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a3b5bbd91bd6853c82f206e405458c19a5ac4f5f | wikidoc | CARM1 | CARM1
CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), is an enzyme (EC 2.1.1.125) encoded by the CARM1 gene found in human beings, as well as many other mammals. It has a polypeptide (L) chain type that is 348 residues long, and is made up of alpha helices and beta sheets. Its main function includes catalyzing the transfer of a methyl group from S-adenosyl-L-methionine to the side chain nitrogens of arginine residues within proteins to form methylated arginine derivatives and S-adenosyl-L-homocysteine. CARM1 is a secondary coactivator through its association with p160 family (SRC-1, GRIP1, AIB) of coactivators. It is responsible for moving cells toward the inner cell mass in developing blastocysts.
# Clinical significance
CARM1 plays an important role in androgen receptors and may play a role in prostate cancer progression.
CARM1 exerts both oncogenic and tumor-suppressive functions. In breast cancer, CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. In pancreatic cancer, CARM1 methylates and inhibits MDH1 by disrupting its dimerization, which represses mitochondria respiration and inhibits glutamine utilization. CARM1-mediated MDH1 methylation reduces cellular NADPH level and sensitizes cells to oxidative stress, thereby suppressing cell proliferation and colony formation. | CARM1
CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), is an enzyme (EC 2.1.1.125) encoded by the CARM1 gene found in human beings, as well as many other mammals.[2] It has a polypeptide (L) chain type that is 348 residues long, and is made up of alpha helices and beta sheets.[3] Its main function includes catalyzing the transfer of a methyl group from S-adenosyl-L-methionine to the side chain nitrogens of arginine residues within proteins to form methylated arginine derivatives and S-adenosyl-L-homocysteine.[4] CARM1 is a secondary coactivator through its association with p160 family (SRC-1, GRIP1, AIB) of coactivators. It is responsible for moving cells toward the inner cell mass in developing blastocysts.[5]
# Clinical significance
CARM1 plays an important role in androgen receptors and may play a role in prostate cancer progression.[6][7]
CARM1 exerts both oncogenic and tumor-suppressive functions. In breast cancer, CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis.[8] In pancreatic cancer, CARM1 methylates and inhibits MDH1 by disrupting its dimerization, which represses mitochondria respiration and inhibits glutamine utilization. CARM1-mediated MDH1 methylation reduces cellular NADPH level and sensitizes cells to oxidative stress, thereby suppressing cell proliferation and colony formation.[9] | https://www.wikidoc.org/index.php/CARM1 | |
eb4a80793e2e234086608387359b7f3a9739dc17 | wikidoc | CASC5 | CASC5
CASC5 is a protein that is encoded by the CASC5 gene in humans.
# Function
CASC5 is part of the kinetochore. It is involved in microtubule attachment to chromosome centromeres and in the activation of the spindle checkpoint during mitosis. The CASC5 gene is upregulated in the areas of cell proliferation surrounding the ventricles during fetal brain development.
# Interactions
CASC5 has been shown to interact with MIS12, BUB1, BUBR1 and ZWINT-1.
# Polymorphisms
Homozygous polymorphisms in the CASC5 gene have been seen in patients with autosomal recessive primary microcephaly (MCPH). The mutation resulted in the skipping of exon 18 transcription, causing a frameshift and the production of a truncated protein. This truncation inhibits the binding ability of MIS12. | CASC5
CASC5 is a protein that is encoded by the CASC5 gene in humans.[1][2][3][4]
# Function
CASC5 is part of the kinetochore. It is involved in microtubule attachment to chromosome centromeres and in the activation of the spindle checkpoint during mitosis. The CASC5 gene is upregulated in the areas of cell proliferation surrounding the ventricles during fetal brain development.[5]
# Interactions
CASC5 has been shown to interact with MIS12,[6][7] BUB1, BUBR1 and ZWINT-1.[5]
# Polymorphisms
Homozygous polymorphisms in the CASC5 gene have been seen in patients with autosomal recessive primary microcephaly (MCPH). The mutation resulted in the skipping of exon 18 transcription, causing a frameshift and the production of a truncated protein. This truncation inhibits the binding ability of MIS12.[5] | https://www.wikidoc.org/index.php/CASC5 | |
4dcb18914b5cf92048609b3ff7a7ce10a13f0230 | wikidoc | CASPR | CASPR
CASPR also known as Contactin associated protein 1, Paranodin and CASPR1 is a protein that in humans is encoded by the CNTNAP1 gene.
CASPR is a part of the neurexin family of proteins, hence its another name "Neurexin IV". CASPR is a membrane protein found in the neuronal membrane in the paranodal section of the axon in myelinated neurons, between the Nodes of Ranvier containing Na+ channels, and juxtaparanode, which contains K+ channels. During myelination, caspr associates with contactin in a cis complex, though its precise role in myelination is not yet understood.
# Function
The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. .
Mutations in CNTNAP1 cause arthrogryposis multiplex congenita . | CASPR
CASPR also known as Contactin associated protein 1, Paranodin and CASPR1 is a protein that in humans is encoded by the CNTNAP1 gene.[1]
CASPR is a part of the neurexin family of proteins, hence its another name "Neurexin IV".[2] CASPR is a membrane protein found in the neuronal membrane in the paranodal section of the axon in myelinated neurons, between the Nodes of Ranvier containing Na+ channels, and juxtaparanode, which contains K+ channels.[3] