotic cell death.[18] Additionally, FOXO1 trans-activate Bim protein, which a member of the Bcl-2 family that promotes apoptosis and plays a role in the intrinsic mitochondrial apoptotic pathway.[18] Further, it was revealed that DNA damage-induced cell death in p53-deficient and p53-proficient cells reduced when human FOXO1 silenced by siRNA.[18]
## Cell Cycle Regulation
FOXO1 activation plays a role in cell cycle progression regulation.[18] The transcription and half- life of cyclin-dependent kinase inhibitor p27KIP1 rises when FOXO1 is active.[18] A study detects that FOXO1 regulates the nuclear localization of p27KIP1 in porcine granulosa cells and impacts cell cycle progression.[18] Furthermore, FOXO1-mediated cell cycle arrest is linked with cyclin D1 and cyclin D2 suppression in mammals.[18] It was detected that human FOXO1 is linked with the cyclin D1 promoter using chromatin immunoprecipitation assays (ChIP assays).[18] H215R is a human FOXO1 mutant, which cannot bind to the canonical FRE to induce expression of p27KIP1, repress cyclin D1 and cyclin D2 promoter activity and encourages cell cycle arrest at cyclin G1 (CCNG1).[18] As a result of that, activation of FOXO1 prevents the cell-division cycle at cyclin G1 (CCNG1) out of one of two ways stimulating or suppressing gene transcription.[18]
# Mechanism of action
In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production.[15] However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.
# Regulation
There are three processes, namely acetylation, phosphorylation, and ubiquitination that are responsible for regulation of the activity of forkhead box O1 (FOXO1).[19]
## Phosphorylation
Phosphorylation of the FOXO1 protein is a result of the activation of the PI3K /AKT pathway.[19] Serum and glucocorticoid-inducible kinase SGK can also phosphorylate and inactivate FOXO1 transcription factor.[18] FOXO1 translocate from the nucleus to cytoplasm and inactivate through phosphorylation at well-defined sites by AKT/SGK1 protein kinases.[19] FOXO1 transcription factor can phosphorylate directly by AKT/SGK1 on three sites T24, S256 and S319.[20] Additionally, FOXO1 loses its interactions with DNA when phosphorylated by AKT/SGK1 because S256, which is one of the three AKT/SGK sites, changes the DNA-binding domain charge from a positive charge to a negative charge.[19]
Insulin signaling substrates 1 and 2 of the insulin-signaling cascade also regulate FOXO1 through phosphorylation by AKT.[19] AKT, which is referred to as protein kinase B, phosphorylates FOXO1 and accumulates in the cytosol.[19]
Casein kinase 1, a growth factor-activated protein kinase, also phosphorylates and potentiates FOXO1 and translocates FOXO1 to the cytoplasm.[19]
# Research
Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of type 2 diabetes. In the insulin-resistant murine model, there is increased hepatic glucose production due to a loss in insulin sensitivity; the rates of hepatic gluconeogenesis and glycogenolysis are increased when compared to normal mice; this is presumably due to un-regulated FOXO1. When the same experiment was repeated with haploinsufficient FOXO1, insulin sensitivity was partially restored, and hepatic glucose production subsequently decreased.[21] Similarly, in mice fed with a high fat diet (HFD), there is increased insulin resistance in skeletal and liver cells. However, when haploinsufficient FOXO1 mice were treated with the same HFD, there was a notable decrease in insulin resistance in both skeletal and liver cells. This effect was significantly augmented by the simultaneous administration of rosiglitazone, which is a commonly prescribed anti-diabetic drug.[22] These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes.
In HFD-fed mice, the combination of FOXO1 and Notch-1 haploinsufficiency was more effective at restoring insulin sensitivity than FOXO1 haploinsufficiency alone.[23]
Insulin-producing cells could be generated through the inhibition of FOXO1 in intestinal organoids generated from intestinal stem cells isolated from adult tissue.[24]
# Clinical significance
- Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma.[1][25]
- In Gluconeogenesis, FOXO1 gene regulates the glucose levels due to the low output of hepatic glucose.[19] In mice, it cuts fasting blood glucose levels by inhibiting formulation of the gluconeogenic genes.[19]
- FOXO1 plays a role in the protection of cells from oxidative stress.[19] It seems to promote cell death when oxidative stress is high in tissues that are involved in diabetic complications.[19] In such situations, it has a destructive role instead of a protective role.[19]
- FOXO1 helps in wound healing in mice through coordination of response of keratinocytes and functions in keratinocytes to bring down oxidative stress.[19] Wound healing is a very complicated biological process and studies have indicated that FOXO1 transcription factor helps in orchestrating events that enhance the healing process in keratinocytes.[26] Localization of FOXO1 nuclear increased four times in wound-healing keratinocytes.[26] It encourages the migration of the keratinocytes through upregulating the growth factor.[26]
- In the Innate Immune system, FOXO1 has been proved to enhance inflammation through increasing formulation of several proinflammatory genes.[19] It mediates formulation of proinflammatory cytokines in response to high glucose levels, TNF and LPS stimulation.[19]
- In Adaptive Immunity system, FOXO1 regulates the return of peripheral B cells by upregulation of L-section and controls class-switch recombination of peripheral B cells and in T cells it enhances survival of CD8 memory.[19]
- In Carcinogenesis, FOXO1 plays a role of a tumor suppressor and its inactivation has been documented in many kinds of human cancer.[19] It suppresses survival of tumor cells by inducing apoptosis in prostate cancer cells and glioma cells by upregulating the proapoptotic factors.[19] Increased activation of FOXO1 may inhibit the metastasis of the prostate cancer cells to other organs by suppressing the migration and invasion or suppressing the Runt-domain containing Runx2 transcriptional activity.[19]
# Interactions
FOXO1 has been shown to interact with:
- androgen receptor,[27]
- estrogen receptor alpha,[28]
- CREB-binding protein,[29] and
- tuberous sclerosis protein 2.[30] | https://www.wikidoc.org/index.php/FOXO1 | |
ef1aff5fdf01b42799da4b83ef5ffcefb5a2e6a4 | wikidoc | FOXO3 | FOXO3
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.
# Function
FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear). Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.
This protein likely functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA, or downregulation of anti-apoptotic proteins such as FLIP.
Gopinath et al.(2014) demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration.
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.
# Clinical significance
Deregulation of FOXO3a is involved in tumorigenesis, for example translocation of this gene with the MLL gene is associated with secondary acute leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor.
Alternatively spliced transcript variants encoding the same protein have been observed.
# Association with longevity
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world. The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms. | FOXO3
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.[1]
# Function
FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear).[2] Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.
This protein likely functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[3] or downregulation of anti-apoptotic proteins such as FLIP.[4]
Gopinath et al.(2014)[5] demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration.
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.
# Clinical significance
Deregulation of FOXO3a is involved in tumorigenesis,[6] for example translocation of this gene with the MLL gene is associated with secondary acute leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor.
Alternatively spliced transcript variants encoding the same protein have been observed.[7]
# Association with longevity
A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[8][9] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms. | https://www.wikidoc.org/index.php/FOXO3 | |
7284dcf35d6e3d327d5d09968e165f011af6b732 | wikidoc | FOXO4 | FOXO4
Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene. It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.
# Structure and function
FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding. There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation. Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis. Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.
# Clinical significance
## Associations with longevity
FOXO transcription factors have been shown to be the down downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans. FOXO's activation of these pathways produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.
## Cancer
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation. FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1. In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size. Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia. The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.
In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ. When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin. These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).
In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4. As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.
# Interactions
FOXO4 has been shown to interact with PIN1 and Mdm2. | FOXO4
Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.[1][2] It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.[3]
# Structure and function
FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding.[4][5] There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.[6] Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis.[7][8][9][10][11] Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB.[12][13] Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.
# Clinical significance
## Associations with longevity
FOXO transcription factors have been shown to be the down downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans.[14] FOXO's activation of these pathways produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.[15][16]
## Cancer
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.[17][18][19] FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.[20] In HER-2 positive tumor cells, increasing FOXO4 activity reduces tumor size.[20] Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.[21] The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.[21]
In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.[22] When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin.[23] These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).
In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.[24] As with gastric cancer, these cancers with the lowest levels of FOXO4 also had the lowest levels of E-cadherin and highest levels of vimentin, consistent with FOXO4 acting as a suppressor of the EMT phenotype.[24]
# Interactions
FOXO4 has been shown to interact with PIN1[25] and Mdm2.[26] | https://www.wikidoc.org/index.php/FOXO4 | |
ae2823c5e832f33c0eaf6ae74491709b2ee63cef | wikidoc | FOXP1 | FOXP1
Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.
# Function
This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Forkhead box P1 protein contains both DNA-binding- and protein-protein binding-domains. This gene may act as a tumor suppressor as it is lost in several tumor types and maps to a chromosomal region (3p14.1) reported to contain a tumor suppressor gene(s). Alternative splicing results in multiple transcript variants encoding different isoforms.
Foxp1 is a transcription factor; specifically it is a transcriptional repressor. Fox genes are part of a forkhead DNA-binding domain family. This domain binds to sequences in promoters and enhancers of many genes. Foxp1 regulates a variety of important aspects of development including tissue development of: the lungs, brain, thymus and heart. In the heart Foxp1 has 3 vital roles, these include the regulation of cardiac myocyte maturation and proliferation, outflow tract separation of the pulmonary artery and aorta, and expression of Sox4 in cushions and myocardium. Foxp1 is also an important gene in muscle development of the esophagus and esophageal epithelium. Foxp1 is also an important regulator of lung airway morphogenesis. Foxp1 knockout embryos display severe defects in cardiac morphogenesis. A few of these defects include myocyte maturation and proliferation defects that cause a thin ventricular myocardial compact zone, non-separation of the pulmonary artery and aorta, and cardiomyocyte proliferation increase and defective differentiation. These defects, caused by Foxp1 inactivation, lead to fetal death. Disruptions of FoxP1 have been identified in very rare human patients and – similarly to FoxP2 - lead to cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment.
It was shown that the embryonic stem cell (ESC)-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including OCT4, NANOG, NR5A2, and GDF3, while concomitantly repressing genes required for ESC differentiation. This isoform also promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells. These results reveal a pivotal role for an Alternative splicing event in the regulation of pluripotency through the control of critical ESC-specific transcriptional programs.
The expression of FOXP1 was also implicated in the biology of B cell malignancies, and is regulated by non-coding RNA (miRNA) termed miR-150. | FOXP1
Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.
# Function
This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Forkhead box P1 protein contains both DNA-binding- and protein-protein binding-domains. This gene may act as a tumor suppressor as it is lost in several tumor types and maps to a chromosomal region (3p14.1) reported to contain a tumor suppressor gene(s). Alternative splicing results in multiple transcript variants encoding different isoforms.[1]
Foxp1 is a transcription factor; specifically it is a transcriptional repressor. Fox genes are part of a forkhead DNA-binding domain family. This domain binds to sequences in promoters and enhancers of many genes. Foxp1 regulates a variety of important aspects of development including tissue development of: the lungs, brain, thymus and heart. In the heart Foxp1 has 3 vital roles, these include the regulation of cardiac myocyte maturation and proliferation, outflow tract separation of the pulmonary artery and aorta, and expression of Sox4 in cushions and myocardium. Foxp1 is also an important gene in muscle development of the esophagus and esophageal epithelium. Foxp1 is also an important regulator of lung airway morphogenesis. Foxp1 knockout embryos display severe defects in cardiac morphogenesis. A few of these defects include myocyte maturation and proliferation defects that cause a thin ventricular myocardial compact zone, non-separation of the pulmonary artery and aorta, and cardiomyocyte proliferation increase and defective differentiation. These defects, caused by Foxp1 inactivation, lead to fetal death. Disruptions of FoxP1 have been identified in very rare human patients and – similarly to FoxP2 - lead to cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment.[2]
It was shown that the embryonic stem cell (ESC)-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including OCT4, NANOG, NR5A2, and GDF3, while concomitantly repressing genes required for ESC differentiation. This isoform also promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells. These results reveal a pivotal role for an Alternative splicing event in the regulation of pluripotency through the control of critical ESC-specific transcriptional programs.[3]
The expression of FOXP1 was also implicated in the biology of B cell malignancies, and is regulated by non-coding RNA (miRNA) termed miR-150.[4] | https://www.wikidoc.org/index.php/FOXP1 | |
82c38771bc3a17c766d7aaad65c041654dd331ae | wikidoc | FOXP2 | FOXP2
Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene, also known as CAGH44, SPCH1 or TNRC10, and is required for proper development of speech and language. The gene is shared with many vertebrates, where it generally plays a role in communication (for instance, the development of bird song).
Initially identified as the genetic factor of speech disorder in KE family, FOXP2 is the first gene discovered associated with speech and language. The gene is located on chromosome 7 (7q31, at the SPCH1 locus) and is expressed in fetal and adult brain, heart, lung and gut. FOXP2 orthologs have also been identified in other mammals for which complete genome data are available. The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper. The gene is more active in females than in males, to which could be attributed better language learning in females.
In humans, mutations of FOXP2 cause a severe speech and language disorder. Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice and in songbirds indicate that it is important for modulating plasticity of neural circuits. Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.
FOXP2 is popularly dubbed the "language gene", but this is only partly correct since there are other genes involved in language development. It directly regulates a number of other genes, including CNTNAP2, CTBP1, and SRPX2.
Two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these changes is unique to humans. Evidence from genetically manipulated mice and human neuronal cell models suggests that these changes affect the neural functions of FOXP2.
# Discovery
FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family, half of whom (fifteen individuals across three generations) suffered from a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London. In 1990 Myrna Gopnik, Professor of Linguistics at McGill University, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits. She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability. (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic. Remarkably, the inheritance of the disorder from one generation to the next was consistent with autosomal dominant inheritance, i.e., mutation of only a single gene on an autosome (non-sex chromosome) acting in a dominant fashion. This is one of the few known examples of Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.
In 1998, Oxford University geneticists Simon Fisher, Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members. The chromosomal region (locus) contained 70 genes. The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of bacterial artificial chromosome clones. Around this time, the researchers identified an individual who was unrelated to the KE family, but had a similar type of speech and language disorder. In this case the child, known as CS, carried a chromosomal rearrangement (a translocation) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.
In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene. Using a combination of bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to the forkhead-box (FOX) group of transcription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family, they found a heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people. This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein. Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations and chromosomal rearrangements, providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.
# Function
FOXP2 is required for proper brain and lung development. Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups. Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die an average of 21 days after birth from inadequate lung development.
FOXP2 is expressed in many areas of the brain including the basal ganglia and inferior frontal cortex where it is essential for brain maturation and speech and language development.
A knockout mouse model has been used to examine FOXP2's role in brain development and how mutations in the two copies of FOXP2 affect vocalization. Mutations in one copy result in reduced speech while abnormalities in both copies cause major brain and lung developmental issues.
The expression of FOXP2 is subject to post-transcriptional regulation, particularly micro RNA, which binds to multiple miRNA binding-sites in the neocortex, causing the repression of FOXP2 3’UTR.
# Clinical significance
There are several abnormalities linked to FOXP2. The most common mutation results in severe speech impairment known as developmental verbal dyspraxia (DVD) which is caused by a translocation in the 7q31.2 region . A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2. Although DVD associated with FOXP2 disruptions are thought to be rare (~2% by one estimate), genetic links from FOXP2 to disease usually relate to speech or language problems.
Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene. Such individuals have little or no cognitive handicap but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "language gene". People with this mutation also experience symptoms not related to language (not surprisingly, as FOXP2 is known to affect development in other parts of the body as well). Scientists have also looked for associations between FOXP2 and autism, and both positive and negative findings have been reported.
There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. For examples, the impairments include difficulties in comprehension. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal/ganglia regions, demonstrating that the problems extend beyond the motor system.
# Evolution
The FOXP2 gene is highly conserved in mammals. The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S). In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids. One of the two amino acid differences between human and chimps also arose independently in carnivores and bats. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.
DNA sampling from Homo neanderthalensis bones indicates that their FOXP2 gene is a little different, though largely similar to those of Homo sapiens (i.e. humans).
The FOXP2 gene showed indications of recent positive selection. Some researchers have speculated that positive selection is crucial for the evolution of language in humans. Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2. Recent data from a large sample of globally distributed genomes showed no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition. Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from the human and chimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.
However, FOXP2 is extremely diverse in echolocating bats. Twenty-two sequences of non-bat eutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations. All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans. Within bats, however, amino acid variation correlated with different echolocating types.
# Interactions
FOXP2 interacts with a regulatory gene CTBP1. It also downregulates CNTNAP2 gene, a member of the neurexin family found in neurons. The target gene is associated with common forms of language impairment. It regulates the repeat-containing protein X-linked 2 (SRPX2), which is an epilepsy and language-associated gene in humans, and sound-controlling gene in mice.
# Mice
In a mouse FOXP2 knockout study, loss of both copies of the gene caused severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers. These vocalizations have important communicative roles in mother-offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song. Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.
# Birds
In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.
Gene knockdown of FOXP2 in Area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation. Overexpression of FoxP2 was accomplished through injection of adeno-associated virus serotype 1 (AAV1) into Area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors. Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.
Levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts. “Directed” singing refers to when a male is singing to a female usually for a courtship display. “Undirected” singing occurs when for example, a male sings when other males are present or is alone. Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song.
Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.
FOXP2 also has possible implications in the development of bat echolocation. | FOXP2
Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene, also known as CAGH44, SPCH1 or TNRC10, and is required for proper development of speech and language.[1] The gene is shared with many vertebrates, where it generally plays a role in communication (for instance, the development of bird song).
Initially identified as the genetic factor of speech disorder in KE family, FOXP2 is the first gene discovered associated with speech and language.[2] The gene is located on chromosome 7 (7q31, at the SPCH1 locus) and is expressed in fetal and adult brain, heart, lung and gut.[3][4] FOXP2 orthologs[5] have also been identified in other mammals for which complete genome data are available. The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper. The gene is more active in females than in males, to which could be attributed better language learning in females.[6]
In humans, mutations of FOXP2 cause a severe speech and language disorder.[1][7] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[8] and in songbirds[9] indicate that it is important for modulating plasticity of neural circuits.[10] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[11]
FOXP2 is popularly dubbed the "language gene", but this is only partly correct since there are other genes involved in language development.[12] It directly regulates a number of other genes, including CNTNAP2, CTBP1, and SRPX2.[13][14]
Two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees,[15] but only one of these changes is unique to humans.[11] Evidence from genetically manipulated mice[16] and human neuronal cell models[17] suggests that these changes affect the neural functions of FOXP2.
# Discovery
FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family, half of whom (fifteen individuals across three generations) suffered from a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London.[18] In 1990 Myrna Gopnik, Professor of Linguistics at McGill University, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits.[19] She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.[20] (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.[21][22]) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.[23] Remarkably, the inheritance of the disorder from one generation to the next was consistent with autosomal dominant inheritance, i.e., mutation of only a single gene on an autosome (non-sex chromosome) acting in a dominant fashion. This is one of the few known examples of Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.[24]
In 1998, Oxford University geneticists Simon Fisher, Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members.[3] The chromosomal region (locus) contained 70 genes.[25] The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of bacterial artificial chromosome clones.[4] Around this time, the researchers identified an individual who was unrelated to the KE family, but had a similar type of speech and language disorder. In this case the child, known as CS, carried a chromosomal rearrangement (a translocation) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.[4]
In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.[1] Using a combination of bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to the forkhead-box (FOX) group of transcription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family, they found a heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people.[1] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.[26] Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations[7] and chromosomal rearrangements,[27] providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.
# Function
FOXP2 is required for proper brain and lung development. Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups.[28] Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die an average of 21 days after birth from inadequate lung development.[11]
FOXP2 is expressed in many areas of the brain[15] including the basal ganglia and inferior frontal cortex where it is essential for brain maturation and speech and language development.[13]
A knockout mouse model has been used to examine FOXP2's role in brain development and how mutations in the two copies of FOXP2 affect vocalization. Mutations in one copy result in reduced speech while abnormalities in both copies cause major brain and lung developmental issues.[11]
The expression of FOXP2 is subject to post-transcriptional regulation, particularly micro RNA, which binds to multiple miRNA binding-sites in the neocortex, causing the repression of FOXP2 3’UTR.[29]
# Clinical significance
There are several abnormalities linked to FOXP2. The most common mutation results in severe speech impairment known as developmental verbal dyspraxia (DVD) which is caused by a translocation in the 7q31.2 region [t(5;7)(q22;q31.2)].[1][4] A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.[30] A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members.[7] R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.[31][32] Although DVD associated with FOXP2 disruptions are thought to be rare (~2% by one estimate),[7] genetic links from FOXP2 to disease usually relate to speech or language problems.
Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.[27][33][34][35] Such individuals have little or no cognitive handicap but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "language gene". People with this mutation also experience symptoms not related to language (not surprisingly, as FOXP2 is known to affect development in other parts of the body as well).[36] Scientists have also looked for associations between FOXP2 and autism, and both positive and negative findings have been reported.[37][38]
There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. For examples, the impairments include difficulties in comprehension. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal/ganglia regions, demonstrating that the problems extend beyond the motor system.
# Evolution
The FOXP2 gene is highly conserved in mammals.[39] The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S).[30] In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids.[15][40][41] One of the two amino acid differences between human and chimps also arose independently in carnivores and bats.[11][42] Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.[43][44]
DNA sampling from Homo neanderthalensis bones indicates that their FOXP2 gene is a little different, though largely similar to those of Homo sapiens (i.e. humans). [45][46]
The FOXP2 gene showed indications of recent positive selection.[39][47] Some researchers have speculated that positive selection is crucial for the evolution of language in humans.[15] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[43][44] Recent data from a large sample of globally distributed genomes showed no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition.[48] Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from the human and chimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[16]
However, FOXP2 is extremely diverse in echolocating bats.[49] Twenty-two sequences of non-bat eutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations.[42] All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans.[42] Within bats, however, amino acid variation correlated with different echolocating types.[42]
# Interactions
FOXP2 interacts with a regulatory gene CTBP1.[50] It also downregulates CNTNAP2 gene, a member of the neurexin family found in neurons. The target gene is associated with common forms of language impairment.[51] It regulates the repeat-containing protein X-linked 2 (SRPX2), which is an epilepsy and language-associated gene in humans, and sound-controlling gene in mice.[52]
# Mice
In a mouse FOXP2 knockout study, loss of both copies of the gene caused severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers.[28] These vocalizations have important communicative roles in mother-offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song.[53] Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.[8]
# Birds
In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.[9][54]
Gene knockdown of FOXP2 in Area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation.[9] Overexpression of FoxP2 was accomplished through injection of adeno-associated virus serotype 1 (AAV1) into Area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors.[55] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[41]
Levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts.[54] “Directed” singing refers to when a male is singing to a female usually for a courtship display. “Undirected” singing occurs when for example, a male sings when other males are present or is alone.[56] Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song.[57]
Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.
FOXP2 also has possible implications in the development of bat echolocation.[30][42][58] | https://www.wikidoc.org/index.php/FOXP2 | |
d9ff276c404f031f8d20237ed377b8c6b0c83818 | wikidoc | FOXP3 | FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.
While the precise control mechanism has not yet been established, FOX proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may repress transcription of key genes following stimulation of T cell receptors.
# Structure
The human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. By genomic sequence analysis, the FOXP3 gene maps to the p arm of the X chromosome (specifically, Xp11.23).
# Physiology
Foxp3 is a specific marker of natural T regulatory cells (nTregs, a lineage of T cells) and adaptive/induced T regulatory cells (a/iTregs), also identified by other less specific markers such as CD25 or CD45RB. In animal studies, Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance.
The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in (autoimmune) disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease. Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy.
Further work has shown that T cells are more plastic in nature than originally thought. This means that the use of regulatory T cells in therapy may be risky, as the T regulatory cell transferred to the patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells. Th17 cells are proinflammatory and are produced under similar environments as a/iTregs. Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. Murine studies point to IL-6 whereas human studies have shown IL-21. Foxp3 is the major transcription factor controlling T-regulatory cells (Treg or CD4+ cells). CD4+ cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses. Defects in this gene's ability to function can cause IPEX syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome as well as numerous cancers. While CD4+ cells are heavily regulated and require multiple transcription factors such as STAT-5 and AhR in order to become active and function properly, Foxp3 has been identified as the master regulator for Treg lineage. Foxp3 can either act as a transcriptional activator or suppressor depending on what specific transcriptional factors such as deacetylases and histone acetylases are acting on it. The Foxp3 gene is also known to convert naïve T-cells to Treg cells, which are capable of an in vivo and in vitro suppressive capabilities suggesting that Foxp3 is capable of regulating the expression of suppression-mediating molecules. Clarifying the gene targets of Foxp3 could be crucial to the comprehension of the suppressive abilities of Treg cells.
# Pathophysiology
In human disease, alterations in numbers of regulatory T cells – and in particular those that express Foxp3 – are found in a number of disease states. For example, patients with tumors have a local relative excess of Foxp3 positive T cells which inhibits the body's ability to suppress the formation of cancerous cells. Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells. The Foxp3 gene is also mutated in IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked). These mutations were in the forkhead domain of FOXP3, indicating that the mutations may disrupt critical DNA interactions.
In mice, a Foxp3 mutation (a frameshift mutation that result in protein lacking the forkhead domain) is responsible for 'Scurfy', an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth. These mice have overproliferation of CD4+ T-lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines. This phenotype is similar to those that lack expression of CTLA-4, TGF-β, human disease IPEX, or deletion of the Foxp3 gene in mice ("scurfy mice"). The pathology observed in scurfy mice seems to result from an inability to properly regulate CD4+ T-cell activity. In mice overexpressing the Foxp3 gene, fewer T cells are observed. The remaining T cells have poor proliferative and cytolytic responses and poor interleukin-2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs, particularly lymph nodes, lack the proper number of cells.
# Role in cancer
In addition to FoxP3's role in regulatory T cell differentiation, multiple lines of evidence have indicated that FoxP3 play important roles in cancer development.
Down-regulation of FoxP3 expression has been reported in tumour specimens derived from breast, prostate, and ovarian cancer patients, indicating that FoxP3 is a potential tumour suppressor gene. Expression of FoxP3 was also detected in tumour specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers. However, in these reports, no corresponding normal tissues was analyzed, therefore it remained unclear whether FoxP3 is a pro- or anti-tumourigeneic molecule in these tumours.
Two lines of functional evidence strongly supported that FoxP3 serves as tumour suppressive transcription factor in cancer development. First, FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FoxP3 in melanoma, glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies.
Foxp3 is a recruiter of other anti-tumor enzymes such as CD39 and CD8. The overexpression of CD39 is found in patients with multiple cancer types such as melanoma, leukemia, pancreatic cancer, colon cancer, and ovarian cancer. This overexpression may be protecting tumorous cells, allowing them to create their “escape phase”. A cancerous tumor's “escape phase” is where the tumor grows quickly and it becomes clinically invisible by becoming independent of the extracellular matrix and creating its own immunosuppressive tumor microenvironment. The consequences of a cancer cell reaching the “escape phase” is that it allows it to completely evade the immune system, which reduces the immunogenicity and ability to become clinically detected, allowing it to progress and spread throughout the body. Some cancer patients have also been known to display higher numbers of mutated CD4+ cells. These mutated cells will then produce large quantities of TGF-β and IL-10, (a Transforming Growth Factor β and an inhibitory cytokine respectively,) which will suppress signals to the immune system and allow for tumor escape. In one experiment a 15-mer synthetic peptide, P60, was able to inhibit Foxp3's ability to function. P60 did this by entering the cells and then binding to Foxp3, where it hinders Foxp3's ability to translocate to the nucleus. Due to this, Foxp3 could no longer properly suppress the transcription factors NF-kB and NFAT; both of which are protein complexes that regulate transcription of DNA, cytokine production and cell survival. This would inhibit a cell's ability to perform apoptosis and stop its own cell cycle, which could potentially allow an affected cancerous cell to survive and reproduce.
# Autoimmune
Mutations or disruptions of the Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus. These mutations affect thymocytes developing within the thymus. Regulated by Foxp3, it's these thymocytes that during thymopoiesis, are transformed into mature Treg cells by the thymus. It was found that patients who have the autoimmune disease systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect the thymopoiesis process, preventing the proper development of Treg cells within the thymus. These malfunctioning Treg cells aren’t efficiently being regulated by its transcription factors, which cause them to attack cells that are healthy, leading to these organ-specific autoimmune diseases. Another way that Foxp3 helps keep the autoimmune system at homeostasis is through its regulation of the expression of suppression-mediating molecules. For instance, Foxp3 is able to facilitate the translocation of extracellular adenosine into the cytoplasm. It does this by recruiting CD39, a rate-limiting enzyme that's vital in tumor suppression to hydrolyze ATP to ADP in order to regulate immunosuppression on different cell populations. | FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses.[1] A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells.[2][3][4] Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.[5][6]
While the precise control mechanism has not yet been established, FOX proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may repress transcription of key genes following stimulation of T cell receptors.[7]
# Structure
The human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. By genomic sequence analysis, the FOXP3 gene maps to the p arm of the X chromosome (specifically, Xp11.23).[1][8]
# Physiology
Foxp3 is a specific marker of natural T regulatory cells (nTregs, a lineage of T cells) and adaptive/induced T regulatory cells (a/iTregs), also identified by other less specific markers such as CD25 or CD45RB.[2][3][4] In animal studies, Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance.[9]
The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in (autoimmune) disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease.[10] Human trials using regulatory T cells to treat graft-versus-host disease have shown efficacy.[11][12]
Further work has shown that T cells are more plastic in nature than originally thought.[13][14][15] This means that the use of regulatory T cells in therapy may be risky, as the T regulatory cell transferred to the patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells.[13] Th17 cells are proinflammatory and are produced under similar environments as a/iTregs.[13] Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. Murine studies point to IL-6 whereas human studies have shown IL-21.[citation needed] Foxp3 is the major transcription factor controlling T-regulatory cells (Treg or CD4+ cells).[16] CD4+ cells are leukocytes responsible for protecting animals from foreign invaders such as bacteria and viruses.[16] Defects in this gene's ability to function can cause IPEX syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome as well as numerous cancers.[17] While CD4+ cells are heavily regulated and require multiple transcription factors such as STAT-5 and AhR in order to become active and function properly, Foxp3 has been identified as the master regulator for Treg lineage.[16] Foxp3 can either act as a transcriptional activator or suppressor depending on what specific transcriptional factors such as deacetylases and histone acetylases are acting on it.[16] The Foxp3 gene is also known to convert naïve T-cells to Treg cells, which are capable of an in vivo and in vitro suppressive capabilities suggesting that Foxp3 is capable of regulating the expression of suppression-mediating molecules.[16] Clarifying the gene targets of Foxp3 could be crucial to the comprehension of the suppressive abilities of Treg cells.
# Pathophysiology
In human disease, alterations in numbers of regulatory T cells – and in particular those that express Foxp3 – are found in a number of disease states. For example, patients with tumors have a local relative excess of Foxp3 positive T cells which inhibits the body's ability to suppress the formation of cancerous cells.[18] Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells.[19] The Foxp3 gene is also mutated in IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked).[20] These mutations were in the forkhead domain of FOXP3, indicating that the mutations may disrupt critical DNA interactions.[citation needed]
In mice, a Foxp3 mutation (a frameshift mutation that result in protein lacking the forkhead domain) is responsible for 'Scurfy', an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth.[1] These mice have overproliferation of CD4+ T-lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines. This phenotype is similar to those that lack expression of CTLA-4, TGF-β, human disease IPEX, or deletion of the Foxp3 gene in mice ("scurfy mice"). The pathology observed in scurfy mice seems to result from an inability to properly regulate CD4+ T-cell activity. In mice overexpressing the Foxp3 gene, fewer T cells are observed. The remaining T cells have poor proliferative and cytolytic responses and poor interleukin-2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs, particularly lymph nodes, lack the proper number of cells.[citation needed]
# Role in cancer
In addition to FoxP3's role in regulatory T cell differentiation, multiple lines of evidence have indicated that FoxP3 play important roles in cancer development.
Down-regulation of FoxP3 expression has been reported in tumour specimens derived from breast, prostate, and ovarian cancer patients, indicating that FoxP3 is a potential tumour suppressor gene. Expression of FoxP3 was also detected in tumour specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers. However, in these reports, no corresponding normal tissues was analyzed, therefore it remained unclear whether FoxP3 is a pro- or anti-tumourigeneic molecule in these tumours.[citation needed]
Two lines of functional evidence strongly supported that FoxP3 serves as tumour suppressive transcription factor in cancer development. First, FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FoxP3 in melanoma,[21] glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies.[citation needed]
Foxp3 is a recruiter of other anti-tumor enzymes such as CD39 and CD8.[17] The overexpression of CD39 is found in patients with multiple cancer types such as melanoma, leukemia, pancreatic cancer, colon cancer, and ovarian cancer.[17] This overexpression may be protecting tumorous cells, allowing them to create their “escape phase”.[17] A cancerous tumor's “escape phase” is where the tumor grows quickly and it becomes clinically invisible by becoming independent of the extracellular matrix and creating its own immunosuppressive tumor microenvironment.[17] The consequences of a cancer cell reaching the “escape phase” is that it allows it to completely evade the immune system, which reduces the immunogenicity and ability to become clinically detected, allowing it to progress and spread throughout the body. Some cancer patients have also been known to display higher numbers of mutated CD4+ cells. These mutated cells will then produce large quantities of TGF-β and IL-10, (a Transforming Growth Factor β and an inhibitory cytokine respectively,) which will suppress signals to the immune system and allow for tumor escape.[17] In one experiment a 15-mer synthetic peptide, P60, was able to inhibit Foxp3's ability to function. P60 did this by entering the cells and then binding to Foxp3, where it hinders Foxp3's ability to translocate to the nucleus.[22] Due to this, Foxp3 could no longer properly suppress the transcription factors NF-kB and NFAT; both of which are protein complexes that regulate transcription of DNA, cytokine production and cell survival.[22] This would inhibit a cell's ability to perform apoptosis and stop its own cell cycle, which could potentially allow an affected cancerous cell to survive and reproduce.
# Autoimmune
Mutations or disruptions of the Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus.[23] These mutations affect thymocytes developing within the thymus. Regulated by Foxp3, it's these thymocytes that during thymopoiesis, are transformed into mature Treg cells by the thymus.[23] It was found that patients who have the autoimmune disease systemic lupus erythematosus (SLE) possess Foxp3 mutations that affect the thymopoiesis process, preventing the proper development of Treg cells within the thymus.[23] These malfunctioning Treg cells aren’t efficiently being regulated by its transcription factors, which cause them to attack cells that are healthy, leading to these organ-specific autoimmune diseases. Another way that Foxp3 helps keep the autoimmune system at homeostasis is through its regulation of the expression of suppression-mediating molecules. For instance, Foxp3 is able to facilitate the translocation of extracellular adenosine into the cytoplasm.[24] It does this by recruiting CD39, a rate-limiting enzyme that's vital in tumor suppression to hydrolyze ATP to ADP in order to regulate immunosuppression on different cell populations.[24] | https://www.wikidoc.org/index.php/FOXP3 | |
ab7ea8465fdbcce9005904b1d0283ccf820e5518 | wikidoc | FSTL1 | FSTL1
Follistatin-related protein 1 is a protein that in humans is encoded by the FSTL1 gene.
# Structure
This gene encodes a protein with similarity to follistatin, an BMP-4-binding protein. It binds to BMP-4 and TGF-β1, but not Activin A. It contains an FS module (a follistatin-like sequence containing 10 conserved cysteine residues), a Kazal-type serine protease inhibitor domain, 2 EF hand domains, and a Von Willebrand factor type C domain.
# Clinical significance
## Development
FSTL1 has a role in development, such as lung development, ureter development, central nervous system development, and skeletal development.
## Arthritis
This gene product is thought to be an autoantigen associated with rheumatoid arthritis.
FSTL1 up-regulates proinflammatory mediators important in the pathology of arthritis, and serum levels of FSTL1 correlate with severity of arthritis.
## Cardiovascular diseases
FSTL1 protein seems to have a cardioprotective role. FSTL1 attenuated hypertrophy following pressure overload and prevented myocardial ischemia/reperfusion injury in a mouse or pig model of ischemia/reperfusion. Muscle-derived Fstl1 modulates vascular remodelling in response to injury.
FSTL1 has been shown to have a pronounced ability as a possible therapeutic to stimulate regeneration following myocardial infarction. Treating experimental animals (mouse and pig) with FSTL1 after myocardial infarction progressively restored heart function, at least in part by stimulating replication of normally non-dividing heart muscle cells | FSTL1
Follistatin-related protein 1 is a protein that in humans is encoded by the FSTL1 gene.[1][2][3]
# Structure
This gene encodes a protein with similarity to follistatin, an BMP-4-binding protein.[4] It binds to BMP-4 and TGF-β1, but not Activin A.[4] It contains an FS module (a follistatin-like sequence containing 10 conserved cysteine residues), a Kazal-type serine protease inhibitor domain, 2 EF hand domains, and a Von Willebrand factor type C domain.[3]
# Clinical significance
## Development
FSTL1 has a role in development,[5][6] such as lung development,[4][7] ureter development,[8] central nervous system development,[9] and skeletal development.[7]
## Arthritis
This gene product is thought to be an autoantigen associated with rheumatoid arthritis.[3]
FSTL1 up-regulates proinflammatory mediators important in the pathology of arthritis, and serum levels of FSTL1 correlate with severity of arthritis.[10][11][12]
## Cardiovascular diseases
FSTL1 protein seems to have a cardioprotective role. FSTL1 attenuated hypertrophy following pressure overload[13] and prevented myocardial ischemia/reperfusion injury in a mouse or pig model of ischemia/reperfusion.[14] Muscle-derived Fstl1 modulates vascular remodelling in response to injury.[15]
FSTL1 has been shown to have a pronounced ability as a possible therapeutic to stimulate regeneration following myocardial infarction. Treating experimental animals (mouse and pig) with FSTL1 after myocardial infarction progressively restored heart function, at least in part by stimulating replication of normally non-dividing heart muscle cells[16] | https://www.wikidoc.org/index.php/FSTL1 | |
54c88ece172907c53f1b35decf1190746a3d4937 | wikidoc | FXYD3 | FXYD3
FXYD domain-containing ion transport regulator 3 is a protein that in humans is encoded by the FXYD3 gene.
# Function
This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. The protein encoded by this gene may function as a chloride channel or as a chloride channel regulator. Two transcript variants encode two different isoforms of the protein; in addition, transcripts utilizing alternative polyA signals have been described in the literature.
# Model organisms
Model organisms have been used in the study of FXYD3 function. A conditional knockout mouse line called Fxyd3tm1a(KOMP)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 | FXYD3
FXYD domain-containing ion transport regulator 3 is a protein that in humans is encoded by the FXYD3 gene.[1][2][3]
# Function
This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. The protein encoded by this gene may function as a chloride channel or as a chloride channel regulator. Two transcript variants encode two different isoforms of the protein; in addition, transcripts utilizing alternative polyA signals have been described in the literature.[3]
# Model organisms
Model organisms have been used in the study of FXYD3 function. A conditional knockout mouse line called Fxyd3tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10] | https://www.wikidoc.org/index.php/FXYD3 | |
99fbf40742f9ffc58ed3a9de194d41e3959c58d0 | wikidoc | FXYD5 | FXYD5
FXYD domain-containing ion transport regulator 5 also named dysadherin (human) or RIC (mouse) is a protein that in humans is encoded by the FXYD5 gene.
# Function
This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. This gene product, FXYD5, has not been characterized as a protein. Two transcript variants have been found for this gene, and they are both predicted to encode the same protein.
Dysadherin is the gamma5 subunit the human Na,K-ATPase. Of all the FXYD members, dysadherin is the only member that has a large extracellular sequence of 140 amino acids. Dysadherin has been observed to be over-expressed on the surface of cells that have down regulated levels of surface E-cadherin. CCL2 (bone homing cytokine)is a protein that is highly affected by silencing dysadherin expression. Dysadherin interferes with cell adhesion via beta1 subunit interactions. Dysdaherin is a target for an extracellular antibody drug conjugate where the antibody to dysadherin is attached to a cardiac glycoside.
# Clinical significance
Dysadherin has been found to be a marker for metastatic cancers and found up-regulated in multiple cancer types. | FXYD5
FXYD domain-containing ion transport regulator 5 also named dysadherin (human) or RIC (mouse) is a protein that in humans is encoded by the FXYD5 gene.[1]
# Function
This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. This gene product, FXYD5, has not been characterized as a protein. Two transcript variants have been found for this gene, and they are both predicted to encode the same protein.[1]
Dysadherin is the gamma5 subunit the human Na,K-ATPase. Of all the FXYD members, dysadherin is the only member that has a large extracellular sequence of 140 amino acids. Dysadherin has been observed to be over-expressed on the surface of cells that have down regulated levels of surface E-cadherin. CCL2 (bone homing cytokine)is a protein that is highly affected by silencing dysadherin expression. Dysadherin interferes with cell adhesion via beta1 subunit interactions.[2] Dysdaherin is a target for an extracellular antibody drug conjugate where the antibody to dysadherin is attached to a cardiac glycoside.[3]
# Clinical significance
Dysadherin has been found to be a marker for metastatic cancers and found up-regulated in multiple cancer types.[3] | https://www.wikidoc.org/index.php/FXYD5 | |
8a35f8e1398a270e165c1356a9eea5ff62c82d68 | wikidoc | FXYD6 | FXYD6
FXYD6 (pronounced fix-id six), or FXYD domain-containing ion transport regulator 6, is a gene which is located at the 11q23.3 (chromosome 11 locus 23.3). The FXYD6 protein contains 95 amino acids, and can be found in all human tissues except blood.
This gene belongs to the FXYD family of ion transport regulators
# Pathology
According to recent research, mutations in the FXYD6 gene, or in sequences close by this gene, can predispose to the schizophrenia which is known to be strongly heritable. | FXYD6
FXYD6 (pronounced fix-id six), or FXYD domain-containing ion transport regulator 6, is a gene which is located at the 11q23.3 (chromosome 11 locus 23.3). The FXYD6 protein contains 95 amino acids, and can be found in all human tissues except blood.
This gene belongs to the FXYD family of ion transport regulators [1]
# Pathology
According to recent research, mutations in the FXYD6 gene, or in sequences close by this gene, can predispose to the schizophrenia which is known to be strongly heritable.[2][3] | https://www.wikidoc.org/index.php/FXYD6 | |
364dd7a37dabd07681c2ff98a65b3ea4c32175b8 | wikidoc | Lipid | Lipid
Lipids are broadly defined as any fat-soluble (lipophilic), naturally-occurring molecule, such as fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The main biological functions of lipids include energy storage, acting as structural components of cell membranes, and participating as important signaling molecules.
Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides and should not be confused with the term fatty acid. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids), as well as other sterol-containing metabolites such as cholesterol.
Lipids are a diverse group of compounds that have many key biological functions, such as acting as structural components of cell membranes, serving as energy storage sources and participating in signaling pathways. Lipids may be broadly defined as hydrophobic or amphiphilic small molecules that originate entirely or in part from two distinct types of biochemical subunits or "building blocks": ketoacyl and isoprene groups. Using this approach, lipids may be divided into eight categories : fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
# Categories of Lipids
- Fatty acyls (including fatty acids) are a diverse group of molecules synthesized by chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA groups. The fatty acyl structure represents the major lipid building block of complex lipids and therefore is one of the most fundamental categories of biological lipids. The carbon chain may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens, nitrogen and sulfur. Examples of biologically interesting fatty acyls are the eicosanoids which are in turn derived from arachidonic acid which include prostaglandins, leukotrienes, and thromboxanes. Other major lipid classes in the fatty acyl category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as wax esters, fatty acyl thioester coenzyme A derivatives, fatty acyl thioester ACP derivatives and fatty acyl carnitines. The fatty amides include N-acyl ethanolamines such as anandamide.
- Glycerolipids are composed mainly of mono-, di- and tri-substituted glycerols, the most well-known being the fatty acid esters of glycerol (triacylglycerols), also known as triglycerides. these comprise the bulk of storage fat in animal tissues. Additional subclasses are represented by glycosylglycerols, which are characterized by the presence of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes and seminolipid from mammalian spermatazoa.
- Glycerophospholipids, also referred to as phospholipids, are ubiquitous in nature and are key components of the lipid bilayer of cells, as well as being involved in metabolism and signaling. Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria or the sn-1 position in the case of archaebacteria. Examples of glycerophospholipids found in biological membranes are phosphatidylcholine (also known as PC or GPCho, and lecithin), phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (PS or GPSer). In addition to serving as a primary component of cellular membranes and binding sites for intra- and intercellular proteins, some glycerophospholipids in eukaryotic cells, such as phosphatidylinositols and phosphatidic acids are either precursors of, or are themselves, membrane-derived second messengers. Typically one or both of these hydroxyl groups are acylated with long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as well as dialkylether variants in prokaryotes.
- Sphingolipids are a complex family of compounds that share a common structural feature, a sphingoid base backbone that is synthesized de novo from serine and a long-chain fatty acyl CoA, then converted into ceramides, phosphosphingolipids, glycosphingolipids and other species. The major sphingoid base of mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 14 to 26 carbon atoms. The major phosphosphingolipids of mammals are sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines and fungi have phytoceramidephosphoinositols and mannose containing headgroups. The Glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.
- Sterol lipids, such as cholesterol and its derivatives are an important component of membrane lipids, along with the glycerophospholipids and sphingomyelins. The steroids, which also contain the same fused four-ring core structure, have different biological roles as hormones and signaling molecules. The C18 steroids include the estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21 subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids. The secosteroids, comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure. Other examples of sterols are the bile acids and their conjugates, which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver.
- Prenol lipids are synthesized from the 5-carbon precursors isopentenyl diphosphate and dimethylallyl diphosphate that are produced mainly via the mevalonic acid (MVA) pathway. The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids are important simple isoprenoids that function as anti-oxidants and as precursors of vitamin A. Another biologically important class of molecules is exemplified by the quinones and hydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin. Vitamin E and vitamin K, as well as the ubiquinones, are examples of this class. Bacteria synthesize polyprenols (called bactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.
- Saccharolipids describe compounds in which fatty acids are linked directly to a sugar backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, a sugar substitutes for the glycerol backbone that is present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylated glucosamine precursors of the Lipid A component of the lipopolysaccharides in Gram-negative bacteria. Typical lipid A molecules are disaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth in E. coli is Kdo2-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.
- Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise a very large number of secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources, and have great structural diversity. Many polyketides are cyclic molecules whose backbones are often further modified by glycosylation, methylation, hydroxylation, oxidation, and/or other processes. Many commonly used anti-microbial, anti-parasitic, and anti-cancer agents are polyketides or polyketide derivatives, such as erythromycins, tetracylines, avermectins, and antitumor epothilones.
# Biological Functions
## Membranes
The glycerophospholipids are the main structural component of biological membranes, such as the cellular plasma membrane and the intracellular membranes of organelles. In animal cells the plasma membrane physically separates the intracellular components from the extracellular environment. All eukaryotic cells are compartmentalized into membrane-bound organelles which carry out different functions. These glycerophospholipids are amphipathic molecules that contain a glycerol core linked to two fatty acid-derived "tails" by ester or, more rarely, ether linkages and to one "head" group by a phosphate ester linkage. While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological membranes. In plants and algae, the galactosyldiacylglycerols, and sulfoquinovosyldiacylglycerol, which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.
A biological membrane is a form of lipid bilayer, as is a liposome. The formation of lipid bilayers is an energetically-preferred process when the glycerophospholipids described above are in an aqueous environment. In an aqueous system, the polar heads of lipids orientate towards the polar, aqueous environment, while the hydrophobic tails minimise their contact with water. The lipophilic tails of lipids (U) tend to cluster together, forming a lipid bilayer (1) or a micelle (2). Other aggregations are also observed and form part of the polymorphism of amphiphile (lipid) behaviour. The polar heads (P) face the aqueous environment, curving away from the water. Phase behaviour is a complicated area within biophysics and is the subject of current academic research.
Micelles and bilayers form in the polar medium by a process known as the hydrophobic effect. When dissolving a lipophilic or amphiphilic substance in a polar environment, the polar molecules (i.e. water in an aqueous solution) become more ordered around the dissolved lipophilic substance, since the polar molecules cannot form hydrogen bonds to the lipophilic areas of the amphiphile. So in an aqueous environment the water molecules form an ordered "clathrate" cage around the dissolved lipophilic molecule.
## Energy storage and metabolism
Triacylglycerols, stored in adipose tissue, are a major form of energy storage in animals.
Animals use triglycerides for energy storage because of its high caloric content (9 KCal/g), whereas plants, which do not require energy for movement, can afford to store food for energy in a less compact but more easily accessible form, such as starch (carbohydrate). Triglycerides and phospholipids are broken down into free fatty acids by the action of lipases. Beta oxidation is the process by which fatty acids, in the form of acyl-CoA molecules, are broken down in the mitochondria and/or in peroxisomes to generate acetyl-CoA. The acetyl CoA is then ultimately converted into ATP, CO2, and H2O using the citric acid cycle and the electron transport chain. Conversely, fatty acid biosynthesis (Lipogenesis) takes place in the cytoplasm, using acetyl-CoA (derived from carbohydrates, amino acids or fatty acids) as the precursor. The fatty acids may be subsequently converted to triacylglycerols that are packaged in lipoproteins (VLDL's) and secreted from the liver.
## Signaling
In recent years, evidence has emerged showing that lipid signaling is a vital part of the cell signaling. Lipid signaling may occur via activation of GPCR's or nuclear receptors, and members of several different lipid categories have been identified as signaling molecules and cellular messengers. These include sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization, cell growth, apoptosis; diacylglycerol(DAG) and the phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C; the prostaglandins, arachidonic acid -derived fatty acids involved in inflammation and immunity; the steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are Liver X receptor (LXR) agonists.
## Other functions
The "fat-soluble" vitamins (A, D, E and K) which are isoprene-based lipids are essential nutrients stored in the liver and fatty tissues. These have a diverse range of functions discussed elsewhere. Acyl-carnitines are involved in the transport and metabolism of fatty acids in and out of mitochondria, where they undergo beta oxidation. Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides across membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic glycosylation reactions, in extra-cellular polysaccharide biosynthesis (for instance peptidoglycan polymerization in bacteria), and in eukaryotic protein N-glycosylation. Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane. They are believed to activate enzymes involved with oxidative phosphorylation.
# Nutrition and health
Lipids play diverse and important roles in nutrition and health. Many lipids are absolutely essential for life. However, there is also considerable awareness that abnormal levels of certain lipids, particularly cholesterol (in hypercholesterolemia) and trans fatty acids, are risk factors for heart disease amongst others.
Humans have a requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) in the diet because they cannot be synthesized from simple precursors in the diet. Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic acid is found in the green leaves of plants, and in selected seeds, nuts and legumes (flax, canola, walnuts and soy). Fish oils are particularly rich in the longer-chain omega-6 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Most of the lipid found in food is in the form of triacylglycerols, cholesterol and phospholipids.
Most of the saturated fatty acids (as triacylglycerols) in the diet are incorporated into adipose tissue stores, because the absence of double bonds allows a higher energy yield per carbon than is obtained from oxidation of unsaturated fatty acids. The longer chain fatty acids are incorporated into cell membranes as phospholipids regardless of degree of saturation. Since dietary fatty acids are exchanged with membrane fatty acids, dietary fat composition is reflected in membrane lipid composition. Thus dietary fatty acids can influence cell function through effects on membrane properties. Dietary fat provides an average energy intake which is approximately twice that of carbohydrate or protein. A minimum amount of dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A, D, E and K) and carotenoids. A minimal amount of body fat is also necessary to provide insulation that prevents heat loss and protects vital organs from shock due to ordinary activities.
High fat intake contributes to increased risk of obesity, diabetes and atherosclerosis. Atherosclerosis is the primary cause of coronary and cardiovascular diseases and is primary due to the buildup of plaque on the inside walls of arteries. Plaque is made up of cholesterol-rich low density lipoproteins (LDL), macrophages, smooth muscle cells, platelets, and other substances. In North America and most other western countries, atherosclerosis is the leading cause of illness and death, almost doubling the number of deaths from cancers. Despite significant medical advances, coronary artery disease and atherosclerotic stroke are responsible for more deaths than all other causes combined. A substantial amount of scientific evidence supports the impact of dietary fatty acids on cardiovascular health. Saturated fats have a profound hypercholesterolemic (increase blood cholesterol levels) effect and tend to increase plasma LDL. They are found predominantly in animal products (butter, cheese and meat) but coconut oil and palm oil are common vegetable sources. Intake of monounsaturated fats in oils such as olive oil is thought to be preferable to consumption of polyunsaturated fats in oils such as corn oil because the monounsaturated fats apparently do not lower high-density-lipoprotein (HDL) cholesterol levels. Keeping cholesterol in the normal range not only helps prevent heart attacks and strokes but may also prevent the progression of atherosclerosis. "Statins" are a class of drugs that lowers the level of cholesterol in the blood by inhibiting the enzyme HMG-CoA reductase. This is a key enzyme involved in the biosynthesis of cholesterol in the liver. | Lipid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Lipids are broadly defined as any fat-soluble (lipophilic), naturally-occurring molecule, such as fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The main biological functions of lipids include energy storage, acting as structural components of cell membranes, and participating as important signaling molecules.
Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides and should not be confused with the term fatty acid. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids), as well as other sterol-containing metabolites such as cholesterol. [1]
Lipids are a diverse group of compounds that have many key biological functions, such as acting as structural components of cell membranes, serving as energy storage sources and participating in signaling pathways. Lipids may be broadly defined as hydrophobic or amphiphilic small molecules that originate entirely or in part from two distinct types of biochemical subunits or "building blocks": ketoacyl and isoprene groups.[2] Using this approach, lipids may be divided into eight categories : fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
# Categories of Lipids
- Fatty acyls (including fatty acids) are a diverse group of molecules synthesized by chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA groups.[3][4] The fatty acyl structure represents the major lipid building block of complex lipids and therefore is one of the most fundamental categories of biological lipids. The carbon chain may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens, nitrogen and sulfur. Examples of biologically interesting fatty acyls are the eicosanoids which are in turn derived from arachidonic acid which include prostaglandins, leukotrienes, and thromboxanes. Other major lipid classes in the fatty acyl category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as wax esters, fatty acyl thioester coenzyme A derivatives, fatty acyl thioester ACP derivatives and fatty acyl carnitines. The fatty amides include N-acyl ethanolamines such as anandamide.
- Glycerolipids are composed mainly of mono-, di- and tri-substituted glycerols,[5] the most well-known being the fatty acid esters of glycerol (triacylglycerols), also known as triglycerides. these comprise the bulk of storage fat in animal tissues. Additional subclasses are represented by glycosylglycerols, which are characterized by the presence of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes and seminolipid from mammalian spermatazoa.
- Glycerophospholipids, also referred to as phospholipids, are ubiquitous in nature and are key components of the lipid bilayer of cells, as well as being involved in metabolism and signaling. Glycerophospholipids[6] may be subdivided into distinct classes, based on the nature of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria or the sn-1 position in the case of archaebacteria. Examples of glycerophospholipids found in biological membranes are phosphatidylcholine (also known as PC or GPCho, and lecithin), phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (PS or GPSer). In addition to serving as a primary component of cellular membranes and binding sites for intra- and intercellular proteins, some glycerophospholipids in eukaryotic cells, such as phosphatidylinositols and phosphatidic acids are either precursors of, or are themselves, membrane-derived second messengers. Typically one or both of these hydroxyl groups are acylated with long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as well as dialkylether variants in prokaryotes.
- Sphingolipids are a complex family of compounds[7] that share a common structural feature, a sphingoid base backbone that is synthesized de novo from serine and a long-chain fatty acyl CoA, then converted into ceramides, phosphosphingolipids, glycosphingolipids and other species. The major sphingoid base of mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 14 to 26 carbon atoms. The major phosphosphingolipids of mammals are sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines and fungi have phytoceramidephosphoinositols and mannose containing headgroups. The Glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.
- Sterol lipids, such as cholesterol and its derivatives are an important component of membrane lipids,[8] along with the glycerophospholipids and sphingomyelins. The steroids, which also contain the same fused four-ring core structure, have different biological roles as hormones and signaling molecules. The C18 steroids include the estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21 subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids. The secosteroids, comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure. Other examples of sterols are the bile acids and their conjugates,[9] which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver.
- Prenol lipids are synthesized from the 5-carbon precursors isopentenyl diphosphate and dimethylallyl diphosphate that are produced mainly via the mevalonic acid (MVA) pathway.[10] The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids are important simple isoprenoids that function as anti-oxidants and as precursors of vitamin A. Another biologically important class of molecules is exemplified by the quinones and hydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin. Vitamin E and vitamin K, as well as the ubiquinones, are examples of this class. Bacteria synthesize polyprenols (called bactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.
- Saccharolipids describe compounds in which fatty acids are linked directly to a sugar backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, a sugar substitutes for the glycerol backbone that is present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylated glucosamine precursors of the Lipid A component of the lipopolysaccharides in Gram-negative bacteria. Typical lipid A molecules are disaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth in E. coli is Kdo2-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.[11]
- Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise a very large number of secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources, and have great structural diversity.[12] Many polyketides are cyclic molecules whose backbones are often further modified by glycosylation, methylation, hydroxylation, oxidation, and/or other processes. Many commonly used anti-microbial, anti-parasitic, and anti-cancer agents are polyketides or polyketide derivatives, such as erythromycins, tetracylines, avermectins, and antitumor epothilones.
# Biological Functions
## Membranes
The glycerophospholipids are the main structural component of biological membranes, such as the cellular plasma membrane and the intracellular membranes of organelles. In animal cells the plasma membrane physically separates the intracellular components from the extracellular environment. All eukaryotic cells are compartmentalized into membrane-bound organelles which carry out different functions. These glycerophospholipids are amphipathic molecules that contain a glycerol core linked to two fatty acid-derived "tails" by ester or, more rarely, ether linkages and to one "head" group by a phosphate ester linkage. While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological membranes. In plants and algae, the galactosyldiacylglycerols,[13] and sulfoquinovosyldiacylglycerol,[14] which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.
A biological membrane is a form of lipid bilayer, as is a liposome. The formation of lipid bilayers is an energetically-preferred process when the glycerophospholipids described above are in an aqueous environment. In an aqueous system, the polar heads of lipids orientate towards the polar, aqueous environment, while the hydrophobic tails minimise their contact with water. The lipophilic tails of lipids (U) tend to cluster together, forming a lipid bilayer (1) or a micelle (2). Other aggregations are also observed and form part of the polymorphism of amphiphile (lipid) behaviour. The polar heads (P) face the aqueous environment, curving away from the water. Phase behaviour is a complicated area within biophysics and is the subject of current academic research.
Micelles and bilayers form in the polar medium by a process known as the hydrophobic effect.[15] When dissolving a lipophilic or amphiphilic substance in a polar environment, the polar molecules (i.e. water in an aqueous solution) become more ordered around the dissolved lipophilic substance, since the polar molecules cannot form hydrogen bonds to the lipophilic areas of the amphiphile. So in an aqueous environment the water molecules form an ordered "clathrate" cage around the dissolved lipophilic molecule.[16]
## Energy storage and metabolism
Triacylglycerols, stored in adipose tissue, are a major form of energy storage in animals.
Animals use triglycerides for energy storage because of its high caloric content (9 KCal/g), whereas plants, which do not require energy for movement, can afford to store food for energy in a less compact but more easily accessible form, such as starch (carbohydrate). Triglycerides and phospholipids are broken down into free fatty acids by the action of lipases. Beta oxidation is the process by which fatty acids, in the form of acyl-CoA molecules, are broken down in the mitochondria and/or in peroxisomes to generate acetyl-CoA. The acetyl CoA is then ultimately converted into ATP, CO2, and H2O using the citric acid cycle and the electron transport chain. Conversely, fatty acid biosynthesis (Lipogenesis) takes place in the cytoplasm, using acetyl-CoA (derived from carbohydrates, amino acids or fatty acids) as the precursor[17]. The fatty acids may be subsequently converted to triacylglycerols that are packaged in lipoproteins (VLDL's) and secreted from the liver.
## Signaling
In recent years, evidence has emerged showing that lipid signaling is a vital part of the cell signaling.[18] Lipid signaling may occur via activation of GPCR's or nuclear receptors, and members of several different lipid categories have been identified as signaling molecules and cellular messengers.[19] These include sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization, cell growth, apoptosis; diacylglycerol(DAG) and the phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C; the prostaglandins, arachidonic acid -derived fatty acids involved in inflammation and immunity; the steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are Liver X receptor (LXR) agonists.
## Other functions
The "fat-soluble" vitamins (A, D, E and K) which are isoprene-based lipids are essential nutrients stored in the liver and fatty tissues. These have a diverse range of functions discussed elsewhere. Acyl-carnitines are involved in the transport and metabolism of fatty acids in and out of mitochondria, where they undergo beta oxidation. Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides across membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic glycosylation reactions, in extra-cellular polysaccharide biosynthesis (for instance peptidoglycan polymerization in bacteria), and in eukaryotic protein N-glycosylation.[20] Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane. They are believed to activate enzymes involved with oxidative phosphorylation.[21]
# Nutrition and health
Lipids play diverse and important roles in nutrition and health.[22] Many lipids are absolutely essential for life. However, there is also considerable awareness that abnormal levels of certain lipids, particularly cholesterol (in hypercholesterolemia) and trans fatty acids, are risk factors for heart disease amongst others.
Humans have a requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) in the diet because they cannot be synthesized from simple precursors in the diet. Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic acid is found in the green leaves of plants, and in selected seeds, nuts and legumes (flax, canola, walnuts and soy). Fish oils are particularly rich in the longer-chain omega-6 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Most of the lipid found in food is in the form of triacylglycerols, cholesterol and phospholipids.
Most of the saturated fatty acids (as triacylglycerols) in the diet are incorporated into adipose tissue stores, because the absence of double bonds allows a higher energy yield per carbon than is obtained from oxidation of unsaturated fatty acids. The longer chain fatty acids are incorporated into cell membranes as phospholipids regardless of degree of saturation. Since dietary fatty acids are exchanged with membrane fatty acids, dietary fat composition is reflected in membrane lipid composition. Thus dietary fatty acids can influence cell function through effects on membrane properties. Dietary fat provides an average energy intake which is approximately twice that of carbohydrate or protein. A minimum amount of dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A, D, E and K) and carotenoids. A minimal amount of body fat is also necessary to provide insulation that prevents heat loss and protects vital organs from shock due to ordinary activities.
High fat intake contributes to increased risk of obesity, diabetes and atherosclerosis. Atherosclerosis is the primary cause of coronary and cardiovascular diseases and is primary due to the buildup of plaque on the inside walls of arteries. Plaque is made up of cholesterol-rich low density lipoproteins (LDL), macrophages, smooth muscle cells, platelets, and other substances. In North America and most other western countries, atherosclerosis is the leading cause of illness and death, almost doubling the number of deaths from cancers. Despite significant medical advances, coronary artery disease and atherosclerotic stroke are responsible for more deaths than all other causes combined. A substantial amount of scientific evidence supports the impact of dietary fatty acids on cardiovascular health. Saturated fats have a profound hypercholesterolemic (increase blood cholesterol levels) effect and tend to increase plasma LDL. They are found predominantly in animal products (butter, cheese and meat) but coconut oil and palm oil are common vegetable sources. Intake of monounsaturated fats in oils such as olive oil is thought to be preferable to consumption of polyunsaturated fats in oils such as corn oil because the monounsaturated fats apparently do not lower high-density-lipoprotein (HDL) cholesterol levels.[23] Keeping cholesterol in the normal range not only helps prevent heart attacks and strokes but may also prevent the progression of atherosclerosis. "Statins" are a class of drugs that lowers the level of cholesterol in the blood by inhibiting the enzyme HMG-CoA reductase. This is a key enzyme involved in the biosynthesis of cholesterol in the liver. | https://www.wikidoc.org/index.php/Fats | |
1bc908b2b42b016ebbd6ec22bf1df98301cdeb4c | wikidoc | Favus | Favus
Favus (Latin for "honeycomb") is a disease of the scalp, but occurring occasionally on any part of the skin, and even at times on mucous membranes. The uncomplicated appearance is that of a number of yellowish, circular, cup-shaped crusts (scutula) grouped in patches like a piece of honeycomb, each about the size of a split pea, with a hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen round the edge of the scab. Growth continues to take place for several months, when scab and scutulum come away, leaving a shining bare patch destitute of hair. The disease is essentially chronic, lasting from ten to twenty years. It is caused by the growth of a fungus, and pathologically is the reaction of the tissues to the growth. It was the first disease in which a fungus was discovered by J. L. Schönlein in 1839; the discovery was published in a brief note of twenty lines in Millers Archive for that year (p. 82), the fungus having been subsequently named by Robert Remak; Achorion schoenleinii after its discoverer. The fungus was named after a microscopic structure termed "achorion" (a term not used in modern science), seen in scrapings of infected skin, which consists of slender, mycelial threads matted together, bearing oval, nucleated fungal substrate-arthroconidia either free or jointed. This structure is currently called "scutula." The fungus itself is now called Trichophyton schoenleinii.
During initial infection, the fungal spores would appear to enter through the unbroken cutaneous surface, and to germinate mostly in and around the hair follicle and sometimes in the shaft of the hair. In 1892, two additional "species" of the fungus were described by Paul Gerson Unna, the Favus griseus, giving rise to greyish-yellow scutula, and the Favus sulphureus celerior, causing sulfur-yellow scutula of a rapid growth. This was in the days before scientists learned to rigorously distinguish microorganism identities from disease identities, and these antique, ambiguous disease-based names no longer have status either in mycology or in dermatology.
Up until the advent of modern therapies, favus was widespread worldwide; prior to Schönlein's recognition of it as a fungal disease, it was frequently confused with Hansen's disease, better known as leprosy, and European sufferers were sometimes committed to leprosaria. Today, due to this species' high susceptibility to the antifungal drug griseofulvin, it has been eliminated from most parts of the world except rural central Asia and scattered rural areas of Africa. It is mainly a disease connected to demographic poverty and isolation, but is so readily treatable that it is among the diseases most likely to be completely eliminated by modern medicine.
Similar looking infections, sometimes diagnosed as favus but more often as atypical inflammatory tinea, may rarely be produced by agents of more common dermatophyte fungal infections, in particular Microsporum gypseum, the most common soil-borne dermatophyte fungus, and Trichophyton mentagrophytes (name used in post-1999 sense for a phylogenetic species formerly referred to as Trichophyton mentagrophytes var. quinckeanum), the agent of favus infection of the mouse. | Favus
Favus (Latin for "honeycomb") is a disease of the scalp, but occurring occasionally on any part of the skin, and even at times on mucous membranes. The uncomplicated appearance is that of a number of yellowish, circular, cup-shaped crusts (scutula) grouped in patches like a piece of honeycomb, each about the size of a split pea, with a hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen round the edge of the scab. Growth continues to take place for several months, when scab and scutulum come away, leaving a shining bare patch destitute of hair. The disease is essentially chronic, lasting from ten to twenty years. It is caused by the growth of a fungus, and pathologically is the reaction of the tissues to the growth. It was the first disease in which a fungus was discovered by J. L. Schönlein in 1839; the discovery was published in a brief note of twenty lines in Millers Archive for that year (p. 82), the fungus having been subsequently named by Robert Remak; Achorion schoenleinii after its discoverer. The fungus was named after a microscopic structure termed "achorion" (a term not used in modern science), seen in scrapings of infected skin, which consists of slender, mycelial threads matted together, bearing oval, nucleated fungal substrate-arthroconidia either free or jointed. This structure is currently called "scutula." The fungus itself is now called Trichophyton schoenleinii.
During initial infection, the fungal spores would appear to enter through the unbroken cutaneous surface, and to germinate mostly in and around the hair follicle and sometimes in the shaft of the hair. In 1892, two additional "species" of the fungus were described by Paul Gerson Unna, the Favus griseus, giving rise to greyish-yellow scutula, and the Favus sulphureus celerior, causing sulfur-yellow scutula of a rapid growth. This was in the days before scientists learned to rigorously distinguish microorganism identities from disease identities, and these antique, ambiguous disease-based names no longer have status either in mycology or in dermatology.
Up until the advent of modern therapies, favus was widespread worldwide; prior to Schönlein's recognition of it as a fungal disease, it was frequently confused with Hansen's disease, better known as leprosy, and European sufferers were sometimes committed to leprosaria. Today, due to this species' high susceptibility to the antifungal drug griseofulvin, it has been eliminated from most parts of the world except rural central Asia and scattered rural areas of Africa. It is mainly a disease connected to demographic poverty and isolation, but is so readily treatable that it is among the diseases most likely to be completely eliminated by modern medicine.
Similar looking infections, sometimes diagnosed as favus but more often as atypical inflammatory tinea, may rarely be produced by agents of more common dermatophyte fungal infections, in particular Microsporum gypseum, the most common soil-borne dermatophyte fungus, and Trichophyton mentagrophytes (name used in post-1999 sense for a phylogenetic species formerly referred to as Trichophyton mentagrophytes var. quinckeanum), the agent of favus infection of the mouse. | https://www.wikidoc.org/index.php/Favus | |
c1d7ec5d0d676fd895a23d93399350a01b6758b7 | wikidoc | Meter | Meter
# Overview
The metre or meter (symbol: m) is the fundamental unit of length in the International System of Units (SI). The metre was originally defined by a prototype object meant to represent 1⁄10,000,000 the distance between the poles and the Equator. Today, it is defined as 1⁄299,792,458 of a light-second.
Because it is the base unit of length in the SI, all SI units that involve length (such as area or speed) are defined relative to the metre. Additionally, because the metre is the only SI base unit used to measure a vector (e.g., displacement), all vector units are defined relative to the metre. However, decimal multiples and submultiples of the metre – such as kilometre (1000 metres) and centimetre (0.01 metres) – can be formed by adding SI prefixes to metre (see the table below).
# Etymology
The word metre is from the Greek metron (Template:Polytonic), "a measure" via the French mètre. Its first recorded usage in English meaning this unit of length is from 1797.
# History
## Meridional definition
In the eighteenth century, there were two favoured approaches to the definition of the standard unit of length. One suggested defining the metre as the length of a pendulum with a half-period of one second. The other suggested defining the metre as one ten-millionth of the length of the Earth's meridian along a quadrant, that is the distance from the equator to the north pole. In 1791, the French Academy of Sciences selected the meridional definition.
In order to establish a universally accepted foundation for the definition of the metre, measurements of this meridian more accurate than those available at that time were imperative. The Bureau des Longitudes commissioned an expedition led by Delambre and Pierre Méchain, lasting from 1792 to 1799, which measured the length of the meridian between Dunkerque and Barcelona. This portion of the meridian, which also passes through Paris, was to serve as the basis for the length of the half meridian, connecting the North Pole with the Equator.
However, in 1793 France adopted a metre that was based on provisional results from the expedition as its official unit of length. Although it was later determined that the first prototype metre bar was short by a fifth of a millimetre due to miscalculation of the flattening of the Earth, this length became the standard. The circumference of the Earth through the poles is therefore approximately forty million metres.
## Prototype metre bar
In the 1870s, a series of international conferences were held to devise new metric standards. The Metre Convention (Convention du Mètre) of 1875 mandated the establishment of a permanent International Bureau of Weights and Measures (BIPM: Bureau International des Poids et Mesures) to be located in Sèvres, France. This new organisation would preserve the new prototype metre and kilogram standards when they were constructed, distribute national metric prototypes, and maintain comparisons between them and non-metric measurement standards. The organization created a new prototype bar in 1889 at the first General Conference on Weights and Measures (CGPM: Conférence Générale des Poids et Mesures), establishing the International Prototype Metre as the distance between two lines on a standard bar composed of an alloy of ninety percent platinum and ten percent iridium, measured at 0 °C.
## Standard wavelength of krypton-86 emission
In 1893, the standard metre was first measured with an interferometer by Albert A. Michelson, the inventor of the device and an advocate of using some particular wavelength of light as a standard of distance. By 1925, interferometry was in regular use at the BIPM. However, the International Prototype Metre remained the standard until 1960, when the eleventh CGPM defined the metre in the new SI system as equal to 1,650,763.73 wavelengths of the orange-red emission line in the electromagnetic spectrum of the krypton-86 atom in a vacuum. The original international prototype of the metre is still kept at the BIPM under the conditions specified in 1889.
## Standard wavelength of helium-neon laser light
To further reduce uncertainty, the seventeenth CGPM in 1983 replaced the definition of the metre with its current definition, thus fixing the length of the metre in terms of time and the speed of light:
Note that this definition had the effect of defining the speed of light in a vacuum as precisely 299,792,458 metres per second. Although the metre is now defined in terms of time-of-flight, actual laboratory realisations of the metre are still delineated by counting the required number of wavelengths of light along the distance. An intended byproduct of the 17th CGPM’s definition was that it enabled scientists to measure the wavelength of their lasers with one-fifth the uncertainty. To further facilitate reproducibility from lab to lab, the 17th CGPM also made the iodine-stabilised helium-neon laser “a recommended radiation” for realising the metre. For purposes of delineating the metre, the BIPM currently considers the HeNe laser wavelength to be as follows: λHeNe = 632.99139822 nm with an estimated relative standard uncertainty (U) of 2.5 × 10–11. This uncertainty is currently the limiting factor in laboratory realisations of the metre as it is several orders of magnitude poorer than that of the second (U = 5 × 10–16). Consequently, a practical realisation of the metre is usually delineated (not defined) today in labs as 1,579,800.298728(39) wavelengths of helium-neon laser light in a vacuum.
## Timeline of definition
- 1790May 8 — The French National Assembly decides that the length of the new metre would be equal to the length of a pendulum with a half-period of one second.
- 1791March 30 — The French National Assembly accepts the proposal by the French Academy of Sciences that the new definition for the metre be equal to one ten-millionth of the length of the Earth's meridian along a quadrant through Paris, that is the distance from the equator to the north pole.
- 1795 — Provisional metre bar constructed of brass.
- 1799December 10 — The French National Assembly specifies the platinum metre bar, constructed on 23 June 1799 and deposited in the National Archives, as the final standard.
- 1889September 28 — The first General Conference on Weights and Measures (CGPM) defines the length as the distance between two lines on a standard bar of an alloy of platinum with ten percent iridium, measured at the melting point of ice.
- 1927October 6 — The seventh CGPM adjusts the definition of the length to be the distance, at 0 °C, between the axes of the two central lines marked on the prototype bar of platinum-iridium, this bar being subject to one standard atmosphere of pressure and supported on two cylinders of at least one centimetre diameter, symmetrically placed in the same horizontal plane at a distance of 571 millimetres from each other.
- 1960October 20 — The eleventh CGPM defines the length to be equal to 1,650,763.73 wavelengths in vacuum of the radiation corresponding to the transition between the 2p10 and 5d5 quantum levels of the krypton-86 atom.
- 1983October 21 — The seventeenth CGPM defines the length as equal to the distance travelled by light in vacuum during a time interval of 1/299,792,458 of a second.
# SI prefixed forms of metre
SI prefixes are often employed to denote decimal multiples and submultiples of the metre, as shown in the table below.
# Equivalents in other units | Meter
Template:Unit of length
# Overview
The metre or meter[1] (symbol: m) is the fundamental unit of length in the International System of Units (SI). The metre was originally defined by a prototype object meant to represent 1⁄10,000,000 the distance between the poles and the Equator. Today, it is defined as 1⁄299,792,458 of a light-second.
Because it is the base unit of length in the SI, all SI units that involve length (such as area or speed) are defined relative to the metre. Additionally, because the metre is the only SI base unit used to measure a vector (e.g., displacement), all vector units are defined relative to the metre. However, decimal multiples and submultiples of the metre – such as kilometre (1000 metres) and centimetre (0.01 metres) – can be formed by adding SI prefixes to metre (see the table below).
# Etymology
The word metre is from the Greek metron (Template:Polytonic), "a measure" via the French mètre. Its first recorded usage in English meaning this unit of length is from 1797.
# History
## Meridional definition
In the eighteenth century, there were two favoured approaches to the definition of the standard unit of length. One suggested defining the metre as the length of a pendulum with a half-period of one second. The other suggested defining the metre as one ten-millionth of the length of the Earth's meridian along a quadrant, that is the distance from the equator to the north pole. In 1791, the French Academy of Sciences selected the meridional definition.
In order to establish a universally accepted foundation for the definition of the metre, measurements of this meridian more accurate than those available at that time were imperative. The Bureau des Longitudes commissioned an expedition led by Delambre and Pierre Méchain, lasting from 1792 to 1799, which measured the length of the meridian between Dunkerque and Barcelona. This portion of the meridian, which also passes through Paris, was to serve as the basis for the length of the half meridian, connecting the North Pole with the Equator.
However, in 1793 France adopted a metre that was based on provisional results from the expedition as its official unit of length. Although it was later determined that the first prototype metre bar was short by a fifth of a millimetre due to miscalculation of the flattening of the Earth, this length became the standard. The circumference of the Earth through the poles is therefore approximately forty million metres.
## Prototype metre bar
In the 1870s, a series of international conferences were held to devise new metric standards. The Metre Convention (Convention du Mètre) of 1875 mandated the establishment of a permanent International Bureau of Weights and Measures (BIPM: Bureau International des Poids et Mesures) to be located in Sèvres, France. This new organisation would preserve the new prototype metre and kilogram standards when they were constructed, distribute national metric prototypes, and maintain comparisons between them and non-metric measurement standards. The organization created a new prototype bar in 1889 at the first General Conference on Weights and Measures (CGPM: Conférence Générale des Poids et Mesures), establishing the International Prototype Metre as the distance between two lines on a standard bar composed of an alloy of ninety percent platinum and ten percent iridium, measured at 0 °C.
## Standard wavelength of krypton-86 emission
In 1893, the standard metre was first measured with an interferometer by Albert A. Michelson, the inventor of the device and an advocate of using some particular wavelength of light as a standard of distance. By 1925, interferometry was in regular use at the BIPM. However, the International Prototype Metre remained the standard until 1960, when the eleventh CGPM defined the metre in the new SI system as equal to 1,650,763.73 wavelengths of the orange-red emission line in the electromagnetic spectrum of the krypton-86 atom in a vacuum. The original international prototype of the metre is still kept at the BIPM under the conditions specified in 1889.
## Standard wavelength of helium-neon laser light
To further reduce uncertainty, the seventeenth CGPM in 1983 replaced the definition of the metre with its current definition, thus fixing the length of the metre in terms of time and the speed of light:
Note that this definition had the effect of defining the speed of light in a vacuum as precisely 299,792,458 metres per second. Although the metre is now defined in terms of time-of-flight, actual laboratory realisations of the metre are still delineated by counting the required number of wavelengths of light along the distance. An intended byproduct of the 17th CGPM’s definition was that it enabled scientists to measure the wavelength of their lasers with one-fifth the uncertainty. To further facilitate reproducibility from lab to lab, the 17th CGPM also made the iodine-stabilised helium-neon laser “a recommended radiation” for realising the metre. For purposes of delineating the metre, the BIPM currently considers the HeNe laser wavelength to be as follows: λHeNe = 632.99139822 nm with an estimated relative standard uncertainty (U) of 2.5 × 10–11.[3] This uncertainty is currently the limiting factor in laboratory realisations of the metre as it is several orders of magnitude poorer than that of the second (U = 5 × 10–16).[4] Consequently, a practical realisation of the metre is usually delineated (not defined) today in labs as 1,579,800.298728(39) wavelengths of helium-neon laser light in a vacuum.
## Timeline of definition
- 1790May 8 — The French National Assembly decides that the length of the new metre would be equal to the length of a pendulum with a half-period of one second.
- 1791March 30 — The French National Assembly accepts the proposal by the French Academy of Sciences that the new definition for the metre be equal to one ten-millionth of the length of the Earth's meridian along a quadrant through Paris, that is the distance from the equator to the north pole.
- 1795 — Provisional metre bar constructed of brass.
- 1799December 10 — The French National Assembly specifies the platinum metre bar, constructed on 23 June 1799 and deposited in the National Archives, as the final standard.
- 1889September 28 — The first General Conference on Weights and Measures (CGPM) defines the length as the distance between two lines on a standard bar of an alloy of platinum with ten percent iridium, measured at the melting point of ice.
- 1927October 6 — The seventh CGPM adjusts the definition of the length to be the distance, at 0 °C, between the axes of the two central lines marked on the prototype bar of platinum-iridium, this bar being subject to one standard atmosphere of pressure and supported on two cylinders of at least one centimetre diameter, symmetrically placed in the same horizontal plane at a distance of 571 millimetres from each other.
- 1960October 20 — The eleventh CGPM defines the length to be equal to 1,650,763.73 wavelengths in vacuum of the radiation corresponding to the transition between the 2p10 and 5d5 quantum levels of the krypton-86 atom.
- 1983October 21 — The seventeenth CGPM defines the length as equal to the distance travelled by light in vacuum during a time interval of 1/299,792,458 of a second.
# SI prefixed forms of metre
Template:Associations/Orders of magnitude (length)
SI prefixes are often employed to denote decimal multiples and submultiples of the metre, as shown in the table below.
Template:SI multiples
# Equivalents in other units | https://www.wikidoc.org/index.php/Femtometre | |
8b1699c1c6e86407a9c0d2f9afa2bb8ab93e04d1 | wikidoc | Femur | Femur
In humans, it is the longest, most voluminous, and strongest bone. The average human femur is 48 centimeters (19 in) in length and 2.34 cm (0.92 in) in diameter and can support up to 30 times the weight of an adult. It forms part of the hip (at the acetabulum) and part of the knee.
The word femur is Latin for thigh. Theoretically in strict usage, femur bone is more proper than femur, as in classical Latin femur means "thigh", and os femoris means "the bone within it".
In medical Latin its genitive is always femoris, but in classical Latin its genitive is often feminis, and should not be confused with case forms of femina, which means "woman".
# Fractures
Femur bone fractures, on occasion, are liable to cause permanent disability because the thigh muscles pull the fragments so they overlap, and the fragments re-unite incorrectly. To avoid this, femur fracture patients should be put into traction to keep the fragments pulled into proper alignment.
With modern medical procedures, such as the insertion of rods and screws by way of surgery (known as Antegrade or Retrograde femoral rodding), those suffering from femur fractures can now generally expect to make a full recovery, though one that generally takes 3 to 6 months due to the bone's size. Patients should not put weight on the leg without permission from an orthopedic surgeon since this can delay the healing process.
The thigh is generally not put in a cast since the surgical hardware does the job of straightening the bone and holding the fracture together while it heals. Permanent complications with this procedure include the risk of intra-articular sepsis, arthritis and knee stiffness. After the bone is healed, there is no further need for the hardware but, while it is left in some patients permanently, those who lead an active lifesytle may experience discomfort where the hardware projects into the leg muscle and, in such cases, the hardware can be removed, most commonly by means of out-patient surgery.
## Hip fracture
If bone is weakened, the proximal end of the femur bone near the hip joint is prone to fragility fracture. Most at risk are European descent, post-menopausal women, and osteoporosis severely increases this risk. Out of all the bones in the skeleton, the femur takes the longest to heal. This bone is the longest and strongest bone in the human body. When the average human being jumps this bone withstands a force of half a ton just a testament to its strength.
# Intercondylar Fossa
The intercondylar fossa is present between the condyles at the distal end of the femur. In addition to the intercondylar eminence on the tibial plateau, there is both an anterior and posterior intercondylar fossa (area), the sites of anterior cruciate and posterior cruciate ligament attachment, respectively.
# In other animals
Parallel structures by the same name exist in other complex animals, such as the bone inside a ham or a leg of lamb. The name femur is also given to the most proximal full-length jointed segment of an arthropod's leg. | Femur
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In humans, it is the longest, most voluminous, and strongest bone. The average human femur is 48 centimeters (19 in) in length and 2.34 cm (0.92 in) in diameter and can support up to 30 times the weight of an adult.[1] It forms part of the hip (at the acetabulum) and part of the knee.
The word femur is Latin for thigh. Theoretically in strict usage, femur bone is more proper than femur, as in classical Latin femur means "thigh", and os femoris means "the bone within it".
In medical Latin its genitive is always femoris, but in classical Latin its genitive is often feminis, and should not be confused with case forms of femina, which means "woman".
# Fractures
Femur bone fractures, on occasion, are liable to cause permanent disability because the thigh muscles pull the fragments so they overlap, and the fragments re-unite incorrectly. To avoid this, femur fracture patients should be put into traction to keep the fragments pulled into proper alignment.
With modern medical procedures, such as the insertion of rods and screws by way of surgery (known as Antegrade [through the hip] or Retrograde [through the knee] femoral rodding), those suffering from femur fractures can now generally expect to make a full recovery, though one that generally takes 3 to 6 months due to the bone's size. Patients should not put weight on the leg without permission from an orthopedic surgeon since this can delay the healing process.
The thigh is generally not put in a cast since the surgical hardware does the job of straightening the bone and holding the fracture together while it heals. Permanent complications with this procedure include the risk of intra-articular sepsis, arthritis and knee stiffness. After the bone is healed, there is no further need for the hardware but, while it is left in some patients permanently, those who lead an active lifesytle may experience discomfort where the hardware projects into the leg muscle and, in such cases, the hardware can be removed, most commonly by means of out-patient surgery.
## Hip fracture
If bone is weakened, the proximal end of the femur bone near the hip joint is prone to fragility fracture. Most at risk are European descent, post-menopausal women, and osteoporosis severely increases this risk. Out of all the bones in the skeleton, the femur takes the longest to heal. This bone is the longest and strongest bone in the human body. When the average human being jumps this bone withstands a force of half a ton just a testament to its strength.
# Intercondylar Fossa
The intercondylar fossa is present between the condyles at the distal end of the femur. In addition to the intercondylar eminence on the tibial plateau, there is both an anterior and posterior intercondylar fossa (area), the sites of anterior cruciate and posterior cruciate ligament attachment, respectively.
# In other animals
Parallel structures by the same name exist in other complex animals, such as the bone inside a ham or a leg of lamb. The name femur is also given to the most proximal full-length jointed segment of an arthropod's leg. | https://www.wikidoc.org/index.php/Femur | |
000a9c1168691e24777f5c8f9b638dcd00e4ea2d | wikidoc | Fetus | Fetus
A fetus (or foetus, or fœtus) is a developing mammal or other viviparous vertebrate, after the embryonic stage and before birth. The plural is fetuses (foetuses, fœtuses) or, very rarely, foeti.
In humans, the fetal stage of prenatal development begins about eight weeks after fertilization, when the major structures and organ systems have formed, until birth.
# Etymology and spelling variations
The word "fetus" is from the Latin fetus, meaning "offspring", "bringing forth", or "hatching of young". It has Indo-European roots related to sucking or suckling.
Foetus is an English variation on this, rather than a Latin or Greek word, but has been in use since at least 1594 according to the Oxford English Dictionary, which describes "fetus" as the etymologically preferable spelling. The word "fetus" is not derived from the Latin verb foetare, and therefore the superior etymological spelling does not include the letter "o". The variant foetus or fœtus may have originated with an error by Saint Isidore of Seville, in AD 620. The preferred spelling in the United States is fetus, but the variant foetus or fœtus persists in other English-speaking countries, and in some medical contexts, as well as in some other languages (e.g. French).
# Human fetus
The fetal stage begins eight weeks after fertilization. The fetus is not as sensitive to damage from environmental exposures as the embryo was, though toxic exposures can often cause physiological abnormalities or minor congenital malformation. Fetal growth can be terminated by various factors, including miscarriage, feticide committed by a third party, or induced abortion.
## Development
The following timeline describes some of the specific changes in fetal anatomy and physiology by fertilization age (i.e. the time elapsed since fertilization). However, it should be noted that obstetricians often use "gestational age" which, by convention, is measured from 2 weeks earlier than fertilization. For purposes of this article, age is measured from fertilization, except as noted.
### Variation in growth
There is much variation in the growth of the fetus. When fetal size is less than expected, that condition is known as intrauterine growth restriction (IUGR) also called fetal growth restriction (FGR); factors affecting fetal growth can be maternal, placental, or fetal.
Maternal factors include maternal weight, body mass index, nutritional state, emotional stress, toxin exposure (including tobacco, alcohol, heroin, and other drugs which can also harm the fetus in other ways), and uterine blood flow. A woman's primiparity also may affect fetal weight (firstborns tend to weigh less).
Placental factors include size, microstructure (densities and architecture), umbilical blood flow, transporters and binding proteins, nutrient utilization and nutrient production.
Fetal factors include the fetus genome, nutrient production, and hormone output. Also, female fetuses tend to weigh less than males, at full term.
Fetal growth is often classified as follows: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). SGA can result in low birth weight, although premature birth can also result in low birth weight. Low birth weight increases risk for perinatal mortality (death shortly after birth), asphyxia, hypothermia, polycythemia, hypocalcemia, immune dysfunction, neurologic abnormalities, and other long-term health problems. SGA may be associated with growth delay, or it may instead be associated with absolute stunting of growth.
## Viability
Five months is currently the lower limit of viability, and viability usually occurs later. According to The Developing Human:
Viability is defined as the ability of fetuses to survive in the extrauterine environment... There is no sharp limit of development, age, or weight at which a fetus automatically becomes viable or beyond which survival is assured, but experience has shown that it is rare for a baby to survive whose weight is less than 500 gm or whose fertilization age is less than 22 weeks. Even fetuses born between 26 and 28 weeks have difficulty surviving, mainly because the respiratory system and the central nervous system are not completely differentiated... If given expert postnatal care, some fetuses weighing less than 500 gm may survive; they are referred to as extremely low birth weight or immature infants.... Prematurity is one of the most common causes of morbidity and prenatal death.
During the past several decades, expert postnatal care has improved with advances in medical science, and therefore the point of viability has moved earlier. As of 2006, the youngest child to survive a premature birth was a girl born at the Baptist Hospital of Miami at 21 weeks and 6 days' gestational age.
## Fetal pain
The subject of fetal pain and suffering is controversial. The ability of a fetus to feel pain is often part of the abortion debate. However, according to Arthur Caplan, "there is no consensus among the medical and scientific experts about precisely when a fetus becomes pain-capable." Different sources have estimated that the earliest point for pain sensation may be during the first 12 weeks or after 20, 24, or 26 weeks gestation, or months after birth.
## Circulatory system
The circulatory system of a human fetus works differently from that of born humans, mainly because the lungs are not in use: the fetus obtains oxygen and nutrients from the woman through the placenta and the umbilical cord.
Blood from the placenta is carried to the fetus by the umbilical vein. About half of this enters the fetal ductus venosus and is carried to the inferior vena cava, while the other half enters the liver proper from the inferior border of the liver. The branch of the umbilical vein that supplies the right lobe of the liver first joins with the portal vein. The blood then moves to the right atrium of the heart. In the fetus, there is an opening between the right and left atrium (the foramen ovale), and most of the blood flows from the right into the left atrium, thus bypassing pulmonary circulation. The majority of blood flow is into the left ventricle from where it is pumped through the aorta into the body. Some of the blood moves from the aorta through the internal iliac arteries to the umbilical arteries, and re-enters the placenta, where carbon dioxide and other waste products from the fetus are taken up and enter the woman's circulation.
Some of the blood from the right atrium does not enter the left atrium, but enters the right ventricle and is pumped into the pulmonary artery. In the fetus, there is a special connection between the pulmonary artery and the aorta, called the ductus arteriosus, which directs most of this blood away from the lungs (which aren't being used for respiration at this point as the fetus is suspended in amniotic fluid).
### Postnatal development
With the first breath after birth, the system changes suddenly. The pulmonary resistance is dramatically reduced ("pulmo" is from the Latin for "lung"). More blood moves from the right atrium to the right ventricle and into the pulmonary arteries, and less flows through the foramen ovale to the left atrium. The blood from the lungs travels through the pulmonary veins to the left atrium, increasing the pressure there. The decreased right atrial pressure and the increased left atrial pressure pushes the septum primum against the septum secundum, closing the foramen ovale, which now becomes the fossa ovalis. This completes the separation of the circulatory system into two halves, the left and the right.
The ductus arteriosus normally closes off within one or two days of birth, leaving behind the ligamentum arteriosum. The umbilical vein and the ductus venosus closes off within two to five days after birth, leaving behind the ligamentum teres and the ligamentum venosus of the liver respectively.
### Differences from the adult circulatory system
Remnants of the fetal circulation can be found in adults:
In addition to differences in circulation, the developing fetus also employs a different type of oxygen transport molecule than adults (adults use adult hemoglobin). Fetal hemoglobin enhances the fetus' ability to draw oxygen from the placenta. Its association curve to oxygen is shifted to the left, meaning that it will take up oxygen at a lower concentration than adult hemoglobin will. This enables fetal hemoglobin to absorb oxygen from adult hemoglobin in the placenta, which has a lower pressure of oxygen than at the lungs.
## Developmental problems
Congenital anomalies are anomalies that are acquired before birth. Infants with certain congenital anomalies of the heart can survive only as long as the ductus remains open: in such cases the closure of the ductus can be delayed by the administration of prostaglandins to permit sufficient time for the surgical correction of the anomalies. Conversely, in cases of patent ductus arteriosus, where the ductus does not properly close, drugs that inhibit prostaglandin synthesis can be used to encourage its closure, so that surgery can be avoided.
A developing fetus is highly susceptible to anomalies in its growth and metabolism, increasing the risk of birth defects. One area of concern is the mother's lifestyle choices made during pregnancy Diet is especially important in the early stages of development. Studies show that supplementation of the mother's diet with folic acid reduces the risk of spina bifida and other neural tube defects. Another dietary concern is the consumption of breakfast by the mother. This one factor could lead to extended periods of lower than normal nutrients in the mother's blood, leading to a higher risk of prematurity, or other birth defects in the fetus.
During this time alcohol consumption may increase the risk of the development of Fetal alcohol syndrome, a condition leading to mental retardation in some infants.
Smoking during pregnancy may also lead to reduced birth weight. Low birth weight is defined as 2500 grams (5.5 lb). Low birth weight is a concern for medical providers due to the tendency of these infants, described as premature by weight, to have a higher risk of secondary medical problems.
## Legal issues
Especially since the 1970s, there has been continuing debate over the "personhood" of the human fetus. Although abortion of a fetus before viability is generally legal in the United States following the case of Roe v. Wade, the third-party-killing of a fetus can be punishable as feticide or homicide throughout the pregnancy, depending on jurisdiction.
# Non-human fetuses
The fetus of most mammals develops similarly to the Homo sapiens fetus. After the first stages of development, the human embryo reaches a stage very similar to all other vertebrates. The anatomy of the area surrounding a fetus is different in litter-bearing animals compared to humans: each fetus is surrounded by placental tissue and is lodged along one of two long uteri instead of the single uterus found in a human female. Development at birth is similar, with animals also having a poorly developed sense of vision and other senses. | Fetus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A fetus (or foetus, or fœtus) is a developing mammal or other viviparous vertebrate, after the embryonic stage and before birth. The plural is fetuses (foetuses, fœtuses) or, very rarely, foeti.
In humans, the fetal stage of prenatal development begins about eight weeks after fertilization, when the major structures and organ systems have formed, until birth.[1]
# Etymology and spelling variations
The word "fetus" is from the Latin fetus, meaning "offspring", "bringing forth", or "hatching of young".[2] It has Indo-European roots related to sucking or suckling.[3]
Foetus is an English variation on this, rather than a Latin or Greek word, but has been in use since at least 1594 according to the Oxford English Dictionary, which describes "fetus" as the etymologically preferable spelling. The word "fetus" is not derived from the Latin verb foetare, and therefore the superior etymological spelling does not include the letter "o".[4] The variant foetus or fœtus may have originated with an error by Saint Isidore of Seville, in AD 620.[5] The preferred spelling in the United States is fetus, but the variant foetus or fœtus persists in other English-speaking countries, and in some medical contexts, as well as in some other languages (e.g. French).
# Human fetus
The fetal stage begins eight weeks after fertilization. The fetus is not as sensitive to damage from environmental exposures as the embryo was, though toxic exposures can often cause physiological abnormalities or minor congenital malformation. Fetal growth can be terminated by various factors, including miscarriage, feticide committed by a third party, or induced abortion.
## Development
The following timeline describes some of the specific changes in fetal anatomy and physiology by fertilization age (i.e. the time elapsed since fertilization). However, it should be noted that obstetricians often use "gestational age" which, by convention, is measured from 2 weeks earlier than fertilization. For purposes of this article, age is measured from fertilization, except as noted.
### Variation in growth
Template:Seealso
There is much variation in the growth of the fetus. When fetal size is less than expected, that condition is known as intrauterine growth restriction (IUGR) also called fetal growth restriction (FGR); factors affecting fetal growth can be maternal, placental, or fetal.[22]
Maternal factors include maternal weight, body mass index, nutritional state, emotional stress, toxin exposure (including tobacco, alcohol, heroin, and other drugs which can also harm the fetus in other ways), and uterine blood flow. A woman's primiparity also may affect fetal weight (firstborns tend to weigh less).
Placental factors include size, microstructure (densities and architecture), umbilical blood flow, transporters and binding proteins, nutrient utilization and nutrient production.
Fetal factors include the fetus genome, nutrient production, and hormone output. Also, female fetuses tend to weigh less than males, at full term.[22]
Fetal growth is often classified as follows: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA).[23] SGA can result in low birth weight, although premature birth can also result in low birth weight. Low birth weight increases risk for perinatal mortality (death shortly after birth), asphyxia, hypothermia, polycythemia, hypocalcemia, immune dysfunction, neurologic abnormalities, and other long-term health problems. SGA may be associated with growth delay, or it may instead be associated with absolute stunting of growth.
## Viability
Five months is currently the lower limit of viability, and viability usually occurs later.[24] According to The Developing Human:
Viability is defined as the ability of fetuses to survive in the extrauterine environment... There is no sharp limit of development, age, or weight at which a fetus automatically becomes viable or beyond which survival is assured, but experience has shown that it is rare for a baby to survive whose weight is less than 500 gm or whose fertilization age is less than 22 weeks. Even fetuses born between 26 and 28 weeks have difficulty surviving, mainly because the respiratory system and the central nervous system are not completely differentiated... If given expert postnatal care, some fetuses weighing less than 500 gm may survive; they are referred to as extremely low birth weight or immature infants.... Prematurity is one of the most common causes of morbidity and prenatal death.[25]
During the past several decades, expert postnatal care has improved with advances in medical science, and therefore the point of viability has moved earlier.[26] As of 2006, the youngest child to survive a premature birth was a girl born at the Baptist Hospital of Miami at 21 weeks and 6 days' gestational age.[27]
## Fetal pain
The subject of fetal pain and suffering is controversial. The ability of a fetus to feel pain is often part of the abortion debate. However, according to Arthur Caplan, "there is no consensus among the medical and scientific experts about precisely when a fetus becomes pain-capable."[28] Different sources have estimated that the earliest point for pain sensation may be during the first 12 weeks or after 20, 24, or 26 weeks gestation, or months after birth.
## Circulatory system
The circulatory system of a human fetus works differently from that of born humans, mainly because the lungs are not in use: the fetus obtains oxygen and nutrients from the woman through the placenta and the umbilical cord.[29]
Blood from the placenta is carried to the fetus by the umbilical vein. About half of this enters the fetal ductus venosus and is carried to the inferior vena cava, while the other half enters the liver proper from the inferior border of the liver. The branch of the umbilical vein that supplies the right lobe of the liver first joins with the portal vein. The blood then moves to the right atrium of the heart. In the fetus, there is an opening between the right and left atrium (the foramen ovale), and most of the blood flows from the right into the left atrium, thus bypassing pulmonary circulation. The majority of blood flow is into the left ventricle from where it is pumped through the aorta into the body. Some of the blood moves from the aorta through the internal iliac arteries to the umbilical arteries, and re-enters the placenta, where carbon dioxide and other waste products from the fetus are taken up and enter the woman's circulation.[29]
Some of the blood from the right atrium does not enter the left atrium, but enters the right ventricle and is pumped into the pulmonary artery. In the fetus, there is a special connection between the pulmonary artery and the aorta, called the ductus arteriosus, which directs most of this blood away from the lungs (which aren't being used for respiration at this point as the fetus is suspended in amniotic fluid).[29]
### Postnatal development
With the first breath after birth, the system changes suddenly. The pulmonary resistance is dramatically reduced ("pulmo" is from the Latin for "lung"). More blood moves from the right atrium to the right ventricle and into the pulmonary arteries, and less flows through the foramen ovale to the left atrium. The blood from the lungs travels through the pulmonary veins to the left atrium, increasing the pressure there. The decreased right atrial pressure and the increased left atrial pressure pushes the septum primum against the septum secundum, closing the foramen ovale, which now becomes the fossa ovalis. This completes the separation of the circulatory system into two halves, the left and the right.
The ductus arteriosus normally closes off within one or two days of birth, leaving behind the ligamentum arteriosum. The umbilical vein and the ductus venosus closes off within two to five days after birth, leaving behind the ligamentum teres and the ligamentum venosus of the liver respectively.
### Differences from the adult circulatory system
Remnants of the fetal circulation can be found in adults:[30][31]
In addition to differences in circulation, the developing fetus also employs a different type of oxygen transport molecule than adults (adults use adult hemoglobin). Fetal hemoglobin enhances the fetus' ability to draw oxygen from the placenta. Its association curve to oxygen is shifted to the left, meaning that it will take up oxygen at a lower concentration than adult hemoglobin will. This enables fetal hemoglobin to absorb oxygen from adult hemoglobin in the placenta, which has a lower pressure of oxygen than at the lungs.
## Developmental problems
Template:Seealso
Congenital anomalies are anomalies that are acquired before birth. Infants with certain congenital anomalies of the heart can survive only as long as the ductus remains open: in such cases the closure of the ductus can be delayed by the administration of prostaglandins to permit sufficient time for the surgical correction of the anomalies. Conversely, in cases of patent ductus arteriosus, where the ductus does not properly close, drugs that inhibit prostaglandin synthesis can be used to encourage its closure, so that surgery can be avoided.
A developing fetus is highly susceptible to anomalies in its growth and metabolism, increasing the risk of birth defects. One area of concern is the mother's lifestyle choices made during pregnancy [32] Diet is especially important in the early stages of development. Studies show that supplementation of the mother's diet with folic acid reduces the risk of spina bifida and other neural tube defects. Another dietary concern is the consumption of breakfast by the mother. This one factor could lead to extended periods of lower than normal nutrients in the mother's blood, leading to a higher risk of prematurity, or other birth defects in the fetus.
During this time alcohol consumption may increase the risk of the development of Fetal alcohol syndrome, a condition leading to mental retardation in some infants.[33]
Smoking during pregnancy may also lead to reduced birth weight. Low birth weight is defined as 2500 grams (5.5 lb). Low birth weight is a concern for medical providers due to the tendency of these infants, described as premature by weight, to have a higher risk of secondary medical problems.
## Legal issues
Especially since the 1970s, there has been continuing debate over the "personhood" of the human fetus. Although abortion of a fetus before viability is generally legal in the United States following the case of Roe v. Wade, the third-party-killing of a fetus can be punishable as feticide or homicide throughout the pregnancy, depending on jurisdiction.
# Non-human fetuses
The fetus of most mammals develops similarly to the Homo sapiens fetus. After the first stages of development, the human embryo reaches a stage very similar to all other vertebrates.[34] The anatomy of the area surrounding a fetus is different in litter-bearing animals compared to humans: each fetus is surrounded by placental tissue and is lodged along one of two long uteri instead of the single uterus found in a human female. Development at birth is similar, with animals also having a poorly developed sense of vision and other senses. | https://www.wikidoc.org/index.php/Fetal | |
43550c06844fd4564a882a294a4672325168253f | wikidoc | Fique | Fique
Fique or Cabuya is a natural fiber that grows in the leaves of the fique plant (Furcraea sp.), a xerophytic monocot native to Andean regions of Colombia. From here it was extended to Venezuela and the east coast of Brazil. Common names: Fique, Cabuya, Pita, Penca, Maguey, Cabui, Chuchao or Coquiza.
The fique plant is often confused with the agave plant. The differences are that the Agave leaves are yellowish and stiff, with a strong spike in the tips, while the Fique plant leaves are droppy and greenish without spike.
# History
The pre-Columbian inhabitants extracted and used the fique fibers for several centuries before the arrival of Spanish conquerors to make garments, ropes, hammocks and many other applications.
In the 17th century, the Dutch colonists carried the plant from their Brazilian colonies in Pernambuco to the island of Mauritius. The native inhabitants of the island learned to use the fiber and called it “caraguatá-acú” “croatá-acu” or “gravata”-acú”.
The fiber was also introduced to St. Helena, India, Sri Lanka, Algeria, Madagascar, East Africa, Mexico and Costa Rica.
In the 18th century, in Dagua, Valle del Cauca, Colombia, the priest Feliciano Villalobos started the first rope and wrapping materials manufacturing industry; his products were made of fique. In 1880 the Colombian government reported a yearly production of three million kilograms of fibers, the exportation to Venezuela of two million, the fabrication of five millions pairs of alpargatas and four million meters of rope.
Between 1970 and 1975 the fique industry suffered a crisis brought about by the development of polypropylene, which costs less and is produced much faster.
Today, fique is considered the Colombian national fiber and is used in the fabrication of ethnic products, handcrafts and recently has been used for the heath protectors (handmade in Barichara) placed around the Colombian coffee cups sold in the Juan Valdez coffee shops worldwide.
# Uses
- Packing: The main use of the colombian cabuya is for the fabrication of sacks and packages for agriculture. According with the number of threads, the products are classified as:
- Dense: 6000 to 10,000 threads per square meter. Used for flour and small grains such rice.
Semidense: 4800 to 5500. Used for bigger grains such coffee and beans.
Loose: 300 to 360. Used for fruits, vegetables and panela.
- Dense: 6000 to 10,000 threads per square meter. Used for flour and small grains such rice.
- Semidense: 4800 to 5500. Used for bigger grains such coffee and beans.
- Loose: 300 to 360. Used for fruits, vegetables and panela.
- Ropes: with cabuya one can make very resistant ropes and strings of different calibres, from threads to manilas one inch in diameter. Such ropes are used in the industries of transportation, construction, sailing and many others.
- Arriería accesories: many of the elements used in the pack animals such as enjalmas, cinchas, retrancas, lazos, pretales, tapa de enjalma, and cinchos are handmade with fique.
- Tapestry: the mixed and crude cabuya is used in rugs and tapestry of different size and quality. The fibers can be mixed with different organic materials such as avocado seed, achiote and eucalyptus cortex.
- Others: handcrafts, purses, bags, handbags, matresses, curtains, shoes, umbrellas, baskets and many other products.
## Subproducts:
- Pulp: Used to produce organic fertilizant and paper
- Leaves juice: Can be used for fabrication of soap, fungicides, alcoholic beverages (homemade tapetusa, organic fuel and animal food.
- Floral stem: The strong floral stem of the fique plant is used in the construction of houses and ladders.
- Bulbs: The pickled terminal bulbs of the plant are edible.
- Medicinal uses: The peasants use the leaves in topic preparations for treatment of boils. The extract of leaves is used against the horse lice.
# Cultivation
The fique can be obtained from several species of Furcraea, such as macrophylla Baker, cabuya Trel, andina Trel, and castilla. Depending of the process of the fiber and the species used, many varieties of fique fibers can be obtained . Among others:
## Main varieties:
- Ceniza (ash-colored)
- Espinosa (rough texture)
- Castilla or Golden border
- Sisal
## Secondary varieties:
- Cabuya verde (green)
- Uña de águila (eagle nail)
- Negra común (black common)
- Chachagueña
- Genoia
- Tunosa común (common spiked)
- Jardineña
- Espadilla
- Rabo de chucha (opossum tail).
Optimal conditions for the growing of the fique plant are:
- Temperature: 19ºC - 23ºC
- Altitude: 1,300 m - 1,900 m
- Annual rainfall: 1,000 mm - 1,600 mm
- Sunlight: 5-6 hours/day
- Soil: dry, rich in silicates.
The fique crops bring nitrogen to the soil, improving its fertility. The plant is very adaptable to different ecological conditions. A fique plant can produce 1 to 6 kg of fibers each year.
# Diseases
- Llaga Macana or Rayadilla: a viral disease that attacks all varieties of fique and all the parts of the plant, specially in crops over 1900 m altitude. The disease have no chemical control. It must be managed with preventive measures.
- Pink disease: caused by the fungus Corticium salmonicolor. The disease damages the leaves, disrupting the fibers. Treatment is undertaked with copper-based fungicides. The peasants treat this disease by applying ashes to the base of the leaves.
- Leaf Cochineal (Diaspis bromelia): caused by a parasitic insect.
- Leaf Beetle: a beetle that perforates the base of the leaves. | Fique
Fique or Cabuya is a natural fiber that grows in the leaves of the fique plant (Furcraea sp.), a xerophytic monocot native to Andean regions of Colombia. From here it was extended to Venezuela and the east coast of Brazil. Common names: Fique, Cabuya, Pita, Penca, Maguey, Cabui, Chuchao or Coquiza[1].
The fique plant is often confused with the agave plant. The differences are that the Agave leaves are yellowish and stiff, with a strong spike in the tips, while the Fique plant leaves are droppy and greenish without spike.
# History
The pre-Columbian inhabitants extracted and used the fique fibers for several centuries before the arrival of Spanish conquerors to make garments, ropes, hammocks and many other applications.
In the 17th century, the Dutch colonists carried the plant from their Brazilian colonies in Pernambuco to the island of Mauritius. The native inhabitants of the island learned to use the fiber and called it “caraguatá-acú” “croatá-acu” or “gravata”-acú”.
The fiber was also introduced to St. Helena, India, Sri Lanka, Algeria, Madagascar, East Africa, Mexico and Costa Rica.
In the 18th century, in Dagua, Valle del Cauca, Colombia, the priest Feliciano Villalobos started the first rope and wrapping materials manufacturing industry; his products were made of fique. In 1880 the Colombian government reported a yearly production of three million kilograms of fibers, the exportation to Venezuela of two million, the fabrication of five millions pairs of alpargatas and four million meters of rope.
Between 1970 and 1975 the fique industry suffered a crisis brought about by the development of polypropylene, which costs less and is produced much faster.
Today, fique is considered the Colombian national fiber and is used in the fabrication of ethnic products, handcrafts and recently has been used for the heath protectors (handmade in Barichara) placed around the Colombian coffee cups sold in the Juan Valdez coffee shops worldwide[2].
# Uses
- Packing: The main use of the colombian cabuya is for the fabrication of sacks and packages for agriculture. According with the number of threads, the products are classified as:
- Dense: 6000 to 10,000 threads per square meter. Used for flour and small grains such rice.
Semidense: 4800 to 5500. Used for bigger grains such coffee and beans.
Loose: 300 to 360. Used for fruits, vegetables and panela.
- Dense: 6000 to 10,000 threads per square meter. Used for flour and small grains such rice.
- Semidense: 4800 to 5500. Used for bigger grains such coffee and beans.
- Loose: 300 to 360. Used for fruits, vegetables and panela.
- Ropes: with cabuya one can make very resistant ropes and strings of different calibres, from threads to manilas one inch in diameter. Such ropes are used in the industries of transportation, construction, sailing and many others.
- Arriería accesories: many of the elements used in the pack animals such as enjalmas, cinchas, retrancas, lazos, pretales, tapa de enjalma, and cinchos are handmade with fique.
- Tapestry: the mixed and crude cabuya is used in rugs and tapestry of different size and quality. The fibers can be mixed with different organic materials such as avocado seed, achiote and eucalyptus cortex.
- Others: handcrafts, purses, bags, handbags, matresses, curtains, shoes, umbrellas, baskets and many other products.
## Subproducts:
- Pulp: Used to produce organic fertilizant and paper
- Leaves juice: Can be used for fabrication of soap, fungicides, alcoholic beverages (homemade tapetusa, organic fuel and animal food.
- Floral stem: The strong floral stem of the fique plant is used in the construction of houses and ladders.
- Bulbs: The pickled terminal bulbs of the plant are edible.
- Medicinal uses: The peasants use the leaves in topic preparations for treatment of boils. The extract of leaves is used against the horse lice.
# Cultivation
The fique can be obtained from several species of Furcraea, such as macrophylla Baker, cabuya Trel, andina Trel, and castilla. Depending of the process of the fiber and the species used, many varieties of fique fibers can be obtained[3] . Among others:
## Main varieties:
- Ceniza (ash-colored)
- Espinosa (rough texture)
- Castilla or Golden border
- Sisal
## Secondary varieties:
- Cabuya verde (green)
- Uña de águila (eagle nail)
- Negra común (black common)
- Chachagueña
- Genoia
- Tunosa común (common spiked)
- Jardineña
- Espadilla
- Rabo de chucha (opossum tail).
Optimal conditions for the growing of the fique plant are:
- Temperature: 19ºC - 23ºC
- Altitude: 1,300 m - 1,900 m
- Annual rainfall: 1,000 mm - 1,600 mm
- Sunlight: 5-6 hours/day
- Soil: dry, rich in silicates.
The fique crops bring nitrogen to the soil, improving its fertility. The plant is very adaptable to different ecological conditions. A fique plant can produce 1 to 6 kg of fibers each year.
# Diseases
- Llaga Macana or Rayadilla: a viral disease that attacks all varieties of fique and all the parts of the plant, specially in crops over 1900 m altitude. The disease have no chemical control. It must be managed with preventive measures.
- Pink disease: caused by the fungus Corticium salmonicolor. The disease damages the leaves, disrupting the fibers. Treatment is undertaked with copper-based fungicides. The peasants treat this disease by applying ashes to the base of the leaves.
- Leaf Cochineal (Diaspis bromelia): caused by a parasitic insect.
- Leaf Beetle: a beetle that perforates the base of the leaves. | https://www.wikidoc.org/index.php/Fique | |
82972dd28fa126a572c2e32d28bb7305c62cc90d | wikidoc | Flame | Flame
# Overview
A flame is often defined as the visible (light-emitting) part of a fire. Physically, it is caused by a highly exothermic reaction (for example, combustion, a self-sustaining oxidation reaction) taking place in a thin zone. A flame generally emits light, by two different mechanisms which will be described below.
The color and temperature of a flame are dependent on the type of fuel involved in the combustion, as, for example, when a lighter is held to a candle. The applied heat causes the fuel molecules in the wick to vaporize. In this state they can then readily react with oxygen in the air, which gives off enough heat in the subsequent exothermic reaction to vaporize yet more fuel, thus sustaining a consistent flame. The high temperature of the flame tears apart the vaporized fuel molecules, forming various incomplete combustion products and free radicals, and these products then react with each other and with the oxidizer involved in the reaction. Sufficient energy in the flame will excite the electrons in some of the transient reaction intermediates such as CH and C2, which results in the emission of visible light as these substances release their excess energy (see spectrum below for an explanation of which specific radical species produce which specific colors). As the combustion temperature of a flame increases (if the flame contains small particles of unburnt carbon or other material), so does the average energy of the electromagnetic radiation given off by the flame (see blackbody).
Other oxidizers besides oxygen can be used to produce a flame. Hydrogen burning in chlorine produces a flame and in the process emits gaseous hydrogen chloride (HCl) as the combustion product. Another of many possible chemical combinations is hydrazine and nitrogen tetroxide which is hypergolic and commonly used in rocket engines.
The chemical kinetics occurring in the flame is very complex and involves typically a large number of chemical reactions and intermediate species, most of them radicals. For instance, a well-known chemical kinetics scheme, GRI-Mech
, uses 53 species and 325 elementary reactions to describe combustion of natural gas.
There are different methods of distributing the required components of combustion to a flame. In a diffusion flame, oxygen and fuel diffuse into each other; where they meet the flame occurs. In a premixed flame, the oxygen and fuel are premixed beforehand, which results in a different type of flame. Candle flames (a diffusion flame) operate through evaporation of the fuel which rises in a laminar flow of hot gas which then mixes with surrounding oxygen and combusts.
# Flame color
Flame color depends on several factors, the most important typically being blackbody radiation and spectral band emission, with both spectral line emission and spectral line absorption playing smaller roles. In the most common type of flame, hydrocarbon flames, the most important factor determining color is oxygen supply and the extent of fuel-oxygen "pre-mixture", which determines the rate of combustion and thus the temperature and reaction paths, thereby producing different color hues.
In a laboratory under normal gravity conditions and with a closed oxygen valve, a Bunsen burner burns with yellow flame (also called a safety flame) at around 1,000°C. This is due to incandescence of very fine soot particles that are produced in the flame. With increasing oxygen supply, less blackbody-radiating soot is produced due to a more complete combustion and the reaction creates enough energy to excite and ionize gas molecules in the flame, leading to a blue appearance. The spectrum of a premixed (complete combustion) butane flame on the right shows that the blue color arises specifically due to emission of excited molecular radicals in the flame, which emit most of their light well below ~565 nanometers in the blue and green regions of the visible spectrum.
Flame temperatures of common items include a blow torch at 1,300°C, a candle at 1,400°C , or a much hotter oxyacetylene combustion at 3,000°C. Cyanogen produces an ever-hotter flame with a temperature of over 4525°C (8180°F) when it burns in oxygen.
Generally speaking, the coolest part of a diffusion (incomplete combustion) flame will be red, transitioning to orange, yellow, and white the temperature increases as evidenced by changes in the blackbody radiation spectrum. For a given flame's region, the closer to white on this scale, the hotter that section of the flame is. The transitions are often apparent in TV pictures of fires, in which the color emitted closest to the fuel is white, with an orange section above it, and reddish flames the highest of all. Beyond the red the temperature is too low to sustain combustion, and black soot escapes. A blue-colored flame only emerges when the amount of soot decreases and the blue emissions from excited molecular radicals become dominant, though the blue can often be seen near the base of candles where airborne soot is less concentrated.
# Flames in microgravity
In the year 2000 the National Aeronautics and Space Administration (NASA) of the United States discovered that gravity also plays an indirect role in flame formation and composition.
The common distribution of a flame under normal gravity conditions depends on convection, as soot tends to rise to the top of a flame (such as in a candle in normal gravity conditions), making it yellow. In microgravity or zero gravity, such as an outer space environment, convection no longer occurs and the flame becomes spherical, with a tendency to become bluer and more efficient. There are several possible explanations for this difference, of which the most likely is the hypothesis that the temperature is sufficiently evenly distributed that soot is not formed and complete combustion occurs. Experiments by NASA reveal that diffusion flames in microgravity allow more soot to be completely oxidized after they are produced than do diffusion flames on Earth, because of a series of mechanisms that behave differently in microgravity when compared to normal gravity conditions. These discoveries have potential applications in applied science and industry, especially concerning fuel efficiency. A video of a microgravity flame in the NASA Glenn 5 s drop facility is at . | Flame
# Overview
A flame is often defined as the visible (light-emitting) part of a fire. Physically, it is caused by a highly exothermic reaction (for example, combustion, a self-sustaining oxidation reaction) taking place in a thin zone. A flame generally emits light, by two different mechanisms which will be described below.
The color and temperature of a flame are dependent on the type of fuel involved in the combustion, as, for example, when a lighter is held to a candle. The applied heat causes the fuel molecules in the wick to vaporize. In this state they can then readily react with oxygen in the air, which gives off enough heat in the subsequent exothermic reaction to vaporize yet more fuel, thus sustaining a consistent flame. The high temperature of the flame tears apart the vaporized fuel molecules, forming various incomplete combustion products and free radicals, and these products then react with each other and with the oxidizer involved in the reaction. Sufficient energy in the flame will excite the electrons in some of the transient reaction intermediates such as CH and C2, which results in the emission of visible light as these substances release their excess energy (see spectrum below for an explanation of which specific radical species produce which specific colors). As the combustion temperature of a flame increases (if the flame contains small particles of unburnt carbon or other material), so does the average energy of the electromagnetic radiation given off by the flame (see blackbody).
Other oxidizers besides oxygen can be used to produce a flame. Hydrogen burning in chlorine produces a flame and in the process emits gaseous hydrogen chloride (HCl) as the combustion product.[1] Another of many possible chemical combinations is hydrazine and nitrogen tetroxide which is hypergolic and commonly used in rocket engines.
The chemical kinetics occurring in the flame is very complex and involves typically a large number of chemical reactions and intermediate species, most of them radicals. For instance, a well-known chemical kinetics scheme, GRI-Mech [2]
, uses 53 species and 325 elementary reactions to describe combustion of natural gas.
There are different methods of distributing the required components of combustion to a flame. In a diffusion flame, oxygen and fuel diffuse into each other; where they meet the flame occurs. In a premixed flame, the oxygen and fuel are premixed beforehand, which results in a different type of flame. Candle flames (a diffusion flame) operate through evaporation of the fuel which rises in a laminar flow of hot gas which then mixes with surrounding oxygen and combusts.
# Flame color
Flame color depends on several factors, the most important typically being blackbody radiation and spectral band emission, with both spectral line emission and spectral line absorption playing smaller roles. In the most common type of flame, hydrocarbon flames, the most important factor determining color is oxygen supply and the extent of fuel-oxygen "pre-mixture", which determines the rate of combustion and thus the temperature and reaction paths, thereby producing different color hues.
In a laboratory under normal gravity conditions and with a closed oxygen valve, a Bunsen burner burns with yellow flame (also called a safety flame) at around 1,000°C. This is due to incandescence of very fine soot particles that are produced in the flame. With increasing oxygen supply, less blackbody-radiating soot is produced due to a more complete combustion and the reaction creates enough energy to excite and ionize gas molecules in the flame, leading to a blue appearance. The spectrum of a premixed (complete combustion) butane flame on the right shows that the blue color arises specifically due to emission of excited molecular radicals in the flame, which emit most of their light well below ~565 nanometers in the blue and green regions of the visible spectrum.
Flame temperatures of common items include a blow torch at 1,300°C, a candle at 1,400°C [1], or a much hotter oxyacetylene combustion at 3,000°C. Cyanogen produces an ever-hotter flame with a temperature of over 4525°C (8180°F) when it burns in oxygen.[3]
Generally speaking, the coolest part of a diffusion (incomplete combustion) flame will be red, transitioning to orange, yellow, and white the temperature increases as evidenced by changes in the blackbody radiation spectrum. For a given flame's region, the closer to white on this scale, the hotter that section of the flame is. The transitions are often apparent in TV pictures of fires, in which the color emitted closest to the fuel is white, with an orange section above it, and reddish flames the highest of all. Beyond the red the temperature is too low to sustain combustion, and black soot escapes. A blue-colored flame only emerges when the amount of soot decreases and the blue emissions from excited molecular radicals become dominant, though the blue can often be seen near the base of candles where airborne soot is less concentrated.
# Flames in microgravity
In the year 2000 the National Aeronautics and Space Administration (NASA) of the United States discovered that gravity also plays an indirect role in flame formation and composition. [4]
The common distribution of a flame under normal gravity conditions depends on convection, as soot tends to rise to the top of a flame (such as in a candle in normal gravity conditions), making it yellow. In microgravity or zero gravity, such as an outer space environment, convection no longer occurs and the flame becomes spherical, with a tendency to become bluer and more efficient. There are several possible explanations for this difference, of which the most likely is the hypothesis that the temperature is sufficiently evenly distributed that soot is not formed and complete combustion occurs. [5] Experiments by NASA reveal that diffusion flames in microgravity allow more soot to be completely oxidized after they are produced than do diffusion flames on Earth, because of a series of mechanisms that behave differently in microgravity when compared to normal gravity conditions. [6][7] These discoveries have potential applications in applied science and industry, especially concerning fuel efficiency. A video of a microgravity flame in the NASA Glenn 5 s drop facility is at [2]. | https://www.wikidoc.org/index.php/Flame | |
9a4008c7a5f5c8f05cc06c14b6caace1c0f098be | wikidoc | Flora | Flora
# Overview
In botany, flora (plural: floras or florae) has two meanings. The first meaning, or flora of an area or of time period, refers to all plant life occurring in an area or time period, especially the naturally occurring or indigenous plant life. The second meaning refers to a book or other work which describes the plant species occurring in an area or time period, with the aim of allowing identification. Some classic and modern floras are listed below.
The term flora comes from Latin language Flora, the goddess of flowers in Roman mythology. The corresponding term for animal life is fauna. Flora, fauna and other forms of life such as fungi are collectively referred to as biota. In relation to all the flora and fauna of a region, it is collectively referred to as biota.
# Flora classifications
Plants are grouped into floras based on region, period, special environment, or climate. Regions can be geographically distinct habitats like mountain vs. flatland. Floras can mean plant life of an historic era as in fossil flora. Lastly, floras may be subdivided by special environments:
- Native flora. The native and indigenous flora of an area.
- Agricultural and garden flora. The plants that are deliberately grown by humans.
- Weed flora. Traditionally this classification was applied to plants regarded as undesirable, and studied in efforts to control or eradicate them. Today the designation is less often used as a classification of plant life, since it includes three different types of plants: weedy species, invasive species (that may or may not be weedy), and native and introduced non-weedy species that are agriculturally undesirable. Many native plants previously considered weeds have been shown to be beneficial or even necessary to various ecosystems.
Bacterial organisms are sometimes included in a flora . Other times, the terms bacterial flora and plant flora are used separately.
# Flora treatises
Traditionally floras are books, but some are now published on CD-ROM or websites. The area that a flora covers can be either geographically or politically defined. Floras usually require some specialist botanical knowledge to use with any effectiveness.
A flora often contains diagnostic keys. Often these are dichotomous keys, which require the user to repeatedly examine a plant, and decide which one of two alternatives given in the flora best applies to the plant.
## Classic floras
- Flora Londinensis, William Curtis. England 1777- 1798
- Flora Graeca, John Sibthorp. (England) 1806 - 1840
- Flora Danica, Simon Paulli. Denmark, 1847.
- Flora Jenensis, Heinrich Bernhard Rupp Germany, 1718.
- Flora Scorer, Paolo Di Canio. 1723.
- Flora Suecica, Carolus Linnaeus. 1745.
- Hortus indicus malabaricus, Hendrik van Rheede 1683–1703
- Flora Javae, Carl Ludwig Blume and Joanne Baptista Fischer. 1828.
## Modern floras
### Americas
- Britton, N. L., and Percy Wilson. Scientific Survey of Porto Rico and the Virgin Islands — Volume V, Part 1: Botany of Porto Rico and the Virgin Islands: Pandanales to Thymeleales. New York: New York Academy of Sciences, 1924.
- Flora Brasiliensis
- Flora of São Paulo in Brazil
- Flora de Chile
- Manual de Plantas de Costa Rica
- Flora of Ecuador
- Flora of Guatemala
- Flora de Nicaragua
- Flora of Peru
- Flora of the Guianas
- Flora of Panama
- Flora del Paraguay
- Flora of Suriname
- Flora Mesoamericana (1994-ongoing) Introduction
- Flora of the Venezuelan Guayana
- Flora Neotropica (1968-ongoing) Organising committee website.
- Flora of North America
- Kearney, Thomas H. Arizona Flora. University of California Press, 1940.
- Hickman, James C., editor. The Jepson Manual: Higher Plants of California. University of California Press, 1993.
- Hultén, Eric. Flora of Alaska and Neighboring Territories: A Manual of the Vascular Plants. Stanford University Press, 1968.
- Radford, Albert E. Manual of the Vascular Flora of the Carolinas. University of North Carolina Press, 1968.
- Hitchcock, C. Leo, and Arthur Cronquist. Flora of the Pacific Northwest. University of Washington Press, 1973.
- Chadde, Steve W., and Steve Chadde. A Great Lakes Wetland Flora. 2nd ed. Pocketflora Press, 2002. ISBN 0-9651385-5-0
- P. D. Strausbaugh and Earl L. Core. Flora of West Virginia. 2nd ed. Seneca Books Inc., 1964. ISBN 0-89092-010-9
- Ann Fouler Rhoads and Timothy A. Block. The Plants of Pennsylvania. University of Pennsylvania Press, 2000. ISBN 0-8122-3535-5
- Nathaniel Lord Britton and Hon. Addison Brown. An Illustrated Flora of the Northern United States and Canada. In three volumes. Dover Publications, 1913, 1970. ISBN 0-486-22642-5
### Asia
- Flora of China
- Flora of China in eFloras
- Flora of Japan
- Flora of Thailand
- Florae Siamensis Enumeratio
- Flora Malesiana (1984-ongoing) About Flora Malesiana.
- Flora of the Malay Peninsula
- Flore du Cambodge, du Laos et du Viêt-Nam
- Flora of Bhutan
- Flora of the Presidency of Madras by J.S. Gamble (1915-36)
- Flora of Nepal
- Bengal Plants by D. Prain (1903)
- Flora of the upper Gangetic plains by J. F. Duthie (1903-29)
- Botany of Bihar and Orissa by H.H. Haines (1921-25)
- Flora of British India (1872-1897) by Sir J.D. Hooker
- Flora of Turkey
- Flora Iranica
- Flora Palaestina:
M. Zohary (1966). Flora Palaestina part 1.
M. Zohary (1972). Flora Palaestina part 2.
N. Feinbrun (1978). Flora Palaestina part 3.
N. Feinbrun (1986). Flora Palaestina part 4.
A. Danin, (2004). Distribution Atlas of Plants in the Flora Palaestina Area (Flora Palaestina part 5).
Online updates:
- M. Zohary (1966). Flora Palaestina part 1.
- M. Zohary (1972). Flora Palaestina part 2.
- N. Feinbrun (1978). Flora Palaestina part 3.
- N. Feinbrun (1986). Flora Palaestina part 4.
- A. Danin, (2004). Distribution Atlas of Plants in the Flora Palaestina Area (Flora Palaestina part 5).
- Online updates:
### Australasia
- Flora of Australia
- Flora of New Zealand series:
Allan, H.H. 1961, reprinted 1982. Flora of New Zealand. Volume I: Indigenous Tracheophyta - Psilopsida, Lycopsida, Filicopsida, Gymnospermae, Dicotyledons. ISBN 0-477-01056-3.
Moore, L.B.; Edgar, E. 1970, reprinted 1976. Flora of New Zealand. Volume II: Indigenous Tracheophyta - Monocotyledons except Graminae. ISBN 0-477-01889-0.
Healy, A.J.; Edgar, E. 1980. Flora of New Zealand Volume III. Adventive Cyperaceous, Petalous & Spathaceous Monocotyledons. ISBN 0-477-01041-5.
Webb, C.J.; Sykes, W.R.;Garnock-Jones, P.J. 1988. Flora of New Zealand Volume IV: Naturalised Pteridophytes, Gymnosperms, Dicotyledons. ISBN 0-477-02529-3.
Edgar, E.; Connor, H.E. 2000. Flora of New Zealand Volume V: Grasses. ISBN 0-478-09331-4.
Volumes I-V: First electronic edition, Landcare Research, June 2004. Transcribed by A.D. Wilton and I.M.L. Andres.
- Allan, H.H. 1961, reprinted 1982. Flora of New Zealand. Volume I: Indigenous Tracheophyta - Psilopsida, Lycopsida, Filicopsida, Gymnospermae, Dicotyledons. ISBN 0-477-01056-3.
- Moore, L.B.; Edgar, E. 1970, reprinted 1976. Flora of New Zealand. Volume II: Indigenous Tracheophyta - Monocotyledons except Graminae. ISBN 0-477-01889-0.
- Healy, A.J.; Edgar, E. 1980. Flora of New Zealand Volume III. Adventive Cyperaceous, Petalous & Spathaceous Monocotyledons. ISBN 0-477-01041-5.
- Webb, C.J.; Sykes, W.R.;Garnock-Jones, P.J. 1988. Flora of New Zealand Volume IV: Naturalised Pteridophytes, Gymnosperms, Dicotyledons. ISBN 0-477-02529-3.
- Edgar, E.; Connor, H.E. 2000. Flora of New Zealand Volume V: Grasses. ISBN 0-478-09331-4.
- Volumes I-V: First electronic edition, Landcare Research, June 2004. Transcribed by A.D. Wilton and I.M.L. Andres.
- Galloway, D.J. 1985. Flora of New Zealand: Lichens. ISBN 0-477-01266-3.
- Croasdale, H.; Flint, E.A. 1986. Flora of New Zealand: Desmids. Volume I. ISBN 0-477-02530-7.
- Croasdale, H.; Flint, E.A. 1988. Flora of New Zealand: Desmids. Volume II. ISBN 0-477-01353-8.
- Croasdale, H.; Flint, E.A.;Racine, M.M. 1994. Flora of New Zealand: Desmids. Volume III. ISBN 0-477-01642-1.
- Sykes, W.R.; West, C.J.; Beever, J.E.; Fife, A.J. 2000. Kermadec Islands Flora - Special Edition. ISBN 0-478-09339-X.
### Pacific Islands
- Flora Vitiensis Nova, a New Flora of Fiji
- Manual of the Flowering Plants of Hawai‘i, Warren L. Wagner and Derral R. Herbst (1991) + suppl.
- Flore de la Nouvelle-Calédonie
- Flore de la Polynésie Française (J. Florence, vol. 1 & 2, 1997 & 2004)
### Europe
- Morton, O.1994. Marine Algae of Northern Ireland. Ulster Museum, Belfast. ISBN 0 900761 28 8
- Stace, Clive Anthony, and Hilli Thompson (illustrator). A New Flora of the British Isles. 2nd ed. Cambridge University Press, 1997. ISBN 0-521-58935-5.
- Beesley, S. and J. Wilde. Urban Flora of Belfast. Belfast: Institute of Irish Studies, Queen's University of Belfast, 1997.
- Killick, John, Roy Perry and Stan Woodell. Flora of Oxfordshire. Pisces Publications, 1998. ISBN 1-874357-07-2.
- Bowen, Humphry. The Flora of Dorset. Pisces Publications, 2000. ISBN 1-874357-16-1.
- Flora Celtica Plants and people in Celtic Europe
- Flora Europaea at the site of The Royal Botanical Gardens of Edinburgh Flora Europaea
- Flora of Europe
- Flora iberica
- Flora of Acores
- Flora Danica
- Flora of Romania
### Africa and Madagascar
- Flore du Gabon
- Flore du Cameroun
- Flora of Tropical Africa
- Flora of Tropical East Africa
- Flora Capensis
- Flora Zambesiaca
- Flora of South Africa
- Flore du Rwanda
- Flore de Madagascar et des Comores
# Flora on WikiDoc
WikiDoc has the following mainly flora categories:
- Flora by continent
- Flora by country
- Flora by region | Flora
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In botany, flora (plural: floras or florae) has two meanings. The first meaning, or flora of an area or of time period, refers to all plant life occurring in an area or time period, especially the naturally occurring or indigenous plant life. The second meaning refers to a book or other work which describes the plant species occurring in an area or time period, with the aim of allowing identification. Some classic and modern floras are listed below.
The term flora comes from Latin language Flora, the goddess of flowers in Roman mythology. The corresponding term for animal life is fauna. Flora, fauna and other forms of life such as fungi are collectively referred to as biota. In relation to all the flora and fauna of a region, it is collectively referred to as biota.
# Flora classifications
Plants are grouped into floras based on region, period, special environment, or climate. Regions can be geographically distinct habitats like mountain vs. flatland. Floras can mean plant life of an historic era as in fossil flora. Lastly, floras may be subdivided by special environments:
- Native flora. The native and indigenous flora of an area.
- Agricultural and garden flora. The plants that are deliberately grown by humans.
- Weed flora. Traditionally this classification was applied to plants regarded as undesirable, and studied in efforts to control or eradicate them. Today the designation is less often used as a classification of plant life, since it includes three different types of plants: weedy species, invasive species (that may or may not be weedy), and native and introduced non-weedy species that are agriculturally undesirable. Many native plants previously considered weeds have been shown to be beneficial or even necessary to various ecosystems.
Bacterial organisms are sometimes included in a flora [2] [3]. Other times, the terms bacterial flora and plant flora are used separately.
# Flora treatises
Traditionally floras are books, but some are now published on CD-ROM or websites. The area that a flora covers can be either geographically or politically defined. Floras usually require some specialist botanical knowledge to use with any effectiveness.
A flora often contains diagnostic keys. Often these are dichotomous keys, which require the user to repeatedly examine a plant, and decide which one of two alternatives given in the flora best applies to the plant.
## Classic floras
- Flora Londinensis, William Curtis. England 1777- 1798
- Flora Graeca, John Sibthorp. (England) 1806 - 1840
- Flora Danica, Simon Paulli. Denmark, 1847.
- Flora Jenensis, Heinrich Bernhard Rupp Germany, 1718.
- Flora Scorer, Paolo Di Canio. 1723.
- Flora Suecica, Carolus Linnaeus. 1745.
- Hortus indicus malabaricus, Hendrik van Rheede 1683–1703
- Flora Javae, Carl Ludwig Blume and Joanne Baptista Fischer. 1828.
## Modern floras
### Americas
- Britton, N. L., and Percy Wilson. Scientific Survey of Porto Rico and the Virgin Islands — Volume V, Part 1: Botany of Porto Rico and the Virgin Islands: Pandanales to Thymeleales. New York: New York Academy of Sciences, 1924.
- Flora Brasiliensis
- Flora of São Paulo in Brazil
- Flora de Chile
- Manual de Plantas de Costa Rica
- Flora of Ecuador
- Flora of Guatemala
- Flora de Nicaragua
- Flora of Peru
- Flora of the Guianas
- Flora of Panama
- Flora del Paraguay
- Flora of Suriname
- Flora Mesoamericana (1994-ongoing) Introduction
- Flora of the Venezuelan Guayana
- Flora Neotropica (1968-ongoing) Organising committee website.
- Flora of North America
- Kearney, Thomas H. Arizona Flora. University of California Press, 1940.
- Hickman, James C., editor. The Jepson Manual: Higher Plants of California. University of California Press, 1993.
- Hultén, Eric. Flora of Alaska and Neighboring Territories: A Manual of the Vascular Plants. Stanford University Press, 1968.
- Radford, Albert E. Manual of the Vascular Flora of the Carolinas. University of North Carolina Press, 1968.
- Hitchcock, C. Leo, and Arthur Cronquist. Flora of the Pacific Northwest. University of Washington Press, 1973.
- Chadde, Steve W., and Steve Chadde. A Great Lakes Wetland Flora. 2nd ed. Pocketflora Press, 2002. ISBN 0-9651385-5-0
- P. D. Strausbaugh and Earl L. Core. Flora of West Virginia. 2nd ed. Seneca Books Inc., 1964. ISBN 0-89092-010-9
- Ann Fouler Rhoads and Timothy A. Block. The Plants of Pennsylvania. University of Pennsylvania Press, 2000. ISBN 0-8122-3535-5
- Nathaniel Lord Britton and Hon. Addison Brown. An Illustrated Flora of the Northern United States and Canada. In three volumes. Dover Publications, 1913, 1970. ISBN 0-486-22642-5
### Asia
- Flora of China
- Flora of China in eFloras
- Flora of Japan
- Flora of Thailand
- Florae Siamensis Enumeratio
- Flora Malesiana (1984-ongoing) About Flora Malesiana.
- Flora of the Malay Peninsula
- Flore du Cambodge, du Laos et du Viêt-Nam
- Flora of Bhutan
- Flora of the Presidency of Madras by J.S. Gamble (1915-36)
- Flora of Nepal
- Bengal Plants by D. Prain (1903)
- Flora of the upper Gangetic plains by J. F. Duthie (1903-29)
- Botany of Bihar and Orissa by H.H. Haines (1921-25)
- Flora of British India (1872-1897) by Sir J.D. Hooker
- Flora of Turkey
- Flora Iranica
- Flora Palaestina:
M. Zohary (1966). Flora Palaestina part 1.
M. Zohary (1972). Flora Palaestina part 2.
N. Feinbrun (1978). Flora Palaestina part 3.
N. Feinbrun (1986). Flora Palaestina part 4.
A. Danin, (2004). Distribution Atlas of Plants in the Flora Palaestina Area (Flora Palaestina part 5).
Online updates: http://flora.huji.ac.il/browse.asp?lang=en&action=showfile&fileid=14005
- M. Zohary (1966). Flora Palaestina part 1.
- M. Zohary (1972). Flora Palaestina part 2.
- N. Feinbrun (1978). Flora Palaestina part 3.
- N. Feinbrun (1986). Flora Palaestina part 4.
- A. Danin, (2004). Distribution Atlas of Plants in the Flora Palaestina Area (Flora Palaestina part 5).
- Online updates: http://flora.huji.ac.il/browse.asp?lang=en&action=showfile&fileid=14005
### Australasia
- Flora of Australia
- Flora of New Zealand series:
Allan, H.H. 1961, reprinted 1982. Flora of New Zealand. Volume I: Indigenous Tracheophyta - Psilopsida, Lycopsida, Filicopsida, Gymnospermae, Dicotyledons. ISBN 0-477-01056-3.
Moore, L.B.; Edgar, E. 1970, reprinted 1976. Flora of New Zealand. Volume II: Indigenous Tracheophyta - Monocotyledons except Graminae. ISBN 0-477-01889-0.
Healy, A.J.; Edgar, E. 1980. Flora of New Zealand Volume III. Adventive Cyperaceous, Petalous & Spathaceous Monocotyledons. ISBN 0-477-01041-5.
Webb, C.J.; Sykes, W.R.;Garnock-Jones, P.J. 1988. Flora of New Zealand Volume IV: Naturalised Pteridophytes, Gymnosperms, Dicotyledons. ISBN 0-477-02529-3.
Edgar, E.; Connor, H.E. 2000. Flora of New Zealand Volume V: Grasses. ISBN 0-478-09331-4.
Volumes I-V: First electronic edition, Landcare Research, June 2004. Transcribed by A.D. Wilton and I.M.L. Andres.
- Allan, H.H. 1961, reprinted 1982. Flora of New Zealand. Volume I: Indigenous Tracheophyta - Psilopsida, Lycopsida, Filicopsida, Gymnospermae, Dicotyledons. ISBN 0-477-01056-3.
- Moore, L.B.; Edgar, E. 1970, reprinted 1976. Flora of New Zealand. Volume II: Indigenous Tracheophyta - Monocotyledons except Graminae. ISBN 0-477-01889-0.
- Healy, A.J.; Edgar, E. 1980. Flora of New Zealand Volume III. Adventive Cyperaceous, Petalous & Spathaceous Monocotyledons. ISBN 0-477-01041-5.
- Webb, C.J.; Sykes, W.R.;Garnock-Jones, P.J. 1988. Flora of New Zealand Volume IV: Naturalised Pteridophytes, Gymnosperms, Dicotyledons. ISBN 0-477-02529-3.
- Edgar, E.; Connor, H.E. 2000. Flora of New Zealand Volume V: Grasses. ISBN 0-478-09331-4.
- Volumes I-V: First electronic edition, Landcare Research, June 2004. Transcribed by A.D. Wilton and I.M.L. Andres.
- Galloway, D.J. 1985. Flora of New Zealand: Lichens. ISBN 0-477-01266-3.
- Croasdale, H.; Flint, E.A. 1986. Flora of New Zealand: Desmids. Volume I. ISBN 0-477-02530-7.
- Croasdale, H.; Flint, E.A. 1988. Flora of New Zealand: Desmids. Volume II. ISBN 0-477-01353-8.
- Croasdale, H.; Flint, E.A.;Racine, M.M. 1994. Flora of New Zealand: Desmids. Volume III. ISBN 0-477-01642-1.
- Sykes, W.R.; West, C.J.; Beever, J.E.; Fife, A.J. 2000. Kermadec Islands Flora - Special Edition. ISBN 0-478-09339-X.
### Pacific Islands
- Flora Vitiensis Nova, a New Flora of Fiji
- Manual of the Flowering Plants of Hawai‘i, Warren L. Wagner and Derral R. Herbst (1991) + suppl. [4]
- Flore de la Nouvelle-Calédonie
- Flore de la Polynésie Française (J. Florence, vol. 1 & 2, 1997 & 2004)
### Europe
- Morton, O.1994. Marine Algae of Northern Ireland. Ulster Museum, Belfast. ISBN 0 900761 28 8
- Stace, Clive Anthony, and Hilli Thompson (illustrator). A New Flora of the British Isles. 2nd ed. Cambridge University Press, 1997. ISBN 0-521-58935-5.
- Beesley, S. and J. Wilde. Urban Flora of Belfast. Belfast: Institute of Irish Studies, Queen's University of Belfast, 1997.
- Killick, John, Roy Perry and Stan Woodell. Flora of Oxfordshire. Pisces Publications, 1998. ISBN 1-874357-07-2.
- Bowen, Humphry. The Flora of Dorset. Pisces Publications, 2000. ISBN 1-874357-16-1.
- Flora Celtica Plants and people in Celtic Europe
- Flora Europaea at the site of The Royal Botanical Gardens of Edinburgh Flora Europaea
- Flora of Europe
- Flora iberica
- Flora of Acores
- Flora Danica
- Flora of Romania
### Africa and Madagascar
- Flore du Gabon
- Flore du Cameroun
- Flora of Tropical Africa
- Flora of Tropical East Africa
- Flora Capensis
- Flora Zambesiaca
- Flora of South Africa
- Flore du Rwanda
- Flore de Madagascar et des Comores
# Flora on WikiDoc
WikiDoc has the following mainly flora categories:
- Flora by continent
- Flora by country
- Flora by region | https://www.wikidoc.org/index.php/Flora | |
b83aa2c2c9184e89c2bec79bab5b2334d772465c | wikidoc | Fluid | Fluid
# Overview
A fluid is defined as a substance that continually deforms (flows) under an applied shear stress regardless of how small the applied stress. All liquids and all gases are fluids. Fluids are a subset of the phases of matter and include liquids, gases, plasmas and, to some extent, plastic solids.
Liquids form a free surface (that is, a surface not created by the container) while gases do not. The distinction between solids and fluids is not entirely obvious. The distinction is made by evaluating the viscosity of the substance. Silly Putty can be considered either a solid or a fluid, depending on the time period over which it is observed.
Fluids display such properties as:
- not resisting deformation, or resisting it only lightly (viscosity), and
- the ability to flow (also described as the ability to take on the shape of the container).
These properties are typically a function of their inability to support a shear stress in static equilibrium.
Solids can be subjected to shear stresses, and to normal stresses - both compressive and tensile. In contrast, ideal fluids can only be subjected to normal, compressive stress which is called pressure. Real fluids display viscosity and so are capable of being subjected to low levels of shear stress.
In a solid, shear stress is a function of strain, but in a fluid, shear stress is a function of rate of strain. A consequence of this behavior is Pascal's law which describes the role of pressure in characterizing a fluid's state.
Depending on the relationship between shear stress, and the rate of strain and its derivatives, fluids can be characterized as:
- Newtonian fluids : where stress is directly proportional to rate of strain, and
- Non-Newtonian fluids : where stress is proportional to rate of strain, its higher powers and derivatives.
The behavior of fluids can be described by the Navier-Stokes equations - a set of partial differential equations which are based on:
- continuity (conservation of mass),
- conservation of linear momentum
- conservation of angular momentum
- conservation of energy.
The study of fluids is fluid mechanics, which is subdivided into fluid dynamics and fluid statics depending on whether the fluid is in motion. | Fluid
Template:Continuum mechanics
# Overview
A fluid is defined as a substance that continually deforms (flows) under an applied shear stress regardless of how small the applied stress. All liquids and all gases are fluids. Fluids are a subset of the phases of matter and include liquids, gases, plasmas and, to some extent, plastic solids.
Liquids form a free surface (that is, a surface not created by the container) while gases do not. The distinction between solids and fluids is not entirely obvious. The distinction is made by evaluating the viscosity of the substance. Silly Putty can be considered either a solid or a fluid, depending on the time period over which it is observed.
Fluids display such properties as:
- not resisting deformation, or resisting it only lightly (viscosity), and
- the ability to flow (also described as the ability to take on the shape of the container).
These properties are typically a function of their inability to support a shear stress in static equilibrium.
Solids can be subjected to shear stresses, and to normal stresses - both compressive and tensile. In contrast, ideal fluids can only be subjected to normal, compressive stress which is called pressure. Real fluids display viscosity and so are capable of being subjected to low levels of shear stress.
In a solid, shear stress is a function of strain, but in a fluid, shear stress is a function of rate of strain. A consequence of this behavior is Pascal's law which describes the role of pressure in characterizing a fluid's state.
Depending on the relationship between shear stress, and the rate of strain and its derivatives, fluids can be characterized as:
- Newtonian fluids : where stress is directly proportional to rate of strain, and
- Non-Newtonian fluids : where stress is proportional to rate of strain, its higher powers and derivatives.
The behavior of fluids can be described by the Navier-Stokes equations - a set of partial differential equations which are based on:
- continuity (conservation of mass),
- conservation of linear momentum
- conservation of angular momentum
- conservation of energy.
The study of fluids is fluid mechanics, which is subdivided into fluid dynamics and fluid statics depending on whether the fluid is in motion. | https://www.wikidoc.org/index.php/Fluid | |
7c9f45ae7366fdc24830ebfc7a945ef1db0e1b9b | wikidoc | GLUT5 | GLUT5
GLUT5 is a fructose transporter expressed on the apical border of enterocytes in the small intestine. GLUT5 allows for fructose to be transported from the intestinal lumen into the enterocyte by facilitated diffusion due to fructose's high concentration in the intestinal lumen. GLUT5 is also expressed in skeletal muscle, testis, kidney, fat tissue (adipocytes), and brain.
Fructose malabsorption or Dietary Fructose Intolerance is a dietary disability of the small intestine, where the amount of fructose carrier in enterocytes is deficient.
In humans the GLUT5 protein is encoded by the SLC2A5 gene.
# Regulation
Fructose uptake rate by GLUT5 is significantly affected by diabetes mellitus, hypertension, obesity, fructose malabsorption, and inflammation. However, age-related changes in fructose intake capability are not explained by the rate of expression of GLUT5. The absorption of fructose in the simultaneous presence of glucose is improved, while sorbitol is inhibitory.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | GLUT5
GLUT5 is a fructose transporter expressed on the apical border of enterocytes in the small intestine.[1] GLUT5 allows for fructose to be transported from the intestinal lumen into the enterocyte by facilitated diffusion due to fructose's high concentration in the intestinal lumen. GLUT5 is also expressed in skeletal muscle,[2] testis, kidney, fat tissue (adipocytes), and brain.[3]
Fructose malabsorption or Dietary Fructose Intolerance is a dietary disability of the small intestine, where the amount of fructose carrier in enterocytes is deficient.[4]
In humans the GLUT5 protein is encoded by the SLC2A5 gene.[5]
# Regulation
Fructose uptake rate by GLUT5 is significantly affected by diabetes mellitus, hypertension, obesity, fructose malabsorption, and inflammation. However, age-related changes in fructose intake capability are not explained by the rate of expression of GLUT5.[6][7][8] The absorption of fructose in the simultaneous presence of glucose is improved, while sorbitol is inhibitory.[9]
# 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: "GlycolysisGluconeogenesis_WP534"..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/Fructose_carrier | |
c68633486ad17ff39aadfbd1c19d9c1b86907416 | wikidoc | Furan | Furan
# Overview
Furan, also known as furane and furfuran, is a heterocyclic organic compound. It is typically derived by the thermal decomposition of pentose-containing materials, cellolosic solids especially pine-wood. Furan is a colorless, flammable, highly volatile liquid with a boiling point close to room temperature. It is toxic and may be carcinogenic. Catalytic hydrogenation (see redox) of furan with a palladium catalyst gives tetrahydrofuran.
Furan is aromatic because one of the lone pairs of electrons on the oxygen atom is delocalized into the ring, creating a 4n+2 aromatic system (see Hückel's rule) similar to benzene. Because of the aromaticity, the molecule is flat and lacks discrete double bonds. The other lone pair of electrons of the oxygen atom extends in the plane of the flat ring system. The sp2 hybridization is to allow one of the lone pairs of oxygen to reside in a p orbital and thus allow it to interact within the pi-system.
The name furan comes from the Latin furfur, which means bran. The first furan derivative to be described was 2-furoic acid, by Carl Wilhelm Scheele in 1780. Another important derivative, furfural, was reported by Johann Wolfgang Döbereiner in 1831 and characterised nine years later by John Stenhouse. Furan itself was first prepared by Heinrich Limpricht in 1870, although he called it tetraphenol.
# Synthesis and isolation
- Furan can be obtained from furfural by oxidation and decarboxylation of the resulting furan-2-carboxylic acid, the furfural being derived by destructive distillation of corn cobs in the presence of sulfuric acid.
- A classic furan organic synthesis is the Feist-Benary synthesis.
- One of the most simple synthesis methods for furans is the reaction of 1,4-diketones with phosphorus pentoxide (P2O5) in the Paal-Knorr Synthesis. It is interesting that the thiophene formation reaction of 1,4-diketones with Lawesson's reagent also forms furans as side products.
# Reactions
Due to its aromaticity, furan's behavior is quite dissimilar to that of the more typical heterocyclic ethers such as tetrahydrofuran. It is considerably more reactive than benzene in electrophilic substitution reactions. Furan serves as a diene in Diels-Alder reactions with electron-deficient dienophiles such as ethyl (E)-3-nitroacrylate. The reaction product is a mixture of isomers with preference for the endo isomer:
Hydrogenation of furans affords sequentially dihydrofurans and tetrahydrofurans. | Furan
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Furan, also known as furane and furfuran, is a heterocyclic organic compound. It is typically derived by the thermal decomposition of pentose-containing materials, cellolosic solids especially pine-wood. Furan is a colorless, flammable, highly volatile liquid with a boiling point close to room temperature. It is toxic and may be carcinogenic. Catalytic hydrogenation (see redox) of furan with a palladium catalyst gives tetrahydrofuran.
Furan is aromatic because one of the lone pairs of electrons on the oxygen atom is delocalized into the ring, creating a 4n+2 aromatic system (see Hückel's rule) similar to benzene. Because of the aromaticity, the molecule is flat and lacks discrete double bonds. The other lone pair of electrons of the oxygen atom extends in the plane of the flat ring system. The sp2 hybridization is to allow one of the lone pairs of oxygen to reside in a p orbital and thus allow it to interact within the pi-system.
The name furan comes from the Latin furfur, which means bran.[1] The first furan derivative to be described was 2-furoic acid, by Carl Wilhelm Scheele in 1780. Another important derivative, furfural, was reported by Johann Wolfgang Döbereiner in 1831 and characterised nine years later by John Stenhouse. Furan itself was first prepared by Heinrich Limpricht in 1870, although he called it tetraphenol.[2][3]
# Synthesis and isolation
- Furan can be obtained from furfural by oxidation and decarboxylation of the resulting furan-2-carboxylic acid, the furfural being derived by destructive distillation of corn cobs in the presence of sulfuric acid.[4]
- A classic furan organic synthesis is the Feist-Benary synthesis.
- One of the most simple synthesis methods for furans is the reaction of 1,4-diketones with phosphorus pentoxide (P2O5) in the Paal-Knorr Synthesis. It is interesting that the thiophene formation reaction of 1,4-diketones with Lawesson's reagent also forms furans as side products.
# Reactions
Due to its aromaticity, furan's behavior is quite dissimilar to that of the more typical heterocyclic ethers such as tetrahydrofuran. It is considerably more reactive than benzene in electrophilic substitution reactions. Furan serves as a diene in Diels-Alder reactions with electron-deficient dienophiles such as ethyl (E)-3-nitroacrylate.[5] The reaction product is a mixture of isomers with preference for the endo isomer:
Hydrogenation of furans affords sequentially dihydrofurans and tetrahydrofurans. | https://www.wikidoc.org/index.php/Furan | |
2e3dd398a2dac8cfd5561872e37fe9a2b042a1a0 | wikidoc | Furin | Furin
Furin is a protein that in humans is encoded by the FURIN gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these sections and activates the proteins. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR (FES Upstream Region) and therefore the protein was named furin. Furin is also known as PACE (Paired basic Amino acid Cleaving Enzyme).
# Function
The protein encoded by this gene is an enzyme which belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin), a gene involved in a severe iron-overload disorder called juvenile hemochromatosis. Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.
Furin is one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly. This gene is thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for this gene.
Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms. Furin cleaves proteins just downstream of a basic amino acid target sequence (canonically, Arg-X-(Arg/Lys) -Arg'). In addition to processing cellular precursor proteins, furin is also utilized by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza, dengue fever and several filoviruses including ebola and marburg virus must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. Inhibitors of furin are under consideration as therapeutic agents for treating anthrax infection.
The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP and PiTou.
Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.
# Interactions
Furin has been shown to interact with PACS1. | Furin
Furin is a protein that in humans is encoded by the FURIN gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these sections and activates the proteins.[1][2][3][4] It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR (FES Upstream Region) and therefore the protein was named furin. Furin is also known as PACE (Paired basic Amino acid Cleaving Enzyme).
# Function
The protein encoded by this gene is an enzyme which belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin), a gene involved in a severe iron-overload disorder called juvenile hemochromatosis. Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.[5][6]
Furin is one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly.[7] This gene is thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for this gene.[3]
Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms.[8] Furin cleaves proteins just downstream of a basic amino acid target sequence (canonically, Arg-X-(Arg/Lys) -Arg'). In addition to processing cellular precursor proteins, furin is also utilized by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza, dengue fever and several filoviruses including ebola and marburg virus must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. Inhibitors of furin are under consideration as therapeutic agents for treating anthrax infection.[9]
The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP [10] and PiTou.[11]
Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.[12]
# Interactions
Furin has been shown to interact with PACS1.[13] | https://www.wikidoc.org/index.php/Furin | |
e03fd5fe095ec8a9d10365b73f0dedc52d72b77c | wikidoc | G-LOC | G-LOC
# Overview
G-LOC, abbreviated from G-force induced Loss Of Consciousness, is a term generally used in aerospace physiology to describe a loss of consciousness arising from excessive and sustained g-forces draining blood away from the brain causing cerebral hypoxia. The condition is most likely to affect pilots of high performance fighter and aerobatic aircraft or astronauts but is possible on some extreme amusement park rides. G-LOC incidents have caused fatal accidents in high performance aircraft capable of sustaining high g for extended periods. High-G training for pilots of high performance aircraft or spacecraft often includes the simulation of G-LOC in special centrifuges. Such man-rated centrifuges are made by AMST Systemtechnik in Austria (Austria Metall SystemTechnik), Latacoere in France, the Environmental Tectonics Corporation (ETC) and Wyle Laboratories in the USA.
# Effects of g-forces
As g-force increases, or the longer it is sustained, the victim may suffer progressively:
- Brownout- a loss of colour vision
- Tunnel vision - loss of peripheral vision, retaining only the centre vision
- Blackout a complete loss of vision but retaining consciousness.
- G-LOC where consciousness is lost.
Recovery is usually prompt following removal of g-force but a period of several seconds of disorientation may occur. Brief but vivid dreams have been reported to follow G-LOC.
The human body is much more tolerant of g-force when it is applied laterally (across the body) than when applied longitudinally (along the length of the body). Unfortunately most sustained g-forces incurred by pilots is applied longitudinally. This has led to experimentation with prone pilot aircraft designs which lies the pilot face down or (more successfully) reclined positions for astronauts.
# Thresholds
The g thresholds at which these effects occur depend on the training, age and fitness of the individual. An un-trained individual not used to the g-straining manoeuvre, can black out between 4 and 6 g, particularly if this is pulled suddenly. A trained, fit individual wearing a g suit and practising the straining manoeuvre, can, with some difficulty, sustain up to 9g without loss of consciousness. Prone position designs in aircraft have not proved successful and the problem has been addressed largely by the development of the G-suit. | G-LOC
# Overview
G-LOC, abbreviated from G-force induced Loss Of Consciousness, is a term generally used in aerospace physiology to describe a loss of consciousness arising from excessive and sustained g-forces draining blood away from the brain causing cerebral hypoxia. The condition is most likely to affect pilots of high performance fighter and aerobatic aircraft or astronauts but is possible on some extreme amusement park rides. G-LOC incidents have caused fatal accidents in high performance aircraft capable of sustaining high g for extended periods. High-G training for pilots of high performance aircraft or spacecraft often includes the simulation of G-LOC in special centrifuges. Such man-rated centrifuges are made by AMST Systemtechnik in Austria (Austria Metall SystemTechnik), Latacoere in France, the Environmental Tectonics Corporation (ETC) and Wyle Laboratories in the USA.
# Effects of g-forces
As g-force increases, or the longer it is sustained, the victim may suffer progressively:
- Brownout- a loss of colour vision
- Tunnel vision - loss of peripheral vision, retaining only the centre vision
- Blackout a complete loss of vision but retaining consciousness.
- G-LOC where consciousness is lost.
Recovery is usually prompt following removal of g-force but a period of several seconds of disorientation may occur. Brief but vivid dreams have been reported to follow G-LOC.
The human body is much more tolerant of g-force when it is applied laterally (across the body) than when applied longitudinally (along the length of the body). Unfortunately most sustained g-forces incurred by pilots is applied longitudinally. This has led to experimentation with prone pilot aircraft designs which lies the pilot face down or (more successfully) reclined positions for astronauts.
# Thresholds
The g thresholds at which these effects occur depend on the training, age and fitness of the individual. An un-trained individual not used to the g-straining manoeuvre, can black out between 4 and 6 g, particularly if this is pulled suddenly. A trained, fit individual wearing a g suit and practising the straining manoeuvre, can, with some difficulty, sustain up to 9g without loss of consciousness. Prone position designs in aircraft have not proved successful and the problem has been addressed largely by the development of the G-suit.
# External links
G-LOC, Could It Happen To You?
fa:کاهش هوشیاری ناشی از افزایش گرانش
ko:G-LOC
Template:WH
Template:WS | https://www.wikidoc.org/index.php/G-LOC | |
de3d3215319e14cafcf5eb6e83b1333634827a88 | wikidoc | G6PC3 | G6PC3
Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.
# Function
This gene encodes the catalytic subunit of glucose 6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose 6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways.
# Clinical significance
Mutations in this gene result in autosomal recessive severe congenital neutropenia.
G6PC3 deficiency results in a phenotypic continuum. At one end the affected individuals have only neutropenia and related complications but no other organ is affected. This is sometimes referred to as non-syndromic or isolated severe congenital neutropenia. Most affected individuals have a classic form of the disease with severe congenital neutropenia and cardiovascular and/or urogenital abnormalities. Some individuals have severe G6PC3 deficiency (also known as Dursun syndrome) and they have all the features of classic G6PC3 deficiency but in addition show involvement of non-myeloid hematopoietic cell lines, some other extra-hematologic features and pulmonary hypertension. | G6PC3
Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.[1][2][3]
# Function
This gene encodes the catalytic subunit of glucose 6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose 6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways.[1]
# Clinical significance
Mutations in this gene result in autosomal recessive severe congenital neutropenia.[4]
G6PC3 deficiency results in a phenotypic continuum.[5] [6] At one end the affected individuals have only neutropenia and related complications but no other organ is affected. This is sometimes referred to as non-syndromic or isolated severe congenital neutropenia.[7] Most affected individuals have a classic form of the disease with severe congenital neutropenia and cardiovascular and/or urogenital abnormalities.[8][9] Some individuals have severe G6PC3 deficiency (also known as Dursun syndrome) and they have all the features of classic G6PC3 deficiency but in addition show involvement of non-myeloid hematopoietic cell lines, some other extra-hematologic features and pulmonary hypertension.[10] | https://www.wikidoc.org/index.php/G6PC3 | |
b4fec3dfc6c543c7c374fd56b29e168b36ef28f5 | wikidoc | GABPA | GABPA
GA-binding protein alpha chain is a protein that in humans is encoded by the GABPA gene.
# Function
This gene encodes one of three GA-binding protein transcription factor subunits which functions as a DNA-binding subunit. Since this subunit shares identity with a subunit encoding the nuclear respiratory factor 2 gene, it is likely involved in activation of cytochrome oxidase expression and nuclear control of mitochondrial function. This subunit also shares identity with a subunit constituting the transcription factor E4TF1, responsible for expression of the adenovirus E4 gene. Because of its chromosomal localization and ability to form heterodimers with other polypeptides, this gene may play a role in the Down Syndrome phenotype.
# Interactions
GABPA has been shown to interact with Host cell factor C1, Sp1 transcription factor and Sp3 transcription factor. | GABPA
GA-binding protein alpha chain is a protein that in humans is encoded by the GABPA gene.[1]
# Function
This gene encodes one of three GA-binding protein transcription factor subunits which functions as a DNA-binding subunit. Since this subunit shares identity with a subunit encoding the nuclear respiratory factor 2 gene, it is likely involved in activation of cytochrome oxidase expression and nuclear control of mitochondrial function. This subunit also shares identity with a subunit constituting the transcription factor E4TF1, responsible for expression of the adenovirus E4 gene. Because of its chromosomal localization and ability to form heterodimers with other polypeptides, this gene may play a role in the Down Syndrome phenotype.[2]
# Interactions
GABPA has been shown to interact with Host cell factor C1,[3] Sp1 transcription factor[4] and Sp3 transcription factor.[4] | https://www.wikidoc.org/index.php/GABPA | |
e1951c01114c9a05386861f36aa41c9554e23d8b | wikidoc | GABRD | GABRD
Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene.
# Function
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels. The GABAA receptor is generally pentameric. Its five subunits are alpha, beta, gamma, delta, and rho. The GABRD gene encodes the delta subunit. Specifically, the δ-subunit is usually expressed in GABAA receptors associated with extrasynaptic activity. The most common GABAA receptors have the gamma subunit, which allows the receptor to bind benzodiazepines. For this reason, receptors containing δ-subunits are sometimes referred to as “benzodiazepine insensitive” GABAA receptors. The δ-subunit containing receptors are also known to be involved in the ventral tegmental area (VTA) pathway in the brain's hippocampus, which means that they may have implications in learning, memory, and reward.
# Cell type-specific expression
In a technical comparison between quantitative reverse transcriptase PCR and digital PCR, the expression of the rat gabrd gene was examined across three cell types in the somatosensory cortex: neurogliaform cells, fast spiking basket cells and pyramidal cells. Gene expression was detected in all three cell types, but showed marked enrichment in neurogliaform cells versus the other cell types examined. | GABRD
Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene.[1][2][3]
# Function
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels. The GABAA receptor is generally pentameric. Its five subunits are alpha, beta, gamma, delta, and rho. The GABRD gene encodes the delta subunit.[3] Specifically, the δ-subunit is usually expressed in GABAA receptors associated with extrasynaptic activity. The most common GABAA receptors have the gamma subunit, which allows the receptor to bind benzodiazepines. For this reason, receptors containing δ-subunits are sometimes referred to as “benzodiazepine insensitive” GABAA receptors. The δ-subunit containing receptors are also known to be involved in the ventral tegmental area (VTA) pathway in the brain's hippocampus, which means that they may have implications in learning, memory, and reward.[4]
# Cell type-specific expression
In a technical comparison between quantitative reverse transcriptase PCR and digital PCR, the expression of the rat gabrd gene was examined across three cell types in the somatosensory cortex: neurogliaform cells, fast spiking basket cells and pyramidal cells.[5] Gene expression was detected in all three cell types, but showed marked enrichment in neurogliaform cells versus the other cell types examined.[5] | https://www.wikidoc.org/index.php/GABRD | |
988450ee1a5a4dca99752c103f65d2719676bc0a | wikidoc | GABRE | GABRE
Gamma-aminobutyric acid receptor subunit epsilon is a protein that in humans is encoded by the GABRE gene.
The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A receptor which is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes an epsilon subunit. It is mapped to chromosome Xq28 in a cluster of genes encoding alpha 3, beta 4 and theta subunits of the same receptor. Alternatively spliced transcript variants encoding different isoforms have been identified.
Brainstem expression of ε subunit-containing GABAA receptors is upregulated during pregnancy, particularly in the ventral respiratory group. | GABRE
Gamma-aminobutyric acid receptor subunit epsilon is a protein that in humans is encoded by the GABRE gene.[1][2][3]
The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A receptor which is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes an epsilon subunit. It is mapped to chromosome Xq28 in a cluster of genes encoding alpha 3, beta 4 and theta subunits of the same receptor. Alternatively spliced transcript variants encoding different isoforms have been identified.[3]
Brainstem expression of ε subunit-containing GABAA receptors is upregulated during pregnancy, particularly in the ventral respiratory group.[4] | https://www.wikidoc.org/index.php/GABRE | |
86e43b804715439b1b60e32795dee3d244571b45 | wikidoc | GATA1 | GATA1
GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.
GATA1 regulates the expression (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the maturation of precursor cells, e.g. erythroblasts, to red blood cells and stimulating these cells to erect their cytoskeleton and biosynthesize their oxygen-carrying components viz., hemoglobin and heme. GATA1 plays a similarly critical role in the maturation of blood platelets from megakaryoblasts, promegakaryocytes, and megakaryocytes; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood.
In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, inactivating mutations in the GATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause X chromosome-linked anemic and/or bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include transient myeloproliferative disorder occurring in Down syndrome, acute megakaryoblastic leukemia occurring in Down syndrome, Diamond-Blackfan anemia, and various combined anemia-thrombocytopenia syndromes including a gray platelet syndrome-type disorder.
Reduced levels of GATA1 due to reductions in the translation of GATA1 mRNA into its transcription factor product are associated with promoting the progression of myelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the bone marrow.
# Gene
The human GATA1 gene is located on the short (i.e. "p") arm of the X chromosome at position 11.23. It is 7.74 kilobases in length, consists of 6 exons, and codes for a full length protein, GATA1, of 414 amino acids as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids. GATA1 codes for two zinc finger structural motifs, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1.
Studies in Gata1-knockout mice, i.e. mice lacking the Gata1 gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly red blood cells and platelets but also eosinophils, basophils, mast cells, and dendritic cells. The knock-out mice die by day 11.5 of their embryonic development due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of platelets. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet precursor cells. Studies using mice depleted of their Gata1 gene during adulthood show that: 1) Gata1 is required for the stimulation of erythropoiesis (i.e. increase in red blood cell formation) in response to stress and 2) Gata1-deficient adult mice invariably develop a form of myelofibrosis.
# GATA1 proteins
In both GATA1 and GATA1-S, C-ZnF (i.e. C-terminus zinc finger) binds to DNA-specific nucleic acid sequences sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e. N-terminus zinc fingers) interacts with an essential transcription factor-regulating nuclear protein, FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of Gata1, knockout of the mouse gene for FOG1, Zfpm1, causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes, Mi-2/NuRD complex (a chromatin remodeler) and CTBP1 (a histone deacetylase) and three gene expression-regulating proteins, SET8 (a GATA1-inhibiting histone methyltransferase), BRG1 (a transcription activator), and Mediator (a transcription co-activator). Other interactions include those with: BRD3 (remodels DNA nucleosomes), BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility), FLI1 (a transcription factor that blocks erythroid differentiation), HDAC1 (a histone deacetylase), LMO2 (regulator of erythrocyte development), ZBTB16 (transcription factor regulating cell cycle progression), TAL1 (a transcription factor), FOG2 (a transcription factor regulator), and GATA2 (Displacement of GATA2 by GATA1, i.e. the "GATA switch", at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans). GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans.
# Physiology and Pathology
GATA1 was first described as a transcription factor that activates the hemoglobin B gene in the red blood cell precursors of chickens. Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g. erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew. GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their cytoskeleton and that make enzymes necessary for the biosynthesis of hemoglobins and heme, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells. Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This maturation involves the stimulation of megakaryoblasts to mature ultimately to megakaryocytes which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets.
Reduced levels of GATA1 due to defective translation of GATA1 mRNA in human megakaryocytes is associated with myelofibrosis, i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow stromal cells to become fiber-secreting fibroblasts and osteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic enlargement and extramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.
The clinical features associated with inactivating GATA1 mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors. First, inactivating mutations in GATA1 cause X-linked recessive diseases. Males, with only one GATA1 gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation is dominant negative, i.e. inhibiting the good gene's function. Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity. Third, inactivating GATA1 mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus thalassemia-type and porphyria-type symptoms. Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example, GATA1-inactivating mutations in individuals with the extra chromosome 21 of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results in acute megakaryoblastic leukemia.
# Genetic disorders
GATA1 gene mutations are associated with the development of various genetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with its GATA1 gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead to X-linked diseases occurring predominantly in males. Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemaia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur in thalassemia, gray platelet syndrome, congenital erythropoietic porphyria, and myelofibrosis.
## Down syndrome-related disorders
### Transient myeloproliferative disorder
Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutaions is restriced to cells bearing the trisomy 21 karyotype (i.e. extra chromosome 21) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder. Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarily megakaryoblasts, which often show an abnormal morphology that resembles immature myeloblasts (i.e. unipotent stem cells which differentiate into granulocytes and are the malignant proliferating cell in acute myeloid leukemia). Phenotype analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive blast cell numbers, reduced platelet and red blood cell levels, increased circulating white blood cell levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin. The disorder is thought to develop in utero and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a myelodysplastic syndrome disease.
### Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without Down syndrome. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. Their GATA1 mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia. During this 1-3 year interval, individuals accumulate multiple somatic mutations in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the GATAT1 mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including: TP53, RUNX1, FLT3, ERG, DYRK1A, CHAF1B, HLCS, CTCF, STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS, SH2B3, and MIR125B2 which is the gene for microRNA MiR125B2.
## Diamond–Blackfan anemia
Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in infancy or, less commonly, later childhood as aplastic anemia and the circulation of abnormally enlarged red blood cells. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of afflicted individuals have various birth defects. The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases, autosomal recessive inactivating mutations occur in any one of 20 of the 80 genes encoding ribosomal proteins. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., RPS19, RPL5, RPS26, RPL11, RPL35A, and RPS24. However, several cases of familial Diamond-Blackfan anemia have been associated with GATA1 gene mutations in the apparent absence of a mutation in ribosomal protein genes. These GATA1 mutations occur in an exon 2 splice site or the start codon of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that these GATA1 mutations are a cause for Diamond Blackfan anemia.
## Combined anemia-thrombocytopenia syndromes
Certain GATA1-inactivatng mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. These GATA1 mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=valine; M=methionine; G=glycine; S=serine, D=aspartic acid; Y=tyrosine, R=arginine; W=tryptophan, Q=glutamine). These mutations and some key abnormalities they cause are:
- V205M: familial disease characterized by severe anemia in fetuses and newborns; bone marrow has increased numbers of malformed platelet and red blood cell precursors.
- G208S and D218G: familial disease characterized by severe bleeding, reduced number of circulating platelets which are malformed (i.e. enlarged), and mild anemia.
- D218Y: familial disease similar to but more severe that the disease cause by G209S and D218G mutations.
- R216W: characterized by a beta thalassemia-type disease, i.e. microcytic anemia, absence of hemoglobin B, and hereditary persistence of fetal hemoglobin; symptoms of congenital erythropoietic porphyria; mild to moderately severe thrombocytopenia with features of the gray platelet syndrome.
- R216Q: familial disease characterized by mild anemia with features of heterozygous rather than homozygous (i.e. overt) beta thalassemia; mild thrombocytopenia with features of the gray platelet syndrome.
- G208R: disease characterized by mild anemia and severe thrombocytopenia with malformed erythroblasts and megakaryoblasts in the bone marrow. Structural features of these cells were similar to those observed in congenital dyserythropoietic anemia.
- -183G>A: rare Single-nucleotide polymorphism (rs113966884) in which the nucleotide adenine replaces guanine in DNA at the position 183 nucleotides upstream of the start of GATA1; disorder characterized as mild anemia with structural features in bone marrow red cell precursors similar to those observed in congenital dyserythropoietic anemia.
The Gray platelet syndrome is a rare congenital bleeding disorder caused by reductions or absence of alpha-granules in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in the NBEAL2 gene located on human chromosome 3 at position p21. In these cases, the syndrome follows autosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in neutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease of Arc syndrome caused by mutations in either the VPS33B (on human chromosome 15 at q26) or VIPAS39 (on chromosome 14 at q34); the autosomal dominant disease of GFI1B-related syndrome caused by mutations in GFI1B (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused by NBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e. thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from the NBEAL2-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, a thalassemia-like disorder due to unbalanced hemoglobin production, and/or a porphyria-like disorder. A recent study found that GATA1 is a strong enhancer of NBEAL2 expression and that the R216W and R216Q inactivating mutations in GATA1 may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein. Given these differences, the GATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.
# GATA1 in myelofibrosis
Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow, extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformed megakaryocytes in the bone marrow. Ultimately, the disease may progress to leukemia. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in translating GATA1 mRNA into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to its leukemic transformation. | GATA1
GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.[1][2]
GATA1 regulates the expression (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the maturation of precursor cells, e.g. erythroblasts, to red blood cells and stimulating these cells to erect their cytoskeleton and biosynthesize their oxygen-carrying components viz., hemoglobin and heme. GATA1 plays a similarly critical role in the maturation of blood platelets from megakaryoblasts, promegakaryocytes, and megakaryocytes; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood.[1][3]
In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, inactivating mutations in the GATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause X chromosome-linked anemic and/or bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include transient myeloproliferative disorder occurring in Down syndrome, acute megakaryoblastic leukemia occurring in Down syndrome, Diamond-Blackfan anemia, and various combined anemia-thrombocytopenia syndromes including a gray platelet syndrome-type disorder.[4][5][6]
Reduced levels of GATA1 due to reductions in the translation of GATA1 mRNA into its transcription factor product are associated with promoting the progression of myelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the bone marrow.[7][8]
# Gene
The human GATA1 gene is located on the short (i.e. "p") arm of the X chromosome at position 11.23. It is 7.74 kilobases in length, consists of 6 exons, and codes for a full length protein, GATA1, of 414 amino acids as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids.[9][10][11] GATA1 codes for two zinc finger structural motifs, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1.[4][11]
Studies in Gata1-knockout mice, i.e. mice lacking the Gata1 gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly red blood cells and platelets but also eosinophils, basophils, mast cells, and dendritic cells. The knock-out mice die by day 11.5 of their embryonic development due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of platelets. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet precursor cells. Studies using mice depleted of their Gata1 gene during adulthood show that: 1) Gata1 is required for the stimulation of erythropoiesis (i.e. increase in red blood cell formation) in response to stress and 2) Gata1-deficient adult mice invariably develop a form of myelofibrosis.[12][13]
# GATA1 proteins
In both GATA1 and GATA1-S, C-ZnF (i.e. C-terminus zinc finger) binds to DNA-specific nucleic acid sequences sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e. N-terminus zinc fingers) interacts with an essential transcription factor-regulating nuclear protein, FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of Gata1, knockout of the mouse gene for FOG1, Zfpm1, causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes, Mi-2/NuRD complex (a chromatin remodeler) and CTBP1 (a histone deacetylase) and three gene expression-regulating proteins, SET8 (a GATA1-inhibiting histone methyltransferase), BRG1 (a transcription activator), and Mediator (a transcription co-activator). Other interactions include those with: BRD3 (remodels DNA nucleosomes),[14][15][16] BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility),[14] FLI1 (a transcription factor that blocks erythroid differentiation),[17][18] HDAC1 (a histone deacetylase),[19] LMO2 (regulator of erythrocyte development),[20] ZBTB16 (transcription factor regulating cell cycle progression),[21] TAL1 (a transcription factor),[22] FOG2 (a transcription factor regulator),[23] and GATA2 (Displacement of GATA2 by GATA1, i.e. the "GATA switch", at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans).[13][24][25] GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans.[13]
# Physiology and Pathology
GATA1 was first described as a transcription factor that activates the hemoglobin B gene in the red blood cell precursors of chickens.[26] Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g. erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew.[27][28] GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their cytoskeleton and that make enzymes necessary for the biosynthesis of hemoglobins and heme, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells.[1] Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This maturation involves the stimulation of megakaryoblasts to mature ultimately to megakaryocytes which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets.[1][3]
Reduced levels of GATA1 due to defective translation of GATA1 mRNA in human megakaryocytes is associated with myelofibrosis, i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow stromal cells to become fiber-secreting fibroblasts and osteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic enlargement and extramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.[7][8][29][30]
The clinical features associated with inactivating GATA1 mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors. First, inactivating mutations in GATA1 cause X-linked recessive diseases. Males, with only one GATA1 gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation is dominant negative, i.e. inhibiting the good gene's function. Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity. Third, inactivating GATA1 mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus thalassemia-type and porphyria-type symptoms. Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example, GATA1-inactivating mutations in individuals with the extra chromosome 21 of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results in acute megakaryoblastic leukemia.[11][31]
# Genetic disorders
GATA1 gene mutations are associated with the development of various genetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with its GATA1 gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead to X-linked diseases occurring predominantly in males.[11] Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemaia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur in thalassemia, gray platelet syndrome, congenital erythropoietic porphyria, and myelofibrosis.[4]
## Down syndrome-related disorders
### Transient myeloproliferative disorder
Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutaions is restriced to cells bearing the trisomy 21 karyotype (i.e. extra chromosome 21) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder.[31] Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarily megakaryoblasts, which often show an abnormal morphology that resembles immature myeloblasts (i.e. unipotent stem cells which differentiate into granulocytes and are the malignant proliferating cell in acute myeloid leukemia). Phenotype analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive blast cell numbers, reduced platelet and red blood cell levels, increased circulating white blood cell levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.[31] The disorder is thought to develop in utero and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a myelodysplastic syndrome disease.[3][4][12][31]
### Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without Down syndrome. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. Their GATA1 mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia.[3] During this 1-3 year interval, individuals accumulate multiple somatic mutations in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the GATAT1 mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including: TP53, RUNX1, FLT3, ERG, DYRK1A, CHAF1B, HLCS, CTCF, STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS, SH2B3, and MIR125B2 which is the gene for microRNA MiR125B2.[3][32]
## Diamond–Blackfan anemia
Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in infancy or, less commonly, later childhood as aplastic anemia and the circulation of abnormally enlarged red blood cells. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of afflicted individuals have various birth defects.[6] The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases, autosomal recessive inactivating mutations occur in any one of 20 of the 80 genes encoding ribosomal proteins. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., RPS19, RPL5, RPS26, RPL11, RPL35A, and RPS24.[4][6] However, several cases of familial Diamond-Blackfan anemia have been associated with GATA1 gene mutations in the apparent absence of a mutation in ribosomal protein genes. These GATA1 mutations occur in an exon 2 splice site or the start codon of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that these GATA1 mutations are a cause for Diamond Blackfan anemia.[4][11][12]
## Combined anemia-thrombocytopenia syndromes
Certain GATA1-inactivatng mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. These GATA1 mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=valine; M=methionine; G=glycine; S=serine, D=aspartic acid; Y=tyrosine, R=arginine; W=tryptophan, Q=glutamine). These mutations and some key abnormalities they cause are:[4][12][33][34]
- V205M: familial disease characterized by severe anemia in fetuses and newborns; bone marrow has increased numbers of malformed platelet and red blood cell precursors.
- G208S and D218G: familial disease characterized by severe bleeding, reduced number of circulating platelets which are malformed (i.e. enlarged), and mild anemia.
- D218Y: familial disease similar to but more severe that the disease cause by G209S and D218G mutations.
- R216W: characterized by a beta thalassemia-type disease, i.e. microcytic anemia, absence of hemoglobin B, and hereditary persistence of fetal hemoglobin; symptoms of congenital erythropoietic porphyria; mild to moderately severe thrombocytopenia with features of the gray platelet syndrome.
- R216Q: familial disease characterized by mild anemia with features of heterozygous rather than homozygous (i.e. overt) beta thalassemia; mild thrombocytopenia with features of the gray platelet syndrome.
- G208R: disease characterized by mild anemia and severe thrombocytopenia with malformed erythroblasts and megakaryoblasts in the bone marrow. Structural features of these cells were similar to those observed in congenital dyserythropoietic anemia.
- -183G>A: rare Single-nucleotide polymorphism (rs113966884[35]) in which the nucleotide adenine replaces guanine in DNA at the position 183 nucleotides upstream of the start of GATA1; disorder characterized as mild anemia with structural features in bone marrow red cell precursors similar to those observed in congenital dyserythropoietic anemia.
The Gray platelet syndrome is a rare congenital bleeding disorder caused by reductions or absence of alpha-granules in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in the NBEAL2 gene located on human chromosome 3 at position p21. In these cases, the syndrome follows autosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in neutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease of Arc syndrome caused by mutations in either the VPS33B (on human chromosome 15 at q26) or VIPAS39 (on chromosome 14 at q34); the autosomal dominant disease of GFI1B-related syndrome caused by mutations in GFI1B (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused by NBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e. thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from the NBEAL2-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, a thalassemia-like disorder due to unbalanced hemoglobin production, and/or a porphyria-like disorder.[36][33] A recent study found that GATA1 is a strong enhancer of NBEAL2 expression and that the R216W and R216Q inactivating mutations in GATA1 may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein.[37] Given these differences, the GATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.[36]
# GATA1 in myelofibrosis
Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow, extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformed megakaryocytes in the bone marrow. Ultimately, the disease may progress to leukemia. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in translating GATA1 mRNA into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to its leukemic transformation.[8][29][30] | https://www.wikidoc.org/index.php/GATA1 | |
fc62ea9edaff7628e8ab16cf647050dc27d7981f | wikidoc | GATA2 | GATA2
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates a large number of genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.
Inactivating mutations of the GATA2 gene cause a reduction in the cellular levels of GATA2 and the development of a wide range of familial hematological, immunological, lymphatic, and/or other disorders that are grouped together into a common disease termed GATA2 deficiency. Less commonly, these disorders are associated with non-familial (i.e. sporadic or acquired) GATA inactivating mutations. GATA2 deficiency often begins with seemingly benign abnormalities but if untreated progresses to life-threatening opportunistic infections, virus-induced cancers, lung failure, the myelodysplastic syndrome (i.e. MDS), and/or acute myeloid leukemia, principally acute myeloid leukemia (AML), less commonly chronic myelomonocytic leukemia (CMML), and rarely a lymphoid leukemia.
Overexpression of the GATA2 transcription factor that is not due to mutations in the GATA2 gene appears to be a secondary factor that promotes the aggressiveness of non-familial EVI1 positive AML as well as the progression of prostate cancer.
# GATA2 gene
The GATA2 gene is a member of the evolutionarily conserved GATA transcription factor gene family. All vertebrate species tested so far, including humans and mice, express 6 GATA genes, GATA1 through GATA6. The human GATA2 gene is located on the long (or "q") arm of chromosome 3 at position 21.3 (i.e. the 3q21.3 locus) and consists of 8 exons. Two sites, termed C-ZnF and N-ZnF, of the gene code for two Zinc finger structural motifs of the GATA2 transcription factor. These sites are critical for regulating the ability of the transcription factor to stimulate its target genes.
The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in intron 4. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression. Regulation of GATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression. In an example of a negative feedback circuit, the GATA2 transcription factor indirectly causes activation of the G protein coupled receptor, GPR65, which then acts, also indirectly, to repress GATA2 gene expression. In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the GATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions.
The human GATA2 gene is expressed in hematological bone marrow cells at the stem cell and later progenitor cell stages of their development. Increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz., erythrocytess, certain types of lymphocytes (i.e. B cells, NK cells, and T helper cells), monocytes, neutrophils, platelets, plasmacytoid dendritic cells, macrophages and mast cells. The gene is likewise critical for the formation of the lymphatic system, particularly for the development of its valves. The human gene is also expressed in endothelium, some non-hematological stem cells, the central nervous system, and, to lesser extents, prostate, endometrium, and certain cancerous tissues.
The Gata2 gene in mice has a structure similar to its human counterpart, Deletion of both parental Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse Gata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental GATA2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells. As GATA2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe. The role of GATA2 deficiency in leading to any of the leukemia types is not understood. Likewise, the role of GATA2 overexpression in non-familial AML as well as development of the blast crisis in chronic myelogenous leukemia and progression of prostate cancer is not understood.
## Mutations
Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's C-ZnF, N-ZnF, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.
One GATA2 mutation is a gain of function type, i.e. it is associated with an increase in the activity rather than levels of GATA2. This mutation substitutes valine for leucine in the 359 ammino acid position (i.e. within the N-ZnF site) of the transcription factor and has been detected in individuals undergoing the blast crisis of chronic myelogenous leukemia.
## Pathological inhibition
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promotor. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency.
## Pathological stimulation
Non-mutational stimulation of GATA2 expression and consequential aggressiveness in EVI1-positive AML appears due to the ability of EVI1, a transcription factor, to directly stimulate the expression of the GATA2 gene. The reason for the overexpression of GATA2 that begins in the early stages of prostate cancer is unclear but may involve the ability of FOXA1 to act indirect to stimulate the expression of the GATA2 gene.
# GATA2
The full length GATA2 transcription factor is a moderately sized protein consisting of 480 amino acids. Of its two zinc fingers, C-ZnF (located toward the protein's C-terminus) is responsible for binding to specific DNA sites while its N-ZnF (located toward the proteins N-terminus) is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two transactivation domains and one negative regulatory domain which interact with other nuclear proteins to up-regulate and down-regulate, respectively, its activity. In promoting embryonic and/or adult-type haematopoiesis (i.e. maturation of hematological and immunological cells), GATA2 interacts with other transcription factors (viz., RUNX1, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1, LYL1) and cellular receptors (viz., MPL, GPR56). In a wide range of tissues, GATA2 similarly interacts with HDAC3, LMO2, POU1F1, POU5F1, PML SPI1, and ZBTB16.
GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but for unknown reasons GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2, particularly with referenced to its interactions with many other gene-regulating factors, in controlling its target genes is extremely complex and not fully understood.
# GATA2-related disorders
## Inactivating GATA2 mutations
Familial and sporadic inactivating mutations in one of the two parental GATA2 genes causes a reduction, i.e. a haploinsufficiency, in the cellular levels of the GATA2 transcription factor. In consequence, individuals commonly develop a disease termed GATA2 deficiency. GATA2 deficiency is a grouping of various clinical presentations in which GATA2 haploinsufficiency results in the development over time of hematological, immunological, lymphatic, and/or other presentations that may begin as apparently benign abnormalities but commonly progress to life-threatening opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemias, particularly AML. The various presentations of GATA2 deficiency include all cases of Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC) and the Emberger syndrome as well as a significant percentage of cases of familial myelodysplastic syndrome/acute myeloid leukemia, congenital neutropenia, chronic myelomonocytic leukemia, aplastic anemia, and several other presentations.
## Activating GATA2 mutation
The L359V gain of function mutation (see above section on mutation) increases the activity of the GATA2 transcription factor. The mutation occurs during the blast crisis of chronic myelogenous leukemia and is proposed to play a role in the transformation of the chronic and/or accelerated phases of this disease to its blast crisis phase.
## Repression of GATA2
The repression of GATA2 expression due to methylation of promotor sites in the GATA2 gene rather than a mutation in this gene has been suggested to be an alternate cause for the GATA2 deficiency syndrome. This epigenetic gene silencing also occurs in certain types of non-small-cell lung carcinoma and is suggested to have a protective effect on progression of the disease.
## Overexpression of GATA2
Elevated levels of GATA2 transcription factor due to overexpression of its gene GATA2 is a common finding in AML. It is associated with a poor prognosis, appears to promote progression of the disease, and therefore proposed to be a target for therapeutic intervention. This overexpression is not due to mutation but rather caused at least in part by the overexpression of EVI1, a transcription factor that stimulates GATA2 expression. GATA2 overexpression also occurs in prostate cancer where it appears to increase metastasis in the early stages of androgen-dependent disease and
to stimulate prostate cancer cell survival and proliferation through activating by an unknown mechanism the androgen pathway in androgen-independent (i.e. castration-resistant) disease). | GATA2
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes.[1] It regulates a large number of genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.[2][3]
Inactivating mutations of the GATA2 gene cause a reduction in the cellular levels of GATA2 and the development of a wide range of familial hematological, immunological, lymphatic, and/or other disorders that are grouped together into a common disease termed GATA2 deficiency. Less commonly, these disorders are associated with non-familial (i.e. sporadic or acquired) GATA inactivating mutations. GATA2 deficiency often begins with seemingly benign abnormalities but if untreated progresses to life-threatening opportunistic infections, virus-induced cancers, lung failure, the myelodysplastic syndrome (i.e. MDS), and/or acute myeloid leukemia, principally acute myeloid leukemia (AML), less commonly chronic myelomonocytic leukemia (CMML), and rarely a lymphoid leukemia.[2][3]
Overexpression of the GATA2 transcription factor that is not due to mutations in the GATA2 gene appears to be a secondary factor that promotes the aggressiveness of non-familial EVI1 positive AML as well as the progression of prostate cancer.[4][5][6][7]
# GATA2 gene
The GATA2 gene is a member of the evolutionarily conserved GATA transcription factor gene family. All vertebrate species tested so far, including humans and mice, express 6 GATA genes, GATA1 through GATA6.[8] The human GATA2 gene is located on the long (or "q") arm of chromosome 3 at position 21.3 (i.e. the 3q21.3 locus) and consists of 8 exons.[9] Two sites, termed C-ZnF and N-ZnF, of the gene code for two Zinc finger structural motifs of the GATA2 transcription factor. These sites are critical for regulating the ability of the transcription factor to stimulate its target genes.[10][11]
The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in intron 4. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression.[10] Regulation of GATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression. In an example of a negative feedback circuit, the GATA2 transcription factor indirectly causes activation of the G protein coupled receptor, GPR65, which then acts, also indirectly, to repress GATA2 gene expression.[10][11] In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the GATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions.[12]
The human GATA2 gene is expressed in hematological bone marrow cells at the stem cell and later progenitor cell stages of their development. Increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz., erythrocytess, certain types of lymphocytes (i.e. B cells, NK cells, and T helper cells), monocytes, neutrophils, platelets, plasmacytoid dendritic cells, macrophages and mast cells.[10][13][14] The gene is likewise critical for the formation of the lymphatic system, particularly for the development of its valves. The human gene is also expressed in endothelium, some non-hematological stem cells, the central nervous system, and, to lesser extents, prostate, endometrium, and certain cancerous tissues.[2][8][10]
The Gata2 gene in mice has a structure similar to its human counterpart, Deletion of both parental Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse Gata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental GATA2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells.[10][13][15] As GATA2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe.[5] The role of GATA2 deficiency in leading to any of the leukemia types is not understood. Likewise, the role of GATA2 overexpression in non-familial AML as well as development of the blast crisis in chronic myelogenous leukemia and progression of prostate cancer is not understood.[5][11]
## Mutations
Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's C-ZnF, N-ZnF, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.[2][13]
One GATA2 mutation is a gain of function type, i.e. it is associated with an increase in the activity rather than levels of GATA2. This mutation substitutes valine for leucine in the 359 ammino acid position (i.e. within the N-ZnF site) of the transcription factor and has been detected in individuals undergoing the blast crisis of chronic myelogenous leukemia.[5][16]
## Pathological inhibition
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promotor. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency.[15]
## Pathological stimulation
Non-mutational stimulation of GATA2 expression and consequential aggressiveness in EVI1-positive AML appears due to the ability of EVI1, a transcription factor, to directly stimulate the expression of the GATA2 gene.[6][7] The reason for the overexpression of GATA2 that begins in the early stages of prostate cancer is unclear but may involve the ability of FOXA1 to act indirect to stimulate the expression of the GATA2 gene.[7]
# GATA2
The full length GATA2 transcription factor is a moderately sized protein consisting of 480 amino acids. Of its two zinc fingers, C-ZnF (located toward the protein's C-terminus) is responsible for binding to specific DNA sites while its N-ZnF (located toward the proteins N-terminus) is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two transactivation domains and one negative regulatory domain which interact with other nuclear proteins to up-regulate and down-regulate, respectively, its activity.[10][17] In promoting embryonic and/or adult-type haematopoiesis (i.e. maturation of hematological and immunological cells), GATA2 interacts with other transcription factors (viz., RUNX1, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1, LYL1) and cellular receptors (viz., MPL, GPR56).[11] In a wide range of tissues, GATA2 similarly interacts with HDAC3,[18] LMO2,[19] POU1F1,[20] POU5F1,[21] PML[22] SPI1,[23] and ZBTB16.[24]
GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but for unknown reasons GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2, particularly with referenced to its interactions with many other gene-regulating factors, in controlling its target genes is extremely complex and not fully understood.[2][10][11][12]
# GATA2-related disorders
## Inactivating GATA2 mutations
Familial and sporadic inactivating mutations in one of the two parental GATA2 genes causes a reduction, i.e. a haploinsufficiency, in the cellular levels of the GATA2 transcription factor. In consequence, individuals commonly develop a disease termed GATA2 deficiency. GATA2 deficiency is a grouping of various clinical presentations in which GATA2 haploinsufficiency results in the development over time of hematological, immunological, lymphatic, and/or other presentations that may begin as apparently benign abnormalities but commonly progress to life-threatening opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemias, particularly AML.[2][3] The various presentations of GATA2 deficiency include all cases of Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC) and the Emberger syndrome as well as a significant percentage of cases of familial myelodysplastic syndrome/acute myeloid leukemia, congenital neutropenia, chronic myelomonocytic leukemia, aplastic anemia, and several other presentations.[2][3][25][26]
## Activating GATA2 mutation
The L359V gain of function mutation (see above section on mutation) increases the activity of the GATA2 transcription factor. The mutation occurs during the blast crisis of chronic myelogenous leukemia and is proposed to play a role in the transformation of the chronic and/or accelerated phases of this disease to its blast crisis phase.[5][16]
## Repression of GATA2
The repression of GATA2 expression due to methylation of promotor sites in the GATA2 gene rather than a mutation in this gene has been suggested to be an alternate cause for the GATA2 deficiency syndrome.[15] This epigenetic gene silencing also occurs in certain types of non-small-cell lung carcinoma and is suggested to have a protective effect on progression of the disease.[17][27]
## Overexpression of GATA2
Elevated levels of GATA2 transcription factor due to overexpression of its gene GATA2 is a common finding in AML. It is associated with a poor prognosis, appears to promote progression of the disease, and therefore proposed to be a target for therapeutic intervention. This overexpression is not due to mutation but rather caused at least in part by the overexpression of EVI1, a transcription factor that stimulates GATA2 expression.[4] GATA2 overexpression also occurs in prostate cancer where it appears to increase metastasis in the early stages of androgen-dependent disease and
to stimulate prostate cancer cell survival and proliferation through activating by an unknown mechanism the androgen pathway in androgen-independent (i.e. castration-resistant) disease).[6][7] | https://www.wikidoc.org/index.php/GATA2 | |
20d76fc71f8c693bdb2986998efc9ce57a0af9c2 | wikidoc | GATA3 | GATA3
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
The GATA3 transcription factor is critical for the embryonic development of various tissues as well as for inflammatory and humoral immune responses and the proper functioning of the endothelium of blood vessels. GATA3 haploinsufficiency (i.e. lose of one or the two inherited GATA3 genes) results in a congenital disorder termed the Barakat syndrome.
Current clinical and laboratory research is focusing on determining the benefits of directly or indirectly blocking the action of GATA3 in inflammatory and allergic diseases such as asthma. It is also proposed to be a clinically important marker for various types of cancer, particularly those of the breast. However, the role, if any, of GATA3 in the development of these cancers is under study and remains unclear.
# Gene
The GATA3 gene is located close to the end of the short arm of chromosome 10 at position p14. It consists of 8 exons, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2. Expression of GATA3 may be regulated in part or at times by the antisense RNA, GATA3-AS1, whose gene is located close to the GATA3 gene on the short arm of chromosome 10 at position p14. Various types of mutations including point mutations as well as small- and large-scale delitional mutations cause an autosomal dominant genetic disorder, the Barakat syndrome (also termed hypoparathyroidism, deafness, and renal dysplasia syndrome). The location of GATA3 borders that of other critical sites on chromosome 10, particularly a site located at 10p14-p13. Mutations in this site cause the congenital disorder DiGeorge syndrome/velocardiofacial syndrome complex 2 (or DiGeorge syndrome 2). Large-scale deletions in GATA3 may span into the DiGeorge syndrome 2 area and thereby cause a complex syndrome with features of the Barakat syndrome combined with some of those of the DiGeorge syndrome 2. Knockout of both GATA3 genes in mice is fatal: these animals die at embryonic days 11 and 12 due to internal bleeding. They also exhibit gross deformities in the brain and spine as well as aberrations in fetal liver hematopoiesis.
# Protein
GATA3 variant 1 is a linear protein consisting of 444 amino acids. GATA3 variant 2 protein is an identically structured isoform of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported. With respect to the best studied variant, variant 1, but presumably also variant 2, one of the zinc finger structural motifs, ZNF2, is located at the protein's C-terminus and binds to specific gene promoter DNA sequences to regulate the expression of the genes controlled by these promoters. The other zinc finger, ZNF1, is at the protein's N-terminus and interacts with various nuclear factors, including Zinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1 ) and ZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.
# Pathophysiology
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in physiological as well as pathological humoral inflammatory and allergic responses.
# Function
GATA3 belongs to the GATA family of transcription factors. Gene-deletion studies in mice indicate that Gata3 (mouse gene equivalent to GATA3) is critical for the embryonic development and/or function of various cell types (e.g. fat cells, neural crest cells, lymphocytes) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland). Studies in humans implicate GATA3 in the following:
- 1) GATA3 is required for the development of the parathyroid gland, sensory component(s) of the auditory system, and the kidney in animals and humans. It may also contribure to the development of the vagina and uterus in humans.
- 2) In humans, GATA3 is required for the development and/or function of innate lymphoid cells (ILCs), particularly Group 2 ILCs as well as for the development of T helper cells,(Th cells), particularly Th2 cells. Group 2 ILCs and Th2 cells, and thereby GATA3, are critical for the development of allergic and humoral immune responses in humans. Comparable studies in animals implicate GATA3 in the development of lymphocytes that mediate allergic and humoral immunity as well as allergic and humeral immune responses.
- 3) GATA3 promotes the secretion of IL-4, IL-5, and IL-13 from Th2 cells in humans and has similar actions on comparable mouse lymphocytes. All three of these interleukins serve to promote allergic responses,
- 4) GATA3 induces the maturation of precursor cells into breast epithelial cells and maintains these cells in their mature state in mice and possibly humans.
- 5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the thymus, and the nervous system.
# Clinical significance
## Mutations
Inactivating mutations in one of the two parental GATA3 genes cause the congenital disorder of hypoparathyroidism with sensorineural deafness and kidney malformations, i.e. the Barakat syndrome. This rare syndrome may occur in families or as a new mutation in an individual from a family with no history of the disorder. Mutations in GATA3 cause variable degrees of hypoparathyroidism, deafness, and kidney disease birth defects because of 1) individual differences in the penetrance of the mutation, 2) a sporadic, and as yet unexplained, association with malformation of uterus and vagina, and 3) mutations which extend beyond the GATA3 gene into chromosomal areas where mutations are responsible for developing other types of abnormalities which are characteristics of the DeGeorge syndrome 2. The Barakat syndrome is due to a haploinsufficiency in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues during embryogenesis.
## Allergy
Mouse studies indicate that inhibiting the expression of GATA3 using antisense RNA methods suppresses allergic inflammation. The protein is overexpressed in the afflicted tissues of individuals with various forms of allergy including asthma, rhinitis, nasal polyps, and atopic eczema. This suggests that it may have a role in promoting these disorders. In a phase IIA clinical study of individuals suffering allergen-induced asthma, inhalation of Deoxyribozyme ST010, which specifically inactivates GATA3 messenger RNA, for 28 days reduced early and late immune lung responses to inhaled allergen. The clinical benefit of inhibiting GATA3 in this disorder is thought to be due to interfering with the function of Group 2 ILCs and Th2 cells by, for example, reducing there production of IL-4, IL-13, and especially IL-5. Reduction in these eosinophil-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses. For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.
## Tumors
### Breast tumors
GATA3 is one of the three genes mutated in >10% of breast cancers (Cancer Genome Atlas). Studies in mice indicate that the gene is critical for the normal development of breast tissue and directly regulates luminal cell (i.e. cells lining mammary ducts) differentiation in experimentally induced breast cancer. Analytic studies of human breast cancer tissues suggest that GATA3 is required for specific type of low risk breast cancer (i.e. luminal A), is integral to the expression of estrogen receptor alpha, and (in estrogen receptor negative/androgen receptor positive cancers) androgen receptor signaling. These studies suggest that GATA3 is involved in the development of at least certain types of breast cancer in humans. However, there is disagreement on this, with some studies suggesting that the expression of the GATA3 acts to inhibit and other studies suggesting that it acts to promote the development, growth, and/or spread of this cancer. Further studies are needed to elucidate the role, if any, of GATA3 in the development of breast cancer.
Immuocytochemical analysis of GATA3 protein in breast cells is a valuable marker for diagnosing primary breast cancer, being tested as positive in up to 94% of cases. It is especially valuable for estrogen receptor positive breast cancers but is less sensitive (435-66% elevated), although still more valuable than many other markers, for diagnosing triple-negative breast cancers. This analysis is widely used as a clinically valuable marker for breast cancer.
### Other tumor types
Similar to breast tumors, the role of GATA3 in the genesis of other tumor types is unclear but detection of its transcription factor product may be diagnostically useful. Immuocytochemical analysis of GATA3 protein is considered a valuable marker for certain types of urinary bladder and urethral cancers as well as for parathyroid gland tumors (cancerous or benign), Single series reports suggest that this analysis might also be of value for diagnosing salivary gland tumors, salivary duct carcinomas, mammary analog secretory carcinomas, benign ovarian Brenner tumors, benign Walthard cell rests, and paragangliomas.
# Interactions
GATA3 has been shown to interact with the following transcription factor regulators: ZFPM1 and ZFPM2; LMO1; and FOXA1. These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes. | GATA3
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.[1][2][3]
The GATA3 transcription factor is critical for the embryonic development of various tissues as well as for inflammatory and humoral immune responses and the proper functioning of the endothelium of blood vessels. GATA3 haploinsufficiency (i.e. lose of one or the two inherited GATA3 genes) results in a congenital disorder termed the Barakat syndrome.[4][5][6]
Current clinical and laboratory research is focusing on determining the benefits of directly or indirectly blocking the action of GATA3 in inflammatory and allergic diseases such as asthma.[4] It is also proposed to be a clinically important marker for various types of cancer, particularly those of the breast. However, the role, if any, of GATA3 in the development of these cancers is under study and remains unclear.[7]
# Gene
The GATA3 gene is located close to the end of the short arm of chromosome 10 at position p14. It consists of 8 exons, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2.[8] Expression of GATA3 may be regulated in part or at times by the antisense RNA, GATA3-AS1, whose gene is located close to the GATA3 gene on the short arm of chromosome 10 at position p14.[9] Various types of mutations including point mutations as well as small- and large-scale delitional mutations cause an autosomal dominant genetic disorder, the Barakat syndrome (also termed hypoparathyroidism, deafness, and renal dysplasia syndrome). The location of GATA3 borders that of other critical sites on chromosome 10, particularly a site located at 10p14-p13. Mutations in this site cause the congenital disorder DiGeorge syndrome/velocardiofacial syndrome complex 2 (or DiGeorge syndrome 2).[10] Large-scale deletions in GATA3 may span into the DiGeorge syndrome 2 area and thereby cause a complex syndrome with features of the Barakat syndrome combined with some of those of the DiGeorge syndrome 2.[6][11] Knockout of both GATA3 genes in mice is fatal: these animals die at embryonic days 11 and 12 due to internal bleeding. They also exhibit gross deformities in the brain and spine as well as aberrations in fetal liver hematopoiesis.[12]
# Protein
GATA3 variant 1 is a linear protein consisting of 444 amino acids. GATA3 variant 2 protein is an identically structured isoform of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported.[13] With respect to the best studied variant, variant 1, but presumably also variant 2, one of the zinc finger structural motifs, ZNF2, is located at the protein's C-terminus and binds to specific gene promoter DNA sequences to regulate the expression of the genes controlled by these promoters. The other zinc finger, ZNF1, is at the protein's N-terminus and interacts with various nuclear factors, including Zinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1 [i.e. FOG-1]) and ZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.[14]
# Pathophysiology
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved in physiological as well as pathological humoral inflammatory and allergic responses.[6][4]
# Function
GATA3 belongs to the GATA family of transcription factors. Gene-deletion studies in mice indicate that Gata3 (mouse gene equivalent to GATA3) is critical for the embryonic development and/or function of various cell types (e.g. fat cells, neural crest cells, lymphocytes) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland).[5] Studies in humans implicate GATA3 in the following:
- 1) GATA3 is required for the development of the parathyroid gland, sensory component(s) of the auditory system, and the kidney in animals and humans.[6] It may also contribure to the development of the vagina and uterus in humans.[15]
- 2) In humans, GATA3 is required for the development and/or function of innate lymphoid cells (ILCs), particularly Group 2 ILCs as well as for the development of T helper cells,(Th cells), particularly Th2 cells. Group 2 ILCs and Th2 cells, and thereby GATA3, are critical for the development of allergic and humoral immune responses in humans. Comparable studies in animals implicate GATA3 in the development of lymphocytes that mediate allergic and humoral immunity as well as allergic and humeral immune responses.[16][15]
- 3) GATA3 promotes the secretion of IL-4, IL-5, and IL-13 from Th2 cells in humans and has similar actions on comparable mouse lymphocytes. All three of these interleukins serve to promote allergic responses,[17]
- 4) GATA3 induces the maturation of precursor cells into breast epithelial cells and maintains these cells in their mature state in mice and possibly humans.[18][19]
- 5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, the thymus, and the nervous system.[20][15]
# Clinical significance
## Mutations
Inactivating mutations in one of the two parental GATA3 genes cause the congenital disorder of hypoparathyroidism with sensorineural deafness and kidney malformations, i.e. the Barakat syndrome. This rare syndrome may occur in families or as a new mutation in an individual from a family with no history of the disorder. Mutations in GATA3 cause variable degrees of hypoparathyroidism, deafness, and kidney disease birth defects because of 1) individual differences in the penetrance of the mutation, 2) a sporadic, and as yet unexplained, association with malformation of uterus and vagina, and 3) mutations which extend beyond the GATA3 gene into chromosomal areas where mutations are responsible for developing other types of abnormalities which are characteristics of the DeGeorge syndrome 2. The Barakat syndrome is due to a haploinsufficiency in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues during embryogenesis.[5][6][11]
## Allergy
Mouse studies indicate that inhibiting the expression of GATA3 using antisense RNA methods suppresses allergic inflammation. The protein is overexpressed in the afflicted tissues of individuals with various forms of allergy including asthma, rhinitis, nasal polyps, and atopic eczema. This suggests that it may have a role in promoting these disorders.[21] In a phase IIA clinical study of individuals suffering allergen-induced asthma, inhalation of Deoxyribozyme ST010, which specifically inactivates GATA3 messenger RNA, for 28 days reduced early and late immune lung responses to inhaled allergen. The clinical benefit of inhibiting GATA3 in this disorder is thought to be due to interfering with the function of Group 2 ILCs and Th2 cells by, for example, reducing there production of IL-4, IL-13, and especially IL-5. Reduction in these eosinophil-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses.[4][22] For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.[21]
## Tumors
### Breast tumors
GATA3 is one of the three genes mutated in >10% of breast cancers (Cancer Genome Atlas).[23] Studies in mice indicate that the gene is critical for the normal development of breast tissue and directly regulates luminal cell (i.e. cells lining mammary ducts) differentiation in experimentally induced breast cancer.[12][24] Analytic studies of human breast cancer tissues suggest that GATA3 is required for specific type of low risk breast cancer (i.e. luminal A), is integral to the expression of estrogen receptor alpha, and (in estrogen receptor negative/androgen receptor positive cancers) androgen receptor signaling.[25][26][27] These studies suggest that GATA3 is involved in the development of at least certain types of breast cancer in humans. However, there is disagreement on this, with some studies suggesting that the expression of the GATA3 acts to inhibit and other studies suggesting that it acts to promote the development, growth, and/or spread of this cancer. Further studies are needed to elucidate the role, if any, of GATA3 in the development of breast cancer.[12]
Immuocytochemical analysis of GATA3 protein in breast cells is a valuable marker for diagnosing primary breast cancer, being tested as positive in up to 94% of cases. It is especially valuable for estrogen receptor positive breast cancers but is less sensitive (435-66% elevated), although still more valuable than many other markers, for diagnosing triple-negative breast cancers. This analysis is widely used as a clinically valuable marker for breast cancer.[28][29]
### Other tumor types
Similar to breast tumors, the role of GATA3 in the genesis of other tumor types is unclear but detection of its transcription factor product may be diagnostically useful. Immuocytochemical analysis of GATA3 protein is considered a valuable marker for certain types of urinary bladder and urethral cancers as well as for parathyroid gland tumors (cancerous or benign), Single series reports suggest that this analysis might also be of value for diagnosing salivary gland tumors, salivary duct carcinomas, mammary analog secretory carcinomas, benign ovarian Brenner tumors, benign Walthard cell rests, and paragangliomas.[30][7]
# Interactions
GATA3 has been shown to interact with the following transcription factor regulators: ZFPM1 and ZFPM2;[14] LMO1;[31][32] and FOXA1.[33] These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes. | https://www.wikidoc.org/index.php/GATA3 | |
ed04765dd97ea7fff25585de95d08a170793bf85 | wikidoc | GATA4 | GATA4
Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.
# Function
This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function. Mutations in this gene have been associated with cardiac septal defects as well as reproductive defects.
GATA4 is a critical transcription factor for proper mammalian cardiac development and essential for survival of the embryo. GATA4 works in combination with other essential cardiac transcription factors as well, such as Nkx2-5 and Tbx5. GATA4 is expressed in both embryo and adult cardiomyocytes where it functions as a transcriptional regulator for many cardiac genes, and also regulates hypertrophic growth of the heart. GATA4 promotes cardiac morphogenesis, cardiomyocytes survival, and maintains cardiac function in the adult heart.
Mutations or defects in the GATA4 gene can lead to a variety of cardiac problems including congenital heart disease, abnormal ventral folding, and defects in the cardiac septum separating the atria and ventricles, and hypoplasia of the ventricular myocardium. As seen from the abnormalities from deletion of GATA4, it is essential for cardiac formation and the survival of the embryo during fetal development.
GATA4 is not only important for cardiac development, but also development and function of the mammalian fetal ovary and contributes to fetal male gonadal development and mutations may lead to defects in reproductive development. GATA4 has also been discovered to have an integral role in controlling the early stages of pancreatic and hepatic development.
GATA4 is regulated through the autophagy-lysosome pathway in eukaryotic cells. In cellular senescence, ATM and ATR inhibit p62, an autophagy adaptor responsible for selective autophagy of GATA4. Inhibition of p62 leads to increased GATA4 levels, resulting in NF-kB activation and subsequent SASP induction.
# Atrioventricular valve formation
GATA4 expression during cardiac development has been shown to be essential to proper atrioventricular (AV) formation and function. Endocardial cells undergo epithelial to mesenchymal transitions (EMT) into the AV cushions during development. Their proliferation and fusion leads to division of the ventricular inlet into two different passageways with two AV valves, and they are thought to be under the influence of the GATA4 transcription factor. GATA4 inactivation, with GATA4-null mice, leads to down regulation of Erbb3 and altered Erk expression, two other important molecules in EMT and ventricular inlet separation. This has been shown to lead to pericardial effusion and peripheral hemorrhage in E12.5 mice, which succumb due to heart failure before weaning age. This data could have important implications for human medicine by suggesting that mutations with the GATA4 transcription factor could be responsible for AV cushion defects in humans with improper septal formation leading to congenital heart disease.
# Interactions
GATA4 has been shown to interact with NKX2-5, TBX5, Serum response factor HAND2, and HDAC2.
GATA4 has also been shown to interact with Erbb3, FOG-1, and FOG-2.
# Clinical relevance
Mutations in this gene have been associated to cases of congenital diaphragmatic hernia. Atrial septal defects, tetralogy of Fallot, and ventricular septal defects associated with GATA4 mutation were also seen in South Indian patients. | GATA4
Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.[1]
# Function
This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function. Mutations in this gene have been associated with cardiac septal defects as well as reproductive defects.[2][3]
GATA4 is a critical transcription factor for proper mammalian cardiac development and essential for survival of the embryo. GATA4 works in combination with other essential cardiac transcription factors as well, such as Nkx2-5 and Tbx5. GATA4 is expressed in both embryo and adult cardiomyocytes where it functions as a transcriptional regulator for many cardiac genes, and also regulates hypertrophic growth of the heart.[4] GATA4 promotes cardiac morphogenesis, cardiomyocytes survival, and maintains cardiac function in the adult heart.[4]
Mutations or defects in the GATA4 gene can lead to a variety of cardiac problems including congenital heart disease, abnormal ventral folding, and defects in the cardiac septum separating the atria and ventricles, and hypoplasia of the ventricular myocardium.[5] As seen from the abnormalities from deletion of GATA4, it is essential for cardiac formation and the survival of the embryo during fetal development.[6]
GATA4 is not only important for cardiac development, but also development and function of the mammalian fetal ovary and contributes to fetal male gonadal development and mutations may lead to defects in reproductive development. GATA4 has also been discovered to have an integral role in controlling the early stages of pancreatic and hepatic development.[7]
GATA4 is regulated through the autophagy-lysosome pathway in eukaryotic cells. In cellular senescence, ATM and ATR inhibit p62, an autophagy adaptor responsible for selective autophagy of GATA4. Inhibition of p62 leads to increased GATA4 levels, resulting in NF-kB activation and subsequent SASP induction.[8]
# Atrioventricular valve formation
GATA4 expression during cardiac development has been shown to be essential to proper atrioventricular (AV) formation and function.[9] Endocardial cells undergo epithelial to mesenchymal transitions (EMT) into the AV cushions during development. Their proliferation and fusion leads to division of the ventricular inlet into two different passageways with two AV valves, and they are thought to be under the influence of the GATA4 transcription factor.[9] GATA4 inactivation, with GATA4-null mice, leads to down regulation of Erbb3 and altered Erk expression, two other important molecules in EMT and ventricular inlet separation.[9] This has been shown to lead to pericardial effusion and peripheral hemorrhage in E12.5 mice, which succumb due to heart failure before weaning age.[9] This data could have important implications for human medicine by suggesting that mutations with the GATA4 transcription factor could be responsible for AV cushion defects in humans with improper septal formation leading to congenital heart disease.[9]
# Interactions
GATA4 has been shown to interact with NKX2-5,[10][11][12] TBX5,[13] Serum response factor[14][15] HAND2,[16] and HDAC2.[17]
GATA4 has also been shown to interact with Erbb3, FOG-1, and FOG-2.[9]
# Clinical relevance
Mutations in this gene have been associated to cases of congenital diaphragmatic hernia.[18] Atrial septal defects, tetralogy of Fallot, and ventricular septal defects associated with GATA4 mutation were also seen in South Indian patients.[19] | https://www.wikidoc.org/index.php/GATA4 | |
fe87dd77a92a6b7b169840172e0621868b188455 | wikidoc | GATA5 | GATA5
Transcription factor GATA-5 is a protein that in humans is encoded by the GATA5 gene.
# Function
The protein encoded by this gene is a transcription factor that contains two GATA-type zinc fingers. The encoded protein is known to bind to hepatocyte nuclear factor-1alpha (HNF-1alpha), and this interaction is essential for cooperative activation of the intestinal lactase-phlorizin hydrolase promoter. In other organisms, similar proteins may be involved in the establishment of cardiac smooth muscle cell diversity.
# Role in development
Gata5 is a transcription factor. Gata5 regulates the proper development of the heart. Early in embryo development, Gata5 helps in making sure that there are enough heart muscle precursor cells produced to differentiate into the final myocardial cells. It also regulates other genes that are crucial to successful heart development. As pregnancy progresses, Gata 5 is involved in the specification of the heart tissue that becomes the ventricles. Problems can arise when Gata5 is overexpressed. This overexpression can lead to ectopic foci. Ectopic foci are also known as ectopic pacemakers. They are bundles of cells that can cause cardiac pacing that are located in places in the heart where they’re not supposed to be. These cells can become excited before the heart is supposed to be excited. This causes the heart to beat and thus contract before it should. Oftentimes, this is not a big deal and the heart naturally reverts to its normal pacing. However, if it’s caused by problems with development in the heart – if Gata5 did not express properly in the embryo- then this can lead to constant ectopic foci problems. These problems include tachycardia (the heart beating too fast), bradycardia (the heart beating too slow), or ventricular fibrillation which is a serious condition where the ventricles of the heart aren’t pumping consistently and can’t get blood out to the body. | GATA5
Transcription factor GATA-5 is a protein that in humans is encoded by the GATA5 gene.[1][2]
# Function
The protein encoded by this gene is a transcription factor that contains two GATA-type zinc fingers. The encoded protein is known to bind to hepatocyte nuclear factor-1alpha (HNF-1alpha), and this interaction is essential for cooperative activation of the intestinal lactase-phlorizin hydrolase promoter. In other organisms, similar proteins may be involved in the establishment of cardiac smooth muscle cell diversity.[2]
# Role in development
Gata5 is a transcription factor. Gata5 regulates the proper development of the heart. Early in embryo development, Gata5 helps in making sure that there are enough heart muscle precursor cells produced to differentiate into the final myocardial cells. It also regulates other genes that are crucial to successful heart development.[3] As pregnancy progresses, Gata 5 is involved in the specification of the heart tissue that becomes the ventricles. Problems can arise when Gata5 is overexpressed. This overexpression can lead to ectopic foci. Ectopic foci are also known as ectopic pacemakers. They are bundles of cells that can cause cardiac pacing that are located in places in the heart where they’re not supposed to be. These cells can become excited before the heart is supposed to be excited. This causes the heart to beat and thus contract before it should. Oftentimes, this is not a big deal and the heart naturally reverts to its normal pacing. However, if it’s caused by problems with development in the heart – if Gata5 did not express properly in the embryo- then this can lead to constant ectopic foci problems. These problems include tachycardia (the heart beating too fast), bradycardia (the heart beating too slow), or ventricular fibrillation[4] which is a serious condition where the ventricles of the heart aren’t pumping consistently and can’t get blood out to the body. | https://www.wikidoc.org/index.php/GATA5 | |
0f67216832830cdfa029f09be61c59f29d2bed85 | wikidoc | GATA6 | GATA6
Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the GATA6 gene. The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence.
# Clinical significance
Mutations in the gene have been linked with pancreatic agenesis and congenital heart defects.
## Lung Endodermal Epithelial Development
GATA-6, a zinc finger transcription factor, is important in the endodermal differentiation of organ tissues. It is also indicated in proper lung development by controlling the late differentiation stages of alveolar epithelium and aquaporin-5 promoter activation. Furthermore, GATA-6 has been linked to the production of LIF, a cytokine that encourages proliferation of endodermal embryonic stem cells and blocks early epiblast differentiation. If left unregulated in the developing embryo, this cytokine production and chemical signal contributes to the phenotypes discussed further below.
Upon the disruption of GATA-6 in an embryo, the distal lung epithelial development is stunted in transgenic mice models The progenitor cells, or stem cells, for alveolar epithelial tissues develop and are specified appropriately, however further differentiation does not occur. Also the distal-proximal bronchiole development is affected, resulting in a reduced quantity of airway exchange sites.
This branching deficit, which will cause bilateral pulmonary hypoplasia after birth, has been locally associated with areas lacking differentiated alveolar epithelium, implicating this phenotype as inherent to endodermal function, and thus may be indirectly linked to improper GATA-6 expression. That is, a deficit of bronchiole branching may not be a result of direct transcriptional error in GATA-6, but rather a side effect of such an error. | GATA6
Transcription factor GATA-6, also known as GATA-binding factor 6 (GATA6), is protein that in humans is encoded by the GATA6 gene.[1] The gene product preferentially binds (A/T/C)GAT(A/T)(A) of the consensus binding sequence.[2]
# Clinical significance
Mutations in the gene have been linked with pancreatic agenesis and congenital heart defects.[3]
## Lung Endodermal Epithelial Development
GATA-6, a zinc finger transcription factor, is important in the endodermal differentiation of organ tissues.[4] It is also indicated in proper lung development by controlling the late differentiation stages of alveolar epithelium and aquaporin-5 promoter activation. Furthermore, GATA-6 has been linked to the production of LIF, a cytokine that encourages proliferation of endodermal embryonic stem cells and blocks early epiblast differentiation. If left unregulated in the developing embryo, this cytokine production and chemical signal contributes to the phenotypes discussed further below.[5]
Upon the disruption of GATA-6 in an embryo, the distal lung epithelial development is stunted in transgenic mice models[4] The progenitor cells, or stem cells, for alveolar epithelial tissues develop and are specified appropriately, however further differentiation does not occur. Also the distal-proximal bronchiole development is affected, resulting in a reduced quantity of airway exchange sites.[4]
This branching deficit, which will cause bilateral pulmonary hypoplasia after birth, has been locally associated with areas lacking differentiated alveolar epithelium, implicating this phenotype as inherent to endodermal function, and thus may be indirectly linked to improper GATA-6 expression.[6][7] That is, a deficit of bronchiole branching may not be a result of direct transcriptional error in GATA-6, but rather a side effect of such an error. | https://www.wikidoc.org/index.php/GATA6 | |
db5df6ec5d0a56abcef09c3c1654fdaff0c6f7d0 | wikidoc | GDF10 | GDF10
Growth differentiation factor 10 (GDF10) also known as bone morphogenetic protein 3B (BMP-3B) is a protein that in humans is encoded by the GDF10 gene.
GDF10 belongs to the transforming growth factor beta superfamily that is closely related to bone morphogenetic protein-3 (BMP3). It plays a role in head formation and may have multiple roles in skeletal morphogenesis. GDF10 is also known as BMP-3b, with GDF10 and BMP3 regarded as a separate subgroup within the TGF-beta superfamily.
In mice, GDF10 mRNA is abundant in the brain, inner ear, uterus, prostate, neural tissues, blood vessels and adipose tissue with low expression in spleen and liver. It is also present in bone of both adults and neonatal mice. Human GDF10 mRNA is found in the cochlea and lung of foetuses, and in testis, retina, pineal gland, and other neural tissues of adults. | GDF10
Growth differentiation factor 10 (GDF10) also known as bone morphogenetic protein 3B (BMP-3B) is a protein that in humans is encoded by the GDF10 gene.[1]
GDF10 belongs to the transforming growth factor beta superfamily that is closely related to bone morphogenetic protein-3 (BMP3). It plays a role in head formation and may have multiple roles in skeletal morphogenesis.[1][2] GDF10 is also known as BMP-3b, with GDF10 and BMP3 regarded as a separate subgroup within the TGF-beta superfamily.[1]
In mice, GDF10 mRNA is abundant in the brain, inner ear, uterus, prostate, neural tissues, blood vessels and adipose tissue with low expression in spleen and liver. It is also present in bone of both adults and neonatal mice.[1] Human GDF10 mRNA is found in the cochlea and lung of foetuses, and in testis, retina, pineal gland, and other neural tissues of adults.[3] | https://www.wikidoc.org/index.php/GDF10 | |
7786e2c72cec86ba25577cb0ea9d42b260305d94 | wikidoc | GDF11 | GDF11
Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene.
It acts as a cytokine.
The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues. GDF11 is a myostatin(GDF8)-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin, including stopping the progenitor cell-cycle during G-phase. The similarities between GDF11 and myostatin imply a likelihood that the same regulatory mechanisms are used to control tissue size during both muscular and neural development.
In 2014, GDF11 was described as a life extension factor in two publications based on the results of a parabiosis experiments with mice that were chosen as Science's scientific breakthrough of the year. Later studies questioned these findings. Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources. The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.
# Effects on cell growth and differentiation
GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes. It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.
During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.
In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.
This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium,
and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina. Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.
GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.
GDF11 is closely related to myostatin, a negative regulator of muscle growth. Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis, the production of islet progenitor cells, the regulation of kidney organogenesis, pancreatic development, the rostro-caudal patterning in the development of spinal cords, and is a negative regulator of chondrogenesis.
Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains. WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.
# Effect on cardiac and skeletal muscle aging
GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions. GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes. In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells. In humans, older males who had been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlated with leg power output when cycling. These results have led to claims that GDF11 may be an anti-aging rejuvenation factor.
These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on skeletal muscle regeneration, being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, a Harvard study showed these contrary results to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy. However the Harvard study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in fact myostatin. Also, the Harvard study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters.
In 2016 conflicting reviews from different research teams were published concerning the effects of GDF11 on skeletal and cardiac muscle.
One of the reviews reported an anti-hypertrophic effect in aging mice, but the other team denied that cardiac hypertrophy occurs in old mice, asserting that GDF11 causes muscle wasting. Both teams agreed that whether GDF11 increases or decreases with age had not been established. A 2017 study found that super-physiological levels of GDF11 induced muscle wasting in the skeletal muscle of mice. | GDF11
Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene.[1]
It acts as a cytokine[citation needed].
The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.[2] GDF11 is a myostatin(GDF8)-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin, including stopping the progenitor cell-cycle during G-phase.[3] The similarities between GDF11 and myostatin imply a likelihood that the same regulatory mechanisms are used to control tissue size during both muscular and neural development.[3]
In 2014, GDF11 was described as a life extension factor in two publications based on the results of a parabiosis experiments with mice [4][5] that were chosen as Science's scientific breakthrough of the year.[6] Later studies questioned these findings.[7][8][9][10] Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources.[11] The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.
# Effects on cell growth and differentiation
GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.[12] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.[13]
During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.[14]
In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.[5]
This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium,[15]
and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.[16] Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.[17]
GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.[12]
GDF11 is closely related to myostatin, a negative regulator of muscle growth.[18][19] Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis,[1][15] the production of islet progenitor cells,[20] the regulation of kidney organogenesis,[21] pancreatic development,[22] the rostro-caudal patterning in the development of spinal cords,[13] and is a negative regulator of chondrogenesis.[23]
Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains.[24] WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.[25]
# Effect on cardiac and skeletal muscle aging
GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions.[26] GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes.[26] In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells. In humans, older males who had been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlated with leg power output when cycling.[27] These results have led to claims that GDF11 may be an anti-aging rejuvenation factor.[4]
These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on skeletal muscle regeneration,[7] being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, a Harvard study showed these contrary results to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy.[11] However the Harvard study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in fact myostatin.[7] Also, the Harvard study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters.
In 2016 conflicting reviews from different research teams were published concerning the effects of GDF11 on skeletal and cardiac muscle.[28]
[29] One of the reviews reported an anti-hypertrophic effect in aging mice,[28] but the other team denied that cardiac hypertrophy occurs in old mice, asserting that GDF11 causes muscle wasting.[29] Both teams agreed that whether GDF11 increases or decreases with age had not been established.[28][29] A 2017 study found that super-physiological levels of GDF11 induced muscle wasting in the skeletal muscle of mice.[30] | https://www.wikidoc.org/index.php/GDF11 | |
18ba5bfbc2f9b9f472ccba2c6fa80a3a56357173 | wikidoc | GDF15 | GDF15
Growth/differentiation factor 15 (GDF15) was first identified as Macrophage inhibitory cytokine-1 or MIC-1.
It is a protein belonging to the transforming growth factor beta superfamily. Under normal conditions, GDF-15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as such as liver, kidney, heart and lung.
The function of GDF-15 is not fully cleared but it seems to have a role in regulating inflammatory pathways and to be involved in regulating apoptosis, cell repair and cell growth, which are biological processes observed in cardiovascular and neoplastic disorders. GDF-15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer. | GDF15
Growth/differentiation factor 15 (GDF15) was first identified as Macrophage inhibitory cytokine-1 or MIC-1.[1]
It is a protein belonging to the transforming growth factor beta superfamily. Under normal conditions, GDF-15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as such as liver, kidney, heart and lung.[2][3][4]
The function of GDF-15 is not fully cleared but it seems to have a role in regulating inflammatory pathways and to be involved in regulating apoptosis, cell repair and cell growth, which are biological processes observed in cardiovascular and neoplastic disorders.[2][5][6] GDF-15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer.[7] | https://www.wikidoc.org/index.php/GDF15 | |
3c87baeb331211cb1d3fcc222cd153ccf63fb9f7 | wikidoc | GFRA1 | GFRA1
GDNF family receptor alpha-1 (GFRα1), also known as the GDNF receptor, is a protein that in humans is encoded by the GFRA1 gene.
# Function
Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.
# Interactions
GDNF family receptor alpha 1 has been shown to interact with GDNF and RET proto-oncogene. | GFRA1
GDNF family receptor alpha-1 (GFRα1), also known as the GDNF receptor, is a protein that in humans is encoded by the GFRA1 gene.[1][2]
# Function
Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.[3]
# Interactions
GDNF family receptor alpha 1 has been shown to interact with GDNF[4][5] and RET proto-oncogene.[5][6] | https://www.wikidoc.org/index.php/GFRA1 | |
f125d809b6e62933f7dc02339816e055e8b17ab5 | wikidoc | GGPS1 | GGPS1
Geranylgeranyl pyrophosphate synthase is an enzyme that in humans is encoded by the GGPS1 gene.
# Function
This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
Much like its homolog farnesyl diphosphate synthase, GGPS1 is inhibited by bisphosphonate compounds. | GGPS1
Geranylgeranyl pyrophosphate synthase is an enzyme that in humans is encoded by the GGPS1 gene.[1][2][3]
# Function
This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[3]
Much like its homolog farnesyl diphosphate synthase, GGPS1 is inhibited by bisphosphonate compounds.[4] | https://www.wikidoc.org/index.php/GGPS1 | |
8555715035cd3d11bd01e1f0c173584daa7eea7c | wikidoc | GHITM | GHITM
Growth hormone-inducible transmembrane protein (GHITM), also known as transmembrane BAX inhibitor motif containing protein 5 (TMBIM5), is a protein that in humans is encoded by the GHITM gene on chromosome 10. It is a member of the BAX inhibitor motif containing (TMBIM) family and localizes to the inner mitochondrial membrane (IMM), as well as the endoplasmic reticulum (ER), where it plays a role in apoptosis through mediating mitochondrial morphology and cytochrome c release. Through its apoptotic function, GHITM may be involved in tumor metastasis and innate antiviral responses.
# Structure
This gene encodes a 37 kDa protein which putatively contains six to eight transmembrane domains. As a member of the TMBIM family, GHITM shares a transmembrane BAX inhibitor motif, a semi-hydrophobic transmembrane domain, and similar tertiary structure with the other five members. However, unlike the other members, GHITM possesses a unique acidic (D) instead of a basic (H or R) residue near its second transmembrane domain, as well as an additional transmembrane domain that, after cleavage behind residue 57 (SREY|A), signals for localization to the IMM. Nonetheless, it is possible that cleavage at different sites (XXRR-like motif (LAAR) in the N-terminal and a KKXX-like motif (GNRK) in the C-terminal) or alternative splicing may account for the protein’s observed localization to the ER.
# Function
GHITM is a mitochondrial protein and a member of the TMBIM family and BAX inhibitor-1 (BI1) superfamily. It is ubiquitously expressed but is especially abundant in the brain, heart, liver, kidney, and skeletal muscle and scarce in the intestines and thymus. This protein localizes specifically to the IMM, where it regulates apoptosis through two separate processes: (1) the BAX-independent management of mitochondrial morphology and (2) the release of cytochrome c. In the first process, GHITM maintains cristae organization, and its downregulation results in mitochondrial fragmentation, possibly through inducing fusing of the cristae structures, thus leading to the release of proapoptotic proteins such as cytochrome c, Smac, and Htra2. Meanwhile, in the second process, GHITM is responsible for cross-linking cytochrome c to the IMM, and upregulation of GHITM is associated with delayed cytochrome c release, regardless of outer mitochondrial membrane permeabilization. Thus, GHITM controls the release of cytochrome c from the mitochondria and can potentially interfere with the apoptotic process to promote cell survival. Moreover, GHITM may further plays a role in apoptosis through maintaining calcium ion homeostasis in the ER. However, while overexpression of the other TMBIM proteins exhibit antiapoptotic effects by decreasing calcium ion concentrations, and thus preventing mitochondrial calcium ion overload, depolarization, ATP loss, reactive oxygen species production, cytochrome c release, and ultimately, cell death, overexpression of GHITM produces the opposite effect.
# Clinical significance
GHITM may be involved in tumor metastasis through its interactions with the Bcl-2 family proteins to regulate apoptosis. Its role as an apoptotic regulator may also associate it with innate antiviral responses. Overexpression of GHITM has also been observed to speed up the ageing process in HIV infected patients.
# Interactions
GHITM has been shown to interact with cytochrome c. | GHITM
Growth hormone-inducible transmembrane protein (GHITM), also known as transmembrane BAX inhibitor motif containing protein 5 (TMBIM5), is a protein that in humans is encoded by the GHITM gene on chromosome 10.[1][2][3] It is a member of the BAX inhibitor motif containing (TMBIM) family and localizes to the inner mitochondrial membrane (IMM), as well as the endoplasmic reticulum (ER), where it plays a role in apoptosis through mediating mitochondrial morphology and cytochrome c release.[4][5] Through its apoptotic function, GHITM may be involved in tumor metastasis and innate antiviral responses.[6][7]
# Structure
This gene encodes a 37 kDa protein which putatively contains six to eight transmembrane domains. As a member of the TMBIM family, GHITM shares a transmembrane BAX inhibitor motif, a semi-hydrophobic transmembrane domain, and similar tertiary structure with the other five members. However, unlike the other members, GHITM possesses a unique acidic (D) instead of a basic (H or R) residue near its second transmembrane domain, as well as an additional transmembrane domain that, after cleavage behind residue 57 (SREY|A), signals for localization to the IMM.[4][5][6] Nonetheless, it is possible that cleavage at different sites (XXRR-like motif (LAAR) in the N-terminal and a KKXX-like motif (GNRK) in the C-terminal) or alternative splicing may account for the protein’s observed localization to the ER.[5][6]
# Function
GHITM is a mitochondrial protein and a member of the TMBIM family and BAX inhibitor-1 (BI1) superfamily.[4][5] It is ubiquitously expressed but is especially abundant in the brain, heart, liver, kidney, and skeletal muscle and scarce in the intestines and thymus.[5] This protein localizes specifically to the IMM, where it regulates apoptosis through two separate processes: (1) the BAX-independent management of mitochondrial morphology and (2) the release of cytochrome c. In the first process, GHITM maintains cristae organization, and its downregulation results in mitochondrial fragmentation, possibly through inducing fusing of the cristae structures, thus leading to the release of proapoptotic proteins such as cytochrome c, Smac, and Htra2. Meanwhile, in the second process, GHITM is responsible for cross-linking cytochrome c to the IMM, and upregulation of GHITM is associated with delayed cytochrome c release, regardless of outer mitochondrial membrane permeabilization. Thus, GHITM controls the release of cytochrome c from the mitochondria and can potentially interfere with the apoptotic process to promote cell survival.[4][5] Moreover, GHITM may further plays a role in apoptosis through maintaining calcium ion homeostasis in the ER. However, while overexpression of the other TMBIM proteins exhibit antiapoptotic effects by decreasing calcium ion concentrations, and thus preventing mitochondrial calcium ion overload, depolarization, ATP loss, reactive oxygen species production, cytochrome c release, and ultimately, cell death, overexpression of GHITM produces the opposite effect.[5]
# Clinical significance
GHITM may be involved in tumor metastasis through its interactions with the Bcl-2 family proteins to regulate apoptosis.[6][7] Its role as an apoptotic regulator may also associate it with innate antiviral responses.[7] Overexpression of GHITM has also been observed to speed up the ageing process in HIV infected patients.[8]
# Interactions
GHITM has been shown to interact with cytochrome c.[4] | https://www.wikidoc.org/index.php/GHITM | |
3f038a6b0c6085dffb947c9dc966fe0141d17045 | wikidoc | Hertz | Hertz
# Overview
The hertz (symbol: Hz) is the International System of Units (SI) base unit of frequency. The definition of the hertz is based upon that for the second, namely: the hyperfine splitting in the ground state of the caesium 133 atom is exactly 9 192 631 770 hertz, \nu (hfs Cs) = 9 192 631 770 Hz.
Its base unit is cycle/s or s-1 (also called inverse seconds, reciprocal seconds). In English, hertz is used as both singular and plural. As any SI unit, Hz can be prefixed; commonly used multiples are kHz (kilohertz, 103 Hz), MHz (megahertz, 106 Hz), GHz (gigahertz, 109 Hz) and THz (terahertz, 1012 Hz).
One hertz simply means one cycle per second (typically that which is being counted is a complete cycle); 100 Hz means one hundred cycles per second, and so on. The unit may be applied to any periodic event—for example, a clock might be said to tick at 1 Hz, or a human heart might be said to beat at 1.2 Hz. The frequencies of aperiodic events, such as radioactive decay, are expressed in becquerels.
To avoid confusion, periodically varying angles are typically not expressed in hertz, but rather in an appropriate angular unit such as radians per second. A disc rotating at 60 revolutions per minute (RPM) can thus be said to be rotating at ≈6.283 rad/s or 1 Hz, where the latter reflects the number of complete revolutions per second. The conversion between a frequency f measured in Hertz and an angular frequency ω measured in radians/s are:
\omega = 2\pi f and f = \omega/(2\pi) \,
# History
The hertz is named after the German physicist Heinrich Hertz, who made important scientific contributions to electromagnetism. The name was established by the International Electrotechnical Commission (IEC) in 1930. It was adopted by the General Conference on Weights and Measures (CGPM) (Conférence générale des poids et mesures) in 1960, replacing the previous name for the unit, cycles per second (cps), along with its related multiples, primarily kilocycles per second (kc/s) and megacycles per second (Mc/s). The term cycles per second was largely replaced by hertz by the 1970s.
The term "gigahertz", most commonly used in computer processor speed and radio frequency (RF) applications, can be pronounced either Template:IPA, with a hard Template:IPA sound or Template:IPA or Template:IPA, with a soft Template:IPA sound at the beginning of the word. The prefix "giga-" is derived directly from the Greek "Template:Polytonic" and hence the preferred pronunciation is Template:IPA. Some electrical engineers use Template:IPA, by analogy with "gigantic".
# Applications
## Vibration
Sound is a traveling wave which is an oscillation of pressure. Humans perceive frequency of sound waves as pitch. Each musical note corresponds to a particular frequency which can be measured in hertz. An infant's ear is able to perceive frequencies ranging from 16 Hz to 20,000 Hz; the average human can hear sounds between 20 Hz and 16,000 Hz. The range of ultrasound, infrasound and other physical vibrations such as molecular vibrations extends into the megahertz range and well beyond.
## Electromagnetic radiation
Electromagnetic radiation is often described by its frequency—the number of oscillations of the perpendicular electric and magnetic fields per second—expressed in hertz.
Radio frequency radiation is usually measured in kilohertz, megahertz, or gigahertz; this is why radio dials are commonly labeled with kHz, MHz, and GHz. Light is electromagnetic radiation that is even higher in frequency, and has frequencies in the range of tens (infrared) to thousands (ultraviolet) of terahertz. Electromagnetic radiation with frequencies in the low terahertz range, (intermediate between those of the highest normally-usable radio frequencies and long-wave infrared light), is often called terahertz radiation. Even higher frequencies exist, such as that of gamma rays, which can be measured in exahertz. (For historical reasons, the frequencies of light and higher frequency electromagnetic radiation are more commonly specified in terms of their wavelengths or photon energies: for a more detailed treatment of this and the above frequency ranges, see electromagnetic spectrum.)
## Computing
In computing, most central processing units (CPU) are labeled in terms of their clock speed expressed in megahertz or gigahertz (109 hertz). The number of megahertz refers to the frequency of the CPU's master clock signal ("clock speed"). This signal is simply an electrical voltage which changes from low to high and back again at regular intervals. Hertz has become the primary unit of measurement used by the general populace to determine the speed of a CPU, but many experts have criticized this approach, which they claim is an easily manipulable benchmark. For home-based personal computers, the CPU has ranged from approximately 1 megahertz in the late 1970s (Atari, Commodore, Apple computers) to nearly 4 GHz in the present. This can be increased even further by increasing the frequency of the CPU in the BIOS or other software.
Various computer buses, such as memory buses connecting the CPU and system random access memory (RAM), also transfer data using clock signals operating at different frequencies in the megahertz ranges (for modern products).
# Order of magnitude
## Frequencies not expressed in hertz
Even higher frequencies are believed to occur naturally, in the frequencies of the quantum-mechanical wave functions of high-energy (or, equivalently, massive) particles, although these are not directly observable, and must be inferred from their interactions with other phenomena. For practical reasons, these are typically not expressed in hertz, but in terms of the equivalent energy. | Hertz
# Overview
The hertz (symbol: Hz) is the International System of Units (SI) base unit of frequency. The definition of the hertz is based upon that for the second, namely: the hyperfine splitting in the ground state of the caesium 133 atom is exactly 9 192 631 770 hertz, <math>\nu</math> (hfs Cs) = 9 192 631 770 Hz.[1]
Its base unit is cycle/s or s-1 (also called inverse seconds, reciprocal seconds). In English, hertz is used as both singular and plural. As any SI unit, Hz can be prefixed; commonly used multiples are kHz (kilohertz, 103 Hz), MHz (megahertz, 106 Hz), GHz (gigahertz, 109 Hz) and THz (terahertz, 1012 Hz).
One hertz simply means one cycle per second (typically that which is being counted is a complete cycle); 100 Hz means one hundred cycles per second, and so on. The unit may be applied to any periodic event—for example, a clock might be said to tick at 1 Hz, or a human heart might be said to beat at 1.2 Hz. The frequencies of aperiodic events, such as radioactive decay, are expressed in becquerels.
To avoid confusion, periodically varying angles are typically not expressed in hertz, but rather in an appropriate angular unit such as radians per second. A disc rotating at 60 revolutions per minute (RPM) can thus be said to be rotating at ≈6.283 rad/s or 1 Hz, where the latter reflects the number of complete revolutions per second. The conversion between a frequency f measured in Hertz and an angular frequency ω measured in radians/s are:
\omega = 2\pi f</math> and <math>f = \omega/(2\pi) \,
</math>.
# History
The hertz is named after the German physicist Heinrich Hertz, who made important scientific contributions to electromagnetism. The name was established by the International Electrotechnical Commission (IEC) in 1930.[2] It was adopted by the General Conference on Weights and Measures (CGPM) (Conférence générale des poids et mesures) in 1960, replacing the previous name for the unit, cycles per second (cps), along with its related multiples, primarily kilocycles per second (kc/s) and megacycles per second (Mc/s). The term cycles per second was largely replaced by hertz by the 1970s.
The term "gigahertz", most commonly used in computer processor speed and radio frequency (RF) applications, can be pronounced either Template:IPA, with a hard Template:IPA sound or Template:IPA or Template:IPA, with a soft Template:IPA sound at the beginning of the word. The prefix "giga-" is derived directly from the Greek "Template:Polytonic" and hence the preferred pronunciation is Template:IPA. Some electrical engineers use Template:IPA, by analogy with "gigantic".
# Applications
## Vibration
Sound is a traveling wave which is an oscillation of pressure. Humans perceive frequency of sound waves as pitch. Each musical note corresponds to a particular frequency which can be measured in hertz. An infant's ear is able to perceive frequencies ranging from 16 Hz to 20,000 Hz; the average human can hear sounds between 20 Hz and 16,000 Hz.[3] The range of ultrasound, infrasound and other physical vibrations such as molecular vibrations extends into the megahertz range and well beyond.
## Electromagnetic radiation
Electromagnetic radiation is often described by its frequency—the number of oscillations of the perpendicular electric and magnetic fields per second—expressed in hertz.
Radio frequency radiation is usually measured in kilohertz, megahertz, or gigahertz; this is why radio dials are commonly labeled with kHz, MHz, and GHz. Light is electromagnetic radiation that is even higher in frequency, and has frequencies in the range of tens (infrared) to thousands (ultraviolet) of terahertz. Electromagnetic radiation with frequencies in the low terahertz range, (intermediate between those of the highest normally-usable radio frequencies and long-wave infrared light), is often called terahertz radiation. Even higher frequencies exist, such as that of gamma rays, which can be measured in exahertz. (For historical reasons, the frequencies of light and higher frequency electromagnetic radiation are more commonly specified in terms of their wavelengths or photon energies: for a more detailed treatment of this and the above frequency ranges, see electromagnetic spectrum.)
## Computing
In computing, most central processing units (CPU) are labeled in terms of their clock speed expressed in megahertz or gigahertz (109 hertz). The number of megahertz refers to the frequency of the CPU's master clock signal ("clock speed"). This signal is simply an electrical voltage which changes from low to high and back again at regular intervals. Hertz has become the primary unit of measurement used by the general populace to determine the speed of a CPU, but many experts have criticized this approach, which they claim is an easily manipulable benchmark.[4] For home-based personal computers, the CPU has ranged from approximately 1 megahertz in the late 1970s (Atari, Commodore, Apple computers) to nearly 4 GHz in the present. This can be increased even further by increasing the frequency of the CPU in the BIOS or other software.
Various computer buses, such as memory buses connecting the CPU and system random access memory (RAM), also transfer data using clock signals operating at different frequencies in the megahertz ranges (for modern products).
# Order of magnitude
## Frequencies not expressed in hertz
Even higher frequencies are believed to occur naturally, in the frequencies of the quantum-mechanical wave functions of high-energy (or, equivalently, massive) particles, although these are not directly observable, and must be inferred from their interactions with other phenomena. For practical reasons, these are typically not expressed in hertz, but in terms of the equivalent energy. | https://www.wikidoc.org/index.php/GHz | |
c14ee91e20d876a7f80e0b3dbbe9faea0f672e9c | wikidoc | GIPC3 | GIPC3
PDZ domain-containing protein GIPC3 is a protein that in humans is encoded by the GIPC3 gene. GIPC3 is a member of the GIPC (GAIP-interacting protein C terminus) gene family that also includes GIPC1 and GIPC2. The encoded protein, GIPC3, features a centrally located PDZ domain, which is flanked on each side by a single GIPC-homology domain.
# Function
GIPC3 is thought to be important for acoustic signal acquisition and propagation in hair cells of the mammalian cochlea.
# Gene
The human GIPC3 gene is located on the short arm of chromosome 19 at p13.3. The locus extends over about 8 kbp and contains the six coding exons that give rise to an open reading frame of 639 nucleotides encoding the GIPC3 protein of 312 amino acids. A single PDZ domain is located at amino acid position 122-189.
In the mouse, Gipc3 is located on chromosome 10 at cytogenetic band qC1. The genomic region covers a distance of 5.5 kbp. The six coding exons encode a protein of 297 amino acids. The PDZ domain is located at amino acid position 107-174.
# Genetics
In the mouse, a missense mutation in Gipc3 (c.343G>A) leads to a non-synonymous amino acid replacement (p.G115R) in the loop connecting two beta strands of the PDZ domain. Glycine 115 is conserved in all GIPC proteins.
Missense (c.785C>T; p. L262R) and nonsense (c.903G>A, p.W301X) mutations in human GIPC3 cause congenital sensorineural hearing impairment in families segregating non-syndromic hearing loss DFNB15 and DFNB95.
# Phenotypes
Mice of the Black Swiss strain develop early-onset slowly progressing sensorineural hearing loss. A genetic study identified two quantitative trait loci (QTL) that control hearing function. One QTL, named age-related hearing loss 5 (ahl5) localizes to chromosome 10 and accounted for ca. 60% of the variation in hearing thresholds. A second QTL, ahl6, localized to chromosome 18 and has a smaller effect size. Besides their hearing impairment, Black Swiss mice also are hypersensitive to acoustic stimulation, reacting with seizures (audiogenic seizures) to loud white noise. A genetic locus conferring susceptibility was identified (juvenile audiogenic monogenic seizures1, jams1) on chromosome 10. A positional cloning approach aimed to decipher the genetic basis of both the hearing loss and audiogenic seizure susceptibility subsequently identified the glycine to arginine substitution in Gipc3 as the underlying cause.
In humans, individuals with the p.W301X missense mutation (DFNB95) exhibit bilateral sensorineural hearing loss with threshold shifts of 70-80 dB hearing levels as early as 11 months of age.
# Interactions
The PDZ domain of GIPC family proteins interact with:
- Frizzled-3 (FZD3) class of WNT receptor,
- insulin-like growth factor-I receptor (IGF1R),
- receptor tyrosine kinase TrkA,
- TGF-beta type III receptor (TGF-beta RIII),
- integrin alpha6A (ITGA6),
- transmembrane glycoprotein TPBG, and
- RGS19/RGS-GAIP. | GIPC3
PDZ domain-containing protein GIPC3 is a protein that in humans is encoded by the GIPC3 gene.[1][2] GIPC3 is a member of the GIPC (GAIP-interacting protein C terminus) gene family that also includes GIPC1 and GIPC2.[3] The encoded protein, GIPC3, features a centrally located PDZ domain, which is flanked on each side by a single GIPC-homology domain.[4]
# Function
GIPC3 is thought to be important for acoustic signal acquisition and propagation in hair cells of the mammalian cochlea.
# Gene
The human GIPC3 gene is located on the short arm of chromosome 19 at p13.3. The locus extends over about 8 kbp and contains the six coding exons that give rise to an open reading frame of 639 nucleotides encoding the GIPC3 protein of 312 amino acids. A single PDZ domain is located at amino acid position 122-189.
In the mouse, Gipc3 is located on chromosome 10 at cytogenetic band qC1. The genomic region covers a distance of 5.5 kbp. The six coding exons encode a protein of 297 amino acids. The PDZ domain is located at amino acid position 107-174.
# Genetics
In the mouse, a missense mutation in Gipc3 (c.343G>A) leads to a non-synonymous amino acid replacement (p.G115R) in the loop connecting two beta strands of the PDZ domain. Glycine 115 is conserved in all GIPC proteins.[5]
Missense (c.785C>T; p. L262R) and nonsense (c.903G>A, p.W301X) mutations in human GIPC3 cause congenital sensorineural hearing impairment in families segregating non-syndromic hearing loss DFNB15 and DFNB95.
# Phenotypes
Mice of the Black Swiss strain develop early-onset slowly progressing sensorineural hearing loss. A genetic study identified two quantitative trait loci (QTL) that control hearing function. One QTL, named age-related hearing loss 5 (ahl5) localizes to chromosome 10 and accounted for ca. 60% of the variation in hearing thresholds. A second QTL, ahl6, localized to chromosome 18 and has a smaller effect size.[6] Besides their hearing impairment, Black Swiss mice also are hypersensitive to acoustic stimulation, reacting with seizures (audiogenic seizures) to loud white noise.[7] A genetic locus conferring susceptibility was identified (juvenile audiogenic monogenic seizures1, jams1) on chromosome 10. A positional cloning approach aimed to decipher the genetic basis of both the hearing loss and audiogenic seizure susceptibility subsequently identified the glycine to arginine substitution in Gipc3 as the underlying cause.
In humans, individuals with the p.W301X missense mutation (DFNB95) exhibit bilateral sensorineural hearing loss with threshold shifts of 70-80 dB hearing levels as early as 11 months of age.
# Interactions
The PDZ domain of GIPC family proteins interact with:[3]
- Frizzled-3 (FZD3) class of WNT receptor,
- insulin-like growth factor-I receptor (IGF1R),
- receptor tyrosine kinase TrkA,
- TGF-beta type III receptor (TGF-beta RIII),
- integrin alpha6A (ITGA6),
- transmembrane glycoprotein TPBG, and
- RGS19/RGS-GAIP. | https://www.wikidoc.org/index.php/GIPC3 | |
222f59cf8a0af6f3ebe2b57a1221369548c7e824 | wikidoc | GLE1L | GLE1L
Nucleoporin GLE1 is a protein that in humans is encoded by the GLE1 gene on chromosome 9.
# Function
This gene encodes a predicted 75-kDa polypeptide with high sequence and structure homology to yeast Gle1p, which is nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)+RNA export. Inhibition of human GLE1L by microinjection of antibodies against GLE1L in HeLa cells resulted in inhibition of poly(A)+RNA export. Immunoflourescence studies show that GLE1L is localized at the nuclear pore complexes. This localization suggests that GLE1L may act at a terminal step in the export of mature RNA messages to the cytoplasm. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Clinical significance
A genome-wide screening and linkage analysis assigned the disease locus of lethal congenital contracture syndrome, one of 40 Finnish heritage diseases, to a defined region of 9q34, where the GLE1 gene is located. Mutations in GLEI have been identified in families with foetal motoneuron disease.
# Interactions
GLE1L has been shown to interact with NUP155. | GLE1L
Nucleoporin GLE1 is a protein that in humans is encoded by the GLE1 gene on chromosome 9.[1][2][3]
# Function
This gene encodes a predicted 75-kDa polypeptide with high sequence and structure homology to yeast Gle1p, which is nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)+RNA export. Inhibition of human GLE1L by microinjection of antibodies against GLE1L in HeLa cells resulted in inhibition of poly(A)+RNA export. Immunoflourescence studies show that GLE1L is localized at the nuclear pore complexes. This localization suggests that GLE1L may act at a terminal step in the export of mature RNA messages to the cytoplasm. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.[3]
# Clinical significance
A genome-wide screening and linkage analysis assigned the disease locus of lethal congenital contracture syndrome, one of 40 Finnish heritage diseases, to a defined region of 9q34, where the GLE1 gene is located.[4] Mutations in GLEI have been identified in families with foetal motoneuron disease.[5]
# Interactions
GLE1L has been shown to interact with NUP155.[6] | https://www.wikidoc.org/index.php/GLE1L | |
a0149bef0e28cdc6f13566a4c282a7744d9f9015 | wikidoc | GLIS1 | GLIS1
Glis1 (Glis Family Zinc Finger 1) is gene encoding a Krüppel-like protein of the same name whose locus is found on Chromosome 1p32.3. The gene is enriched in unfertilised eggs and embryos at the one cell stage and it can be used to promote direct reprogramming of somatic cells to induced pluripotent stem cells, also known as iPS cells. Glis1 is a highly promiscuous transcription factor, regulating the expression of numerous genes, either positively or negatively. In organisms, Glis1 does not appear to have any directly important functions. Mice whose Glis1 gene has been removed have no noticeable change to their phenotype.
# Structure
Glis1 is an 84.3 kDa proline rich protein composed of 789 amino acids. No crystal structure has yet been determined for Glis1, however it is homologous to other proteins in many parts of its amino acid sequence whose structures have been solved.
## Zinc finger domain
Glis1 uses a Zinc finger domain comprising five tandem Cys2His2 zinc finger motifs (meaning the zinc atom is coordinated by two cysteine and two histidine residues) to interact with target DNA sequences to regulate gene transcription. The domain interacts sequence specifically with the DNA, following the major groove along the double helix. It has the consensus sequence GACCACCCAC. The individual zinc finger motifs are separated from one another by the amino acid sequence(T/S)GEKP(Y/F)X, where X can be any amino acid and (A/B) can be either A or B. This domain is homologous to the zinc finger domain found in Gli1 and so is thought to interact with DNA in the same way. The alpha helices of the fourth and fifth zinc fingers are inserted into the major groove and make the most extensive contact of all the zinc fingers with the DNA. Very few contact are made by the second and third fingers and the first finger does not contact the DNA at all. The first finger does make numerous protein-protein interactions with the second zinc finger, however.
## Termini
Glis1 has an activation domain at its C-terminus and a repressive domain at its N-terminus. The repressive domain is much stronger than the activation domain meaning transcription is weak. The activation domain of Glis1 is four times stronger in the presence of CaM kinase IV. This may be due to a coactivator. A proline-rich region of the protein is also found towards the N-terminal. The protein's termini are fairly unusual, and have no strong sequence similarity other proteins.
# Use in cell reprogramming
Glis1 can be used as one of the four factors used in reprogramming somatic cells to induced pluripotent stem cells. The three transcription factors Oct3/4, Sox2 and Klf4 are essential for reprogramming but are extremely inefficient on their own, fully reprogramming roughly only 0.005% of the number of cells treated with the factors. When Glis1 is introduced with these three factors, the efficiency of reprogramming is massively increased, producing many more fully reprogrammed cells. The transcription factor c-Myc can also be used as the fourth factor and was the original fourth factor used by Shinya Yamanaka who received the 2012 Nobel Prize in Physiology or Medicine for his work in the conversion of somatic cells to iPS cells. Yamanaka's work allows a way of bypassing the controversy surrounding stem cells.
## Mechanism
Somatic cells are most often fully differentiated in order to perform a specific function, and therefore only express the genes required to perform their function. This means the genes that are required for differentiation to other types of cell are packaged within chromatin structures, so that they are not expressed.
Glis1 reprograms cells by promoting multiple pro-reprogramming pathways. These pathways are activated due to the up regulation of the transcription factors N-Myc, Mycl1, c-Myc, Nanog, ESRRB, FOXA2, GATA4, NKX2-5, as well as the other three factors used for reprogramming. Glis1 also up-regulates expression of the protein LIN28 which binds the let-7 microRNA precursor, preventing production of active let-7. Let-7 microRNAs reduce the expression of pro-reprogramming genes via RNA interference. Glis1 is also able to directly associate with the other three reprogramming factors which may help their function.
The result of the various changes in gene expression is the conversion of heterochromatin, which is very difficult to access, to euchromatin, which can be easily accessed by transcriptional proteins and enzymes such as RNA polymerase. During reprogramming, histones, which make up nucleosomes, the complexes used to package DNA, are generally demethylated and acetylated 'unpacking' the DNA by neutralising the positive charge of the lysine residues on the N-termini of histones.
## Advantages over c-myc
Glis1 has a number of extremely important advantages over c-myc in cell reprogramming.
- No risk of cancer: Although c-myc enhances the efficiency of reprogramming, its major disadvantage is that it is a proto-oncogene meaning the iPS cells produced using c-myc are much more likely to become cancerous. This is an enormous obstacle between iPS cells and their use in medicine. When Glis1 is used in cell reprogramming, there is no increased risk of cancer development.
- Production of fewer 'bad' colonies: While c-myc promotes the proliferation of reprogrammed cells, it also promotes the proliferation of 'bad' cells which have not reprogrammed properly and make up the vast majority of cells in a dish of treated cells. Glis1 actively suppresses the proliferation of cells that have not fully reprogrammed, making the selection and harvesting of the properly reprogrammed cells less laborious. This is likely to be due to many of these 'bad' cells expressing Glis1 but not all four of the reprogramming factors. When expressed on its own, Glis1 inhibits proliferation.
- More efficient reprogramming: The use of Glis1 reportedly produces more fully reprogrammed iPS cells than c-myc. This is an important quality given the inefficiency of reprogramming.
## Disadvantages
- Inhibition of Proliferation: Failure to stop Glis1 expression after reprogramming inhibits cell proliferation and ultimately leads to the death of the reprogrammed cell. Therefore, careful regulation of Glis1 expression is required. This explains why Glis1 expression is switched off in embryos after they have started to divide.
# Roles in disease
Glis1 has been implicated to play a part in a number of diseases and disorders.
## Psoriasis
Glis1 has been shown to be heavily up regulated in psoriasis, a disease which causes chronic inflammation of the skin. Normally, Glis1 is not expressed in the skin at all. However, during inflammation, it is expressed in the spinous layer of the skin, the second layer from the bottom of four layers as a response to the inflammation. This is the last layer where the cells have nuclei and thus the last layer where gene expression occurs. It is believed that the role of Glis1 in this disease is to promote cell differentiation in the skin by changing the increasing the expression of multiple pro-differentation genes such as IGFBP2 which inhibits proliferation and can also promote apoptosis It also decreases the expression of Jagged1, a ligand of notch in the notch signaling pathway and Frizzled10, a receptor in the wnt signaling pathway.
## Late onset Parkinson's Disease
A certain allele of Glis1 which exists due to a single nucleotide polymorphism, a change in a single nucleotide of the DNA sequence of the gene, has been implicated as a risk factor in the neurodegenerative disorder Parkinson's disease. The allele is linked to the late onset variety of Parkinson's, which is acquired in old age. The reason behind this link is not yet known. | GLIS1
Glis1 (Glis Family Zinc Finger 1) is gene encoding a Krüppel-like protein of the same name whose locus is found on Chromosome 1p32.3.[1][2] The gene is enriched in unfertilised eggs and embryos at the one cell stage[3] and it can be used to promote direct reprogramming of somatic cells to induced pluripotent stem cells, also known as iPS cells.[3] Glis1 is a highly promiscuous transcription factor, regulating the expression of numerous genes, either positively or negatively. In organisms, Glis1 does not appear to have any directly important functions. Mice whose Glis1 gene has been removed have no noticeable change to their phenotype.[4]
# Structure
Glis1 is an 84.3 kDa proline rich protein composed of 789 amino acids.[2] No crystal structure has yet been determined for Glis1, however it is homologous to other proteins in many parts of its amino acid sequence whose structures have been solved.
## Zinc finger domain
Glis1 uses a Zinc finger domain comprising five tandem Cys2His2 zinc finger motifs (meaning the zinc atom is coordinated by two cysteine and two histidine residues) to interact with target DNA sequences to regulate gene transcription. The domain interacts sequence specifically with the DNA, following the major groove along the double helix. It has the consensus sequence GACCACCCAC.[2] The individual zinc finger motifs are separated from one another by the amino acid sequence(T/S)GEKP(Y/F)X,[2] where X can be any amino acid and (A/B) can be either A or B. This domain is homologous to the zinc finger domain found in Gli1 and so is thought to interact with DNA in the same way.[2] The alpha helices of the fourth and fifth zinc fingers are inserted into the major groove and make the most extensive contact of all the zinc fingers with the DNA.[5][6] Very few contact are made by the second and third fingers and the first finger does not contact the DNA at all.[6] The first finger does make numerous protein-protein interactions with the second zinc finger, however.[5][6]
## Termini
Glis1 has an activation domain at its C-terminus and a repressive domain at its N-terminus. The repressive domain is much stronger than the activation domain meaning transcription is weak. The activation domain of Glis1 is four times stronger in the presence of CaM kinase IV. This may be due to a coactivator. A proline-rich region of the protein is also found towards the N-terminal. The protein's termini are fairly unusual, and have no strong sequence similarity other proteins.[2]
# Use in cell reprogramming
Glis1 can be used as one of the four factors used in reprogramming somatic cells to induced pluripotent stem cells.[3] The three transcription factors Oct3/4, Sox2 and Klf4 are essential for reprogramming but are extremely inefficient on their own, fully reprogramming roughly only 0.005% of the number of cells treated with the factors.[7] When Glis1 is introduced with these three factors, the efficiency of reprogramming is massively increased, producing many more fully reprogrammed cells. The transcription factor c-Myc can also be used as the fourth factor and was the original fourth factor used by Shinya Yamanaka who received the 2012 Nobel Prize in Physiology or Medicine for his work in the conversion of somatic cells to iPS cells.[8][9][10] Yamanaka's work allows a way of bypassing the controversy surrounding stem cells.[10]
## Mechanism
Somatic cells are most often fully differentiated in order to perform a specific function, and therefore only express the genes required to perform their function. This means the genes that are required for differentiation to other types of cell are packaged within chromatin structures, so that they are not expressed.[11]
Glis1 reprograms cells by promoting multiple pro-reprogramming pathways.[3] These pathways are activated due to the up regulation of the transcription factors N-Myc, Mycl1, c-Myc, Nanog, ESRRB, FOXA2, GATA4, NKX2-5, as well as the other three factors used for reprogramming.[3] Glis1 also up-regulates expression of the protein LIN28 which binds the let-7 microRNA precursor, preventing production of active let-7. Let-7 microRNAs reduce the expression of pro-reprogramming genes via RNA interference.[12][13] Glis1 is also able to directly associate with the other three reprogramming factors which may help their function.[3]
The result of the various changes in gene expression is the conversion of heterochromatin, which is very difficult to access, to euchromatin, which can be easily accessed by transcriptional proteins and enzymes such as RNA polymerase.[14] During reprogramming, histones, which make up nucleosomes, the complexes used to package DNA, are generally demethylated and acetylated 'unpacking' the DNA by neutralising the positive charge of the lysine residues on the N-termini of histones.[14]
## Advantages over c-myc
Glis1 has a number of extremely important advantages over c-myc in cell reprogramming.
- No risk of cancer: Although c-myc enhances the efficiency of reprogramming, its major disadvantage is that it is a proto-oncogene meaning the iPS cells produced using c-myc are much more likely to become cancerous. This is an enormous obstacle between iPS cells and their use in medicine.[15] When Glis1 is used in cell reprogramming, there is no increased risk of cancer development.[3]
- Production of fewer 'bad' colonies: While c-myc promotes the proliferation of reprogrammed cells, it also promotes the proliferation of 'bad' cells which have not reprogrammed properly and make up the vast majority of cells in a dish of treated cells. Glis1 actively suppresses the proliferation of cells that have not fully reprogrammed, making the selection and harvesting of the properly reprogrammed cells less laborious.[3][15] This is likely to be due to many of these 'bad' cells expressing Glis1 but not all four of the reprogramming factors. When expressed on its own, Glis1 inhibits proliferation.[3]
- More efficient reprogramming: The use of Glis1 reportedly produces more fully reprogrammed iPS cells than c-myc. This is an important quality given the inefficiency of reprogramming.[3]
## Disadvantages
- Inhibition of Proliferation: Failure to stop Glis1 expression after reprogramming inhibits cell proliferation and ultimately leads to the death of the reprogrammed cell. Therefore, careful regulation of Glis1 expression is required.[16] This explains why Glis1 expression is switched off in embryos after they have started to divide.[3][16]
# Roles in disease
Glis1 has been implicated to play a part in a number of diseases and disorders.
## Psoriasis
Glis1 has been shown to be heavily up regulated in psoriasis,[17] a disease which causes chronic inflammation of the skin. Normally, Glis1 is not expressed in the skin at all. However, during inflammation, it is expressed in the spinous layer of the skin, the second layer from the bottom of four layers as a response to the inflammation. This is the last layer where the cells have nuclei and thus the last layer where gene expression occurs. It is believed that the role of Glis1 in this disease is to promote cell differentiation in the skin by changing the increasing the expression of multiple pro-differentation genes such as IGFBP2 which inhibits proliferation and can also promote apoptosis[18] It also decreases the expression of Jagged1, a ligand of notch in the notch signaling pathway[19] and Frizzled10, a receptor in the wnt signaling pathway.[20]
## Late onset Parkinson's Disease
A certain allele of Glis1 which exists due to a single nucleotide polymorphism, a change in a single nucleotide of the DNA sequence of the gene, has been implicated as a risk factor in the neurodegenerative disorder Parkinson's disease. The allele is linked to the late onset variety of Parkinson's, which is acquired in old age. The reason behind this link is not yet known.[21] | https://www.wikidoc.org/index.php/GLIS1 | |
f2f4e7cc7d6762226c8d11bfcd3c2ada95e14c4c | wikidoc | GLIS2 | GLIS2
GLIS family zinc finger 2 also known as GLIS2 is a human gene.
# Function
The protein encoded by this gene is a Kruppel-like transcription factor which functions depending on the gene and promoter context as an activator or repressor of gene transcription. GLIS2 plays a role in kidney development and neurogenesis.
Glis2 knockout mice display decreased size and weight. The kidneys in these mice show progressive kidney atrophy and display symptoms similar to human nephronophthisis. Glis2 plays an essential role in the maintenance of renal tissue through prevention of apoptosis and fibrosis.
# Clinical significance
Mutations in the GLIS2 gene are associated with nephronophthisis. | GLIS2
GLIS family zinc finger 2 also known as GLIS2 is a human gene.[1][2]
# Function
The protein encoded by this gene is a Kruppel-like transcription factor which functions depending on the gene and promoter context as an activator or repressor of gene transcription.[2] GLIS2 plays a role in kidney development and neurogenesis.[2]
Glis2 knockout mice display decreased size and weight. The kidneys in these mice show progressive kidney atrophy and display symptoms similar to human nephronophthisis. Glis2 plays an essential role in the maintenance of renal tissue through prevention of apoptosis and fibrosis.[3]
# Clinical significance
Mutations in the GLIS2 gene are associated with nephronophthisis.[3] | https://www.wikidoc.org/index.php/GLIS2 | |
8b3d9aabf4886f79eb0863ca647623031ca7940c | wikidoc | GLRX2 | GLRX2
Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.
Alternative splicing of GLRX2 leads to three isoforms of Grx2. One isoform, Grx2a, localizes to the mitochondria, is ubiquitously expressed in tissues (e.g. heart, skeletal muscle, kidney, and liver), regulates mitochondrial redox homeostasis, and protects cells against oxidative stress. Isoforms Grx2b and Grx2c, both localized to the nucleus and cytosol, are expressed only in testes and cancer cell lines and facilitate cellular differentiation and transformation, potentially inducing tumor progression.
# Structure
## Gene
The transcripts of mitochondrial and nuclear Grx2 isoforms, Grx2a and Grx2b, respectively, differ in the first exon, with the exon 1 in Grx2b located upstream of that in Grx2a. Grx2c is derived from alternative splicing of the Grx2b transcript with a shorter exon 1 than that of Grx2b.
## Protein
As a GRX family protein, Grx2 has an N-terminal thioredoxin domain, possessing a 37CSYC40 active site motif with a serine residue replacing the conserved proline residue. This amino acid substitution allows the main chain of Grx2 to be more flexible, promoting coordination of the iron-sulfur cluster and facilitating deglutathionylation by enhanced glutathione-binding. The cysteine pair (Cys28, Cys113) falls outside of the active site, and it is completely conserved in Grx2 proteins but not found in some other GRX family proteins (i.e. Grx1 and Grx5). A disulfide bond between this cysteine pair increases structural stability and provides resistance to over-oxidation induced enzymatic inactivation.
# Function
Grx2 functions as a part of the cellular redox signaling pathway and antioxidant defense mechanism. As a GRX family protein, Grx2 acts as an electron donor to deglutathionylate proteins. It has also been shown to reduce both thioredoxin 2 and thioredoxin 1 and protects cells from apoptosis induced by auranofin and 4-hydroxynonenal. Grx2 is also an electron acceptor. It can catalyze the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins. Additionally, NADPH and thioredoxin reductase efficiently reduce both the active site disulfide of Grx2 and the GSH-Grx2 intermediate formed in the reduction of glutathionylated substrates.
Enzymatic activity of Grx2 leads to its role in regulating redox-induced apoptosis. Grx2 over-expression protects cells against H2O2-induced damage while Grx2 knockdown showed the opposite effect. The protection role of Grx2 against H2O2-induced apoptosis is likely associated with its ability to preserve the electron transport chain complex I. In addition to H2O2, Grx2a overexpression is resistant to apoptosis induced by other oxidative stress reagents (i.e., doxorubicin (Dox) and phenylarsine oxide), due to reduced cardiolipin oxidation and subsequent cytochrome c release. Interesting, Grx2 has also been found to prevent aggregation of mutant SOD1 in mitochondria and abolish its toxicity.
Being a redox sensor, Grx2 activity is tightly regulated by the oxidative state of the environment via iron-sulfur cluster. In steady state, Grx2 forms dimers to coordinate iron-sulfur clusters, which in turn inactivate Grx2’s activity by sequestering the active-site cysteines. During oxidative stress, the dimers separate into iron-free active monomers, which restore Grx2’s activity.
# Clinical significance
From 42 cases of non-small cell lung cancer patients, the expression level of Grx2 showed a significant correlation with the degree of differentiation in adenocarcinoma and a clear inverse correlation with proliferation. In tumor cells, cells with decreased Grx2 are dramatically sensitized to cell death induced by the anti-cancer drug, DOX.
In cardiovascular disease, Grx2a overexpression protects mouse heart from Dox and ischemia-induced cardiac injury, potentially via increasing mitochondrial protein glutathionylation. Conversely, Grx2 knockout hearts developed left ventricular hypertrophy and fibrosis, leading to hypertension. The mechanistic study shows that Grx2 knockout decreased mitochondrial ATP production, possibly via increased glutathionylation and thereby inhibition of complex I.
# Interactions
Grx2 has been shown to physically interact with MDH2, PITPNB, GPX4, CYCS, BAG3, and TXNRD1 in one independent high-throughput proteomic analysis. | GLRX2
Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.[1]
Alternative splicing of GLRX2 leads to three isoforms of Grx2. One isoform, Grx2a, localizes to the mitochondria, is ubiquitously expressed in tissues (e.g. heart, skeletal muscle, kidney, and liver), regulates mitochondrial redox homeostasis, and protects cells against oxidative stress.[1] Isoforms Grx2b and Grx2c, both localized to the nucleus and cytosol, are expressed only in testes and cancer cell lines and facilitate cellular differentiation and transformation, potentially inducing tumor progression.[2][3][4]
# Structure
## Gene
The transcripts of mitochondrial and nuclear Grx2 isoforms, Grx2a and Grx2b, respectively, differ in the first exon, with the exon 1 in Grx2b located upstream of that in Grx2a.[3] Grx2c is derived from alternative splicing of the Grx2b transcript with a shorter exon 1 than that of Grx2b.[2]
## Protein
As a GRX family protein, Grx2 has an N-terminal thioredoxin domain, possessing a 37CSYC40 active site motif with a serine residue replacing the conserved proline residue. This amino acid substitution allows the main chain of Grx2 to be more flexible, promoting coordination of the iron-sulfur cluster and facilitating deglutathionylation by enhanced glutathione-binding.[5] The cysteine pair (Cys28, Cys113) falls outside of the active site, and it is completely conserved in Grx2 proteins but not found in some other GRX family proteins (i.e. Grx1 and Grx5). A disulfide bond between this cysteine pair increases structural stability and provides resistance to over-oxidation induced enzymatic inactivation.[5]
# Function
Grx2 functions as a part of the cellular redox signaling pathway and antioxidant defense mechanism. As a GRX family protein, Grx2 acts as an electron donor to deglutathionylate proteins. It has also been shown to reduce both thioredoxin 2 and thioredoxin 1 and protects cells from apoptosis induced by auranofin and 4-hydroxynonenal.[6] Grx2 is also an electron acceptor. It can catalyze the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins.[7] Additionally, NADPH and thioredoxin reductase efficiently reduce both the active site disulfide of Grx2 and the GSH-Grx2 intermediate formed in the reduction of glutathionylated substrates.[8]
Enzymatic activity of Grx2 leads to its role in regulating redox-induced apoptosis. Grx2 over-expression protects cells against H2O2-induced damage while Grx2 knockdown showed the opposite effect. The protection role of Grx2 against H2O2-induced apoptosis is likely associated with its ability to preserve the electron transport chain complex I.[9] In addition to H2O2, Grx2a overexpression is resistant to apoptosis induced by other oxidative stress reagents (i.e., doxorubicin (Dox) and phenylarsine oxide), due to reduced cardiolipin oxidation and subsequent cytochrome c release.[10] Interesting, Grx2 has also been found to prevent aggregation of mutant SOD1 in mitochondria and abolish its toxicity.[11]
Being a redox sensor, Grx2 activity is tightly regulated by the oxidative state of the environment via iron-sulfur cluster. In steady state, Grx2 forms dimers to coordinate iron-sulfur clusters, which in turn inactivate Grx2’s activity by sequestering the active-site cysteines. During oxidative stress, the dimers separate into iron-free active monomers, which restore Grx2’s activity.[5]
# Clinical significance
From 42 cases of non-small cell lung cancer patients, the expression level of Grx2 showed a significant correlation with the degree of differentiation in adenocarcinoma and a clear inverse correlation with proliferation.[12] In tumor cells, cells with decreased Grx2 are dramatically sensitized to cell death induced by the anti-cancer drug, DOX.[13]
In cardiovascular disease, Grx2a overexpression protects mouse heart from Dox and ischemia-induced cardiac injury, potentially via increasing mitochondrial protein glutathionylation.[14] Conversely, Grx2 knockout hearts developed left ventricular hypertrophy and fibrosis, leading to hypertension. The mechanistic study shows that Grx2 knockout decreased mitochondrial ATP production, possibly via increased glutathionylation and thereby inhibition of complex I.[15]
# Interactions
Grx2 has been shown to physically interact with MDH2, PITPNB, GPX4, CYCS, BAG3, and TXNRD1 in one independent high-throughput proteomic analysis.[16] | https://www.wikidoc.org/index.php/GLRX2 | |
9120aea5f38681c467611fd732cb584153d6ea8c | wikidoc | GLRX5 | GLRX5
Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the GLRX5 gene located on chromosome 14. This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron- sulfur clusters, which are required for normal iron homeostasis. Mutations in this gene are associated with autosomal recessive pyridoxine-refractory sideroblastic anemia.
# Structure
The GLRX5 gene contains 2 exons and encodes for a protein that is 13 kDa in size. The protein is highly expressed in erythroid cells. Crystal structure of the GLRX5 protein reveals that the protein likely exists as a tetramer with two Fe-S clusters buried in the interior.
# Function
GLRX5 is a mitochondrial protein is conserved evolutionarily and plays a role in the formation of iron-sulfur clusters, which function to maintain iron homeostasis within the mitochondria and in the cell. GLRX5 is required for the steps in haem synthesis that involves mitochondrial enzymes, and is therefore involved in hematopoiesis. GLRX5 activity is required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1. The function of GLRX5 is highly conserved evolutionarily.
# Clinical significance
Mutations in the GLRX5 gene have been associated with sideroblastic anemia, variant glycine encephalopathy (also known as non-ketotic hyperglycinemia, NKH). as well as pyridoxine-refractory, autosomal recessive anemia (PRARSA). Cells with mutations in GLRX5 activity show deficiency in Fe-S cluster synthesis, which is likely causative of the observed symptoms. | GLRX5
Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the GLRX5 gene located on chromosome 14.[1] This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron- sulfur clusters, which are required for normal iron homeostasis. Mutations in this gene are associated with autosomal recessive pyridoxine-refractory sideroblastic anemia.[2]
# Structure
The GLRX5 gene contains 2 exons and encodes for a protein that is 13 kDa in size. The protein is highly expressed in erythroid cells.[3] Crystal structure of the GLRX5 protein reveals that the protein likely exists as a tetramer with two Fe-S clusters buried in the interior.[4]
# Function
GLRX5 is a mitochondrial protein is conserved evolutionarily and plays a role in the formation of iron-sulfur clusters, which function to maintain iron homeostasis within the mitochondria and in the cell. GLRX5 is required for the steps in haem synthesis that involves mitochondrial enzymes,[5] and is therefore involved in hematopoiesis. GLRX5 activity is required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1. The function of GLRX5 is highly conserved evolutionarily.[6]
# Clinical significance
Mutations in the GLRX5 gene have been associated with sideroblastic anemia,[7] variant glycine encephalopathy (also known as non-ketotic hyperglycinemia, NKH).[8] as well as pyridoxine-refractory, autosomal recessive anemia (PRARSA).[6] Cells with mutations in GLRX5 activity show deficiency in Fe-S cluster synthesis, which is likely causative of the observed symptoms.[3] | https://www.wikidoc.org/index.php/GLRX5 | |
23ef21650d194d53c8c47a3d3af4e7336bcab63f | wikidoc | GRIK2 | GRIK2
Glutamate ionotropic receptor kainate type subunit 2 (ionotropic glutamate receptor 6) is a protein that in humans is encoded by the GRIK2 (or GLUR6) gene.
# Function
This gene encodes a subunit of a kainate glutamate receptor. Glutamate receptors mediate the majority of excitatory neurotransmission in the brain. This receptor may have a role in synaptic plasticity and may be important for learning and memory. It also may be involved in the transmission of light information from the retina to the hypothalamus. The structure and function of the encoded protein is changed by RNA editing. Alternatively spliced transcript variants encoding distinct isoforms have been described for this gene.
# Clinical significance
Homozygosity for a GRIK2 deletion-inversion mutation is associated with nonsyndromic autosomal recessive mental retardation.
# Interactions
GRIK2 has been shown to interact with:
- DLG1,
- DLG4,
- GRID2,
- GRIK5,
- GRIP1,
- PICK1 and
- SDCBP.
# RNA Editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g. human Kv1.1 channel). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. Glur2 is a gene product of the pre- mRNA of the GRIK2 gene is subject to RNA editing.
## Type
The type of RNA editing that occurs in the pre-mRNA of GluR-6 is Adenosine to Inosine ( A to I) editing.
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, the result could be a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A to I editing occurs in a noncoding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs( especially Alu repeats) The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
## Location
The pre-mRNA of GLUR-6 is edited at three positions at amino acid positions 567, 571, and 621.
The Q/R position is so called as editing results in an codon change from a glutamine (Q) codon (CAG ) to an arginine (R) codon (CGG). This editing site is located in the " pore loop" of the second membrane domain (M2). Q/R editing site is also observed in glutamate receptor GluR-2 and GluR-5. The Q/R site of GluR-6 pre mRNA occurs in an asymmetrical loop of 3 exonic and four intronic nucleotides. The Q/R site is located in a homologous position in GluR-2 and in GluR-6.
GluR-6 is also edited at I/V and Y/C sites, which are found in the first membrane domain (M1). At the I/V site editing results in a codon change from (ATT) isoleucine (I) to (GTT)valine (V), while at the Y/C site the codon change is from (TAC) tyrosine(Y) to (TGC) cysteine (C).
The RNA fold programme characterised a putative double-stranded RNA(dsRNA) conformation around the Q/R site of the GluR-6 pre-mRNA. This sequence is necessary for editing at the site to occur. The possible editing complementary sequence was observed from transcript analysis to be 1.9 kb downstream from the editing site within intron 12.
The ECS for the editing sites in M1 has yet to be identified but it is likely to occur at a considerable distance from the editing sites.
## Regulation
Editing of the Q/R site in GluR-6 pre-mRNA has been demonstrated to be developmentally regulated in rats ranging from 0% in rat embryo to 80% at birth. This is different from AMPA receptor subunit GluR-B, which is edited nearly 100% and is not developmentally regulated.
Significant amounts of both edited and nonedited forms of GluR-6 transcripts are found in adult brain. The receptor is 90% edited in all grey matter structures. In white matter of the brain the receptor is in edited form in just 10% of cases.
Frequency increases from 0% in rat embryo to 85% in adult rat.
## Consequences
### Structure
The primary of GluR-6 transcripts can be edited in up to three positions. Editing at each of the three positions affect the Ca2+ permeability of the channel
### Function
Editing plays a role in the electrophysiology of the channel.
Editing at the Q/R site has been deemed to be nonessential in GluR-6. It has been reported that unedited version of Glu-R6 functions in the regulation of synaptic plasticity. The edited version is thought to inhibit synaptic plasticity and reduce seizure susceptibility.
Mice lacking the Q/R site are capable of long term potentiation and are more susceptible to kainate induced seizures. The number of seizures inversely correlates with the amount of rna editing. This correlates to the increase in human GluR-6 pre-mRNA editing during seizures. It is thought that editing maybe an adaptive mechanism.
Up to 8 different protein isoforms can occur as a result of different combinations of editing at the three sites.
Editing at the Q/R site affects the calcium permeability of the receptor. The two other editing sites are less well defined (I/V,Y/C) but are also thought to be involved in regulation of calcium permeability.(59) Evidence suggests that if editing does not occur at I/V and Y/C sites
then both edited and nonedited versions of the receptor demonstrate high calcium permeability. When both editing sites in TM1 are edited then the Q/R site edited version of the receptor is more permeable to calcium than the nonedited version at the Q/R site. The co assembly of these two isoforms generate receptor with reduced calcium permeability.
Rna editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid and docosahexaenoic acid For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids.However inclusion of just one nonedited subunit is enough to stop this inhibition.
### Dysregulation
Kainate induced seizures in mice are used as a model of temporal lobe epilepsy in humans. Despite deficiency in editing at the Q/R site of GluR-6 in mice increasing seizure vulnerability, tissue analysis of human patients did not show reduced editing at this site. | GRIK2
Glutamate ionotropic receptor kainate type subunit 2 (ionotropic glutamate receptor 6) is a protein that in humans is encoded by the GRIK2 (or GLUR6) gene.[1][2][3]
# Function
This gene encodes a subunit of a kainate glutamate receptor. Glutamate receptors mediate the majority of excitatory neurotransmission in the brain. This receptor may have a role in synaptic plasticity and may be important for learning and memory. It also may be involved in the transmission of light information from the retina to the hypothalamus. The structure and function of the encoded protein is changed by RNA editing. Alternatively spliced transcript variants encoding distinct isoforms have been described for this gene.[3]
# Clinical significance
Homozygosity for a GRIK2 deletion-inversion mutation is associated with nonsyndromic autosomal recessive mental retardation.[4]
# Interactions
GRIK2 has been shown to interact with:
- DLG1,[5][6]
- DLG4,[5][6][7]
- GRID2,[8]
- GRIK5,[9][10]
- GRIP1,[7][11]
- PICK1[7] and
- SDCBP.[7][11]
# RNA Editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g. human Kv1.1 channel).[12] The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing.[13] The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. Glur2 is a gene product of the pre- mRNA of the GRIK2 gene is subject to RNA editing.
## Type
The type of RNA editing that occurs in the pre-mRNA of GluR-6 is Adenosine to Inosine ( A to I) editing.
[14]
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, the result could be a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A to I editing occurs in a noncoding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs( especially Alu repeats) The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
## Location
The pre-mRNA of GLUR-6 is edited at three positions at amino acid positions 567, 571, and 621.
The Q/R position is so called as editing results in an codon change from a glutamine (Q) codon (CAG ) to an arginine (R) codon (CGG). This editing site is located in the " pore loop" of the second membrane domain (M2). Q/R editing site is also observed in glutamate receptor GluR-2 and GluR-5. The Q/R site of GluR-6 pre mRNA occurs in an asymmetrical loop of 3 exonic and four intronic nucleotides. The Q/R site is located in a homologous position in GluR-2 and in GluR-6.[15]
GluR-6 is also edited at I/V and Y/C sites, which are found in the first membrane domain (M1). At the I/V site editing results in a codon change from (ATT) isoleucine (I) to (GTT)valine (V), while at the Y/C site the codon change is from (TAC) tyrosine(Y) to (TGC) cysteine (C).[16]
The RNA fold programme characterised a putative double-stranded RNA(dsRNA) conformation around the Q/R site of the GluR-6 pre-mRNA. This sequence is necessary for editing at the site to occur. The possible editing complementary sequence was observed from transcript analysis to be 1.9 kb downstream from the editing site within intron 12.[15]
The ECS for the editing sites in M1 has yet to be identified but it is likely to occur at a considerable distance from the editing sites.[17]
## Regulation
Editing of the Q/R site in GluR-6 pre-mRNA has been demonstrated to be developmentally regulated in rats ranging from 0% in rat embryo to 80% at birth. This is different from AMPA receptor subunit GluR-B, which is edited nearly 100% and is not developmentally regulated.[16]
Significant amounts of both edited and nonedited forms of GluR-6 transcripts are found in adult brain. The receptor is 90% edited in all grey matter structures. In white matter of the brain the receptor is in edited form in just 10% of cases.
Frequency increases from 0% in rat embryo to 85% in adult rat.
## Consequences
### Structure
The primary of GluR-6 transcripts can be edited in up to three positions. Editing at each of the three positions affect the Ca2+ permeability of the channel[18]
### Function
Editing plays a role in the electrophysiology of the channel.
Editing at the Q/R site has been deemed to be nonessential in GluR-6.[19] It has been reported that unedited version of Glu-R6 functions in the regulation of synaptic plasticity. The edited version is thought to inhibit synaptic plasticity and reduce seizure susceptibility.[18]
Mice lacking the Q/R site are capable of long term potentiation and are more susceptible to kainate induced seizures. The number of seizures inversely correlates with the amount of rna editing. This correlates to the increase in human GluR-6 pre-mRNA editing during seizures. It is thought that editing maybe an adaptive mechanism.[20][21]
Up to 8 different protein isoforms can occur as a result of different combinations of editing at the three sites.
Editing at the Q/R site affects the calcium permeability of the receptor. The two other editing sites are less well defined (I/V,Y/C) but are also thought to be involved in regulation of calcium permeability.(59) Evidence suggests that if editing does not occur at I/V and Y/C sites
then both edited and nonedited versions of the receptor demonstrate high calcium permeability. When both editing sites in TM1 are edited then the Q/R site edited version of the receptor is more permeable to calcium than the nonedited version at the Q/R site. The co assembly of these two isoforms generate receptor with reduced calcium permeability.[18]
Rna editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid and docosahexaenoic acid[22] For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids.However inclusion of just one nonedited subunit is enough to stop this inhibition.[22]
### Dysregulation
Kainate induced seizures in mice are used as a model of temporal lobe epilepsy in humans. Despite deficiency in editing at the Q/R site of GluR-6 in mice increasing seizure vulnerability, tissue analysis of human patients did not show reduced editing at this site.[19][23][24][25] | https://www.wikidoc.org/index.php/GLUR6 | |
74dadde4794665fb19195e8a81053ab2f7596ee0 | wikidoc | GLUT1 | GLUT1
Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene can cause GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2, idiopathic generalized epilepsy 12, dystonia 9, and stomatin-deficient cryohydrocytosis.
# Discovery
GLUT1 was the first glucose transporter to be characterized. GLUT 1 is highly conserved. GLUT 1 of humans and mice have 98% identity at the amino acid level. GLUT 1 is encoded by the SLC2 gene and is one of a family of 14 genes encoding GLUT proteins.
# Structure
The SLC2A1 gene is located on the p arm of chromosome 1 in position 34.2 and has 10 exons spanning 33,802 base pairs. The gene produces a 54.1 kDa protein composed of 492 amino acids. It is a multi-pass protein located in the cell membrane. This protein lacks a signal sequence; its C-terminus, N-terminus, and the very hydrophilic domain in the protein's center are all predicted to lie on the cytoplasmic side of the cell membrane.
GLUT1 behaves as a Michaelis-Menten enzyme and contains 12 membrane-spanning alpha helices, each containing 20 amino acid residues. A helical wheel analysis shows that the membrane spanning alpha helices are amphipathic, with one side being polar and the other side hydrophobic. Six of these membrane spanning helices are believed to bind together in the membrane to create a polar channel in the center through which glucose can traverse, with the hydrophobic regions on the outside of the channel adjacent to the fatty acid tails of the membrane.
# Function
Energy-yielding metabolism in erythrocytes depends on a constant supply of glucose from the blood plasma, where the glucose concentration is maintained at about 5mM. Glucose enters the erythrocyte by facilitated diffusion via a specific glucose transporter, at a rate about 50,000 times greater than uncatalyzed transmembrane diffusion. The glucose transporter of erythrocytes (called GLUT1 to distinguish it from related glucose transporters in other tissues) is a type III integral protein with 12 hydrophobic segments, each of which is believed to form a membrane-spanning helix. The detailed structure of GLUT1 is not known yet, but one plausible model suggests that the side-by-side assembly of several helices produces a transmembrane channel lined with hydrophilic residues that can hydrogen-bond with glucose as it moves through the channel.
GLUT1 is responsible for the low level of basal glucose uptake required to sustain respiration in all cells. Expression levels of GLUT1 in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels.
GLUT1 is also a major receptor for uptake of Vitamin C as well as glucose, especially in non vitamin C producing mammals as part of an adaptation to compensate by participating in a Vitamin C recycling process. In mammals that do produce Vitamin C, GLUT4 is often expressed instead of GLUT1.
# Tissue distribution
GLUT1 expression occurs in almost all tissues, with the degree of expression typically correlating with the rate of cellular glucose metabolism. In the adult it is expressed at highest levels in erythrocytes and also in the endothelial cells of barrier tissues such as the blood–brain barrier.
# Clinical significance
Mutations in the GLUT1 gene are responsible for GLUT1 deficiency or De Vivo disease, which is a rare autosomal dominant disorder. This disease is characterized by a low cerebrospinal fluid glucose concentration (hypoglycorrhachia), a type of neuroglycopenia, which results from impaired glucose transport across the blood–brain barrier.
## GLUT1 Deficiency Syndrome 1
Many mutations in the SLC2A1 gene, including LYS456TER, TYR449TER, LYS256VAL, ARG126HIS, ARG126LEU and GLY91ASP, have been shown to cause GLUT1 deficiency syndrome 1 (GLUT1DS1), a neurologic disorder showing wide phenotypic variability. This disease can be inherited in either an autosomal recessive or autosomal dominant manner. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation.
## GLUT1 Deficiency Syndrome 2
Other mutations, like GLY314SER, ALA275THR, ASN34ILE, SER95ILE, ARG93TRP, ARG91TRP, a 3-bp insertion (TYR292) and a 12-bp deletion (1022_1033del) in exon 6, have been shown to cause GLUT1 deficiency syndrome 2 (GLUT1DS2), a clinically variable disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy. Mild mental retardation may also occur. In some patients involuntary exertion-induced dystonic, choreoathetotic, and ballistic movements may be associated with macrocytic hemolytic anemia. Inheritance of this disease is autosomal dominant.
## Idiopathic Generalized Epilepsy 12
Some mutations, particularly ASN411SER, ARG458TRP, ARG223PRO and ARG232CYS, have been shown to cause idiopathic generalized epilepsy 12 (EIG12), a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. In some EIG12 patients seizures may remit with age. Inheritance of this disease is autosomal dominant.
## Dystonia 9
Another mutation, ARG212CYS, has been shown to cause Dystonia 9 (DYT9), an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia.
## Stomatin-deficient Cryohydrocytosis
Certain mutations, like GLY286ASP and a 3-bp deletion in ILE435/436, cause Stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN), a rare form of stomatocytosis characterized by episodic hemolytic anemia, cold-induced red cells cation leak, erratic hyperkalemia, neonatal hyperbilirubinemia, hepatosplenomegaly, cataracts, seizures, mental retardation, and movement disorder. Inheritance of this disease is autosomal dominant.
## Role as a Receptor for HTLV
GLUT1 is also a receptor used by the HTLV virus to gain entry into target cells.
## Role as a Histochemical Marker for Hemangioma
Glut1 has also been demonstrated as a powerful histochemical marker for hemangioma of infancy
# Interactions
GLUT1 has been shown to interact with GIPC1. It is found in a complex with ADD2 and DMTN and interacts (via C-terminus cytoplasmic region) with DMTN isoform 2. It also interacts with SNX27; the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane. This protein interacts with STOM. It interacts with SGTA (via Gln-rich region) and has binary interactions with CREB3-2.
GLUT1 has two significant types in brain 45k and 55k. GLUT1 45k is present on astroglia of neurons and GLUT1 55k is present on capillaries in brain and is responsible for glucose transport across blood brain barrier and its deficiency causes low level of glucose in CSF (less than 60 mg/dl) which may manifest as convulsion in deficient individuals.
Recently it has been described a GLUT1 inhibitor, DERL3, that is often methylated in colorectal cancer. In this cancer, DERL3 methylations seems to mediate the Warburg Effect.
# Inhibitors
Fasentin is a small molecule inhibitor of the intracellular domain of GLUT1 preventing glucose uptake.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | GLUT1
Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene.[1] GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells.[2] This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II.[3] Mutations in this gene can cause GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2, idiopathic generalized epilepsy 12, dystonia 9, and stomatin-deficient cryohydrocytosis.[4][5]
# Discovery
GLUT1 was the first glucose transporter to be characterized. GLUT 1 is highly conserved.[1] GLUT 1 of humans and mice have 98% identity at the amino acid level. GLUT 1 is encoded by the SLC2 gene and is one of a family of 14 genes encoding GLUT proteins.[6]
# Structure
The SLC2A1 gene is located on the p arm of chromosome 1 in position 34.2 and has 10 exons spanning 33,802 base pairs.[3] The gene produces a 54.1 kDa protein composed of 492 amino acids.[7][8][9][10] It is a multi-pass protein located in the cell membrane.[4][5] This protein lacks a signal sequence; its C-terminus, N-terminus, and the very hydrophilic domain in the protein's center are all predicted to lie on the cytoplasmic side of the cell membrane.[10][1]
GLUT1 behaves as a Michaelis-Menten enzyme and contains 12 membrane-spanning alpha helices, each containing 20 amino acid residues. A helical wheel analysis shows that the membrane spanning alpha helices are amphipathic, with one side being polar and the other side hydrophobic. Six of these membrane spanning helices are believed to bind together in the membrane to create a polar channel in the center through which glucose can traverse, with the hydrophobic regions on the outside of the channel adjacent to the fatty acid tails of the membrane.[citation needed]
# Function
Energy-yielding metabolism in erythrocytes depends on a constant supply of glucose from the blood plasma, where the glucose concentration is maintained at about 5mM. Glucose enters the erythrocyte by facilitated diffusion via a specific glucose transporter, at a rate about 50,000 times greater than uncatalyzed transmembrane diffusion. The glucose transporter of erythrocytes (called GLUT1 to distinguish it from related glucose transporters in other tissues) is a type III integral protein with 12 hydrophobic segments, each of which is believed to form a membrane-spanning helix. The detailed structure of GLUT1 is not known yet, but one plausible model suggests that the side-by-side assembly of several helices produces a transmembrane channel lined with hydrophilic residues that can hydrogen-bond with glucose as it moves through the channel.[11]
GLUT1 is responsible for the low level of basal glucose uptake required to sustain respiration in all cells. Expression levels of GLUT1 in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels.[citation needed]
GLUT1 is also a major receptor for uptake of Vitamin C as well as glucose, especially in non vitamin C producing mammals as part of an adaptation to compensate by participating in a Vitamin C recycling process. In mammals that do produce Vitamin C, GLUT4 is often expressed instead of GLUT1.[12]
# Tissue distribution
GLUT1 expression occurs in almost all tissues, with the degree of expression typically correlating with the rate of cellular glucose metabolism. In the adult it is expressed at highest levels in erythrocytes and also in the endothelial cells of barrier tissues such as the blood–brain barrier.[13]
# Clinical significance
Mutations in the GLUT1 gene are responsible for GLUT1 deficiency or De Vivo disease, which is a rare autosomal dominant disorder.[14] This disease is characterized by a low cerebrospinal fluid glucose concentration (hypoglycorrhachia), a type of neuroglycopenia, which results from impaired glucose transport across the blood–brain barrier.
## GLUT1 Deficiency Syndrome 1
Many mutations in the SLC2A1 gene, including LYS456TER, TYR449TER, LYS256VAL, ARG126HIS, ARG126LEU and GLY91ASP, have been shown to cause GLUT1 deficiency syndrome 1 (GLUT1DS1), a neurologic disorder showing wide phenotypic variability. This disease can be inherited in either an autosomal recessive or autosomal dominant manner.[10] The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation.[4][5]
## GLUT1 Deficiency Syndrome 2
Other mutations, like GLY314SER, ALA275THR, ASN34ILE, SER95ILE, ARG93TRP, ARG91TRP, a 3-bp insertion (TYR292) and a 12-bp deletion (1022_1033del) in exon 6, have been shown to cause GLUT1 deficiency syndrome 2 (GLUT1DS2), a clinically variable disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy. Mild mental retardation may also occur. In some patients involuntary exertion-induced dystonic, choreoathetotic, and ballistic movements may be associated with macrocytic hemolytic anemia.[4][5] Inheritance of this disease is autosomal dominant.[10]
## Idiopathic Generalized Epilepsy 12
Some mutations, particularly ASN411SER, ARG458TRP, ARG223PRO and ARG232CYS, have been shown to cause idiopathic generalized epilepsy 12 (EIG12), a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. In some EIG12 patients seizures may remit with age.[4][5] Inheritance of this disease is autosomal dominant.[10]
## Dystonia 9
Another mutation, ARG212CYS, has been shown to cause Dystonia 9 (DYT9), an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia.[4][5]
## Stomatin-deficient Cryohydrocytosis
Certain mutations, like GLY286ASP and a 3-bp deletion in ILE435/436, cause Stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN), a rare form of stomatocytosis characterized by episodic hemolytic anemia, cold-induced red cells cation leak, erratic hyperkalemia, neonatal hyperbilirubinemia, hepatosplenomegaly, cataracts, seizures, mental retardation, and movement disorder.[4][5] Inheritance of this disease is autosomal dominant.[10]
## Role as a Receptor for HTLV
GLUT1 is also a receptor used by the HTLV virus to gain entry into target cells.[15]
## Role as a Histochemical Marker for Hemangioma
Glut1 has also been demonstrated as a powerful histochemical marker for hemangioma of infancy[16]
# Interactions
GLUT1 has been shown to interact with GIPC1.[17] It is found in a complex with ADD2 and DMTN and interacts (via C-terminus cytoplasmic region) with DMTN isoform 2.[18] It also interacts with SNX27; the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane.[19] This protein interacts with STOM.[20] It interacts with SGTA (via Gln-rich region) and has binary interactions with CREB3-2.[4][5]
GLUT1 has two significant types in brain 45k and 55k. GLUT1 45k is present on astroglia of neurons and GLUT1 55k is present on capillaries in brain and is responsible for glucose transport across blood brain barrier and its deficiency causes low level of glucose in CSF (less than 60 mg/dl) which may manifest as convulsion in deficient individuals.[citation needed]
Recently it has been described a GLUT1 inhibitor, DERL3, that is often methylated in colorectal cancer. In this cancer, DERL3 methylations seems to mediate the Warburg Effect.[21]
# Inhibitors
Fasentin is a small molecule inhibitor of the intracellular domain of GLUT1 preventing glucose uptake.[22]
# 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: "GlycolysisGluconeogenesis_WP534"..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/GLUT1 | |
c7912023219a9201661fb907dd745dd9a47ac714 | wikidoc | GLUT2 | GLUT2
Glucose transporter 2 (GLUT2) also known as solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood, and has a role in renal glucose reabsorption. It is also capable of transporting fructose. Unlike GLUT4, it does not rely on insulin for facilitated diffusion.
In humans, this protein is encoded by the SLC2A2 gene.
# Tissue distribution
GLUT2 is found in cellular membranes of:
- liver (Primary)
- pancreatic β cell (Primary)
- hypothalamus (Not overly significant)
- basolateral membrane of small intestine and apical GLUT2 is also suggested.
- basolateral membrane of renal tubular cells
# Function
GLUT2 has high capacity for glucose but low affinity (high Km, ca. 15-20 mM) and thus functions as part of the "glucose sensor" in the pancreatic β-cells of rodents, though in human β-cells the role of GLUT2 seems to be a minor one. It is a very efficient carrier for glucose.
GLUT2 also carries glucosamine.
When the glucose concentration in the lumen of the small intestine goes above 30 mM, such as occurs in the fed-state, GLUT2 is up-regulated at the brush border membrane, enhancing the capacity of glucose transport. Basolateral GLUT2 in enterocytes also aids in the transport of fructose into the bloodstream through glucose-dependent cotransport.
# Clinical significance
Defects in the SLC2A2 gene are associated with a particular type of glycogen storage disease called Fanconi-Bickel syndrome.
In drug-treated diabetic pregnancies in which glucose levels in the woman are uncontrolled, neural tube and cardiac defects in the early-developing brain, spine, and heart depend upon functional GLUT2 carriers, and defects in the GLUT2 gene have been shown to be protective against such defects in rats. However, whilst a lack of GLUT2 adaptability is negative, it is important to remember the fact that the main result of untreated gestational diabetes appears to cause babies to be of above-average size, which may well be an advantage that is managed very well with a healthy GLUT2 status.
Maintaining a regulated osmotic balance of sugar concentration between the blood circulation and the interstitial spaces is critical in some cases of edema including cerebral edema.
GLUT2 appears to be particularly important to osmoregulation, and preventing edema-induced stroke, transient ischemic attack or coma, especially when blood glucose concentration is above average. GLUT2 could reasonably be referred to as the "diabetic glucose transporter" or a "stress hyperglycemia glucose transporter."
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | GLUT2
Glucose transporter 2 (GLUT2) also known as solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood, and has a role in renal glucose reabsorption. It is also capable of transporting fructose.[1] Unlike GLUT4, it does not rely on insulin for facilitated diffusion.
In humans, this protein is encoded by the SLC2A2 gene.[2][3]
# Tissue distribution
GLUT2 is found in cellular membranes of:
- liver (Primary)
- pancreatic β cell (Primary)
- hypothalamus (Not overly significant)
- basolateral membrane of small intestine and apical GLUT2 is also suggested.[4]
- basolateral membrane of renal tubular cells[5]
# Function
GLUT2 has high capacity for glucose but low affinity (high Km, ca. 15-20 mM) and thus functions as part of the "glucose sensor" in the pancreatic β-cells of rodents, though in human β-cells the role of GLUT2 seems to be a minor one.[6] It is a very efficient carrier for glucose.[7][8]
GLUT2 also carries glucosamine.[9]
When the glucose concentration in the lumen of the small intestine goes above 30 mM, such as occurs in the fed-state, GLUT2 is up-regulated at the brush border membrane, enhancing the capacity of glucose transport. Basolateral GLUT2 in enterocytes also aids in the transport of fructose into the bloodstream through glucose-dependent cotransport.
# Clinical significance
Defects in the SLC2A2 gene are associated with a particular type of glycogen storage disease called Fanconi-Bickel syndrome.[10]
In drug-treated diabetic pregnancies in which glucose levels in the woman are uncontrolled, neural tube and cardiac defects in the early-developing brain, spine, and heart depend upon functional GLUT2 carriers, and defects in the GLUT2 gene have been shown to be protective against such defects in rats.[11] However, whilst a lack of GLUT2 adaptability[12] is negative, it is important to remember the fact that the main result of untreated gestational diabetes appears to cause babies to be of above-average size, which may well be an advantage that is managed very well with a healthy GLUT2 status.
Maintaining a regulated osmotic balance of sugar concentration between the blood circulation and the interstitial spaces is critical in some cases of edema including cerebral edema.
GLUT2 appears to be particularly important to osmoregulation, and preventing edema-induced stroke, transient ischemic attack or coma, especially when blood glucose concentration is above average.[13] GLUT2 could reasonably be referred to as the "diabetic glucose transporter" or a "stress hyperglycemia glucose transporter."
# 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: "GlycolysisGluconeogenesis_WP534"..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/GLUT2 | |
dd3ba1ad13c87f4bc2db3caedb3458839305b04b | wikidoc | GLUT3 | GLUT3
Glucose transporter 3 (or GLUT3), also known as solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3) is a protein that in humans is encoded by the SLC2A3 gene. GLUT3 facilitates the transport of glucose across the plasma membranes of mammalian cells. GLUT3 is most known for its specific expression in neurons and has originally been designated as the neuronal GLUT. GLUT3 has been studied in other cell types with specific glucose requirements, including sperm, preimplantation embryos, circulating white blood cells and carcinoma cell lines.
# Discovery
GLUT3 was the third glucose transporter to be discovered, first cloned in 1988 from a fetal skeletal muscle cell line, using a GLUT1 cDNA probe and shown to share 64.4% identity with GLUT1.
# Function
Although GLUT3 was found to be expressed in various tissues, it is most specifically expressed in neurons, found predominantly in axons and dendrites and also, but less prominently, in the cell body. GLUT3 has both a higher affinity for glucose and at least a fivefold greater transport capacity than GLUT1, GLUT2 and GLUT4, which is particularly significant for its role in neuronal glucose transport, where ambient glucose levels surrounding the neurons are fivefold lower than in serum.
## Brain
Glucose delivery and utilization in the mammalian brain is mediated primarily by a high molecular weight form of GLUT1 in the blood–brain barrier, GLUT3 in neuronal populations and a less glycosylated form of GLUT1 in the remainder of the parenchyma. GLUT3 is considered the main but not the exclusive neuronal glucose transporter, whereas other glucose transporters have also been observed in neurons.
GLUT3 expression in neurons in the rat coincides with maturation and synaptic connectivity and a positive correlation between protein levels of GLUT1, GLUT3 and regional cerebral glucose utilization was observed in mouse.
The central role of GLUT3 in cerebral metabolism has been challenged by the astrocyte-neuron lactate shuttle (ANLS) hypothesis, which proposes that astrocytes play the key role in the coupling of neuronal activity and cerebral glucose utilization. In this hypothesis, the astrocyte, which relies on GLUT1 for glucose transport, is the primary consumer of glucose in the brain, providing lactate as the primary energetic fuel for neurons. However, by modeling the kinetic characteristics and glucose concentrations in neurons and glia, it was concluded that the glucose capacity of neurons via GLUT3 far exceeds that of astrocytes via GLUT1. Additionally, demonstrations of increase in GLUT3 expression associated with increased cerebral glucose utilization provides further confirmation of the central role of GLUT3.
## Other tissues
Expression of GLUT3 is also found in sperm, embryos, white blood cells and carcinoma cell lines.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | GLUT3
Glucose transporter 3 (or GLUT3), also known as solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3) is a protein that in humans is encoded by the SLC2A3 gene.[1] GLUT3 facilitates the transport of glucose across the plasma membranes of mammalian cells. GLUT3 is most known for its specific expression in neurons and has originally been designated as the neuronal GLUT. GLUT3 has been studied in other cell types with specific glucose requirements, including sperm, preimplantation embryos, circulating white blood cells and carcinoma cell lines.[2]
# Discovery
GLUT3 was the third glucose transporter to be discovered, first cloned in 1988 from a fetal skeletal muscle cell line, using a GLUT1 cDNA probe and shown to share 64.4% identity with GLUT1.[1]
# Function
Although GLUT3 was found to be expressed in various tissues, it is most specifically expressed in neurons, found predominantly in axons and dendrites and also, but less prominently, in the cell body.[3] GLUT3 has both a higher affinity for glucose and at least a fivefold greater transport capacity than GLUT1, GLUT2 and GLUT4, which is particularly significant for its role in neuronal glucose transport, where ambient glucose levels surrounding the neurons are fivefold lower than in serum.[2]
## Brain
Glucose delivery and utilization in the mammalian brain is mediated primarily by a high molecular weight form of GLUT1 in the blood–brain barrier, GLUT3 in neuronal populations and a less glycosylated form of GLUT1 in the remainder of the parenchyma. GLUT3 is considered the main but not the exclusive neuronal glucose transporter, whereas other glucose transporters have also been observed in neurons.[3]
GLUT3 expression in neurons in the rat coincides with maturation and synaptic connectivity[4] and a positive correlation between protein levels of GLUT1, GLUT3 and regional cerebral glucose utilization was observed in mouse.[5]
The central role of GLUT3 in cerebral metabolism has been challenged by the astrocyte-neuron lactate shuttle (ANLS) hypothesis,[6] which proposes that astrocytes play the key role in the coupling of neuronal activity and cerebral glucose utilization. In this hypothesis, the astrocyte, which relies on GLUT1 for glucose transport, is the primary consumer of glucose in the brain, providing lactate as the primary energetic fuel for neurons. However, by modeling the kinetic characteristics and glucose concentrations in neurons and glia, it was concluded that the glucose capacity of neurons via GLUT3 far exceeds that of astrocytes via GLUT1.[7] Additionally, demonstrations of increase in GLUT3 expression associated with increased cerebral glucose utilization provides further confirmation of the central role of GLUT3.[5]
## Other tissues
Expression of GLUT3 is also found in sperm, embryos, white blood cells and carcinoma cell lines.
# 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: "GlycolysisGluconeogenesis_WP534"..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/GLUT3 | |
4aebaec167bb91d920aa83a9f52922b19aef10d6 | wikidoc | GLUT4 | GLUT4
Glucose transporter type 4 (GLUT-4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.
At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.
# Structure
Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 are what allow it to transport glucose across the plasma membrane. In addition to the phenylalanine on the N-terminus, two Leucine residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of endocytosis and exocytosis.
## Other GLUT proteins
There are 14 total GLUT proteins separated into 3 classes based on sequence similarities. Class 1 consists of GLUT 1-4 and 14, class 2 contains GLUT 5, 7, 9 and 11, and class 3 has GLUT 6, 8, 10, 12 and 13.
Although there are some sequence differences between all GLUT proteins, they all have some basic structural components. For example, both the N and C termini in GLUT proteins are exposed to the cytoplasm of the cell, and they all have 12 transmembrane segments.
# Tissue distribution
## Skeletal muscle
In striated skeletal muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction.
During exercise, the body needs to convert glucose to ATP to be used as energy. As G-6-P concentrations decrease, hexokinase becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This also means that muscle cells are able to take in more glucose as its intracellular concentrations decrease. In order to increase glucose levels in the cell, GLUT4 is the primary transporter used in this facilitated diffusion.
Although muscle contractions function in a similar way and also induce the translocation of GLUT4 into the plasma membrane, the two skeletal muscle processes obtain different forms of intracellular GLUT4. The GLUT4 carrier vesicles are either transferrin positive or negative, and are recruited by different stimuli. Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.
## Cardiac muscle
Cardiac muscle is slightly different from skeletal muscle. At rest, they prefer to utilize fatty acids as their main energy source. As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.
An analysis of mRNA levels of GLUT1 and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles. GLUT4, however, is still believed to be the primary transporter for glucose.
Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell.
## Adipose tissue
Adipose tissue, commonly known as fat, is a depository for energy in order to conserve metabolic homeostasis. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen primarily in the liver, muscle cells, or fat.
An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell hypertrophy and hyperplasia, which lead to obesity. In addition, mutations in GLUT4 genes in adipocytes can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. If GLUT4 is over-expressed, it can actually alter nutrient distribution and send excess glucose into adipose tissue, leading to increased adipose tissue mass.
# Regulation
## Insulin
As we eat and glucose levels increase, insulin is released from the pancreas and into the blood stream. Insulin is stored in beta cells in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a signal cascade is initiated inside the cell that results in insulin stored in vesicles in these cells being released into the blood stream. Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors.
Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.
The genetically engineered muscle insulin receptor knock‐out (MIRKO) mouse was designed to be insensitive to glucose uptake caused by insulin, meaning that GLUT4 is absent. Mice with diabetes or fasting hyperglycemia, however, were found to be immune to the negative effects of the insensitivity.
The mechanism for GLUT4 is an example of a cascade effect, where binding of a ligand to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or IRS-1, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by PKB (protein kinase B) and by PDK1, which can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GTPase-activating domain associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form, and stimulates GLUT4 to be expressed on the plasma membrane.
RAC1 is a GTPase also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton which allows for the GLUT4 vesicles to be inserted into the plasma membrane. A RAC1 Knockout mouse has reduced glucose uptake in muscle tissue.
Knockout mice that are heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.
## Muscle contraction
Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction increases the rate of GLUT4 translocation; but is observed to a lesser extent in increased skeletal muscle contraction. In skeletal muscle, muscle contractions increase GLUT4 translocation several fold, and this is likely regulated by RAC1 and AMP-activated protein kinase.
## Muscle stretching
Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via RAC1.
# Interactions
GLUT4 has been shown to interact with death-associated protein 6, also known as Daxx. Daxx, which is used to regulate apoptosis, has been shown to associate with GLUT4 in the cytoplasm. UBX-domains, such as the one found in GLUT4, have been shown to associate with apoptotic signaling. So this interaction aids in the translocation of Daxx within the cell.
In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the hippocampus. Moreover, impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behaviour and cognitive dysfunction.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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} | GLUT4
Glucose transporter type 4 (GLUT-4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988.[1] The gene that encodes GLUT4 was cloned[2][3] and mapped in 1989.[4]
At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. Glucose-6-phosphate cannot diffuse back out of cells, which also serves to maintain the concentration gradient for glucose to passively enter cells.[5]
# Structure
Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 are what allow it to transport glucose across the plasma membrane. In addition to the phenylalanine on the N-terminus, two Leucine residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of endocytosis and exocytosis.[7]
## Other GLUT proteins
There are 14 total GLUT proteins separated into 3 classes based on sequence similarities. Class 1 consists of GLUT 1-4 and 14, class 2 contains GLUT 5, 7, 9 and 11, and class 3 has GLUT 6, 8, 10, 12 and 13.
Although there are some sequence differences between all GLUT proteins, they all have some basic structural components. For example, both the N and C termini in GLUT proteins are exposed to the cytoplasm of the cell, and they all have 12 transmembrane segments.[8]
# Tissue distribution
## Skeletal muscle
In striated skeletal muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction.
During exercise, the body needs to convert glucose to ATP to be used as energy. As G-6-P concentrations decrease, hexokinase becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This also means that muscle cells are able to take in more glucose as its intracellular concentrations decrease. In order to increase glucose levels in the cell, GLUT4 is the primary transporter used in this facilitated diffusion.[10]
Although muscle contractions function in a similar way and also induce the translocation of GLUT4 into the plasma membrane, the two skeletal muscle processes obtain different forms of intracellular GLUT4. The GLUT4 carrier vesicles are either transferrin positive or negative, and are recruited by different stimuli. Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.[11][12]
## Cardiac muscle
Cardiac muscle is slightly different from skeletal muscle. At rest, they prefer to utilize fatty acids as their main energy source. As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.[13]
An analysis of mRNA levels of GLUT1 and GLUT4 in cardiac muscles show that GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles.[14] GLUT4, however, is still believed to be the primary transporter for glucose.[15]
Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell. [16]
## Adipose tissue
Adipose tissue, commonly known as fat,[17] is a depository for energy in order to conserve metabolic homeostasis. As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen primarily in the liver, muscle cells, or fat.[18]
An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell hypertrophy and hyperplasia, which lead to obesity.[19] In addition, mutations in GLUT4 genes in adipocytes can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. If GLUT4 is over-expressed, it can actually alter nutrient distribution and send excess glucose into adipose tissue, leading to increased adipose tissue mass.[19]
# Regulation
## Insulin
As we eat and glucose levels increase, insulin is released from the pancreas and into the blood stream.[20] Insulin is stored in beta cells in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a signal cascade is initiated inside the cell that results in insulin stored in vesicles in these cells being released into the blood stream.[21] Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors.[18]
Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases.[22]
The genetically engineered muscle insulin receptor knock‐out (MIRKO) mouse was designed to be insensitive to glucose uptake caused by insulin, meaning that GLUT4 is absent. Mice with diabetes or fasting hyperglycemia, however, were found to be immune to the negative effects of the insensitivity.[23]
The mechanism for GLUT4 is an example of a cascade effect, where binding of a ligand to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain. The receptor then recruits Insulin Receptor Substrate, or IRS-1, which binds the enzyme PI-3 kinase. PI-3 kinase converts the membrane lipid PIP2 to PIP3. PIP3 is specifically recognized by PKB (protein kinase B) and by PDK1, which can phosphorylate and activate PKB. Once phosphorylated, PKB is in its active form and phosphorylates TBC1D4, which inhibits the GTPase-activating domain associated with TBC1D4, allowing for Rab protein to change from its GDP to GTP bound state. Inhibition of the GTPase-activating domain leaves proteins next in the cascade in their active form, and stimulates GLUT4 to be expressed on the plasma membrane.[24]
RAC1 is a GTPase also activated by insulin. Rac1 stimulates reorganization of the cortical Actin cytoskeleton[25] which allows for the GLUT4 vesicles to be inserted into the plasma membrane.[26][27] A RAC1 Knockout mouse has reduced glucose uptake in muscle tissue.[27]
Knockout mice that are heterozygous for GLUT4 develop insulin resistance in their muscles as well as diabetes.[28]
## Muscle contraction
Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces. This is especially true in cardiac muscle, where continuous contraction increases the rate of GLUT4 translocation; but is observed to a lesser extent in increased skeletal muscle contraction.[29] In skeletal muscle, muscle contractions increase GLUT4 translocation several fold,[30] and this is likely regulated by RAC1 [31][32] and AMP-activated protein kinase.[33]
## Muscle stretching
Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via RAC1.[34]
# Interactions
GLUT4 has been shown to interact with death-associated protein 6, also known as Daxx. Daxx, which is used to regulate apoptosis, has been shown to associate with GLUT4 in the cytoplasm. UBX-domains, such as the one found in GLUT4, have been shown to associate with apoptotic signaling.[6] So this interaction aids in the translocation of Daxx within the cell.[35]
In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system such as the hippocampus. Moreover, impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behaviour and cognitive dysfunction.[36][37][38]
# 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: "GlycolysisGluconeogenesis_WP534"..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/GLUT4 | |
b07432dc8b369fa7688b6f9cc202a6143eaa8ca9 | wikidoc | GLUT8 | GLUT8
GLUT8 also known as SLC2A8 is the eighth member of glucose transporter superfamily.
It is characterized by the presence of two leucine residues in its N-terminal intracellular domain, which influences intracellular trafficking.
# Discovery
GLUT8, originally named GLUTX1, was cloned almost simultaneously by two different groups.
# Tissue distribution
GLUT8 is expressed mostly in neurons and testis, although expression in most other tissues has also been shown at lower levels. GLUT8 is expressed at moderate levels in the brain, most strikingly in hippocampus. Whether the glucose transporter plays any role in these cells remains to be shown.
# Subcellular localization
Contrary to GLUT4, GLUT8 (previously known as GLUTX1) is not insulin-sensitive. In other words, insulin does not promote GLUT8 translocation to the cell surface in neurons as well as in transfected cell lines.
Where in the cell GLUT8 is localized in not yet clear. Most GLUT8 is not present at the cell surface. Some co-localization with both the endoplasmic reticulum and late endosomes/lysosomes has been published.
When the N-terminal di-leucine motif is mutated into a di-alanine motif, GLUT8 is located mostly at the cell surface in Xenopus oocytes and mammalian cells such as HEK 293 cells and differentiated PC12 cells.
# Physiological role
GLUT8 function in vivo remains to be defined, despite suggestions that it may play a role in fertility, being expressed at high levels in testes and in the acrosomal part of spermatozoa. Furthermore, GLUT8 appears to play an important role in the energy metabolism of sperm cells.
The recent description of GLUT8 expression in kidneys and liver suggest that the transporter may play a role in glucose uptake in these organs.
GLUT8, when expressed in Xenopus oocytes, mediates glucose uptake with high affinity. Other hexoses are not good substrates of the transporter. Whether the transporter actually mediates glucose uptake in vivo in the brain has not been evaluated yet.
Mice devoid of both copies of the SLC2A8 gene are viable, fertile and do not show any obvious phenotype. They are not diabetic, showing that GLUT8 is unlikely to play major roles in glucose homeostasis. | GLUT8
GLUT8 also known as SLC2A8 is the eighth member of glucose transporter superfamily.[1]
It is characterized by the presence of two leucine residues in its N-terminal intracellular domain, which influences intracellular trafficking.[2]
# Discovery
GLUT8, originally named GLUTX1, was cloned almost simultaneously by two different groups.[2][3]
# Tissue distribution
GLUT8 is expressed mostly in neurons and testis, although expression in most other tissues has also been shown at lower levels.[citation needed] GLUT8 is expressed at moderate levels in the brain, most strikingly in hippocampus. Whether the glucose transporter plays any role in these cells remains to be shown.[citation needed]
# Subcellular localization
Contrary to GLUT4, GLUT8 (previously known as GLUTX1) is not insulin-sensitive.[citation needed] In other words, insulin does not promote GLUT8 translocation to the cell surface in neurons as well as in transfected cell lines.[citation needed]
Where in the cell GLUT8 is localized in not yet clear. Most GLUT8 is not present at the cell surface. Some co-localization with both the endoplasmic reticulum and late endosomes/lysosomes has been published.[4]
When the N-terminal di-leucine motif is mutated into a di-alanine motif, GLUT8 is located mostly at the cell surface in Xenopus oocytes and mammalian cells such as HEK 293 cells and differentiated PC12 cells.[citation needed]
# Physiological role
GLUT8 function in vivo remains to be defined, despite suggestions that it may play a role in fertility, being expressed at high levels in testes and in the acrosomal part of spermatozoa.[5] Furthermore, GLUT8 appears to play an important role in the energy metabolism of sperm cells.[6]
The recent description of GLUT8 expression in kidneys and liver suggest that the transporter may play a role in glucose uptake in these organs.[citation needed]
GLUT8, when expressed in Xenopus oocytes, mediates glucose uptake with high affinity. Other hexoses are not good substrates of the transporter. Whether the transporter actually mediates glucose uptake in vivo in the brain has not been evaluated yet.[citation needed]
Mice devoid of both copies of the SLC2A8 gene are viable, fertile and do not show any obvious phenotype.[7] They are not diabetic, showing that GLUT8 is unlikely to play major roles in glucose homeostasis.[citation needed] | https://www.wikidoc.org/index.php/GLUT8 | |
6442737a673b3865b92887c1a926c4cd2d0d9d30 | wikidoc | GLYAT | GLYAT
Glycine-N-acyltransferase, also known as GLYAT, is an enzyme which in humans is encoded by the GLYAT gene.
# Function
The glycine-N-acyltransferase protein conjugates glycine with acyl-CoA substrates in the mitochondria primarily in liver and kidney. The glycine N-acyltransferase enzyme is involved in the detoxification of a wide range of xenobiotic and endogenous metabolites. These include benzoic acid, a compound found in fruits and vegetables and used in medicine and foodstuffs as a preservative; salicylic acid, a metabolite of aspirin; and several endogenous metabolites. The diversity is demonstrated by the wide range of acylglycines excreted in the urines of patients with defects of organic acid metabolism. No defect of glycine N-acyltransferase has yet been described, but it has been demonstrated that there is significant inter individual variation in glycine conjugation capacity. Human glycine N-acyltransferase isoform a is a 296 amino acid protein translated from mRNA transcript splice variant 1. It is encoded by exons 2 to 6 of the mRNA transcript.
# Molecular weight
The literature reports it to be approximately 30 kDa, or approximately 27 kDa. The predicted size is 33.9 KDa. For the bovine enzyme a range of sizes between approximately 33 kDa and about 36 KDa is reported (Nandi, 1979, Vessey, 1992, van der Westhuizen, 2000). The predicted size of bovine GLYAT based on its sequence (accession number nm: 177486), is 33.9 kDa. This compares well to the experimentally determined sizes | GLYAT
Glycine-N-acyltransferase, also known as GLYAT, is an enzyme which in humans is encoded by the GLYAT gene.[1][2]
# Function
The glycine-N-acyltransferase protein conjugates glycine with acyl-CoA substrates in the mitochondria primarily in liver and kidney. The glycine N-acyltransferase enzyme is involved in the detoxification of a wide range of xenobiotic and endogenous metabolites. These include benzoic acid, a compound found in fruits and vegetables and used in medicine and foodstuffs as a preservative; salicylic acid, a metabolite of aspirin; and several endogenous metabolites. The diversity is demonstrated by the wide range of acylglycines excreted in the urines of patients with defects of organic acid metabolism. No defect of glycine N-acyltransferase has yet been described, but it has been demonstrated that there is significant inter individual variation in glycine conjugation capacity. Human glycine N-acyltransferase isoform a is a 296 amino acid protein translated from mRNA transcript splice variant 1. It is encoded by exons 2 to 6 of the mRNA transcript.[1]
# Molecular weight
The literature reports it to be approximately 30 kDa,[2] or approximately 27 kDa.[3] The predicted size is 33.9 KDa. For the bovine enzyme a range of sizes between approximately 33 kDa and about 36 KDa is reported (Nandi, 1979, Vessey, 1992, van der Westhuizen, 2000). The predicted size of bovine GLYAT based on its sequence (accession number nm: 177486), is 33.9 kDa. This compares well to the experimentally determined sizes[3][4][5] | https://www.wikidoc.org/index.php/GLYAT | |
154d74ff10518cb0680b6238901f00a9bb0969bd | wikidoc | GNAI1 | GNAI1
Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..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}
# Interactions
GNAI1 has been shown to interact with:
- GPR143,
- RGS12,
- RGS14,
- RGS19,
- RIC8A, and
- S1PR1. | GNAI1
Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.[1][2]
# 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: "NicotineDopaminergic_WP1602"..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}
# Interactions
GNAI1 has been shown to interact with:
- GPR143,[3]
- RGS12,[4]
- RGS14,[4][5]
- RGS19,[6][7]
- RIC8A,[8] and
- S1PR1.[9] | https://www.wikidoc.org/index.php/GNAI1 | |
4f9e2aff61a809b297292649fba3169497bbca98 | wikidoc | GOLM1 | GOLM1
Golgi membrane protein 1 (GOLM1) also known as Golgi phosphoprotein 2 or Golgi membrane protein GP73 is a protein that in humans is encoded by the GOLM1 gene. Two alternatively spliced transcript variants encoding the same protein have been described for this gene.
# Function
The Golgi complex plays a key role in the sorting and modification of proteins exported from the endoplasmic reticulum. The protein encoded by this gene is a type II Golgi transmembrane protein. It processes protein synthesized in the rough endoplasmic reticulum and assists in the transport of protein cargo through the Golgi apparatus. The expression of this encoded protein has been observed to be upregulated in response to viral infection.
# Clinical significance
Golgi membrane protein 1 is overexpressed in prostate cancer and lung adenocarcinoma tissue.
Blood levels of GP73 are higher in patients with liver cancer than in healthy individuals. In addition, levels were not significantly higher in patients with diseases other than liver disease. The current blood test used to screen for early tumors in people at high risk for liver cancer involves the alpha-fetoprotein (AFP). Patients who are at risk for non-metastatic, or primary, liver cancer typically have chronic liver disease such as cirrhosis. Such cases of cirrhosis are usually due to infection caused by infectious hepatitis (usually hepatitis B or hepatitis C, though there are other strains), or because of degenerative fatty liver disease (which can be especially severe in those with alcoholism). However, the AFP test is not usually sensitive enough to detect liver cancer in time and it often generates false positives. So far, the blood samples of more than 1,000 patients with various stages of liver and non-liver disease have been tested for the presence of GP73 in several studies. Several medical diagnostic companies are in the process of developing automated serum tests for the protein that could be performed in routine hospital laboratories. | GOLM1
Golgi membrane protein 1 (GOLM1) also known as Golgi phosphoprotein 2 or Golgi membrane protein GP73 is a protein that in humans is encoded by the GOLM1 gene.[1][2][3] Two alternatively spliced transcript variants encoding the same protein have been described for this gene.
# Function
The Golgi complex plays a key role in the sorting and modification of proteins exported from the endoplasmic reticulum. The protein encoded by this gene is a type II Golgi transmembrane protein. It processes protein synthesized in the rough endoplasmic reticulum and assists in the transport of protein cargo through the Golgi apparatus. The expression of this encoded protein has been observed to be upregulated in response to viral infection.[3]
# Clinical significance
Golgi membrane protein 1 is overexpressed in prostate cancer[4][5] and lung adenocarcinoma tissue.[6]
Blood levels of GP73 are higher in patients with liver cancer than in healthy individuals. In addition, levels were not significantly higher in patients with diseases other than liver disease. The current blood test used to screen for early tumors in people at high risk for liver cancer involves the alpha-fetoprotein (AFP). Patients who are at risk for non-metastatic, or primary, liver cancer typically have chronic liver disease such as cirrhosis. Such cases of cirrhosis are usually due to infection caused by infectious hepatitis (usually hepatitis B or hepatitis C, though there are other strains), or because of degenerative fatty liver disease (which can be especially severe in those with alcoholism). However, the AFP test is not usually sensitive enough to detect liver cancer in time and it often generates false positives. So far, the blood samples of more than 1,000 patients with various stages of liver and non-liver disease have been tested for the presence of GP73 in several studies. Several medical diagnostic companies are in the process of developing automated serum tests for the protein that could be performed in routine hospital laboratories.[7] | https://www.wikidoc.org/index.php/GOLM1 | |
6ce42acaa15760e8a6eeef83df7d2e56ed10a105 | wikidoc | GOSR1 | GOSR1
Golgi SNAP receptor complex member 1 is a protein that in humans is encoded by the GOSR1 gene.
This gene encodes a trafficking membrane protein which transports proteins among the endoplasmic reticulum and the Golgi apparatus and between Golgi compartments. This protein is considered an essential component of the Golgi SNAP receptor (SNARE) complex. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Interactions
GOSR1 has been shown to interact with USO1, BET1L and STX5. | GOSR1
Golgi SNAP receptor complex member 1 is a protein that in humans is encoded by the GOSR1 gene.[1][2][3][4]
This gene encodes a trafficking membrane protein which transports proteins among the endoplasmic reticulum and the Golgi apparatus and between Golgi compartments. This protein is considered an essential component of the Golgi SNAP receptor (SNARE) complex. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[4]
# Interactions
GOSR1 has been shown to interact with USO1,[5] BET1L[5][6] and STX5.[5][7][8][9] | https://www.wikidoc.org/index.php/GOSR1 | |
0702be62853e79d383ddb68dd51557b347d37e4b | wikidoc | GPD1L | GPD1L
GPD1L is a human gene. The protein encoded by this gene contains a glycerol-3-phosphate dehydrogenase (NAD+) motif and shares 72% sequence identity with GPD1.
# Structure
GPD1L contains the following domains:
- N-terminal – NAD+ consensus binding site
- a site homologous to the cardiac sodium channel SCN5A
- C-terminal lysine-206 residue
# Tissue distribution
Northern blot analysis detected a single GPD1L transcript in all tissues examined except liver. Highest expression was in heart and skeletal muscle.
# Disease linkage
Mutations in the GPD1L gene are associated with the Brugada syndrome and sudden infant death syndrome. | GPD1L
GPD1L is a human gene.[1] The protein encoded by this gene contains a glycerol-3-phosphate dehydrogenase (NAD+) motif and shares 72% sequence identity with GPD1.[1]
# Structure
GPD1L contains the following domains:[2]
- N-terminal – NAD+ consensus binding site
- a site homologous to the cardiac sodium channel SCN5A
- C-terminal lysine-206 residue
# Tissue distribution
Northern blot analysis detected a single GPD1L transcript in all tissues examined except liver. Highest expression was in heart and skeletal muscle.[1]
# Disease linkage
Mutations in the GPD1L gene are associated with the Brugada syndrome[2] and sudden infant death syndrome.[3] | https://www.wikidoc.org/index.php/GPD1L | |
b5fd0585726806957866d09ae19e7d9738ce6bc0 | wikidoc | GPLD1 | GPLD1
Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the GPLD1 gene.
Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane.
# Interactions
GPLD1 has been shown to interact with Apolipoprotein A1 and APOA4. | GPLD1
Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the GPLD1 gene.[1][2]
Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane.[2]
# Interactions
GPLD1 has been shown to interact with Apolipoprotein A1[3] and APOA4.[3] | https://www.wikidoc.org/index.php/GPLD1 | |
1edd75e972f97d3de9a5936c3ce078a350de80fc | wikidoc | GPNMB | GPNMB
Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively.
GPNMB is a type I transmembrane glycoprotein which shows homology to the pmel17 precursor, a melanocyte-specific protein.
GPNMB has been reported to be expressed in various cell types, including: melanocytes, osteoclasts, osteoblasts, dendritic cells, and it is overexpressed in various cancer types. In melanocytic cells and osteoclasts the GPNMB gene is transcriptionally regulated by Microphthalmia-associated transcription factor.
# Function
In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization that is mediated at least in part by BMP-2 in a SMAD1 dependent manner to promote osteoblast differentiation. In addition, using a rat fracture model, Osteoactivin (OA) enhances the repairing process in bone fracture, demonstrated by its high expression during chondrogenesis (soft callus) and osteogenesis (hard callus) compared to the intact femurs that is why Osteoactivin (OA) could be a novel therapeutic agent used to treat generalized osteoporosis or localized osteopenia during fracture repair by stimulating bone growth and regeneration. Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.
# Clinical and functional significance in cancer
GPNMB was originally identified as a gene that was expressed in poorly metastatic human melanoma cell lines and xenografts and not expressed in highly metastatic cell lines. However, several recent studies have identified high GPNMB expression in aggressive melanoma, glioma, and breast cancer specimens.
## Breast cancer
Based on Immunohistochemical analysis, two studies have shown that GPNMB is commonly expressed in breast tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors. In the second study, 64% of human breast tumors express GPNMB in the tumor stroma and an additional 10% of tumors express GPNMB in the tumor epithelium. In this study it was reported that GPNMB expression in the tumor epithelium was an independent prognostic indicator of breast cancer recurrence. Moreover, epithelial GPNMB expression was most abundant in triple negative breast cancers and it was found to be a prognostic marker for shorter metastasis-free survival times within this breast cancer subtype. Finally, GPNMB expression in breast cancer cells is capable of promoting cell migration, invasion, and metastasis both in vitro and in vivo.
# GPNMB as a target for therapy
GPNMB is the target of the antibody glembatumumab (CR011) which is used in the antibody-drug conjugate glembatumumab vedotin (CDX-011, CR011-vcMMAE) which is in clinical trials for melanoma and breast cancer. (See glembatumumab vedotin) | GPNMB
Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene.[1] Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans.[2] The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin (OA), respectively.[2]
GPNMB is a type I transmembrane glycoprotein which shows homology to the pmel17 precursor, a melanocyte-specific protein.
GPNMB has been reported to be expressed in various cell types, including: melanocytes, osteoclasts, osteoblasts, dendritic cells, and it is overexpressed in various cancer types. In melanocytic cells and osteoclasts the GPNMB gene is transcriptionally regulated by Microphthalmia-associated transcription factor.[3][4]
# Function
In osteoblast progenitor cells, Osteoactivin works as a positive regulator of osteoblast differentiation during later stages of matrix maturation and mineralization [5] that is mediated at least in part by BMP-2 in a SMAD1 dependent manner to promote osteoblast differentiation.[6] In addition, using a rat fracture model, Osteoactivin (OA) enhances the repairing process in bone fracture, demonstrated by its high expression during chondrogenesis (soft callus) and osteogenesis (hard callus) compared to the intact femurs [7] that is why Osteoactivin (OA) could be a novel therapeutic agent used to treat generalized osteoporosis or localized osteopenia during fracture repair by stimulating bone growth and regeneration.[8] Similarly, Osteoactivin expression increases during osteoclast differentiation and it is functionally implicated in this process, possibly by promoting the fusion of osteoclast progenitor cells.[9]
# Clinical and functional significance in cancer
GPNMB was originally identified as a gene that was expressed in poorly metastatic human melanoma cell lines and xenografts and not expressed in highly metastatic cell lines. However, several recent studies have identified high GPNMB expression in aggressive melanoma,[10] glioma,[11] and breast cancer specimens.[12]
## Breast cancer
Based on Immunohistochemical analysis, two studies have shown that GPNMB is commonly expressed in breast tumors. In the first study, GPNMB was detected in 71% (10/14) of breast tumors.[13] In the second study, 64% of human breast tumors express GPNMB in the tumor stroma and an additional 10% of tumors express GPNMB in the tumor epithelium.[14] In this study it was reported that GPNMB expression in the tumor epithelium was an independent prognostic indicator of breast cancer recurrence. Moreover, epithelial GPNMB expression was most abundant in triple negative breast cancers and it was found to be a prognostic marker for shorter metastasis-free survival times within this breast cancer subtype. Finally, GPNMB expression in breast cancer cells is capable of promoting cell migration, invasion, and metastasis both in vitro and in vivo.[12][14]
# GPNMB as a target for therapy
GPNMB is the target of the antibody glembatumumab (CR011) which is used in the antibody-drug conjugate glembatumumab vedotin (CDX-011, CR011-vcMMAE)[15] which is in clinical trials for melanoma and breast cancer. (See glembatumumab vedotin) | https://www.wikidoc.org/index.php/GPNMB | |
10681df060f05a3aff68e2ba9f7befcd16b4bf6d | wikidoc | GPR17 | GPR17
Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by the GPR17 gene located on chromosome 2 at position q21. The actual activating ligands for and some functions of this receptor are disputed.
# History
Initially discovered in 1998 as an Orphan receptor, i.e. a receptor whose activating ligand(s) and function were unknown, GPR17 was "deorphanized" in a study that reported it to be a receptor for LTC4, LTD4, and uracil nucleotides. In consequence, GPR17 attracted attention as a potential mediator of reactions caused by LTC4 and LTD4 viz., asthma, rhinitis, and urticarial triggered by allergens, nonsteroidal anti-inflammatory drugs, and exercise (see Aspirin-induced asthma). Subsequent reports, however, have varied in results: studies focusing on the allergen and non-allergen reactions find that GPR17-bearing cells do not respond to LTC4, LTD4, and uracil nucleotides while studies focusing on nerve tissue find that certain types of GPR17-bearing oligodendrocytes do indeed respond to them. In 2013 and 2014 reports, the International Union of Basic and Clinical Pharmacology took no position on which of these are true ligands for GPR17. GPR17 is a constitutively active receptor, i.e. a receptor that has baseline activity which is independent of, although potentially increased by, its ligands.
# Biochemistry
GPR17 has a structure which is intermediate between the cysteinyl leukotriene receptor group (i.e. cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2) and the purine P2Y subfamily of 12 receptors (see P2Y receptors), sharing 28 to 48% amino acid identity with them. GPR17 is a G protein coupled receptor that acts primarily through G proteins linked to the Gi alpha subunit but also to Gq alpha subunit. Matching these structural relationships, GPR17 has been reported to be activated by cysteinyl leukotrienes (i.e. LTC4 and LTD4) as well as the purines (i.e., uridine, Uridine diphosphate (UDP), UDP-glucose). Further relating these receptors, GPR17 may dimerize (i.e. associate with) certain of the cited cysteinyl leukotriene or purine receptors in mediating cell responses and this dimerization may explain some of the discrepancies reported for the ability of these ligands to activate GPR17 as expressed in different cell types (see below section of Function). GPR17 is also activated by the emergency-signaling and atherosclerosis-promoting oxysterols and by synthetic compounds with broadly different structures. Relevant to its activating ligands as well as its reported interaction with other G protein coupled receptors, GPR17 is a promiscuous receptor.
Montelukast which inhibits cysteinyl leukotriene receptor 1 and is in clinical use for the chronic and preventative treatment of LTC4- and LTD4-promted allergic and non-allergic diseases, and Cangrelor, which inhibits P2Y purinergic receptors and is approved in the USA as an antiplatelet drug, inhibit the GPR17 receptor.
# Distribution
GPR17 was first clone form and is highly expressed in certain precursors of oligodendrocytes in the nerve tissue of the central nervous system (CNS); it is overexpress in CNS tissues experiencing demyelination injuries; within 48 hours of the latter types of injuries, GPR17 expression is induced in dying neurons within and on the borders of injury, in infiltrating microglia and macrophages, and in activated oligodendrocyte precursor cells.
# Function
Studies focusing on allergic and hypersensitivity reactions have found that the LTC4 and LTD4 ligands for Cysteinyl leukotriene receptor 1 (CysLTR1) and Cysteinyl leukotriene receptor 2, which mediate these reactions, have disputed findings that LTC4 and LTD4 are ligands for GPR17. They have shown that cells co-expressing both CysLTR1 and GPR17 receptors exhibit a marked reduction in binding LTC4 and that mice lacking GPR17 are hyper-responsive to igE-induced passive cutaneous anaphylaxis. They therefore have nominated GPR17 as functioning to inhibit CysLTR1 in these model systems and as such might serve to dampen the acute reactions involving the cited LTs.
Studies focusing on nerve tissue indicate that GPR17 is: a) highly expressed in precursors to mature oligodendrocytes but not expressed in mature oligodendrocytes, suggesting that GPR17 must be down-regulated in order for precursor cells to proceed to terminal oligodendrocyte differentiation; b) activated by uridine, Uridine diphosphate (UDP) and UDP-glucose to stimulate outward K+ channels and the aforementioned maturation responses in oligodenrocyte precursor cells; c) also activated by LTC4 and LTD4; d) more highly expressed in central nervous system (CNS) tissues of animal models undergoing ischemia, Experimental autoimmune encephalomyelitis, and focal demyelination as well as in the CNS tissues of humans suffering brain damage due to ischemia, trauma, and multiple sclerosis; e) expressed in injured neurons and associated with the rapid death and clearance of these neurons in a model of mouse spinal cord crush injury; f) acts to reduce the extent of spinal cord injury in the latter model based on the increased extent of injury in GPR17-depleted mice; and g) acts to reduce inflammation, elevate hippocampus neurogenesis, and improve learning and memory in a rat model of age-related cognitive impairment based on the effects of the GPR17 antagonist, montelukast, as well as of GPR17 depletion. The studies suggest that GPR17 is a sensor of damage in the CNS and participates in the resolution of this damage by clearing and/or promoting the re-myelination of injured neurons caused by a variety of insults perhaps including old age.
The GPR17 gene has also been found to regulate food intake response mediated by FOXO1.
# Clinical significance
GPR17 has been proposed as a potential pharmacological target for the treatment of multiple sclerosis and traumatic brain injury in humans. | GPR17
Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by the GPR17 gene located on chromosome 2 at position q21.[1][2] The actual activating ligands for and some functions of this receptor are disputed.
# History
Initially discovered in 1998 as an Orphan receptor, i.e. a receptor whose activating ligand(s) and function were unknown, GPR17 was "deorphanized" in a study that reported it to be a receptor for LTC4, LTD4, and uracil nucleotides.[3] In consequence, GPR17 attracted attention as a potential mediator of reactions caused by LTC4 and LTD4 viz., asthma, rhinitis, and urticarial triggered by allergens, nonsteroidal anti-inflammatory drugs, and exercise (see Aspirin-induced asthma). Subsequent reports, however, have varied in results: studies focusing on the allergen and non-allergen reactions find that GPR17-bearing cells do not respond to LTC4, LTD4, and uracil nucleotides[4] while studies focusing on nerve tissue find that certain types of GPR17-bearing oligodendrocytes do indeed respond to them.[3] In 2013 and 2014 reports, the International Union of Basic and Clinical Pharmacology took no position on which of these are true ligands for GPR17.[5][6] GPR17 is a constitutively active receptor, i.e. a receptor that has baseline activity which is independent of, although potentially increased by, its ligands.[5]
# Biochemistry
GPR17 has a structure which is intermediate between the cysteinyl leukotriene receptor group (i.e. cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2) and the purine P2Y subfamily of 12 receptors (see P2Y receptors), sharing 28 to 48% amino acid identity with them. GPR17 is a G protein coupled receptor that acts primarily through G proteins linked to the Gi alpha subunit but also to Gq alpha subunit.[3][7] Matching these structural relationships, GPR17 has been reported to be activated by cysteinyl leukotrienes (i.e. LTC4 and LTD4) as well as the purines (i.e., uridine, Uridine diphosphate (UDP), UDP-glucose). Further relating these receptors, GPR17 may dimerize (i.e. associate with) certain of the cited cysteinyl leukotriene or purine receptors in mediating cell responses and this dimerization may explain some of the discrepancies reported for the ability of these ligands to activate GPR17 as expressed in different cell types (see below section of Function). GPR17 is also activated by the emergency-signaling and atherosclerosis-promoting oxysterols and by synthetic compounds with broadly different structures. Relevant to its activating ligands as well as its reported interaction with other G protein coupled receptors, GPR17 is a promiscuous receptor.[3]
Montelukast which inhibits cysteinyl leukotriene receptor 1 and is in clinical use for the chronic and preventative treatment of LTC4- and LTD4-promted allergic and non-allergic diseases, and Cangrelor, which inhibits P2Y purinergic receptors and is approved in the USA as an antiplatelet drug, inhibit the GPR17 receptor.[3]
# Distribution
GPR17 was first clone form and is highly expressed in certain precursors of oligodendrocytes in the nerve tissue of the central nervous system (CNS); it is overexpress in CNS tissues experiencing demyelination injuries; within 48 hours of the latter types of injuries, GPR17 expression is induced in dying neurons within and on the borders of injury, in infiltrating microglia and macrophages, and in activated oligodendrocyte precursor cells.[3]
# Function
Studies focusing on allergic and hypersensitivity reactions have found that the LTC4 and LTD4 ligands for Cysteinyl leukotriene receptor 1 (CysLTR1) and Cysteinyl leukotriene receptor 2, which mediate these reactions, have disputed findings that LTC4 and LTD4 are ligands for GPR17. They have shown that cells co-expressing both CysLTR1 and GPR17 receptors exhibit a marked reduction in binding LTC4 and that mice lacking GPR17 are hyper-responsive to igE-induced passive cutaneous anaphylaxis. They therefore have nominated GPR17 as functioning to inhibit CysLTR1 in these model systems and as such might serve to dampen the acute reactions involving the cited LTs.[8]
Studies focusing on nerve tissue indicate that GPR17 is: a) highly expressed in precursors to mature oligodendrocytes but not expressed in mature oligodendrocytes, suggesting that GPR17 must be down-regulated in order for precursor cells to proceed to terminal oligodendrocyte differentiation; b) activated by uridine, Uridine diphosphate (UDP) and UDP-glucose to stimulate outward K+ channels and the aforementioned maturation responses in oligodenrocyte precursor cells; c) also activated by LTC4 and LTD4; d) more highly expressed in central nervous system (CNS) tissues of animal models undergoing ischemia, Experimental autoimmune encephalomyelitis, and focal demyelination as well as in the CNS tissues of humans suffering brain damage due to ischemia, trauma, and multiple sclerosis; e) expressed in injured neurons and associated with the rapid death and clearance of these neurons in a model of mouse spinal cord crush injury; f) acts to reduce the extent of spinal cord injury in the latter model based on the increased extent of injury in GPR17-depleted mice; and g) acts to reduce inflammation, elevate hippocampus neurogenesis, and improve learning and memory in a rat model of age-related cognitive impairment based on the effects of the GPR17 antagonist, montelukast, as well as of GPR17 depletion. The studies suggest that GPR17 is a sensor of damage in the CNS and participates in the resolution of this damage by clearing and/or promoting the re-myelination of injured neurons caused by a variety of insults perhaps including old age.[3][9][10][11]
The GPR17 gene has also been found to regulate food intake response mediated by FOXO1.[12]
# Clinical significance
GPR17 has been proposed as a potential pharmacological target for the treatment of multiple sclerosis and traumatic brain injury in humans.[3][11][13] | https://www.wikidoc.org/index.php/GPR17 | |
e70b9f1805d09a141bb5c539242fb178c8366516 | wikidoc | GPR31 | GPR31
G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.
# Function
The GPR31 receptor is most closely related in amino acid sequence to the oxoeicosanoid receptor 1, a G-protein coupled receptor encoded by the GPR170 gene. Oxoeicosanoid receptor 1 is the receptor for a family of arachidonic acid metabolites made by 5-lipoxygenase viz., 5-Hydroxyicosatetraenoic acid (5-HETE), 5-oxoicosanoic acid (5-oxo-ETE) and other members of this family of broadly bioactive cell stimuli. The GPR31 receptor is a receptor for very different arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), whose synthesis is catalyzed by 12-lipoxygenase; this conclusion is based on studies that cloned the receptor from the PC-3 prostate cancer cell line and found that the cloned receptor, when expressed in other cell types, bound with high affinity (Kd=5 nM) and mediated the actions of low concentrations of the S but not R stereoisomer of 12-HETE. In a GTPγS binding assay, which indirectly estimates a receptor's binding affinity with a ligand by measuring this ligand's ability to stimulate the receptor to bind GTPγS, 12(S)-HETE stimulated the cloned GPR31 receptor to bind GTPγS with an EC50 (effective concentration causing a 50% of maximal rise in GTPγS binding) was <0.3 nM; it was 42 nm for 15(S)-HETE, 390 nM for 5(S)-HETE, and undetectable for 12(R)-HETE. Importantly, however, we do not known if GPR31 interacts with structural analogs of 12(S)-HETE such as 12-oxo-ETE (a metabolite of 12(S)-HETE), various 5,12-diHETEs including LTB4, and an array of bioactive 12(S)-HETE and 12(R)-HETE metabolites, the Hepoxilins. Further studies will be needed to determine if the GPR31 receptor is dedicated to binding and mediating the aciont of 12(S)-HETE more or less exclusively or, like the oxoeicosanoid receptor 1, binds and mediates the actions of a family of analogs.
GPR31 receptor, like the oxoeicosanoid receptor, activates the MEK-ERK1/2 pathway of intercellular signaling but unlike the oxoeicoanaoid receptor does not trigger rises in the concentration of cytosolic Ca2+; it also activates NFκB. GPR31 receptor therefore exhibits the stereospecificity and some other features generally expected from a true GPR receptor.
12(S)-HETE also: a) binds to and activates the leukotriene B4 receptor-2 (BLT2), a G protein-coupled receptor for the 5-lipoxygenase-derived arachidonic acid metabolite, LTB4 and LTB4 metabolites; b) binds to, but rather than activating, inhibits the G protein-coupled receptor for the cyclooxygenase-derived arachidonic acid metabolites prostaglandin H2 and thromboxane A2; c) binds with high affinity to a 50 kilodalton (Kda) subunit of a 650 kDa cytosolic and nuclear protein complex; and d) binds with low affinity to and activates intracellular Peroxisome proliferator-activated receptor gamma. These alternate binding and cell-activating sites complicate the determination of 12(S)-HETE's dependency on GPR31 in stimulating cells as well as the overall function of GPR31. The effects of GPR31 Gene knockout in animal models, a technique critical to defining the in vivo function of genes, will be critical to shedding light on these issues.
# Tissue distribution
GPR31 receptor mRNA is highly expressed in the PC-3 prostate cancer cell line and to a lesser extent the DU145 prostate cancer cell line and to human umbilical vein endothelial cells (HUVEC), human umbilical vein endothelial cells (HUVEC), human brain microvascular endothelial cells (HBMEC), and human pulmonary aortic endothelial cells (HPAC). Its mRNA is also express but at rather low levels in several other human cell lines including: K562 cells (human myelogenous leukemia cells); Jurkat cells (T lymphocye cells); Hut78 cells (T cell lymphoma cells), HEK 293 cells (primary embryonic kidney cells), MCF-7 cells (mammary adenocarcinoma cellss), and EJ cells (bladder carcinoma cells).
Mice express an ortholog to human GPR31 in their circulating blood platelets.
# Clinical significance
The GPR31 receptor appears to mediate the responses of PC-3 prostate cancer cells to 12(S)-HETE in stimulating the MEK-ERK1/2 and NFκB pathways and therefore may contribute to the growth-promoting and metastasis-promoting actions that 12(S)-HETE is proposed to have in human prostate cancer. However, LNCaP and PC3 human prostate cancer cells also express BLT2 receptors; in LNCaP cells, BLT2 receptors stimulate the expression of the growth- and metastasis-promoting androgen receptor; in PC3 cells, BLT2 receptors stimulate the NF-κB pathway to inhibit the apoptosis induced by cell detachment from surfaces (i.e. Anoikis; and, in BLT2-overexpressing PWR-1E non-malignant prostate cells, 12(S)-HETE diminished anoikis-associated apoptotic cell death. Thus, the roles of 12(S)-HETE in human prostate cancer, if any, may involve its activation of either or both GPR31 and BLT2 receptors.
The many other actions of 12(S)-HETE (see 12-Hydroxyeicosatetraenoic acid) and any other ligands found to interact with this receptor will require studies similar those conducted on PC3 cells and mesenteric arteries to determine the extent to which they interact with BLT2, TXA2/PGH2, and PPARgamma receptors and thereby may contribute in part or whole to their activity. Clues implicating the GPR31, as opposed to the other receptors in the actions of 12(S)-HETE include findings that GPR31 receptors do not respond to 12(R)-HETE nor induce rises in cytosolic Ca2+ whereas the other receptors mediate one or both of these actions. These studies will be important because, in addition to prostate cancer, preliminary studies suggest that the GPR31 receptor is implicated in several other diseases such as malignant megakaryocytis (Acute megakaryoblastic leukemia), arthritis, Alzheimer's disease, progressive B-cell chronic lymphocytic leukemia, Diabetic neuropathy, and high grade astrocytoma. | GPR31
G-protein coupled receptor 31 also known as 12-(S)-HETE receptor is a protein that in humans is encoded by the GPR31 gene. The human gene is located on chromosome 6q27 and encodes a G-protein coupled receptor protein composed of 319 amino acids.[1][2]
# Function
The GPR31 receptor is most closely related in amino acid sequence to the oxoeicosanoid receptor 1, a G-protein coupled receptor encoded by the GPR170 gene.[3][4][5] Oxoeicosanoid receptor 1 is the receptor for a family of arachidonic acid metabolites made by 5-lipoxygenase viz., 5-Hydroxyicosatetraenoic acid (5-HETE), 5-oxoicosanoic acid (5-oxo-ETE) and other members of this family of broadly bioactive cell stimuli. The GPR31 receptor is a receptor for very different arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), whose synthesis is catalyzed by 12-lipoxygenase; this conclusion is based on studies that cloned the receptor from the PC-3 prostate cancer cell line and found that the cloned receptor, when expressed in other cell types, bound with high affinity (Kd=5 nM) and mediated the actions of low concentrations of the S but not R stereoisomer of 12-HETE.[5] In a [35S]GTPγS binding assay, which indirectly estimates a receptor's binding affinity with a ligand by measuring this ligand's ability to stimulate the receptor to bind [35S]GTPγS, 12(S)-HETE stimulated the cloned GPR31 receptor to bind [35S]GTPγS with an EC50 (effective concentration causing a 50% of maximal rise in [35S]GTPγS binding) was <0.3 nM; it was 42 nm for 15(S)-HETE, 390 nM for 5(S)-HETE, and undetectable for 12(R)-HETE.[6] Importantly, however, we do not known if GPR31 interacts with structural analogs of 12(S)-HETE such as 12-oxo-ETE (a metabolite of 12(S)-HETE), various 5,12-diHETEs including LTB4, and an array of bioactive 12(S)-HETE and 12(R)-HETE metabolites, the Hepoxilins. Further studies will be needed to determine if the GPR31 receptor is dedicated to binding and mediating the aciont of 12(S)-HETE more or less exclusively or, like the oxoeicosanoid receptor 1, binds and mediates the actions of a family of analogs.
GPR31 receptor, like the oxoeicosanoid receptor, activates the MEK-ERK1/2 pathway of intercellular signaling but unlike the oxoeicoanaoid receptor does not trigger rises in the concentration of cytosolic Ca2+; it also activates NFκB.[5] GPR31 receptor therefore exhibits the stereospecificity and some other features generally expected from a true GPR receptor.
12(S)-HETE also: a) binds to and activates the leukotriene B4 receptor-2 (BLT2), a G protein-coupled receptor for the 5-lipoxygenase-derived arachidonic acid metabolite, LTB4 and LTB4 metabolites;[5][7][8][9] b) binds to, but rather than activating, inhibits the G protein-coupled receptor for the cyclooxygenase-derived arachidonic acid metabolites prostaglandin H2 and thromboxane A2;[10] c) binds with high affinity to a 50 kilodalton (Kda) subunit of a 650 kDa cytosolic and nuclear protein complex;[11] and d) binds with low affinity to and activates intracellular Peroxisome proliferator-activated receptor gamma.[12] These alternate binding and cell-activating sites complicate the determination of 12(S)-HETE's dependency on GPR31 in stimulating cells as well as the overall function of GPR31. The effects of GPR31 Gene knockout in animal models, a technique critical to defining the in vivo function of genes, will be critical to shedding light on these issues.
# Tissue distribution
GPR31 receptor mRNA is highly expressed in the PC-3 prostate cancer cell line and to a lesser extent the DU145 prostate cancer cell line and to human umbilical vein endothelial cells (HUVEC), human umbilical vein endothelial cells (HUVEC), human brain microvascular endothelial cells (HBMEC), and human pulmonary aortic endothelial cells (HPAC).[5] Its mRNA is also express but at rather low levels in several other human cell lines including: K562 cells (human myelogenous leukemia cells); Jurkat cells (T lymphocye cells); Hut78 cells (T cell lymphoma cells), HEK 293 cells (primary embryonic kidney cells), MCF-7 cells (mammary adenocarcinoma cellss), and EJ cells (bladder carcinoma cells).[1][2]
Mice express an ortholog to human GPR31 in their circulating blood platelets.[13]
# Clinical significance
The GPR31 receptor appears to mediate the responses of PC-3 prostate cancer cells to 12(S)-HETE in stimulating the MEK-ERK1/2 and NFκB pathways and therefore may contribute to the growth-promoting and metastasis-promoting actions that 12(S)-HETE is proposed to have in human prostate cancer.[14][15][16] However, LNCaP and PC3 human prostate cancer cells also express BLT2 receptors; in LNCaP cells, BLT2 receptors stimulate the expression of the growth- and metastasis-promoting androgen receptor;[17] in PC3 cells, BLT2 receptors stimulate the NF-κB pathway to inhibit the apoptosis induced by cell detachment from surfaces (i.e. Anoikis;[18] and, in BLT2-overexpressing PWR-1E non-malignant prostate cells, 12(S)-HETE diminished anoikis-associated apoptotic cell death.[18] Thus, the roles of 12(S)-HETE in human prostate cancer, if any, may involve its activation of either or both GPR31 and BLT2 receptors.
The many other actions of 12(S)-HETE (see 12-Hydroxyeicosatetraenoic acid) and any other ligands found to interact with this receptor will require studies similar those conducted on PC3 cells[6] and mesenteric arteries[13] to determine the extent to which they interact with BLT2, TXA2/PGH2, and PPARgamma receptors and thereby may contribute in part or whole to their activity. Clues implicating the GPR31, as opposed to the other receptors in the actions of 12(S)-HETE include findings that GPR31 receptors do not respond to 12(R)-HETE nor induce rises in cytosolic Ca2+ whereas the other receptors mediate one or both of these actions. These studies will be important because, in addition to prostate cancer, preliminary studies suggest that the GPR31 receptor is implicated in several other diseases such as malignant megakaryocytis (Acute megakaryoblastic leukemia), arthritis, Alzheimer's disease, progressive B-cell chronic lymphocytic leukemia, Diabetic neuropathy, and high grade astrocytoma.[6] | https://www.wikidoc.org/index.php/GPR31 | |
a751abaa332db893416a7fb18a9acca9461cf6f8 | wikidoc | GPR32 | GPR32
G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human Receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.
# Gene
The GPR32 was initially identified and defined by Molecular cloning in 1998 as coding for an Orphan receptor, i.e. a protein with an amino acid sequence similar to known receptors but having no known ligand(s) to which it responds and no known function. The projected amino acid sequence of GPR32, however, shared 35-39% amino acid identity with certain members of the chemotactic factor receptor family, i.e. 39% identity with Formyl peptide receptor 1, which is a receptor for N-Formylmethionine-leucyl-phenylalanine and related N-formyl peptide chemotactic factors, and 35% identity with Formyl peptide receptor 2, which likewise is also a receptor for N-formyl peptides but also a receptor for certain lipoxins which are arachidonic acid metabolites belonging to a set of specialized proresolving mediators that act to resolve or inhibit inflammatory reactions. GPR32 mapped to chromosomal 19, region q13.3. There are no mouse or orthologs of GPR32.
# Receptor
The GPR32 protein is a G protein coupled receptor although the specific G protein subtypes which it activates has not yet been reported. GPR32 is expressed in human blood neutrophils, certain types of blood lymphocytes (i.e. activated CD8+ cells, CD4+ T cells, and T helper 17 cells), tissue macrophages, small airway epithelial cells, and adipose tissue. When expressed in Chinese hamster ovary cells, GPR32 inhibits the Cyclic adenosine monophosphate signaling pathway under both baseline and forskolin-stimulated conditions indicating that it is a member of the class of orphan G protein coupled receptors that possesses constitutive signaling activity.
At least 6 members of the D series of resolvins (RvDs) viz., RvD1, RvD2m AT-RVD1, RvD3, AT-RvD3, and RvD5, activate their target cells through this receptor; these results have led to naming GPR32 the RVD1 receptor (see Resolvin#Mechanisms of Action). RvDs are members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid metabolites. RVDs are metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), and, along with other SRMs contribute to the inhibition and resolution of a diverse range of inflammation and inflammation-related responses as well as to the healing of these inflammatory lesions in animals and humans. The metabolism of DHA to RVD's and the activation of GPR32 by these RVD's are proposed to be one mechanism by which omega-3 fatty acids may ameliorate inflammation as well as various inflammation-based and other diseases. | GPR32
G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human Receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.[1]
# Gene
The GPR32 was initially identified and defined by Molecular cloning in 1998 as coding for an Orphan receptor, i.e. a protein with an amino acid sequence similar to known receptors but having no known ligand(s) to which it responds and no known function. The projected amino acid sequence of GPR32, however, shared 35-39% amino acid identity with certain members of the chemotactic factor receptor family, i.e. 39% identity with Formyl peptide receptor 1, which is a receptor for N-Formylmethionine-leucyl-phenylalanine and related N-formyl peptide chemotactic factors, and 35% identity with Formyl peptide receptor 2, which likewise is also a receptor for N-formyl peptides but also a receptor for certain lipoxins which are arachidonic acid metabolites belonging to a set of specialized proresolving mediators that act to resolve or inhibit inflammatory reactions. GPR32 mapped to chromosomal 19, region q13.3.[2] There are no mouse or orthologs of GPR32.[3]
# Receptor
The GPR32 protein is a G protein coupled receptor although the specific G protein subtypes which it activates has not yet been reported. GPR32 is expressed in human blood neutrophils, certain types of blood lymphocytes (i.e. activated CD8+ cells, CD4+ T cells, and T helper 17 cells), tissue macrophages, small airway epithelial cells, and adipose tissue.[3][4][5] When expressed in Chinese hamster ovary cells, GPR32 inhibits the Cyclic adenosine monophosphate signaling pathway under both baseline and forskolin-stimulated conditions indicating that it is a member of the class of orphan G protein coupled receptors that possesses constitutive signaling activity.[6]
At least 6 members of the D series of resolvins (RvDs) viz., RvD1, RvD2m AT-RVD1, RvD3, AT-RvD3, and RvD5, activate their target cells through this receptor; these results have led to naming GPR32 the RVD1 receptor (see Resolvin#Mechanisms of Action).[7][8][9] RvDs are members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid metabolites. RVDs are metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), and, along with other SRMs contribute to the inhibition and resolution of a diverse range of inflammation and inflammation-related responses as well as to the healing of these inflammatory lesions in animals and humans.[10] The metabolism of DHA to RVD's and the activation of GPR32 by these RVD's are proposed to be one mechanism by which omega-3 fatty acids may ameliorate inflammation as well as various inflammation-based and other diseases.[11] | https://www.wikidoc.org/index.php/GPR32 | |
128afc6442db8ace2670d0ad2b76b5ed3884bba0 | wikidoc | GPR35 | GPR35
G protein-coupled receptor 35 also known as GPR35 is a G protein-coupled receptor which in humans is encoded by the GPR35 gene. Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the crypts of Lieberkühn.
# Ligands
## Endogenous ligands
Although GPR35 is still considered an orphan receptor, there have been attempts to deorphanize it by identifying endogenous molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high potency, a characteristic feature of natural ligands. The following list includes the most prominent examples:
- kynurenic acid
- LPA species
- cyclic guanosine monophosphate
- DHICA
- T3
- reverse T3
## Synthetic agonists
Other synthetic agonists of GPR35 include:
- cromoglicic acid
- nedocromil
- pamoic acid
- zaprinast
- lodoxamide
- bufrolin
Zaprinast is currently the gold standard in the biochemical evaluation of novel synthetic GPR35 agonists, because it remains potent in an animal model. Most other known agonists display high selectivity towards the human GPR35 orthologue. This phenomenon is well established for other GPCRs and complicates the development of pharmaceutical drugs.
## Antagonists
Antagonists of GPR35 include:
- ML145 (CID-2286812)
- ML144 (CID-1542103)
Both ML145 and ML144 unfurl their antagonistic activity through inverse agonism. They are, however, highly species-selective, and practically inactive at the rodent receptor orthologues.
# Clinical significance
Deletion of GPR35 gene may be responsible for brachydactyly mental retardation syndrome and is mutated in 2q37 monosomy and 2q37 deletion syndrome. In one study GPR35 has been recognised as a potential oncogene in stomach cancer. | GPR35
G protein-coupled receptor 35 also known as GPR35 is a G protein-coupled receptor which in humans is encoded by the GPR35 gene.[1] Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the crypts of Lieberkühn.
# Ligands
## Endogenous ligands
Although GPR35 is still considered an orphan receptor, there have been attempts to deorphanize it by identifying endogenous molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high potency, a characteristic feature of natural ligands.[2] The following list includes the most prominent examples:
- kynurenic acid[3][4]
- LPA species [3]
- cyclic guanosine monophosphate [5]
- DHICA [6]
- T3 [6]
- reverse T3 [6]
## Synthetic agonists
Other synthetic agonists of GPR35 include:
- cromoglicic acid [7]
- nedocromil [7]
- pamoic acid[3]
- zaprinast [3][8]
- lodoxamide[9]
- bufrolin[9]
Zaprinast is currently the gold standard in the biochemical evaluation of novel synthetic GPR35 agonists, because it remains potent in an animal model. Most other known agonists display high selectivity towards the human GPR35 orthologue. This phenomenon is well established for other GPCRs and complicates the development of pharmaceutical drugs.[2][10][11]
## Antagonists
Antagonists of GPR35 include:
- ML145 (CID-2286812)[12]
- ML144 (CID-1542103)[12]
Both ML145 and ML144 unfurl their antagonistic activity through inverse agonism. They are, however, highly species-selective, and practically inactive at the rodent receptor orthologues.[13]
# Clinical significance
Deletion of GPR35 gene may be responsible for brachydactyly mental retardation syndrome and is mutated in 2q37 monosomy and 2q37 deletion syndrome.[14] In one study GPR35 has been recognised as a potential oncogene in stomach cancer.[15] | https://www.wikidoc.org/index.php/GPR35 | |
ec26c7d716dc49d5d559095041a1d24359a3b0fb | wikidoc | GPR37 | GPR37
Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the GPR37 gene.
# Interactions
GPR37 has been shown to interact with HSPA1A and Parkin (ligase).
GPR37 is a receptor for prosaposin. It was previously thought to be a receptor for head activator, a neuropeptide found in the hydra, but early reports of head activator in mammals were never confirmed. | GPR37
Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the GPR37 gene.[1][2]
# Interactions
GPR37 has been shown to interact with HSPA1A[3] and Parkin (ligase).[3][4]
GPR37 is a receptor for prosaposin. It was previously thought to be a receptor for head activator, a neuropeptide found in the hydra, but early reports of head activator in mammals were never confirmed.[5] | https://www.wikidoc.org/index.php/GPR37 | |
a8ed1b24614683363480aabef585991803990efc | wikidoc | GPR50 | GPR50
G protein-coupled receptor 50 is a protein which in humans is encoded by the GPR50 gene.
# Function
GPR50 is a member of the G protein-coupled receptor family of integral membrane proteins and is most closely related to the melatonin receptor. GPR50 is able to heterodimerize with both the MT1 and MT2 melatonin receptor subtypes. While GPR50 has no effect on MT2 function, GPR50 prevented MT1 from both binding
melatonin and coupling to G proteins. GPR50 is the mammalian ortholog of melatonin receptor Mel1c described in non-mammalian vertebrates.
# Clinical significance
Certain polymorphisms of the GPR50 gene in females are associated with increased risk of developing bipolar affective disorder, major depressive disorder, and schizophrenia. Other GPR50 gene polymorphism are associated with higher fasting circulating triglyceride levels and lower circulating High-density lipoprotein levels. | GPR50
G protein-coupled receptor 50 is a protein which in humans is encoded by the GPR50 gene.[1][2][3]
# Function
GPR50 is a member of the G protein-coupled receptor family of integral membrane proteins and is most closely related to the melatonin receptor.[2] GPR50 is able to heterodimerize with both the MT1 and MT2 melatonin receptor subtypes. While GPR50 has no effect on MT2 function, GPR50 prevented MT1 from both binding
melatonin and coupling to G proteins.[4] GPR50 is the mammalian ortholog of melatonin receptor Mel1c described in non-mammalian vertebrates.
[5]
# Clinical significance
Certain polymorphisms of the GPR50 gene in females are associated with increased risk of developing bipolar affective disorder, major depressive disorder, and schizophrenia.[6] Other GPR50 gene polymorphism are associated with higher fasting circulating triglyceride levels and lower circulating High-density lipoprotein levels.[7] | https://www.wikidoc.org/index.php/GPR50 | |
5e9e53e75bc766a2cd95c666aad9c565bb3d128d | wikidoc | GPR55 | GPR55
G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.
GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors.
# History
GPR55 was identified and cloned for the first time in 1999. Later it was identified by an in silico screen as a putative cannabinoid receptor because of a similar amino acid sequence in the binding region. Research groups from Glaxo Smith Kline and Astra Zeneca characterized the receptor extensively because it was hoped to be responsible for the blood pressure lowering properties of cannabinoids. GPR55 is indeed activated by endogenous, plant and synthetic cannabinoids but GPR-55 knockout mice generated by a research group from Glaxo Smith Kline showed no altered blood pressure regulation after administration of the cannabidiol-derivative abnormal cannabidiol.
# Signal cascade
GPR55 is coupled to the G-protein G13 and activation of the receptor leads to stimulation of rhoA, cdc42 and rac1.
# Pharmacology
GPR55 is activated by the plant cannabinoids Δ9-THC, and the endocannabinoids anandamide, 2-AG, noladin ether in the low nanomolar range. The synthetic cannabinoid CP-55940 is also able to activate the receptor while the structurally unrelated cannabinoid mimic WIN 55,212-2 fails to activate the receptor. Recent research suggests that lysophosphatidylinositol and its 2-arachidonoyl derivative, 2-arachidonoyl lysophosphatidylinositol (2-ALPI), may be the endogenous ligands for GPR55, and the receptor appears likely to be a possible target for treatment of inflammation and pain as with the other cannabinoid receptors.
This profile as a distinct non-CB1/CB2 receptor which responds to a variety of both endogenous and exogenous cannabinoid ligands, has led some groups to suggest GPR55 should be categorised as the CB3 receptor, and this re-classification may follow in time. However this is complicated by the fact that another possible CB3 receptor has been discovered in the hippocampus, although its gene has not yet been cloned, suggesting that there may be at least four cannabinoid receptors which will eventually be characterised. Evidence accumulated during the last few years suggests that GPR55 plays a relevant role in cancer and opens the possibility of considering this orphan receptor as a new therapeutic target and potential biomarker in oncology.
# Ligands
Ligands found to bind to GPR55 as agonists include:
- Lysophosphatidylinositol
- 2-Arachidonoyl lysophosphatidylinositol
- Abnormal cannabidiol (Abn-CBD)
- AM-251 (also CB1 antagonist)
- CP 55,940
- GSK-319,197
- GSK-494,581 - also glycine transporter 1 inhibitor
- GSK-522,373
- O-1602
- Δ9-Tetrahydrocannabinol
- 2-Arachidonoylglycerol (2-AG)
- Noladin ether
- Oleoylethanolamide
- Palmitoylethanolamide
- ML-184, ML-185 and ML-186
- CID-16020046 - inverse agonist at GPR55
- O-1918
- ML-191, ML-192 and ML-193
- PSB-SB-487 and PSB-SB-1203
- Cannabidiol
# Physiological function
The physiological role of GPR55 is unclear. Mice with a target deletion of the GPR55 gene show no specific phenotype. GPR55 is widely expressed in the brain, especially in the cerebellum. It is expressed in the jejunum and ileum but apparently not more generally in the periphery. Osteoblasts and osteoclasts express GPR55 and this has been shown to regulate bone cell function. | GPR55
G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.[1]
GPR55, along with GPR119 and GPR18, have been implicated as novel cannabinoid receptors.[2][3]
# History
GPR55 was identified and cloned for the first time in 1999.[4] Later it was identified by an in silico screen as a putative cannabinoid receptor because of a similar amino acid sequence in the binding region.[5] Research groups from Glaxo Smith Kline and Astra Zeneca characterized the receptor extensively because it was hoped to be responsible for the blood pressure lowering properties of cannabinoids. GPR55 is indeed activated by endogenous, plant and synthetic cannabinoids but GPR-55 knockout mice generated by a research group from Glaxo Smith Kline showed no altered blood pressure regulation after administration of the cannabidiol-derivative abnormal cannabidiol.[6]
# Signal cascade
GPR55 is coupled to the G-protein G13 and activation of the receptor leads to stimulation of rhoA, cdc42 and rac1.[7]
# Pharmacology
GPR55 is activated by the plant cannabinoids Δ9-THC,[8] and the endocannabinoids anandamide, 2-AG, noladin ether in the low nanomolar range. The synthetic cannabinoid CP-55940 is also able to activate the receptor[8] while the structurally unrelated cannabinoid mimic WIN 55,212-2 fails to activate the receptor.[6] Recent research suggests that lysophosphatidylinositol and its 2-arachidonoyl derivative, 2-arachidonoyl lysophosphatidylinositol (2-ALPI), may be the endogenous ligands for GPR55,[9][10][11] and the receptor appears likely to be a possible target for treatment of inflammation and pain as with the other cannabinoid receptors.[12][13]
This profile as a distinct non-CB1/CB2 receptor which responds to a variety of both endogenous and exogenous cannabinoid ligands, has led some groups to suggest GPR55 should be categorised as the CB3 receptor, and this re-classification may follow in time.[14][15][16][17] However this is complicated by the fact that another possible CB3 receptor has been discovered in the hippocampus, although its gene has not yet been cloned,[18] suggesting that there may be at least four cannabinoid receptors which will eventually be characterised. Evidence accumulated during the last few years suggests that GPR55 plays a relevant role in cancer and opens the possibility of considering this orphan receptor as a new therapeutic target and potential biomarker in oncology.[19]
# Ligands
Ligands found to bind to GPR55 as agonists include:
- Lysophosphatidylinositol
- 2-Arachidonoyl lysophosphatidylinositol
- Abnormal cannabidiol (Abn-CBD)
- AM-251 (also CB1 antagonist)
- CP 55,940
- GSK-319,197
- GSK-494,581 - also glycine transporter 1 inhibitor [20]
- GSK-522,373
- O-1602
- Δ9-Tetrahydrocannabinol[8]
- 2-Arachidonoylglycerol (2-AG)[8]
- Noladin ether
- Oleoylethanolamide
- Palmitoylethanolamide
- ML-184, ML-185 and ML-186 [21]
- CID-16020046 - inverse agonist at GPR55
- O-1918
- ML-191, ML-192 and ML-193[21]
- PSB-SB-487 and PSB-SB-1203 [22]
- Cannabidiol [8]
# Physiological function
The physiological role of GPR55 is unclear. Mice with a target deletion of the GPR55 gene show no specific phenotype.[6] GPR55 is widely expressed in the brain, especially in the cerebellum. It is expressed in the jejunum and ileum but apparently not more generally in the periphery.[8] Osteoblasts and osteoclasts express GPR55 and this has been shown to regulate bone cell function.[23] | https://www.wikidoc.org/index.php/GPR55 | |
ac798060051b471c61ba0d537302e6963b2e8cc1 | wikidoc | GPR56 | GPR56
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family.
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
GPR56 is expressed in liver, muscle, neural, and cytotoxic lymphoid cells in human as well as in hematopoietic precursor, muscle, and developing neural cells in the mouse.
GPR56 has been shown to have numerous role in cell guidance/adhesion as exemplified by its roles in tumour inhibition and neuron development. More recently it has been shown to be a marker for cytotoxic T cells and a subgroup of Natural killer cells.
# Ligands
GPR56 binds transglutaminase 2 to suppress tumor metastasis and binds collagen III to regulate cortical development and lamination.
# Signaling
GPR56 couples to Gαq/11 protein upon association with the tetraspanins CD9 and CD81. Forced GPR56 expression activates NF-kB, PAI-1, and TCF transcriptional response elements. The splicing of GPR56 induces tumorigenic responses as a result of activating transcription factors, such as COX2, iNOS, and VEGF85. GPR56 couples to the Gα12/13 protein and activates RhoA and mammalian target of rapamycin (mTOR) pathway upon ligand binding. Lack of the N-terminal fragment (NTF) of GPR56 causes stronger RhoA signaling and β-arrestin accumulation, leading to extensive ubiquitination of the C-terminal fragment (CTF). Finally, GPR56 suppresses PKCα activation to regulate angiogenesis.
# Function
Studies in the hematopoietic system disclosed that during endothelial to hematopoietic stem cell transition, Gpr56 is a transcriptional target of the heptad complex of hematopoietic transcription factors, and is required for hematopoietic cluster formation. Recently, two studies showed that GPR56, is a cell autonomous regulator of oligodendrocyte development through Gα12/13 proteins and Rho activation. Della Chiesa et al. demonstrate that GPR56 is expressed on CD56dull natural killer (NK) cells. Lin and Hamann's group show all human cytotoxic lymphocytes, including CD56dull NK cells and CD27–CD45RA+ effector-type CD8+ T cells, express GPR56.
# Clinical significance
GPR56 was the first adhesion GPCR causally linked to a disease. Loss-of-function mutations in GPR56 cause a severe cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP). Investigating the pathological mechanism of disease-associated GPR56 mutations in BFPP has provided mechanistic insights into the functioning of adhesion GPCRs. Researchers demonstrated that disease-associated GPR56 mutations cause BFPP via multiple mechanisms. Li et al. demonstrated that GPR56 regulates pial basement membrane (BM) organization during cortical development. Disruption of the Gpr56 gene in mice leads to neuronal malformation in the cerebral cortex, which resulted in 4 critical pathological morphologies: defective pial BM, abnormal localized radial glial endfeet, malpositioned Cajal-Retzius cells, and overmigrated neurons. Furthermore, the interaction of GPR56 and collagen III inhibits neural migration to regulate lamination of the cerebral cortex. Next to GPR56, the α3β1 integrin is also involved in pial BM maintenance. Study from Itga3 (α3 integrin)/Gpr56 double knockout mice showed increased neuronal overmigration compared to Gpr56 single knockout mice, indicating cooperation of GPR56 and α3β1 integrin in modulation of the development of the cerebral cortex. More recently, the Walsh laboratory showed that alternative splicing of GPR56 regulates regional cerebral cortical patterning.
Outside the nervous system, GPR56 has been linked to muscle function and male fertility. The expression of GPR56 is upregulated during early differentiation of human myoblasts. Investigation of Gpr56 knockout mice and BFPP patients showed that GPR56 is required for in vitro myoblast fusion via signaling of serum response factor (SRF) and nuclear factor of activated T-cell (NFAT), but is not essential for muscle development in vivo. Additionally, GPR56 is a transcriptional target of peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 and regulates overload-induced muscle hypertrophy through Gα12/13 and mTOR signaling. Therefore, the study of knockout mice revealed that GPR56 is involved in testis development and male fertility. In melanocytic cells GPR56 gene expression may be regulated by MITF.
Mutations in GPR56 cause the brain developmental disorder BFPP, characterized by disordered cortical lamination in frontal cortex. Mice lacking expression of GPR56 develop a comparable phenotype. Furthermore, loss of GPR56 leads to reduced fertility in male mice, resulting from a defect in seminiferous tubule development. GPR56 is expressed in glioblastoma/astrocytoma as well as in esophageal squamous cell, breast, colon, non-small cell lung, ovarian, and pancreatic carcinoma. GPR56 was shown to localize together with α-actinin at the leading edge of membrane filopodia in glioblastoma cells, suggesting a role in cell adhesion/migration. In addition, recombinant GPR56-NTF protein interacts with glioma cells to inhibit cellular adhesion. Inactivation of Von Hippel-Lindau (VHL) tumor-suppressor gene and hypoxia suppressed GPR56 in a renal cell carcinoma cell line, but hypoxia influenced GPR56 expression in breast or bladder cancer cell lines. GPR56 is a target gene for vezatin, an adherens junctions transmembrane protein, which is a tumor suppressor in gastric cancer. Xu et al. used an in vivo metastatic model of human melanoma to show that GPR56 is downregulated in highly metastatic cells. Later, by ectopic expression and RNA interference they confirmed that GPR56 inhibits melanoma tumor growth and metastasis. Silenced expression of GPR56 in HeLa cells enhanced apoptosis and anoikis, but suppressed anchorage-independent growth and cell adhesion. High ecotropic viral integration site-1 acute myeloid leukemia (EVI1-high AML) expresses GPR56 that was found to be a transcriptional target of EVI1. Silencing expression of GPR56 decreases adhesion, cell growth and induces apoptosis through reduced RhoA signaling. GPR56 suppresses the angiogenesis and melanoma growth through inhibition of vascular endothelial growth factor (VEGF) via PKCα signaling pathway. Furthermore, GPR56 expression was found to be negatively correlated with the malignancy of melanomas in human patients. | GPR56
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene.[1] GPR56 is a member of the adhesion GPCR family.[2][3]
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[4]
GPR56 is expressed in liver, muscle, neural, and cytotoxic lymphoid cells in human as well as in hematopoietic precursor, muscle, and developing neural cells in the mouse.[5]
GPR56 has been shown to have numerous role in cell guidance/adhesion as exemplified by its roles in tumour inhibition and neuron development.[6][7] More recently it has been shown to be a marker for cytotoxic T cells and a subgroup of Natural killer cells.[8]
# Ligands
GPR56 binds transglutaminase 2 to suppress tumor metastasis[9] and binds collagen III to regulate cortical development and lamination.[10]
# Signaling
GPR56 couples to Gαq/11 protein upon association with the tetraspanins CD9 and CD81.[11] Forced GPR56 expression activates NF-kB, PAI-1, and TCF transcriptional response elements.[12] The splicing of GPR56 induces tumorigenic responses as a result of activating transcription factors, such as COX2, iNOS, and VEGF85. GPR56 couples to the Gα12/13 protein and activates RhoA and mammalian target of rapamycin (mTOR) pathway upon ligand binding.[10][13][14][15] Lack of the N-terminal fragment (NTF) of GPR56 causes stronger RhoA signaling and β-arrestin accumulation, leading to extensive ubiquitination of the C-terminal fragment (CTF).[16] Finally, GPR56 suppresses PKCα activation to regulate angiogenesis.[17]
# Function
Studies in the hematopoietic system disclosed that during endothelial to hematopoietic stem cell transition, Gpr56 is a transcriptional target of the heptad complex of hematopoietic transcription factors, and is required for hematopoietic cluster formation.[18] Recently, two studies showed that GPR56, is a cell autonomous regulator of oligodendrocyte development through Gα12/13 proteins and Rho activation.[14][19] Della Chiesa et al. demonstrate that GPR56 is expressed on CD56dull natural killer (NK) cells.[20] Lin and Hamann's group show all human cytotoxic lymphocytes, including CD56dull NK cells and CD27–CD45RA+ effector-type CD8+ T cells, express GPR56.[8]
# Clinical significance
GPR56 was the first adhesion GPCR causally linked to a disease. Loss-of-function mutations in GPR56 cause a severe cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP).[21][22][23][24][25][26][27] Investigating the pathological mechanism of disease-associated GPR56 mutations in BFPP has provided mechanistic insights into the functioning of adhesion GPCRs. Researchers demonstrated that disease-associated GPR56 mutations cause BFPP via multiple mechanisms.[28][29][30][31] Li et al. demonstrated that GPR56 regulates pial basement membrane (BM) organization during cortical development. Disruption of the Gpr56 gene in mice leads to neuronal malformation in the cerebral cortex, which resulted in 4 critical pathological morphologies: defective pial BM, abnormal localized radial glial endfeet, malpositioned Cajal-Retzius cells, and overmigrated neurons.[32] Furthermore, the interaction of GPR56 and collagen III inhibits neural migration to regulate lamination of the cerebral cortex.[10] Next to GPR56, the α3β1 integrin is also involved in pial BM maintenance. Study from Itga3 (α3 integrin)/Gpr56 double knockout mice showed increased neuronal overmigration compared to Gpr56 single knockout mice, indicating cooperation of GPR56 and α3β1 integrin in modulation of the development of the cerebral cortex.[33] More recently, the Walsh laboratory showed that alternative splicing of GPR56 regulates regional cerebral cortical patterning.[34]
Outside the nervous system, GPR56 has been linked to muscle function and male fertility. The expression of GPR56 is upregulated during early differentiation of human myoblasts. Investigation of Gpr56 knockout mice and BFPP patients showed that GPR56 is required for in vitro myoblast fusion via signaling of serum response factor (SRF) and nuclear factor of activated T-cell (NFAT), but is not essential for muscle development in vivo.[35] Additionally, GPR56 is a transcriptional target of peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 and regulates overload-induced muscle hypertrophy through Gα12/13 and mTOR signaling.[15] Therefore, the study of knockout mice revealed that GPR56 is involved in testis development and male fertility.[36] In melanocytic cells GPR56 gene expression may be regulated by MITF.[37]
Mutations in GPR56 cause the brain developmental disorder BFPP, characterized by disordered cortical lamination in frontal cortex.[21] Mice lacking expression of GPR56 develop a comparable phenotype.[32] Furthermore, loss of GPR56 leads to reduced fertility in male mice, resulting from a defect in seminiferous tubule development.[36] GPR56 is expressed in glioblastoma/astrocytoma[12] as well as in esophageal squamous cell,[38] breast, colon, non-small cell lung, ovarian, and pancreatic carcinoma.[39] GPR56 was shown to localize together with α-actinin at the leading edge of membrane filopodia in glioblastoma cells, suggesting a role in cell adhesion/migration.[12] In addition, recombinant GPR56-NTF protein interacts with glioma cells to inhibit cellular adhesion. Inactivation of Von Hippel-Lindau (VHL) tumor-suppressor gene and hypoxia suppressed GPR56 in a renal cell carcinoma cell line, but hypoxia influenced GPR56 expression in breast or bladder cancer cell lines.[40] GPR56 is a target gene for vezatin, an adherens junctions transmembrane protein, which is a tumor suppressor in gastric cancer.[41] Xu et al. used an in vivo metastatic model of human melanoma to show that GPR56 is downregulated in highly metastatic cells.[9] Later, by ectopic expression and RNA interference they confirmed that GPR56 inhibits melanoma tumor growth and metastasis. Silenced expression of GPR56 in HeLa cells enhanced apoptosis and anoikis, but suppressed anchorage-independent growth and cell adhesion.[39] High ecotropic viral integration site-1 acute myeloid leukemia (EVI1-high AML) expresses GPR56 that was found to be a transcriptional target of EVI1.[42] Silencing expression of GPR56 decreases adhesion, cell growth and induces apoptosis through reduced RhoA signaling. GPR56 suppresses the angiogenesis and melanoma growth through inhibition of vascular endothelial growth factor (VEGF) via PKCα signaling pathway.[43] Furthermore, GPR56 expression was found to be negatively correlated with the malignancy of melanomas in human patients. | https://www.wikidoc.org/index.php/GPR56 | |
6246b7ef95766d0274e5505490ea8edd0638269c | wikidoc | GPR64 | GPR64
G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene. GPR64 is a member of the adhesion GPCR family.
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated. GPR64's N-terminus has been reported to be cleaved at the GPS domain to allow for trafficking to the plasma membrane. After cleavage the N-terminus is believed to remain non-covalently associated with the 7TM. GPR64 expression has been mostly reported in the male reproductive organs, but more recently has been shown to be expressed in the central nervous system. GPR64 is mainly expressed in human and mouse epididymis as well as human prostate and parathyroid. GPR64, together with F-actin scaffold, locates at the nonciliated principal cells of the proximal male excurrent duct epithelia, where reabsorption of testicular fluid and concentration of sperm takes place.
# Function
Targeting of Gpr64 in mice causes reduced fertility or infertility in males; but the reproductive capacity was unaffected in females. Unchanged hormone expression in knockout males indicates that the receptor functions immediately in the male genital tract. Lack of Gpr64 expression causes sperm stasis and duct obstruction due to abnormal fluid reabsorption. In addition, expression of GPR64 has been found in fibroblast-like synovial cells obtained from osteoarthritis but not from rheumatoid arthritis.
# Clinical significance
GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma, as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung. Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1. | GPR64
G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene.[1] GPR64 is a member of the adhesion GPCR family.[2][3]
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[4]
The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated.[5] GPR64's N-terminus has been reported to be cleaved at the GPS domain to allow for trafficking to the plasma membrane. After cleavage the N-terminus is believed to remain non-covalently associated with the 7TM. GPR64 expression has been mostly reported in the male reproductive organs, but more recently has been shown to be expressed in the central nervous system.[6] GPR64 is mainly expressed in human and mouse epididymis as well as human prostate and parathyroid.[7] GPR64, together with F-actin scaffold, locates at the nonciliated principal cells of the proximal male excurrent duct epithelia, where reabsorption of testicular fluid and concentration of sperm takes place.[8][9]
# Function
Targeting of Gpr64 in mice causes reduced fertility or infertility in males; but the reproductive capacity was unaffected in females.[10] Unchanged hormone expression in knockout males indicates that the receptor functions immediately in the male genital tract. Lack of Gpr64 expression causes sperm stasis and duct obstruction due to abnormal fluid reabsorption. In addition, expression of GPR64 has been found in fibroblast-like synovial cells obtained from osteoarthritis but not from rheumatoid arthritis.[11]
# Clinical significance
GPR64 is significantly overexpressed in the Wnt signaling-dependent subgroup of medulloblastoma,[12] as well as in ewing sarcomas and carcinomas derived from prostate, kidney or lung.[13] Richter et al. demonstrated that GPR64 promotes tumor invasion and metastasis through placental growth factor and MMP1.[13] | https://www.wikidoc.org/index.php/GPR64 | |
b0f6da2f8d514dfb7f2722db916d3f5a426ad97e | wikidoc | GPR65 | GPR65
Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.
# Species, tissue, and subcellular distribution
GPR65 (TDAG8) is primarily expressed in lymphoid tissues (spleen, lymph nodes, thymus, and leukocytes), and as a GPCR, the protein is localized to the plasma membrane.
# Function
## Ligand binding
In 2001, GPR65 was reported to be a specific receptor for psychosine (d-galactosyl-β-1,1′ sphingosine) as well as several other related glycosphingolipids. However, the specific binding of psychosine to GPR65 has been contested as the reported ligand binding did not satisfy the appropriate pharmacological criteria.
More recently, 3--1,6-dimethylpyridazinothiadiazin-5-one (referred to as BTB09089) was found to be a specific agonist for GPR65. Furthermore, 4-methyl-2-pyrimidin-2-yl-1,3-thiazole-5-carboxylate (referred to as ZINC62678696) was found to act as a BTB09089 negative allosteric modulator.
## pH sensing
GPR65 senses extracellular pH. Levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with activation of GPCRs in the cAMP-dependent pathway, were found to be elevated in neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR65. In cells with mutated GPR65, this pH-sensing effect was reduced or eliminated. In the presence of psychosine, however, the levels of cAMP increased at a shifted, more acidic pH range. As such, psychosine displayed an inhibitory effect as an antagonist when GPR65 was stimulated with an increasing concentration of protons (increasingly acidic pH). This finding directly contested the previous reporting of psychosine as an activating ligand for GPR65.
The pH-sensing ability of GPR65 was further tested and confirmed, as it was found that cAMP levels increased when GPR65 was stimulated by pH values less than pH 7.2.
GPR65 senses pH by protonation of histidine residues on its extracellular domain, and when activated, GPR65 enables the downstream signaling through the Gq/11, Gs, and G12/13 pathways. The ability of GPR65 to sense pH can modulate several cellular functions in various biological systems including the immune, cardiovascular, respiratory, renal, and nervous systems.
GPR65's ability to sense pH plays a prominent role in tumor development. GPR65 is highly expressed in a variety of human tumors. Tumor development is associated with low extracellular pH due to changes in metabolism of rapidly dividing cells. GPR65 enables tumor growth by sensing the acidic environment. It was found that overexpression of GPR65 prevents tumor cell death in acidic conditions in vitro and facilitates tumor growth in vivo.
## Immune
GPR65 reduces immune-mediated inflammation by regulating cytokine production of T cells (including IL-6, TNF-α and IL-1β) and macrophages.
## Cardiovascular
After myocardial infarction, anaerobic respiration and severe inflammation occurs—both of which are accompanied by an acidic environment. GPR65 knockout mice showed a decline in survival and cardiac function after myocardial infarction, which indicates that GPR65-mediated pH sensing is physiologically relevant. GPR65 exhibits a cardioprotective effect against myocardial infarction by reducing CCL20 expression and the migration of IL-17A-producing γδT cells that express CCR6, a receptor for CCL20.
## Visual
Retinal function is sensitive to changes in pH. It was found that GPR65 is overexpressed in the retina of mouse models of retinal degeneration and that the receptor supports the survival of photoreceptors in a degenerating retina by sensing pH and activating microglia after light-injury.
## Gastrointestinal
Vagal afferents expressing GPR65 innervate intestinal villi. These GPR65-expressing vagal afferents detect nutrients in the intestinal lumen and also slow gut motility.
## Depression
GPR65 was identified as a potential target linking inflammation and depression. GPR65 knockout mice exhibited a significant reduction in mobility in a forced swim test as well as higher consumption of sucrose—both of which are behaviors associated with depression.
# History/Discovery
In 1996, Choi et al. first identified GPR65 (TDAG8) as a G protein-coupled receptor whose expression was induced during activation-induced apoptosis of T cells. The group sought to identify which genes were necessary during T cell receptor-mediated death of immature thymocytes, and using differential mRNA display, they found that TDAG8 expression was induced upon activation of T cells. Because this gene was found to be associated with T-cell death (apoptosis), it was named TDAG8, or T Cell Death Associated Gene 8. | GPR65
Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene.[1][2] GPR65 is also referred to as TDAG8.
# Species, tissue, and subcellular distribution
GPR65 (TDAG8) is primarily expressed in lymphoid tissues (spleen, lymph nodes, thymus, and leukocytes),[3] and as a GPCR, the protein is localized to the plasma membrane.
# Function
## Ligand binding
In 2001, GPR65 was reported to be a specific receptor for psychosine (d-galactosyl-β-1,1′ sphingosine) as well as several other related glycosphingolipids.[4] However, the specific binding of psychosine to GPR65 has been contested as the reported ligand binding did not satisfy the appropriate pharmacological criteria.[5]
More recently, 3-[(2,4-dichlorophenyl)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one (referred to as BTB09089) was found to be a specific agonist for GPR65.[6] Furthermore, [(S)-phenyl(pyridin-4-yl)methyl] 4-methyl-2-pyrimidin-2-yl-1,3-thiazole-5-carboxylate (referred to as ZINC62678696) was found to act as a BTB09089 negative allosteric modulator.[7]
## pH sensing
GPR65 senses extracellular pH.[8] Levels of cyclic adenosine monophosphate (cAMP), a secondary messenger associated with activation of GPCRs in the cAMP-dependent pathway, were found to be elevated in neutral to acidic extracellular pH (pH 7.0-6.5) in cells expressing GPR65. In cells with mutated GPR65, this pH-sensing effect was reduced or eliminated. In the presence of psychosine, however, the levels of cAMP increased at a shifted, more acidic pH range. As such, psychosine displayed an inhibitory effect as an antagonist when GPR65 was stimulated with an increasing concentration of protons (increasingly acidic pH). This finding directly contested the previous reporting of psychosine as an activating ligand for GPR65.
The pH-sensing ability of GPR65 was further tested and confirmed, as it was found that cAMP levels increased when GPR65 was stimulated by pH values less than pH 7.2.[9]
GPR65 senses pH by protonation of histidine residues on its extracellular domain, and when activated, GPR65 enables the downstream signaling through the Gq/11, Gs, and G12/13 pathways.[10] The ability of GPR65 to sense pH can modulate several cellular functions in various biological systems including the immune, cardiovascular, respiratory, renal, and nervous systems.[11]
GPR65's ability to sense pH plays a prominent role in tumor development.[12] GPR65 is highly expressed in a variety of human tumors. Tumor development is associated with low extracellular pH due to changes in metabolism of rapidly dividing cells. GPR65 enables tumor growth by sensing the acidic environment. It was found that overexpression of GPR65 prevents tumor cell death in acidic conditions in vitro and facilitates tumor growth in vivo.
## Immune
GPR65 reduces immune-mediated inflammation by regulating cytokine production of T cells (including IL-6, TNF-α and IL-1β) and macrophages.[13]
## Cardiovascular
After myocardial infarction, anaerobic respiration and severe inflammation occurs—both of which are accompanied by an acidic environment. GPR65 knockout mice showed a decline in survival and cardiac function after myocardial infarction, which indicates that GPR65-mediated pH sensing is physiologically relevant. GPR65 exhibits a cardioprotective effect against myocardial infarction by reducing CCL20 expression and the migration of IL-17A-producing γδT cells that express CCR6, a receptor for CCL20.[14]
## Visual
Retinal function is sensitive to changes in pH. It was found that GPR65 is overexpressed in the retina of mouse models of retinal degeneration and that the receptor supports the survival of photoreceptors in a degenerating retina by sensing pH and activating microglia after light-injury.[15]
## Gastrointestinal
Vagal afferents expressing GPR65 innervate intestinal villi. These GPR65-expressing vagal afferents detect nutrients in the intestinal lumen and also slow gut motility.[16]
## Depression
GPR65 was identified as a potential target linking inflammation and depression. GPR65 knockout mice exhibited a significant reduction in mobility in a forced swim test as well as higher consumption of sucrose—both of which are behaviors associated with depression.[17]
# History/Discovery
In 1996, Choi et al. first identified GPR65 (TDAG8) as a G protein-coupled receptor whose expression was induced during activation-induced apoptosis of T cells.[18] The group sought to identify which genes were necessary during T cell receptor-mediated death of immature thymocytes, and using differential mRNA display, they found that TDAG8 expression was induced upon activation of T cells. Because this gene was found to be associated with T-cell death (apoptosis), it was named TDAG8, or T Cell Death Associated Gene 8. | https://www.wikidoc.org/index.php/GPR65 | |
563c8758b76f37f3e4fbf8f4509ef53279e1cd1c | wikidoc | GPR75 | GPR75
Probable G-protein coupled receptor 75 is a protein that in humans is encoded by the GPR75 gene.
# Function
GPR75 is a member of the G protein-coupled receptor family. GPRs are cell surface receptors that activate guanine-nucleotide binding proteins upon the binding of a ligand.
GPR75 is currently classified as an orphan GPCR and several studies are underway to identify its ligand. In one study, the chemokine CCL5 (RANTES) has been shown to stimulate calcium mobilization and inositol triphosphate formation in GPR75-transfected cells.
Recently, 20-hydroxyeicosatetraenoic acid (20-HETE), a bioactive eicosanoid formed by ω-hydroxylation of arachidonic acid has been shown to mediate its prohypertensive effects on the vasculature through activation of GPR75 (Gq) signalling. This study by Dr. Schwartzman's laboratory at New York Medical college, one of the pioneers in study of 20-HETE biology, has opened new insights into the field of GPR75 pharmacology. | GPR75
Probable G-protein coupled receptor 75 is a protein that in humans is encoded by the GPR75 gene.[1][2]
# Function
GPR75 is a member of the G protein-coupled receptor family. GPRs are cell surface receptors that activate guanine-nucleotide binding proteins upon the binding of a ligand.[2]
GPR75 is currently classified as an orphan GPCR and several studies are underway to identify its ligand. In one study, the chemokine CCL5 (RANTES) has been shown to stimulate calcium mobilization and inositol triphosphate formation in GPR75-transfected cells.[3]
Recently, 20-hydroxyeicosatetraenoic acid (20-HETE), a bioactive eicosanoid formed by ω-hydroxylation of arachidonic acid has been shown to mediate its prohypertensive effects on the vasculature through activation of GPR75 (Gq) signalling.[4] This study by Dr. Schwartzman's laboratory at New York Medical college, one of the pioneers in study of 20-HETE biology, has opened new insights into the field of GPR75 pharmacology. | https://www.wikidoc.org/index.php/GPR75 | |
f0cfd693179449a3c5e321343043b1f1c3ed69e1 | wikidoc | GPR81 | GPR81
G protein-coupled receptor 81, also known as GPR81, is a protein that in humans is encoded by the GPR81 gene.
G protein-coupled receptors (GPCRs, or GPRs), such as GPR81, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins.
Lactate activates the GPR81 receptor which in turn inhibits lipolysis in fat cells. | GPR81
G protein-coupled receptor 81, also known as GPR81, is a protein that in humans is encoded by the GPR81 gene.[1][2]
G protein-coupled receptors (GPCRs, or GPRs), such as GPR81, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins.[1]
Lactate activates the GPR81 receptor which in turn inhibits lipolysis in fat cells.[3][4] | https://www.wikidoc.org/index.php/GPR81 | |
6914efacc32830e123310a8c7e092e1b5e9e6a40 | wikidoc | GPR84 | GPR84
Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.
# Discovery
GPR84 (EX33) was described practically in the same time by two groups. One was the group of Timo Wittenberger in the Zentrum fur Molekulare Neurobiologie, Hamburg, Germany (Wittenberg T. et al.) and the other was the group of Gabor Jarai in Novartis Horsham Research Centre, Horsham, United Kingdom. In their papers they described the sequence and expression profile of five new members of GPC receptor family. One among them was GPR84 which represents a unique GPCR sub-family so far.
# Gene
Hgpr84 locates to chromosome 12q13.13, and its coding sequence is not interrupted by introns.
# Protein
The human and the murine GPR84 ORFs both encode proteins of 396 amino acid residues length with 85% identity and are therefore considered as orthologs. The hgpr84 was found by Northern blot analysis as a transcript of about 1.5 kb in brain, heart, muscle, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, and leukocytes. In addition, a 1.2 kb transcript in heart and a strong band at 1.3 kb in muscle were detected. A Northern blot from different brain regions revealed strongest expression of the 1.5 kb transcript in the medulla and the spinal cord. Somewhat less transcript was found in the substantia nigra, thalamus, and the corpus callosum. The 1.5 kb band was also visible in other brain regions, but at very low levels. EST clones corresponding to hgpr84 were from B cells (leukemia), neuroendocrine lung as well as in microglial cells and adipocytes. A more detailed description of expression profile can be found in www.genecards.org. The resting expression of GPR84 is usually low but it is highly inducible in inflammation. Its expression on neutrophils can be increased with LPS stimulation and reduced with GM-CSF stimulation. The LPS-induced upregulation of GPR84 was not sensitive to dexamathasone pretreatment. There was also a GPR84 downregulation in dentritic cell derived from FcRgamma chain KO mice. In microglial cells, the GPR84 induction with interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) was also demonstrated. 24 h treatment with IL-1β also induced 5.8 times increase in GPR84 expression on PBMC from healthy individuals. . Transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation was studies. It turned out that GPR84 belongs to the Th1 specific subset genes. While another publication suggests that GPR84 is rather a CCL1 related Th2 type gene.
GPR84 was also upregulated on both macrophages and neutrophyl granulocytes after LPS stimulation. Not only LPS challenge but Staphylococcus enterotoxin B was sufficient to cause a 50 times increase in GPR84 expression on isolated human leukocytes stimulated with compared to the expression of naive leukocytes. A viral infection following Japanese encephalitis virus infection also increased GPR84 expression by 2-4.5% in the mice brain.
Ablating lysosomal acid lipase (Lal-/-) in mice led to aberrant expansion of myeloid-derived suppressive cells (MDSCs) (>40% in the blood, and >70% in the bone marrow) that arise from dysregulated production of myeloid progenitor cells in the bone marrow. Ly6G + MDSCs in Lal-/- mice show strong immunosuppression on T cells, which contributes to impaired T cell proliferation and function in vivo. GPR84 was 9.1 fold upregulated in the MDSCs of Lal-/- mice. GPR84 is normally expressed at low levels in myeloid cells and can be induced in vitro by stimulating macrophage or microglial cells with LPS, TNFα, or PMA. Elevated expression of GPR84 was also observed during the demyelination phase of the reversible Cuprizone-Induced Demyelinating Disease mouse model. Finally, it has also shown that GPR84 expression is increased in both the normal appearing white matter and plaque in brains from human Multiple Sclerosis patients. Expression of GPR84 increases in mouse whole brain samples from experimental autoimmune encephalomyelitis before the onset of clinical disease. In cultured microglia in response to simulated blast overpressure the expression of GPR84 was increased 2.9 fold. In ageing TgSwe mice were subjected to traumatic brain injury GPR84 was upregulated by 6.3 fold. GPR84 expression was increased by 49.9 times in M1 type macrophages isolated from aortic atherosclerotic lesions of LDLR-/- mice were fed a western diet. GPR84 is important in regulating the expression of cytokines: CD4+ T cells from GPR84-/- mice show increase IL-4 secretion in the presence of anti-CD3 and anti-CD28 antibodies; GPR84 potentiates LPS-induced IL12p40 secretion in RAW264.7 cells.
Recent work by Nagasaki et al. explored 3T3-L1 adipocytes cocultured with RAW264.7 cells to examine this potential interaction. RAW264.7 coculture increases GPR84 expression in 3T3-L1 adipocytes, and incubation with capric acid can inhibit TNFα-induced adiponectin release. Adiponectin regulates many metabolic processes associated with glucose and fatty acids, including insulin sensitivity and lipid breakdown. Furthermore, a high-fat diet can increase GPR84 expression. The authors suggest that GPR84 may explain the relationship between diabetes and obesity. As adipocytes release fatty acids in the presence of macrophages, the loop of increased GPR84 expression and its stimulation prevent the release of regulating hormones. The work on GPR84 is still very early and needs to be expanded in the context of pathophysiology and immune regulation. Some people presume the role of GPR84 in food intake too. GPR84 is expressed in the gastric corpus mucosa and this receptor can be an important luminal sensors of food intake and are most likely expressed on entero-endocrine cells, where it stimulates the release of peptide hormones including incretins glucagon-like peptide (GLP) 1 and 2.
# Ligands
The ligands for GPR84 suggest also a relationship between inflammation and fatty acid sensing or regulation. Medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in monocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner. IL-12 plays an important role in promoting cell mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 responses and inhibiting T helper 2 responses. Medium chain FFAs inhibited forskolin-induced cAMP production and stimulated GTPgammaS binding in a GPR84-dependent manner. The EC50 values for medium-chain FFAs capric acid, undecanoic acid, and lauric acid at GPR84 (4, 8, and 9 mM, respectively, in the cAMP assay). These results suggest that GPR84 activation by medium-chain FFAs is coupled to a pertussis toxin-sensitive Gi/o pathway. Besides medium-chain FFAs diindolylmethane was also described as GPR84 agonist. However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too. The patent literature mentions that besides medium chain FFAs other substances as 2,5-Dihydroxy-3-undecyl(1,4)benzoquinon, Icosa-5,8,11,14-tetraynoic acid and 5S,6R-Dihydroxy-icosa-7,9,11,14-tetraenoic acid (5S,6RdiHETE) are also ligands of GPR84. These two latest molecules say against the statement that long chain FFAs are not ligands of GPR84. Based on these results it is probable that besides medium chain FFAs some long chain FFAs can also be endogeneous ligands of GPR84. Further work is needed to confirm this hypothesis.
# Major mediator in pathologic fibrotic pathways
GPR84 was discovered to be a major mediator in pathologic fibrotic pathways in 2018.
# Drugs under investigation
The molecule GLPG1205 was under investigation by the Belgian firm Galapagos NV. Its clinical effect against inflammatory disorders like inflammatory bowel disease was being investigated in 2015 in a Phase 2 Proof-of-Concept study in ulcerative colitis patients. The results published in January 2016 showed good pharmacokinetics, safety and tolerability. However, the target efficacy was not met. The development of GLPG1205 for ulcerative colitis was therefore stopped.
The molecule PBI-4050 which inhibits GPR84 signaling is under investigation by the Canadian biotechnology firm Prometic. As of August 2018, it remains a promising drug targeting multiple type of fibrosis entering phase 3 clinical trials.. | GPR84
Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.[1][2]
# Discovery
GPR84 (EX33) was described practically in the same time by two groups. One was the group of Timo Wittenberger in the Zentrum fur Molekulare Neurobiologie, Hamburg, Germany (Wittenberg T. et al.) and the other was the group of Gabor Jarai in Novartis Horsham Research Centre, Horsham, United Kingdom. In their papers they described the sequence and expression profile of five new members of GPC receptor family. One among them was GPR84 which represents a unique GPCR sub-family so far.
# Gene
Hgpr84 locates to chromosome 12q13.13, and its coding sequence is not interrupted by introns.[1]
# Protein
The human and the murine GPR84 ORFs both encode proteins of 396 amino acid residues length with 85% identity and are therefore considered as orthologs.[1] The hgpr84 was found by Northern blot analysis as a transcript of about 1.5 kb in brain, heart, muscle, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, and leukocytes. In addition, a 1.2 kb transcript in heart and a strong band at 1.3 kb in muscle were detected. A Northern blot from different brain regions revealed strongest expression of the 1.5 kb transcript in the medulla and the spinal cord. Somewhat less transcript was found in the substantia nigra, thalamus, and the corpus callosum. The 1.5 kb band was also visible in other brain regions, but at very low levels. EST clones corresponding to hgpr84 were from B cells (leukemia), neuroendocrine lung as well as in microglial cells[3] and adipocytes.[4] A more detailed description of expression profile can be found in www.genecards.org. The resting expression of GPR84 is usually low but it is highly inducible in inflammation. Its expression on neutrophils can be increased with LPS stimulation and reduced with GM-CSF stimulation. The LPS-induced upregulation of GPR84 was not sensitive to dexamathasone pretreatment. There was also a GPR84 downregulation in dentritic cell derived from FcRgamma chain KO mice.[5] In microglial cells, the GPR84 induction with interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) was also demonstrated.[3] 24 h treatment with IL-1β also induced 5.8 times increase in GPR84 expression on PBMC from healthy individuals.[citation needed] . Transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation was studies. It turned out that GPR84 belongs to the Th1 specific subset genes.[6] While another publication suggests that GPR84 is rather a CCL1 related Th2 type gene.[7]
GPR84 was also upregulated on both macrophages and neutrophyl granulocytes after LPS stimulation.[8] Not only LPS challenge but Staphylococcus enterotoxin B was sufficient to cause a 50 times increase in GPR84 expression on isolated human leukocytes stimulated with compared to the expression of naive leukocytes.[9] A viral infection following Japanese encephalitis virus infection also increased GPR84 expression by 2-4.5% in the mice brain.[10]
Ablating lysosomal acid lipase (Lal-/-) in mice led to aberrant expansion of myeloid-derived suppressive cells (MDSCs) (>40% in the blood, and >70% in the bone marrow) that arise from dysregulated production of myeloid progenitor cells in the bone marrow. Ly6G + MDSCs in Lal-/- mice show strong immunosuppression on T cells, which contributes to impaired T cell proliferation and function in vivo. GPR84 was 9.1 fold upregulated in the MDSCs of Lal-/- mice. GPR84 is normally expressed at low levels in myeloid cells and can be induced in vitro by stimulating macrophage or microglial cells with LPS, TNFα, or PMA. Elevated expression of GPR84 was also observed during the demyelination phase of the reversible Cuprizone-Induced Demyelinating Disease mouse model. Finally, it has also shown that GPR84 expression is increased in both the normal appearing white matter and plaque in brains from human Multiple Sclerosis patients. Expression of GPR84 increases in mouse whole brain samples from experimental autoimmune encephalomyelitis before the onset of clinical disease.[11] In cultured microglia in response to simulated blast overpressure the expression of GPR84 was increased 2.9 fold.[12] In ageing TgSwe mice were subjected to traumatic brain injury GPR84 was upregulated by 6.3 fold.[13] GPR84 expression was increased by 49.9 times in M1 type macrophages isolated from aortic atherosclerotic lesions of LDLR-/- mice were fed a western diet.[14] GPR84 is important in regulating the expression of cytokines: CD4+ T cells from GPR84-/- mice show increase IL-4 secretion in the presence of anti-CD3 and anti-CD28 antibodies;[15] GPR84 potentiates LPS-induced IL12p40 secretion in RAW264.7 cells.[16]
Recent work by Nagasaki et al. explored 3T3-L1 adipocytes cocultured with RAW264.7 cells to examine this potential interaction.[4] RAW264.7 coculture increases GPR84 expression in 3T3-L1 adipocytes, and incubation with capric acid can inhibit TNFα-induced adiponectin release. Adiponectin regulates many metabolic processes associated with glucose and fatty acids, including insulin sensitivity and lipid breakdown. Furthermore, a high-fat diet can increase GPR84 expression. The authors suggest that GPR84 may explain the relationship between diabetes and obesity. As adipocytes release fatty acids in the presence of macrophages, the loop of increased GPR84 expression and its stimulation prevent the release of regulating hormones. The work on GPR84 is still very early and needs to be expanded in the context of pathophysiology and immune regulation. Some people presume the role of GPR84 in food intake too. GPR84 is expressed in the gastric corpus mucosa and this receptor can be an important luminal sensors of food intake and are most likely expressed on entero-endocrine cells, where it stimulates the release of peptide hormones including incretins glucagon-like peptide (GLP) 1 and 2.[17]
# Ligands
The ligands for GPR84 suggest also a relationship between inflammation and fatty acid sensing or regulation. Medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent[16] described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in monocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner.[16] IL-12 plays an important role in promoting cell mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 responses and inhibiting T helper 2 responses.[16] Medium chain FFAs inhibited forskolin-induced cAMP production and stimulated [35S]GTPgammaS binding in a GPR84-dependent manner. The EC50 values for medium-chain FFAs capric acid, undecanoic acid, and lauric acid at GPR84 (4, 8, and 9 mM, respectively, in the cAMP assay). These results suggest that GPR84 activation by medium-chain FFAs is coupled to a pertussis toxin-sensitive Gi/o pathway. Besides medium-chain FFAs diindolylmethane was also described as GPR84 agonist.[16] However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too.[18] The patent literature mentions that besides medium chain FFAs other substances as 2,5-Dihydroxy-3-undecyl(1,4)benzoquinon, Icosa-5,8,11,14-tetraynoic acid and 5S,6R-Dihydroxy-icosa-7,9,11,14-tetraenoic acid (5S,6RdiHETE) are also ligands of GPR84.[19] These two latest molecules say against the statement that long chain FFAs are not ligands of GPR84. Based on these results it is probable that besides medium chain FFAs some long chain FFAs can also be endogeneous ligands of GPR84. Further work is needed to confirm this hypothesis.
# Major mediator in pathologic fibrotic pathways
GPR84 was discovered to be a major mediator in pathologic fibrotic pathways in 2018.[20]
# Drugs under investigation
The molecule GLPG1205 was under investigation by the Belgian firm Galapagos NV. Its clinical effect against inflammatory disorders like inflammatory bowel disease was being investigated in 2015 in a Phase 2 Proof-of-Concept study in ulcerative colitis patients. The results published in January 2016 showed good pharmacokinetics, safety and tolerability. However, the target efficacy was not met. The development of GLPG1205 for ulcerative colitis was therefore stopped.[21]
The molecule PBI-4050 which inhibits GPR84 signaling is under investigation by the Canadian biotechnology firm Prometic. As of August 2018, it remains a promising drug targeting multiple type of fibrosis entering phase 3 clinical trials.[22]. | https://www.wikidoc.org/index.php/GPR84 | |
7cce1eaea2cea91ce13dc48af1ed1c971cf7f51f | wikidoc | GPR88 | GPR88
Probable G-protein coupled receptor 88 is a protein that in humans is encoded by the GPR88 gene.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298..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}
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Mizushima K, Miyamoto Y, Tsukahara F, et al. (2001). "A novel G-protein-coupled receptor gene expressed in striatum". Genomics. 69 (3): 314–21. doi:10.1006/geno.2000.6340. PMID 11056049.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Van Waes V, Tseng K, Steiner H (2011). "GPR88 - a putative signaling molecule predominantly expressed in the striatum: Cellular localization and developmental regulation". Basal Ganglia. 1 (2): 83–89. doi:10.1016/j.baga.2011.04.001. PMC 3144573. PMID 21804954. | GPR88
Probable G-protein coupled receptor 88 is a protein that in humans is encoded by the GPR88 gene.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298..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}
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Mizushima K, Miyamoto Y, Tsukahara F, et al. (2001). "A novel G-protein-coupled receptor gene expressed in striatum". Genomics. 69 (3): 314–21. doi:10.1006/geno.2000.6340. PMID 11056049.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Van Waes V, Tseng K, Steiner H (2011). "GPR88 - a putative signaling molecule predominantly expressed in the striatum: Cellular localization and developmental regulation". Basal Ganglia. 1 (2): 83–89. doi:10.1016/j.baga.2011.04.001. PMC 3144573. PMID 21804954. | https://www.wikidoc.org/index.php/GPR88 | |
9252a3272abfc040484409da0ee1c698d2a2cad1 | wikidoc | GPR97 | GPR97
G-protein coupled receptor 97 also known as adhesion G protein-coupled receptor G3 (ADGRG3) is a protein that in humans is encoded by the ADGRG3 gene. GPR97 is a member of the adhesion GPCR family.
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
GPR97 is expressed in human granulocytes and endothelial cells of the vasculature as well as in mouse granulocytes, monocytes, macrophages, and dendritic cells.
# Signaling
The inositol phosphate (IP3) accumulation, aequorin, and 35S isotope binding assays in overexpressing HEK293 cells have demonstrated coupling of GPR97 to Gαo protein triggering cyclic adenosine monophosphate (cAMP). GPR97 actives cAMP response element-binding protein (CREB), NF-κB, and small GTPases to regulate cellular functions.
# Function
Systemic steroid exposure is a therapy to treat a variety of medical conditions and is associated with epigenetic processes such as DNA methylation that may reflect pharmacological responses and/or side effects. GPR97 was found to be differently methylated at CpG sites in the genome of blood cells from patient under systemic steroid treatment. GPR97 is transcribed in immune cells. Gene-deficient mice revealed that Gpr97 is crucial for maintaining B-cell population via constitutive CREB and NF-κB activities. Human lymphatic endothelial cells (LECs) abundantly express GPR97. Silencing GPR97 in human LECs indicated that GPR97 modulates cytoskeletal rearrangement, cell adhesion and migration through regulating the small GTPase RhoA and cdc42. In vertebrates, GPR97 has an indispensable role in the bone morphogenetic proteins (BMP) signaling pathway in bone formation. A microarray meta-analysis revealed that mouse Gpr97 is a direct transcriptional target of BMP signaling in long bone development. | GPR97
G-protein coupled receptor 97 also known as adhesion G protein-coupled receptor G3 (ADGRG3) is a protein that in humans is encoded by the ADGRG3 gene.[1][2][3][4] GPR97 is a member of the adhesion GPCR family.[5][6]
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[7]
GPR97 is expressed in human granulocytes and endothelial cells of the vasculature as well as in mouse granulocytes, monocytes, macrophages, and dendritic cells.[4]
# Signaling
The inositol phosphate (IP3) accumulation, aequorin, and 35S isotope binding assays in overexpressing HEK293 cells have demonstrated coupling of GPR97 to Gαo protein triggering cyclic adenosine monophosphate (cAMP).[8] GPR97 actives cAMP response element-binding protein (CREB), NF-κB, and small GTPases to regulate cellular functions.
# Function
Systemic steroid exposure is a therapy to treat a variety of medical conditions and is associated with epigenetic processes such as DNA methylation that may reflect pharmacological responses and/or side effects. GPR97 was found to be differently methylated at CpG sites in the genome of blood cells from patient under systemic steroid treatment.[9] GPR97 is transcribed in immune cells. Gene-deficient mice revealed that Gpr97 is crucial for maintaining B-cell population via constitutive CREB and NF-κB activities.[10] Human lymphatic endothelial cells (LECs) abundantly express GPR97. Silencing GPR97 in human LECs indicated that GPR97 modulates cytoskeletal rearrangement, cell adhesion and migration through regulating the small GTPase RhoA and cdc42.[11] In vertebrates, GPR97 has an indispensable role in the bone morphogenetic proteins (BMP) signaling pathway in bone formation. A microarray meta-analysis revealed that mouse Gpr97 is a direct transcriptional target of BMP signaling in long bone development.[12] | https://www.wikidoc.org/index.php/GPR97 | |
221cbd8507bc1cdcc3826698089d17e0864acd1c | wikidoc | GPR98 | GPR98
G protein-coupled receptor 98, also known as GPR98 or VLGR1, is a protein that in humans is encoded by the GPR98 gene. Several alternatively spliced transcripts have been described.
The adhesion GPCR Very Large GPCR receptor 1 (Vlg1R1) is the largest GPCR known, with a size of 6300 amino acids and consisting of 90 exons. There are 8 splice variants of VlgR1, named VlgR1a-1e and Mass1.1-1.3. The N-terminus consists of 5800 amino acids containing 35 Calx-beta domains, one pentraxin domain, and one epilepsy associated repeat. Mutations of VlgR1 have been shown to result in Usher's syndrome. Knockouts of Vlgr1 in mice have been shown to phenocopy Usher's syndrome and lead to audiogenic seizures.
# Function
This gene encodes a member of the adhesion-GPCR family of receptors. The protein binds calcium and is expressed in the central nervous system. It is also known as very large G-protein coupled receptor 1 because it is 6300 residues long. It contains a C-terminal 7-transmembrane receptor domain, whereas the large N-terminal segment (5900 residues) includes 35 calcium binding Calx-beta domains, and 6 EAR domains.
# Evolution
The Sea Urchin genome has a homolog of VLGR1 in it.
# Clinical significance
Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. | GPR98
G protein-coupled receptor 98, also known as GPR98 or VLGR1, is a protein that in humans is encoded by the GPR98 gene.[1] Several alternatively spliced transcripts have been described.[1]
The adhesion GPCR Very Large GPCR receptor 1 (Vlg1R1) is the largest GPCR known, with a size of 6300 amino acids and consisting of 90 exons.[2] There are 8 splice variants of VlgR1, named VlgR1a-1e and Mass1.1-1.3. The N-terminus consists of 5800 amino acids containing 35 Calx-beta domains, one pentraxin domain, and one epilepsy associated repeat. Mutations of VlgR1 have been shown to result in Usher's syndrome. Knockouts of Vlgr1 in mice have been shown to phenocopy Usher's syndrome and lead to audiogenic seizures.
# Function
This gene encodes a member of the adhesion-GPCR family of receptors.[3] The protein binds calcium and is expressed in the central nervous system. It is also known as very large G-protein coupled receptor 1 because it is 6300 residues long. It contains a C-terminal 7-transmembrane receptor domain, whereas the large N-terminal segment (5900 residues) includes 35 calcium binding Calx-beta domains, and 6 EAR domains.
# Evolution
The Sea Urchin genome has a homolog of VLGR1 in it.[4]
# Clinical significance
Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures.[1] | https://www.wikidoc.org/index.php/GPR98 | |
8b3fc981a19a43550b660dddac5f1855ec9590b0 | wikidoc | GPSM2 | GPSM2
G-protein-signaling modulator 2, also called LGN for its 10 Leucine-Glycine-Asparagine repeats, is a protein that in humans is encoded by the GPSM2 gene.
# Function
Heterotrimeric G proteins transduce extracellular signals received by cell surface receptors into integrated cellular responses. GPSM2 belongs to a group of proteins that modulate activation of G proteins (Blumer et al., 2002).
# Interactions
GPSM2 has been shown to interact with nuclear mitotic apparatus protein 1 and GNAI2. | GPSM2
G-protein-signaling modulator 2, also called LGN for its 10 Leucine-Glycine-Asparagine repeats, is a protein that in humans is encoded by the GPSM2 gene.[1][2][3]
# Function
Heterotrimeric G proteins transduce extracellular signals received by cell surface receptors into integrated cellular responses. GPSM2 belongs to a group of proteins that modulate activation of G proteins (Blumer et al., 2002).[supplied by OMIM][3]
# Interactions
GPSM2 has been shown to interact with nuclear mitotic apparatus protein 1[4] and GNAI2.[2][5] | https://www.wikidoc.org/index.php/GPSM2 | |
441476fda7c0afbe8fd18c343399c5b7f8018842 | wikidoc | GRACE | GRACE
# Overview
GRACE (the Global Registry of Acute Coronary Events) is a large, prospective, multinational observational study of patients hospitalized with ACS. The aim of GRACE is to improve the quality of care for patients with ACS by describing differences in, and relationships between, patient characteristics, treatment practices, and in-hospital and postdischarge outcomes at hospitals around the world.
# Methods
A total of 73 hospitals with on-site angiographic facility in 14 countries in North America, South America, Europe, Australia, and New Zealand were collaborated in GRACE and enrolled 24,189 patients.
Clusters were chosen on the basis of local demographic characteristics and hospital facilities to ensure a representative sample of patients with ACS from each country. Patients are identified by use of either active or passive surveillance approaches.
A standardized core case report form is completed for all patients. Information on patient demographics, medical history, acute symptoms, clinical characteristics, electrocardiographic findings, treatment approaches, and in-hospital outcomes is collected.
Patients are followed up at 6 months after hospital discharge to identify recurrent coronary events, use of various medications, and mortality.
# Conclusions
The information collected from the GRACE project provides important and extensive insights into patient demographic and clinical characteristics, current practice patterns, and outcomes for patients with ACS from a number of countries throughout the world. Given the pressures of practicing evidence-based medicine, the results of GRACE should provide a multinational perspective into these important outcomes and identify practice variations that will allow new opportunities to improve patient care. | GRACE
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
GRACE (the Global Registry of Acute Coronary Events) is a large, prospective, multinational observational study of patients hospitalized with ACS. The aim of GRACE is to improve the quality of care for patients with ACS by describing differences in, and relationships between, patient characteristics, treatment practices, and in-hospital and postdischarge outcomes at hospitals around the world. [1]
# Methods
A total of 73 hospitals with on-site angiographic facility in 14 countries in North America, South America, Europe, Australia, and New Zealand were collaborated in GRACE and enrolled 24,189 patients.
Clusters were chosen on the basis of local demographic characteristics and hospital facilities to ensure a representative sample of patients with ACS from each country. Patients are identified by use of either active or passive surveillance approaches.
A standardized core case report form is completed for all patients. Information on patient demographics, medical history, acute symptoms, clinical characteristics, electrocardiographic findings, treatment approaches, and in-hospital outcomes is collected.
Patients are followed up at 6 months after hospital discharge to identify recurrent coronary events, use of various medications, and mortality.
# Conclusions
The information collected from the GRACE project provides important and extensive insights into patient demographic and clinical characteristics, current practice patterns, and outcomes for patients with ACS from a number of countries throughout the world. Given the pressures of practicing evidence-based medicine, the results of GRACE should provide a multinational perspective into these important outcomes and identify practice variations that will allow new opportunities to improve patient care. | https://www.wikidoc.org/index.php/GRACE | |
a530eb8cb460e7cbe4e34f675835c134919ecce8 | wikidoc | GRB10 | GRB10
Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.
# Function
The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors (e.g., IGF1R and IGF2R). Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner. Alternatively spliced transcript variants encoding different isoforms have been identified.
# Animal studies
Mice whose paternally inherited Grb10 gene is inactivated are more aggressive while those whose maternally inherited allele is inactivated exhibit foetal overgrowth and are significantly bigger than wild-type litter-mates.
# Interactions
GRB10 has been shown to interact with
- Abl gene,
- BCR gene,
- C-Raf,
- c-Kit,
- Insulin receptor,
- Insulin-like growth factor 1 receptor,
- MAP2K1, and
- RET proto-oncogene. | GRB10
Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.[1][2][3][4]
# Function
The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors (e.g., IGF1R and IGF2R). Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner. Alternatively spliced transcript variants encoding different isoforms have been identified.[1]
# Animal studies
Mice whose paternally inherited Grb10 gene is inactivated are more aggressive while those whose maternally inherited allele is inactivated exhibit foetal overgrowth and are significantly bigger than wild-type litter-mates.[5]
# Interactions
GRB10 has been shown to interact with
- Abl gene,[6][7]
- BCR gene,[6]
- C-Raf,[8][9]
- c-Kit,[10]
- Insulin receptor,[7][11][12][13][14]
- Insulin-like growth factor 1 receptor,[14][15][16][17]
- MAP2K1,[9] and
- RET proto-oncogene.[18] | https://www.wikidoc.org/index.php/GRB10 | |
caa88ec72ada124c4edddbdf80a8c615a3aa48d2 | wikidoc | GRB14 | GRB14
Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the GRB14 gene.
The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Transcript variants have been reported for this gene, but their full-length natures have not been determined to date.
# Interactions
GRB14 has been shown to interact with Epidermal growth factor receptor, Fibroblast growth factor receptor 1 and TNKS2. | GRB14
Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the GRB14 gene.[1][2]
The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor signaling. This gene may play a role in signaling pathways that regulate growth and metabolism. Transcript variants have been reported for this gene, but their full-length natures have not been determined to date.[2]
# Interactions
GRB14 has been shown to interact with Epidermal growth factor receptor,[3] Fibroblast growth factor receptor 1[4] and TNKS2.[5] | https://www.wikidoc.org/index.php/GRB14 | |
406c68e39a5b03ce08a3fce9a31860614f84ab88 | wikidoc | GRIA1 | GRIA1
Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The GRIA1 belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Each of the members (GRIA1-4) include flip and flop isoforms generated by alternative RNA splicing. The receptor subunits encoded by each isoform vary in their signal transduction properties. The isoform presented here is the flop isoform. In situ hybridization experiments showed that human GRIA1 mRNA is present in granule and pyramidal cells in the hippocampal formation.
GRIA1 (GluR1) is centrally involved in synaptic plasticity. Expression of the GluR1 gene is significantly reduced in the human frontal cortex with increasing age.
# Interactions
GRIA1 has been shown to interact with:
- DLG1
- EPB41L2, and
- GRID2. | GRIA1
Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.[1][2]
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The GRIA1 belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Each of the members (GRIA1-4) include flip and flop isoforms generated by alternative RNA splicing. The receptor subunits encoded by each isoform vary in their signal transduction properties. The isoform presented here is the flop isoform. In situ hybridization experiments showed that human GRIA1 mRNA is present in granule and pyramidal cells in the hippocampal formation.[3]
GRIA1 (GluR1) is centrally involved in synaptic plasticity. Expression of the GluR1 gene is significantly reduced in the human frontal cortex with increasing age.[4]
# Interactions
GRIA1 has been shown to interact with:
- DLG1[5][6][7]
- EPB41L2,[8] and
- GRID2.[9] | https://www.wikidoc.org/index.php/GRIA1 | |
9a39be9d4b12be5eb559195e80c3a0a506130e3a | wikidoc | GRIA2 | GRIA2
Glutamate ionotropic receptor AMPA type subunit 2 (ionotropic glutamate receptor 2) is a protein that in humans is encoded by the GRIA2 (or GLUR2) gene.
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled from 4 related subunits, GRIA1-4. The subunit encoded by this gene (GRIA2) is subject to RNA editing (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to render the channel impermeable to Ca(2+). Human and animal studies suggest that pre-mRNA editing is essential for brain function, and defective GRIA2 RNA editing at the Q/R site may be relevant to amyotrophic lateral sclerosis (ALS) etiology. Alternative splicing, resulting in transcript variants encoding different isoforms, has been noted for this gene, which includes the generation of flip and flop isoforms that vary in their signal transduction properties.
# Interactions
GRIA2 has been shown to interact with SPTAN1, GRIP1 and PICK1.
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel, with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. Glur2 is a gene product of the pre-mRNA of the GRIA2 gene and subject to RNA editing.
## Type
The type of RNA editing that occurs in the pre-mRNA of GluR-2 is Adenosine-to-Inosine (A-to-I) editing.
A-to-I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues, while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron, but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, it can result in a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A-to-I editing occurs in a non coding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs (especially Alu repeats). The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
## Location
In the pre-mRNA of GluR-2 the editing site Q/R is found at amino acid position 607. This location is in the pore loop region deep within the ion channel in the proteins membrange segment 2. Editing results in a change from a glutamine(Q) codon to an Arginine (R) codon.
Editing at the R/G site, located at amino acid position 764 results in a codon change from arginine to glycine.
All editing in glutamate receptors occurs in double-stranded RNAs (dsRNAs), which form due to complementary base pairing between the region of the editing site within the exon and an ECS within an intron sequence.
R/G site
## Conservation
## Regulation
Editing occurs at the Q/R site at a frequency of 100% of GluR2 transcripts in the brain. It is the only known editing site to be edited at a frequency of 100%. However some striatal and cortical neurons are edited less frequently. This has been suggested as a reason for the higher level of excitotoxicity of these particular neurons. The R/G site is developmentally regulated, being largely unedited in the embryonic brain with levels rising after birth. (ref 53)
## Consequences
### Structure
Editing results in a codon change from a glutamine codon (CAG) to an arginine codon (CIG). Editing at R/G results in a codon change. The region of the editing site is known to be the region that controls divalent cation permeability. The other ionotropic AMPA glutamate receptors have a genomically encoded have a glutamine residue, while GluR2 has an arginine.
### Function
RNA editing of the GluR-2 (GluR-B) pre-mRNA is the best-characterised example of A-to-I editing. Activated by L-Glutamate, a major excitatory neurotransmitter in vertebrates central nervous systems, it acts as an agonist at NMDA, AMPA, and kainate neurotransmitters.(103) Activation results in neuronal cation entry (CA2+), causing membrane depolarisation required for the process of excitatory neurotransmission.
The calcium permeability of these receptor channels is required for many important events in the CNS, including long-term potentiation.(104)
Since editing occurs in nearly 100% of transcripts and is necessary for life, it is often wondered why edited GluR-B is not genomically encoded instead of being derived by RNA editing. The answer is unknown.
RNA editing at the Q/R site is thought to alter the permeability of the channel rendering it impermeable to Ca2+. The Q/R site also occurs in the Kainate receptors GluR5 and GluR6. Editing at the Q/R site determines the calcium permeability of the channel, with channels containing the edited form being less permeable to calcium. This differs from GluR6 where editing of the Q/R site may increase calcium permeability of the channel especially if the I/V and Y/C sites are also edited. Therefore, the main function of editing is therefore in regulation of electrophysiology of the channel.
Editing in some striatal and cortical neurons is more likely to be subject to excitotoxicity, thought to be due to less than 100% editing of these particular neurons. Editing also has several other function effects. Editing alters the maturation and assembly of the channel, with the unedited form having a tendency to tetramerize and then is transported to the synapse. However, the edited version is assembled as a monomer and resides mainly in the endoplasmic reticulum. The arginine residue in the pore loop of GluR-2 receptor is thought to belong to a retention signal for the endoplasmic reticulum. Therefore, editing - since it occurs at 100% frequency - inhibits the availability of the channel at the synapse. This process occurs before assembly of the channels, thereby preventing glur-2-forming homeric channels, which could interfere with synaptic signalling.
Editing also occurs at the R/G site. Editing at the R/G sites results in variation in the rate that the receptor recovers from desensitisation. Editing at these sites results in faster recovery time from desensitisation
### Dysregulation
Amyotrophic Lateral Sclerosis
Many human and animal studies have determined that RNA editing of the Q/R site in GluR2 pre-mRNA is necessary for normal brain function. Defective editing has been linked to several conditions such as amyotrophic lateral sclerosis (ALS). ALS effects 1 in 2000 people, usually fatal in 1–5 years, with onset in the majority of cases being sporadic and minority being familial. With these conditions motor neurons degenerate leading to eventual paralysis and respiratory failure. Glutamate excitotoxicity is known to contribute to the spread of the sporadic condition. Glutamate levels are increased up 40%, suggesting that activation of glutamate receptors could be the reason for this causing increase Ca influx and then neuronal death. Since decrease nor loss of editing at Q/R site would lead to increase in calcium permeability. In diseased motor neurons editing levels of Glur 2 (62-100%) at this site was discovered to be reduced.
Abnormal editing is thought to be specific for this condition, as editing levels have not been found to be decreased in spinal and bulbar muscular atrophy. Q/R editing is not the only mechanism involved, as editing occurs only in spinal motor neurons not in upper spinal neurons. Also, it is unknown whether editing dysregulation is involved in the initiation of the condition, or whether it occurs during pathogenesis.
Epilepsy
In mouse models, failure of editing leads to epileptic seizures and death within 3 weeks of birth. Why editing exists at this site instead of a genomically encoded arginine is unknown since nearly 100% of transcripts are edited.
Cancer
Decreased editing at the Q/R site is also found in some human brain tumors. Reduction of ADAR2 expression is thought to be associated with epileptic seizures in malignant glioma.
# Use in diagnostic immunochemistry
GRIA2 is a diagnostic immunochemical marker for solitary fibrous tumour (SFT), distinguishing it from most mimics. Among other CD34-positive tumours, GRIA2 is also expressed in dermatofibrosarcoma protuberans (DFSP); however, clinical and histologic features aid in their distinction. GRIA2 shows a limited distribution in other soft tissue tumours. | GRIA2
Glutamate ionotropic receptor AMPA type subunit 2 (ionotropic glutamate receptor 2) is a protein that in humans is encoded by the GRIA2 (or GLUR2) gene.[1][2][3]
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled from 4 related subunits, GRIA1-4. The subunit encoded by this gene (GRIA2) is subject to RNA editing (CAG->CGG; Q->R) within the second transmembrane domain, which is thought to render the channel impermeable to Ca(2+). Human and animal studies suggest that pre-mRNA editing is essential for brain function, and defective GRIA2 RNA editing at the Q/R site may be relevant to amyotrophic lateral sclerosis (ALS) etiology. Alternative splicing, resulting in transcript variants encoding different isoforms, has been noted for this gene, which includes the generation of flip and flop isoforms that vary in their signal transduction properties.[3]
# Interactions
GRIA2 has been shown to interact with SPTAN1,[4] GRIP1[5] and PICK1.[5]
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel, with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel).[6] The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing.[7] The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. Glur2 is a gene product of the pre-mRNA of the GRIA2 gene and subject to RNA editing.
## Type
The type of RNA editing that occurs in the pre-mRNA of GluR-2 is Adenosine-to-Inosine (A-to-I) editing. [11]
A-to-I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues, while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron, but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, it can result in a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A-to-I editing occurs in a non coding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs (especially Alu repeats). The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.
## Location
In the pre-mRNA of GluR-2 the editing site Q/R is found at amino acid position 607. This location is in the pore loop region deep within the ion channel in the proteins membrange segment 2. Editing results in a change from a glutamine(Q) codon to an Arginine (R) codon.
Editing at the R/G site, located at amino acid position 764 results in a codon change from arginine to glycine.
All editing in glutamate receptors occurs in double-stranded RNAs (dsRNAs), which form due to complementary base pairing between the region of the editing site within the exon and an ECS within an intron sequence.[8]
R/G site
## Conservation
## Regulation
Editing occurs at the Q/R site at a frequency of 100% of GluR2 transcripts in the brain. It is the only known editing site to be edited at a frequency of 100%.[6] However some striatal and cortical neurons are edited less frequently. This has been suggested as a reason for the higher level of excitotoxicity of these particular neurons.[9] The R/G site is developmentally regulated, being largely unedited in the embryonic brain with levels rising after birth. (ref 53)
## Consequences
### Structure
Editing results in a codon change from a glutamine codon (CAG) to an arginine codon (CIG).[10] Editing at R/G results in a codon change. The region of the editing site is known to be the region that controls divalent cation permeability. The other ionotropic AMPA glutamate receptors have a genomically encoded have a glutamine residue, while GluR2 has an arginine.
### Function
RNA editing of the GluR-2 (GluR-B) pre-mRNA is the best-characterised example of A-to-I editing. Activated by L-Glutamate, a major excitatory neurotransmitter in vertebrates central nervous systems, it acts as an agonist at NMDA, AMPA, and kainate neurotransmitters.(103) Activation results in neuronal cation entry (CA2+), causing membrane depolarisation required for the process of excitatory neurotransmission.
The calcium permeability of these receptor channels is required for many important events in the CNS, including long-term potentiation.(104)
Since editing occurs in nearly 100% of transcripts and is necessary for life, it is often wondered why edited GluR-B is not genomically encoded instead of being derived by RNA editing. The answer is unknown.
RNA editing at the Q/R site is thought to alter the permeability of the channel rendering it impermeable to Ca2+. The Q/R site also occurs in the Kainate receptors GluR5 and GluR6. Editing at the Q/R site determines the calcium permeability of the channel,[6] with channels containing the edited form being less permeable to calcium. This differs from GluR6 where editing of the Q/R site may increase calcium permeability of the channel especially if the I/V and Y/C sites are also edited. Therefore, the main function of editing is therefore in regulation of electrophysiology of the channel.[11]
Editing in some striatal and cortical neurons is more likely to be subject to excitotoxicity, thought to be due to less than 100% editing of these particular neurons.[9] Editing also has several other function effects. Editing alters the maturation and assembly of the channel, with the unedited form having a tendency to tetramerize and then is transported to the synapse. However, the edited version is assembled as a monomer and resides mainly in the endoplasmic reticulum. The arginine residue in the pore loop of GluR-2 receptor is thought to belong to a retention signal for the endoplasmic reticulum. Therefore, editing - since it occurs at 100% frequency - inhibits the availability of the channel at the synapse. This process occurs before assembly of the channels, thereby preventing glur-2-forming homeric channels, which could interfere with synaptic signalling.
Editing also occurs at the R/G site. Editing at the R/G sites results in variation in the rate that the receptor recovers from desensitisation. Editing at these sites results in faster recovery time from desensitisation [12]
### Dysregulation
Amyotrophic Lateral Sclerosis
Many human and animal studies have determined that RNA editing of the Q/R site in GluR2 pre-mRNA is necessary for normal brain function. Defective editing has been linked to several conditions such as amyotrophic lateral sclerosis (ALS). ALS effects 1 in 2000 people, usually fatal in 1–5 years, with onset in the majority of cases being sporadic and minority being familial.[13] With these conditions motor neurons degenerate leading to eventual paralysis and respiratory failure. Glutamate excitotoxicity is known to contribute to the spread of the sporadic condition. Glutamate levels are increased up 40%, suggesting that activation of glutamate receptors could be the reason for this causing increase Ca influx and then neuronal death.[14] Since decrease nor loss of editing at Q/R site would lead to increase in calcium permeability. In diseased motor neurons editing levels of Glur 2 (62-100%) at this site was discovered to be reduced.[15][16][17][18]
Abnormal editing is thought to be specific for this condition, as editing levels have not been found to be decreased in spinal and bulbar muscular atrophy.[18] Q/R editing is not the only mechanism involved, as editing occurs only in spinal motor neurons not in upper spinal neurons. Also, it is unknown whether editing dysregulation is involved in the initiation of the condition, or whether it occurs during pathogenesis.
Epilepsy
In mouse models, failure of editing leads to epileptic seizures and death within 3 weeks of birth. [6] Why editing exists at this site instead of a genomically encoded arginine is unknown since nearly 100% of transcripts are edited.
Cancer
Decreased editing at the Q/R site is also found in some human brain tumors. Reduction of ADAR2 expression is thought to be associated with epileptic seizures in malignant glioma.[19]
# Use in diagnostic immunochemistry
GRIA2 is a diagnostic immunochemical marker for solitary fibrous tumour (SFT), distinguishing it from most mimics. Among other CD34-positive tumours, GRIA2 is also expressed in dermatofibrosarcoma protuberans (DFSP); however, clinical and histologic features aid in their distinction. GRIA2 shows a limited distribution in other soft tissue tumours.[20] | https://www.wikidoc.org/index.php/GRIA2 | |
512f4036c86e05d401c4d850761c4e05bc59f452 | wikidoc | GRIA3 | GRIA3
Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternative splicing at this locus results in several different isoforms which may vary in their signal transduction properties.
# Interactions
GRIA3 has been shown to interact with GRIP1 and PICK1.
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor: ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as rna splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. GluR3 is a gene product of the GRIA3 gene and its pre-mRNA is subject to RNA editing.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
## Location
The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 and M4 regions. Editing results in a codon change from an arginine (AGA) to a glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor. The R/G site is found at amino acid 769 immediately before the 38-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein. The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site. The predicted double stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing at this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.
## Conservation
Editing also occurs in rat.
## Regulation
Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited. The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.
## Consequences
### Structure
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.
### Function
Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allow sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form. Editing is also thought to affect splicing at this site. | GRIA3
Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.[1][2][3]
# Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternative splicing at this locus results in several different isoforms which may vary in their signal transduction properties.[3]
# Interactions
GRIA3 has been shown to interact with GRIP1[4] and PICK1.[4]
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs.[5] This includes 5 subunits of the glutamate receptor: ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate gated ion channels are made up of four subunits per channel with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel).[6] The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing.[7] The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as rna splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. GluR3 is a gene product of the GRIA3 gene and its pre-mRNA is subject to RNA editing.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS)
## Location
The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 and M4 regions. Editing results in a codon change from an arginine (AGA) to a glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor. The R/G site is found at amino acid 769 immediately before the 38-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.[8] The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site. The predicted double stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing at this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.[8][9]
## Conservation
Editing also occurs in rat.[8]
## Regulation
Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited.[8] The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.[10]
## Consequences
### Structure
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[8]
### Function
Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allow sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.[8] Editing is also thought to affect splicing at this site. | https://www.wikidoc.org/index.php/GRIA3 | |
6d0ef62a82433714d1330afd0df7d37b0defebaf | wikidoc | GRIA4 | GRIA4
Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.
This gene is a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA). Some haplotypes of this gene show a positive association with schizophrenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Interactions
GRIA4 has been shown to interact with CACNG2, GRIP1, PICK1 and PRKCG.
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNa are substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and Kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel. Their function is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing, by RNA editing events of the individual subunits. This give rise to the necessary diversity of the receptors. GluR4 is a gene product of the GRIA4 gene, and its pre-mRNA is subject to RNA editing.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues, while ADAR 3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
## Location
The pre-mRNA of this subunit is edited at one position.
The R/G editing site is located in exon 13 between the M3 to M4 region. Editing results in a codon change from an Arginine (AGA) to a Glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor.((((((37))))))The R/G site is found at amino acid 769 immediately before the 3-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.
The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site, and the predicted double-stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.
## Conservation
Editing also occurs in rat.
## Regulation
Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited. The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.
## Consequences
### Structure
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.
### Function
Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allows sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.
Editing is also thought to affect splicing at this site | GRIA4
Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.[1]
This gene is a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA). Some haplotypes of this gene show a positive association with schizophrenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[1]
# Interactions
GRIA4 has been shown to interact with CACNG2,[2] GRIP1,[3] PICK1[3] and PRKCG.[4]
# RNA editing
Several ion channels and neurotransmitters receptors pre-mRNa are substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and Kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel. Their function is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing, by RNA editing events of the individual subunits. This give rise to the necessary diversity of the receptors. GluR4 is a gene product of the GRIA4 gene, and its pre-mRNA is subject to RNA editing.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues, while ADAR 3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
## Location
The pre-mRNA of this subunit is edited at one position.
The R/G editing site is located in exon 13 between the M3 to M4 region. Editing results in a codon change from an Arginine (AGA) to a Glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor.((((((37))))))The R/G site is found at amino acid 769 immediately before the 3-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.[5]
The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site, and the predicted double-stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.[5][6]
## Conservation
Editing also occurs in rat.[5]
## Regulation
Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited.[5] The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.[7]
## Consequences
### Structure
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[5]
### Function
Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allows sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.[5]
Editing is also thought to affect splicing at this site | https://www.wikidoc.org/index.php/GRIA4 | |
d07e97492d306712a4f508ae43e8ac22b79fbca7 | wikidoc | GRID1 | GRID1
Glutamate receptor delta-1 subunit also known as GluD1 or GluRδ1 is a protein that in humans is encoded by the GRID1 gene.
# Function
This gene encodes a subunit of glutamate receptor ligand-gated ion channel. These channels mediate most of the fast excitatory synaptic transmission in the central nervous system and play key roles in synaptic plasticity.
# Clinical significance
Several genetic epidemiology studies have shown a strong association between several variants of the GRID1 gene and increased risk of developing schizophrenia. | GRID1
Glutamate receptor delta-1 subunit also known as GluD1 or GluRδ1 is a protein[1][2] that in humans is encoded by the GRID1 gene.[3][4]
# Function
This gene encodes a subunit of glutamate receptor ligand-gated ion channel. These channels mediate most of the fast excitatory synaptic transmission in the central nervous system and play key roles in synaptic plasticity.[3]
# Clinical significance
Several genetic epidemiology studies have shown a strong association between several variants of the GRID1 gene and increased risk of developing schizophrenia.[5][6] | https://www.wikidoc.org/index.php/GRID1 | |
08e01aeafd0a9ae03e1c803b2df1c2010ffdc31c | wikidoc | GRID2 | GRID2
Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the GRID2 gene. This protein together with GluD1 belongs to the delta receptor subtype of ionotropic glutamate receptors. They possess 14–24% sequence homology with AMPA, kainate, and NMDA subunits, but, despite their name, do not actually bind glutamate or various other glutamate agonists.
delta iGluRs have long been considered orphan receptors as their endogenous ligand was unknown. They are now believed to bind glycine and D-serine but these do not result in channel opening.
# Function
GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.
GluD2 induces synaptogenesis through interaction of its N-terminal domain with Cbln1, which in turn interacts with presynaptic neurexins, forming a bridge across cerebellar synapses.
The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus. This is regulated by D-serine, which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel. These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter protein-protein interactions.
# Pathology
A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement and tonic upgaze, that can be classified as an ataxia with oculomotor apraxia (AOA) and has been named spinocerebellar ataxia, autosomal recessive type 18 (SCAR18).
A gain of channel function, resulting from a point mutation in mouse GRID2, is associated with the phenotype named 'lurcher', which in the heterozygous state leads to ataxia and motor coordination deficits resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.
# Ligands
9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ2-containing receptors.
# Interactions
GRID2 has been shown to interact with GOPC, GRIK2, PTPN4 and GRIA1. A possible correlation between GRID2 and the pre-B lymphocyte protein 3 (VPREB3) has been suggested, due to the apparent importance of B-lymphocytes in the origins of cerebellar Purkinje neurons in humans. Morphological studies conducted in GRID2-knockout mice suggest that GRID2 may be present in lymphocytes as well as in the adrenal cortex, however further studies must be conducted to confirm these claims. | GRID2
Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the GRID2 gene.[1][2] This protein together with GluD1 belongs to the delta receptor subtype of ionotropic glutamate receptors. They possess 14–24% sequence homology with AMPA, kainate, and NMDA subunits, but, despite their name, do not actually bind glutamate or various other glutamate agonists.[3]
delta iGluRs have long been considered orphan receptors as their endogenous ligand was unknown. They are now believed to bind glycine and D-serine but these do not result in channel opening.[4][5]
# Function
GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum[3][6] where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.[7]
GluD2 induces synaptogenesis through interaction of its N-terminal domain with Cbln1, which in turn interacts with presynaptic neurexins, forming a bridge across cerebellar synapses.[7][8]
The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.[9] This is regulated by D-serine,[10] which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel.[5] These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter protein-protein interactions.
# Pathology
A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement[11] whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement[12] and tonic upgaze,[13] that can be classified as an ataxia with oculomotor apraxia (AOA) and has been named spinocerebellar ataxia, autosomal recessive type 18 (SCAR18).
A gain of channel function, resulting from a point mutation in mouse GRID2, is associated with the phenotype named 'lurcher', which in the heterozygous state leads to ataxia and motor coordination deficits resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development.[14] [15] Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.
# Ligands
9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ2-containing receptors.[16]
# Interactions
GRID2 has been shown to interact with GOPC,[17] GRIK2,[18] PTPN4[19] and GRIA1.[18] A possible correlation between GRID2 and the pre-B lymphocyte protein 3 (VPREB3) has been suggested, due to the apparent importance of B-lymphocytes in the origins of cerebellar Purkinje neurons in humans.[20][21][22][23][24] Morphological studies conducted in GRID2-knockout mice suggest that GRID2 may be present in lymphocytes as well as in the adrenal cortex, however further studies must be conducted to confirm these claims.[23][25] | https://www.wikidoc.org/index.php/GRID2 | |
b0d354bf15ab958ee816fe3d6e3de88d9c6aebc3 | wikidoc | GRIK1 | GRIK1
Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.
# Function
This gene encodes one of the many ionotropic glutamate receptor (GluR) subunits that function as a ligand-gated ion channel. The specific GluR subunit encoded by this gene is of the kainate receptor subtype. Receptor assembly and intracellular trafficking of ionotropic glutamate receptors are regulated by RNA editing and alternative splicing. These receptors mediate excitatory neurotransmission and are critical for normal synaptic function. Two alternatively spliced transcript variants that encode different isoforms have been described. Exons of this gene are interspersed with exons from the C21orf41 gene, which is transcribed in the same orientation as this gene but does not seem to encode a protein.
# Interactions
GRIK1 has been shown to interact with DLG4, PICK1 and SDCBP.
# RNA editing
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues, whereas ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron, but can be an exonic sequence. The region that base-pairs with the editing region is known as an Editing Complementary Sequence (ECS).
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, the result could be a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A to I editing occurs in a noncoding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs( especially Alu repeats). The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus, among others.
## Location
The pre-mRNA of GluR-5 is edited at one position at the Q/R site located at membrane region 2 (M2). There is a codon change as a result of editing. The codon change is (CAG) Glutamine (Q) to (CGG) an Arginine (R).
Like GluR-6 the ECS is located about 2000 nucleotides downstream of the editing site.
## Regulation
Editing of the Q/R site is development- and tissue-regulated. Editing in the spinal cord, corpus callosum, cerebellum is 50%, while editing in the Thalamus, amydala, hippocampus is about 70%.
## Consequences
### Structure
Editing results in a change in amino acid in the second membrane domain of the receptor.
### Function
The editing site is found within the second intracellular domain. It is thought that editing affects the permeability of the receptor to CA2+. Editing of the Q/R site is thought to reduce the permeability of the channel to Ca2+
RNA editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid and docosahexaenoic acid For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids. However, inclusion of just one nonedited subunit is enough to stop this inhibition(. | GRIK1
Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.[1]
# Function
This gene encodes one of the many ionotropic glutamate receptor (GluR) subunits that function as a ligand-gated ion channel. The specific GluR subunit encoded by this gene is of the kainate receptor subtype. Receptor assembly and intracellular trafficking of ionotropic glutamate receptors are regulated by RNA editing and alternative splicing. These receptors mediate excitatory neurotransmission and are critical for normal synaptic function. Two alternatively spliced transcript variants that encode different isoforms have been described. Exons of this gene are interspersed with exons from the C21orf41 gene, which is transcribed in the same orientation as this gene but does not seem to encode a protein.[1]
# Interactions
GRIK1 has been shown to interact with DLG4,[2] PICK1[2] and SDCBP.[2]
# RNA editing
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues, whereas ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron, but can be an exonic sequence. The region that base-pairs with the editing region is known as an Editing Complementary Sequence (ECS).
ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, the result could be a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A to I editing occurs in a noncoding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs( especially Alu repeats). The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus, among others.
## Location
The pre-mRNA of GluR-5 is edited at one position at the Q/R site located at membrane region 2 (M2). There is a codon change as a result of editing. The codon change is (CAG) Glutamine (Q) to (CGG) an Arginine (R).[3]
Like GluR-6 the ECS is located about 2000 nucleotides downstream of the editing site.[4]
## Regulation
Editing of the Q/R site is development- and tissue-regulated. Editing in the spinal cord, corpus callosum, cerebellum is 50%, while editing in the Thalamus, amydala, hippocampus is about 70%.
## Consequences
### Structure
Editing results in a change in amino acid in the second membrane domain of the receptor.
### Function
The editing site is found within the second intracellular domain. It is thought that editing affects the permeability of the receptor to CA2+. Editing of the Q/R site is thought to reduce the permeability of the channel to Ca2+[3]
RNA editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid and docosahexaenoic acid[5] For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids. However, inclusion of just one nonedited subunit is enough to stop this inhibition(.[5] | https://www.wikidoc.org/index.php/GRIK1 | |
73dc0922a34505300c5284f70eda0b23dead7bda | wikidoc | GRIK4 | GRIK4
GRIK4 (glutamate receptor, ionotropic, kainate 4) is a kainate receptor subtype belonging to the family of ligand-gated ion channels which is encoded by the GRIK4 gene.
# Function
This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members.
# Clinical significance
A single nucleotide polymorphism (rs1954787) in the GRIK4 gene has shown a treatment-response-association with antidepressant treatment.
Variation in GRIK4 have been associated with both increased and decreased risk of bipolar disorder. A possible mechanism for this observation is that the sequence variation influences secondary structures in the 3' UTR.
Interfering with GRIK4/KA1 function with a specific anti-KA1 antibody protects against kainate-induced neuronal cell death.
A test of that gene can be made in order to know if a depressed patient will respond to the SSRI citalopram.
# Evolutionary significance
The GRIK4 gene displayed significantly higher rates of evolution in primates than in rodents and especially in the lineage leading from primates to humans. Furthermore, the GRIK4 gene is implicated in the development of the nervous system. Hence evolution of the GRIK4 gene is thought to have played a role in the dramatic increases in size and complexity of the brain that occurred during evolutionary history leading to humans. | GRIK4
GRIK4 (glutamate receptor, ionotropic, kainate 4) is a kainate receptor subtype belonging to the family of ligand-gated ion channels which is encoded by the GRIK4 gene.[1]
# Function
This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. The protein encoded by this gene forms functional heteromeric kainate-preferring ionic channels with the subunits encoded by related gene family members.[2]
# Clinical significance
A single nucleotide polymorphism (rs1954787) in the GRIK4 gene has shown a treatment-response-association with antidepressant treatment.[3]
Variation in GRIK4 have been associated with both increased and decreased risk of bipolar disorder.[4] A possible mechanism for this observation is that the sequence variation influences secondary structures in the 3' UTR.
Interfering with GRIK4/KA1 function with a specific anti-KA1 antibody protects against kainate-induced neuronal cell death.[5][6]
A test of that gene can be made in order to know if a depressed patient will respond to the SSRI citalopram.[3][7]
# Evolutionary significance
The GRIK4 gene displayed significantly higher rates of evolution in primates than in rodents and especially in the lineage leading from primates to humans. Furthermore, the GRIK4 gene is implicated in the development of the nervous system. Hence evolution of the GRIK4 gene is thought to have played a role in the dramatic increases in size and complexity of the brain that occurred during evolutionary history leading to humans.[8] | https://www.wikidoc.org/index.php/GRIK4 | |
72bd8dd114b1ef676b3475a3a8259c48829a89ed | wikidoc | GSDMD | GSDMD
Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8.
It belongs the gasdermin family which is conserved among all vertebrates and comprises six members, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 and DFNB59. Members of the gasdermin family are mainly expressed in epithelial tissues and appear to play a role in regulation of epithelial proliferation and differentiation. GSDMA, GSDMC, GSDMD and DFNA5 have been suggested to act as tumour suppressors.
# Structure
The structure of GSDMD consists of two domains, the 31 kDa N-terminal (GSDMD-N) and 22 kDa C-terminal (GSDMD-C) domains, separated by a linker region. GSDMD-C can be divided into four subdomains and is composed of 10 α-helices and two β-strands, forming a compact globular fold. The linker helix contacts the two helix-repeats which consist of four-helix bundles. The middle domain comprises an antiparallel β-strand and a short α-helix. The first flexible loop of GSDMD-C, which is located between GSDMD-N and the linker helix, stretches out and inserts into the GSDMD-N pocket, stabilising the conformation of the full-length protein.
# Function
Several current studies have revealed that GSDMD serves as a specific substrate of inflammatory caspases (caspase-1, -4, -5 and -11) and as an effector molecule for the lytic and highly inflammatory form of programmed cell death known as pyroptosis. Hence, GSDMD is an essential mediator of host defence against microbial infection and danger signals. The pore-forming activity of the N-terminal cleavage product causes cell swelling and lysis to prevent intracellular pathogens from replicating, and is required for the release of cytoplasmic content such as the inflammatory cytokine interleukin-1β (IL-1β) into the extracellular space to recruit and activate immune cells to the site of infection. GSDMD has an additional potential role as an antimicrobial by binding to cardiolipin (CL) and form pores on bacterial membranes.
# Autoinhibition
Under normal conditions, the full-length GSDMD is inactive as the linker loop between the N-terminal and C-terminal domains stabilises the overall conformation of the full-length protein and allows GSDMD-C to fold back on and auto-inhibit GSDMD-N from inducing pyroptosis.
Upon interdomain cleavage by inflammatory caspases, the auto-inhibition is relieved and GSDMD-N cytotoxicity is triggered.
# Activation
GSDMD can be cleaved and activated by inflammatory caspases through both the canonical and non-canonical pyroptotic pathways.
## Canonical inflammasome pathway
Caspase-1, conserved in vertebrates, is involved in the canonical pathway and is activated by canonical inflammasomes such as NLRP3 and NLRC4 inflammasomes, which are multi-protein complexes that are formed upon recognition of specific inflammatory ligands called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in the cytosol by NOD-like receptors (NLRs). Examples include bacterial type 3 secretion system (T3SS) rod protein and flagellin, which are potent activators of NLRC4 inflammasome, and bacterial toxin nigericin that activates NLRP3 inflammasome.
## Non-canonical inflammasome pathway
Caspase-11 in mice and its human homolog caspase-4 and -5 are involved in the non-canonical pathway and are activated by directly binding cytosolic lipopolysaccharide (LPS) secreted by gram-negative bacteria.
Upon activation of these caspases, GSDMD undergoes proteolytic cleavage at Asp-275, which is sufficient to drive pyroptosis.
# Mechanism
After the proteolytic cleavage, GSDMD-C remains in the cytosol while the N-terminal cleavage product localises to the plasma membrane by anchoring to membrane lipids. GSDMD-N specifically interacts with phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate on the inner leaflet of mammalian cell membrane strongly, through charge-charge interactions between the negatively-charged head groups of PI and the positively-charged surface on GSDMD-N exposed after cleavage. Hence, collateral damage to tissues during an infection is minimised as the extracellular outer leaflet lacks PI. Lipid binding allows GSDMD-N to insert into the lipid bilayer and induces high-order oligomerisation within the membrane, forming extensive pores with approximately 16 subunits and an inner diameter of 10-14 nm. The osmotic potential is disrupted by pore formation, leading to cell swelling and lysis, the morphologic hallmarks of pyroptosis. The pores also serve as a protein secretion channel to facilitate the secretion of inflammatory cytokines for rapid innate immune response. GSDMD-N can also undergo cytoplasmic distribution and selectively bind to CL on inner and outer leaflets of intracellular bacterial membranes, or be secreted from pyroptotic cells through the pores into the extracellular milieu to target and kill extracellular bacteria.
# Clinical significance
Pyroptosis, which can now be defined as gasdermin-mediated necrotic cell death, acts as an immune defence against infection. Hence, failure to express or cleave GSDMD can block pyroptosis and disrupt the secretion of IL-1β, and eventually unable to ablate the replicative niche of intracellular bacteria. Mutation of GSDMD is associated with various genetic diseases and human cancers, including brain, breast, lung, urinary bladder, cervical, skin, oral cavity, pharynx, colon, liver, cecum, stomach, pancreatic, prostate, oesophageal, head and neck, hematologic, thyroid and uterine cancers. Recently, studies have revealed that downregulation of GSDMD promotes gastric cancer proliferation due to the failure to inactivate ERK 1/2, STAT3 and PI3K/AKT pathways, which are involved in cell survival and tumour progression.
However, sepsis and lethal septic shock can be resulted from overactivation of pyroptosis. The critical role of GSDMD in pore formation during pyroptosis provides a new avenue for future drug development for treating inflammatory caspase-associated auto-inflammatory conditions, sepsis and septic shock.
# Interactions
GSDMD-N has been shown to interact with:
- Phosphatidylinositol 4-phosphate
- Phosphatidylinositol (4,5)-bisphosphate
- Phosphatidylinositol 3-phosphate
- Phosphatidylinositol 5-phosphate
- Phosphatidylinositol (3,4)-bisphosphate
- Phosphatidylinositol (3,5)-bisphosphate
- Phosphatidylinositol (3,4,5)-trisphosphate
- Phosphatidic acid
- Phosphatidylserine
- Phosphatidylethanolamine
- Cardiolipin | GSDMD
Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8.
[1]
It belongs the gasdermin family which is conserved among all vertebrates and comprises six members, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 and DFNB59. Members of the gasdermin family are mainly expressed in epithelial tissues and appear to play a role in regulation of epithelial proliferation and differentiation. GSDMA, GSDMC, GSDMD and DFNA5 have been suggested to act as tumour suppressors.[2]
# Structure
The structure of GSDMD consists of two domains, the 31 kDa N-terminal (GSDMD-N) and 22 kDa C-terminal (GSDMD-C) domains, separated by a linker region. GSDMD-C can be divided into four subdomains and is composed of 10 α-helices and two β-strands, forming a compact globular fold. The linker helix contacts the two helix-repeats which consist of four-helix bundles. The middle domain comprises an antiparallel β-strand and a short α-helix. The first flexible loop of GSDMD-C, which is located between GSDMD-N and the linker helix, stretches out and inserts into the GSDMD-N pocket, stabilising the conformation of the full-length protein.[3]
# Function
Several current studies have revealed that GSDMD serves as a specific substrate of inflammatory caspases (caspase-1, -4, -5 and -11) and as an effector molecule for the lytic and highly inflammatory form of programmed cell death known as pyroptosis.[4][5] Hence, GSDMD is an essential mediator of host defence against microbial infection and danger signals. The pore-forming activity of the N-terminal cleavage product causes cell swelling and lysis to prevent intracellular pathogens from replicating, and is required for the release of cytoplasmic content such as the inflammatory cytokine interleukin-1β (IL-1β) into the extracellular space to recruit and activate immune cells to the site of infection.[6] GSDMD has an additional potential role as an antimicrobial by binding to cardiolipin (CL) and form pores on bacterial membranes.
# Autoinhibition
Under normal conditions, the full-length GSDMD is inactive as the linker loop between the N-terminal and C-terminal domains stabilises the overall conformation of the full-length protein and allows GSDMD-C to fold back on and auto-inhibit GSDMD-N from inducing pyroptosis.[3]
Upon interdomain cleavage by inflammatory caspases, the auto-inhibition is relieved and GSDMD-N cytotoxicity is triggered.
# Activation
GSDMD can be cleaved and activated by inflammatory caspases through both the canonical and non-canonical pyroptotic pathways.[7]
## Canonical inflammasome pathway
Caspase-1, conserved in vertebrates, is involved in the canonical pathway and is activated by canonical inflammasomes such as NLRP3 and NLRC4 inflammasomes, which are multi-protein complexes that are formed upon recognition of specific inflammatory ligands called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in the cytosol by NOD-like receptors (NLRs). Examples include bacterial type 3 secretion system (T3SS) rod protein and flagellin, which are potent activators of NLRC4 inflammasome, and bacterial toxin nigericin that activates NLRP3 inflammasome.[5]
## Non-canonical inflammasome pathway
Caspase-11 in mice and its human homolog caspase-4 and -5 are involved in the non-canonical pathway and are activated by directly binding cytosolic lipopolysaccharide (LPS) secreted by gram-negative bacteria.[4]
Upon activation of these caspases, GSDMD undergoes proteolytic cleavage at Asp-275, which is sufficient to drive pyroptosis.[5]
# Mechanism
After the proteolytic cleavage, GSDMD-C remains in the cytosol while the N-terminal cleavage product localises to the plasma membrane by anchoring to membrane lipids. GSDMD-N specifically interacts with phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] on the inner leaflet of mammalian cell membrane strongly, through charge-charge interactions between the negatively-charged head groups of PI and the positively-charged surface on GSDMD-N exposed after cleavage.[8] Hence, collateral damage to tissues during an infection is minimised as the extracellular outer leaflet lacks PI. Lipid binding allows GSDMD-N to insert into the lipid bilayer and induces high-order oligomerisation within the membrane, forming extensive pores with approximately 16 subunits and an inner diameter of 10-14 nm.[3] The osmotic potential is disrupted by pore formation, leading to cell swelling and lysis, the morphologic hallmarks of pyroptosis. The pores also serve as a protein secretion channel to facilitate the secretion of inflammatory cytokines for rapid innate immune response.[9] GSDMD-N can also undergo cytoplasmic distribution and selectively bind to CL on inner and outer leaflets of intracellular bacterial membranes, or be secreted from pyroptotic cells through the pores into the extracellular milieu to target and kill extracellular bacteria.[10]
# Clinical significance
Pyroptosis, which can now be defined as gasdermin-mediated necrotic cell death, acts as an immune defence against infection. Hence, failure to express or cleave GSDMD can block pyroptosis and disrupt the secretion of IL-1β, and eventually unable to ablate the replicative niche of intracellular bacteria. Mutation of GSDMD is associated with various genetic diseases and human cancers, including brain, breast, lung, urinary bladder, cervical, skin, oral cavity, pharynx, colon, liver, cecum, stomach, pancreatic, prostate, oesophageal, head and neck, hematologic, thyroid and uterine cancers.[11] Recently, studies have revealed that downregulation of GSDMD promotes gastric cancer proliferation due to the failure to inactivate ERK 1/2, STAT3 and PI3K/AKT pathways, which are involved in cell survival and tumour progression.[12]
However, sepsis and lethal septic shock can be resulted from overactivation of pyroptosis.[13] The critical role of GSDMD in pore formation during pyroptosis provides a new avenue for future drug development for treating inflammatory caspase-associated auto-inflammatory conditions, sepsis and septic shock.[11]
# Interactions
GSDMD-N has been shown to interact with:[8]
- Phosphatidylinositol 4-phosphate
- Phosphatidylinositol (4,5)-bisphosphate
- Phosphatidylinositol 3-phosphate
- Phosphatidylinositol 5-phosphate
- Phosphatidylinositol (3,4)-bisphosphate
- Phosphatidylinositol (3,5)-bisphosphate
- Phosphatidylinositol (3,4,5)-trisphosphate
- Phosphatidic acid
- Phosphatidylserine
- Phosphatidylethanolamine
- Cardiolipin | https://www.wikidoc.org/index.php/GSDMD | |
07c6e17c9585a924f7a5029dfe612287328ea910 | wikidoc | GSK-3 | GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B).
GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.
# Mechanism
GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).
# Function
Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target. GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis.
GSK-3 was originally discovered in the context of its involvement in regulating glycogen synthase. After being primed by casein kinase 2 (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity. In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor IRS1 and of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6 phosphatase. However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.
GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production. The inactivation of GSK3B by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naïve and memory CD4+ T cells. In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration.
GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate Beta-catenin, thus targeting it for degradation. GSK-3 is therefore a part of the canonical Beta-catenin/Wnt pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis. GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as p53 and inactivating survival-promoting factors through phosphorylation. The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis. Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.
# Regulation
Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.
The speed and efficacy of GSK-3 phosphorylation is regulated by a number of factors. Phosphorylation of certain GSK-3 residues can increase or decrease its ability to bind substrate. Phosphorylation at tyrosine-216 in GSK-3β or tyrosine-279 in GSK-3α enhances the enzymatic activity of GSK-3, while phosphorylation of serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see Figure 1). Further, GSK-3 is unusual among kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate. A phosphorylated serine or threonine residue located four amino acids C-terminal to the target site of phosphorylation allows the substrate to bind a pocket of positive charge formed by arginine and lysine residues.
Depending on the pathway in which it is being utilized, GSK-3 may be further regulated by cellular localization or the formation of protein complexes. The activity of GSK-3 is far greater in the nucleus and mitochondria than in the cytosol in cortical neurons, while the phosphorylation of Beta-catenin by GSK-3 is mediated by the binding of both proteins to Axin, a scaffold protein, allowing Beta-catenin to access the active site of GSK-3.
# Disease relevance
Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in Alzheimer's disease, type 2 diabetes mellitus (T2DM), some forms of cancer, and bipolar disorder.
It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect. Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock. Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.
GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of amyloid-β (Aβ) deposits and the formation of neurofibrillary tangles. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the hyperphosphorylation of tau proteins, which leads to the tangles. Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.
In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote apoptosis in some cases, it has also been reported to be a key factor in tumorigenesis in some cancers. Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.
GSK-3 inhibitors have also shown promise in the treatment of T2DM. Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice. GSK-3 inhibitors may also have therapeutic effects on hemorrhagic transformation after acute ischemic stroke. The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.
GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells. GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.
# Inhibitors
Inhibitors of GSK-3 include:
## Metal cations
- Beryllium
- Copper
- Lithium (IC50=2mM)
- Mercury
- Tungsten (Indirect)
## ATP-competitive
### Marine organism-derived
- 6-BIO (IC50=1.5μM)
- Dibromocantharelline (IC50=3μM)
- Hymenialdesine (IC50=10nM)
- Indirubin (IC50=5-50nM)
- Meridianin
### Aminopyrimidines
IC50=0.6-7nM:
- CT98014
- CT98023
- CT99021
- TWS119
### Arylindolemaleimide
- SB-216763 (IC50=34nM)
- SB-41528 (IC50=77nM)
### Thiazoles
- AR-A014418 (IC50=104nM)
- AZD-1080
### Paullones
IC50=4-80nM:
- Alsterpaullone
- Cazpaullone
- Kenpaullone
### Aloisines
IC50=0.5-1.5μM:
## Non-ATP competitive
### Marine organism-derived
- Manzamine A (IC50=1.5μM)
- Palinurine (IC50=4.5μM)
- Tricantine (IC50=7.5μM)
### Thiadiazolidindiones
- TDZD-8 (IC50=2μM)
- NP00111 (IC50=2μM)
- NP031115 (IC50=4μM)
- Tideglusib
### Halomethylketones
- HMK-32 (IC50=1.5μM)
### Peptides
- L803-mts (IC50=40μM)
Other: Ketamine | GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase,[2] GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways.[3] In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B).
GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.
# Mechanism
GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).[4]
# Function
Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.[5][6][7] GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis.
GSK-3 was originally discovered in the context of its involvement in regulating glycogen synthase.[2] After being primed by casein kinase 2 (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity.[8] In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor IRS1 [9] and of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6 phosphatase.[10] However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.[8]
GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production.[11][12] The inactivation of GSK3B by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naïve and memory CD4+ T cells.[12] In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration.[11]
GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate Beta-catenin, thus targeting it for degradation.[13] GSK-3 is therefore a part of the canonical Beta-catenin/Wnt pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis.[3] GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as p53 [14] and inactivating survival-promoting factors through phosphorylation.[15] The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3β knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis.[16] Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.[17]
# Regulation
Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.
The speed and efficacy of GSK-3 phosphorylation is regulated by a number of factors. Phosphorylation of certain GSK-3 residues can increase or decrease its ability to bind substrate. Phosphorylation at tyrosine-216 in GSK-3β or tyrosine-279 in GSK-3α enhances the enzymatic activity of GSK-3, while phosphorylation of serine-9 in GSK-3β or serine-21 in GSK-3α significantly decreases active site availability (see Figure 1).[11] Further, GSK-3 is unusual among kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate. A phosphorylated serine or threonine residue located four amino acids C-terminal to the target site of phosphorylation allows the substrate to bind a pocket of positive charge formed by arginine and lysine residues.[8][18]
Depending on the pathway in which it is being utilized, GSK-3 may be further regulated by cellular localization or the formation of protein complexes. The activity of GSK-3 is far greater in the nucleus and mitochondria than in the cytosol in cortical neurons,[19] while the phosphorylation of Beta-catenin by GSK-3 is mediated by the binding of both proteins to Axin, a scaffold protein, allowing Beta-catenin to access the active site of GSK-3.[11]
# Disease relevance
Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in Alzheimer's disease, type 2 diabetes mellitus (T2DM), some forms of cancer, and bipolar disorder.[20]
It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect.[11] Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock.[21] Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.[22]
GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of amyloid-β (Aβ) deposits and the formation of neurofibrillary tangles. GSK-3 is thought to directly promote Aβ production and to be tied to the process of the hyperphosphorylation of tau proteins, which leads to the tangles.[3][11] Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.[23]
In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote apoptosis in some cases, it has also been reported to be a key factor in tumorigenesis in some cancers.[24] Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.[16][25]
GSK-3 inhibitors have also shown promise in the treatment of T2DM.[8] Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice.[11] GSK-3 inhibitors may also have therapeutic effects on hemorrhagic transformation after acute ischemic stroke.[26] The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.
GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.[27] GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.
# Inhibitors
Inhibitors of GSK-3 include:[28]
## Metal cations
- Beryllium
- Copper
- Lithium (IC50=2mM)
- Mercury
- Tungsten (Indirect)
## ATP-competitive
### Marine organism-derived
- 6-BIO (IC50=1.5μM)
- Dibromocantharelline (IC50=3μM)
- Hymenialdesine (IC50=10nM)
- Indirubin (IC50=5-50nM)
- Meridianin
### Aminopyrimidines
IC50=0.6-7nM:
- CT98014
- CT98023
- CT99021
- TWS119
### Arylindolemaleimide
- SB-216763 (IC50=34nM)
- SB-41528 (IC50=77nM)
### Thiazoles
- AR-A014418 (IC50=104nM)
- AZD-1080
### Paullones
IC50=4-80nM:
- Alsterpaullone
- Cazpaullone
- Kenpaullone
### Aloisines
IC50=0.5-1.5μM:
## Non-ATP competitive
### Marine organism-derived
- Manzamine A (IC50=1.5μM)
- Palinurine (IC50=4.5μM)
- Tricantine (IC50=7.5μM)
### Thiadiazolidindiones
- TDZD-8 (IC50=2μM)
- NP00111 (IC50=2μM)
- NP031115 (IC50=4μM)
- Tideglusib
### Halomethylketones
- HMK-32 (IC50=1.5μM)
### Peptides
- L803-mts (IC50=40μM)
Other: Ketamine | https://www.wikidoc.org/index.php/GSK-3 | |
aa1513bdde40c9b2e2ae079d66972ba02d1cfd79 | wikidoc | GSK3A | GSK3A
Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene.
Glycogen synthase kinase 3-alpha EC 2.7.1.37 is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' (zeste-white3) and implicated in the control of several regulatory proteins including glycogen synthase and various transcription factors (e.g., JUN). It also plays a role in the WNT and phosphoinositide 3-kinase (especially PIK3CG) signaling pathways.
# Model organisms
Model organisms have been used in the study of GSK3A function. A conditional knockout mouse line, called Gsk3atm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty one tests were carried out on mutant mice but no significant abnormalities were observed. | GSK3A
Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene.[1]
Glycogen synthase kinase 3-alpha EC 2.7.1.37 is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' (zeste-white3) and implicated in the control of several regulatory proteins including glycogen synthase and various transcription factors (e.g., JUN). It also plays a role in the WNT and phosphoinositide 3-kinase (especially PIK3CG) signaling pathways.[2][3]
# Model organisms
Model organisms have been used in the study of GSK3A function. A conditional knockout mouse line, called Gsk3atm1a(EUCOMM)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty one tests were carried out on mutant mice but no significant abnormalities were observed.[4] | https://www.wikidoc.org/index.php/GSK3A |
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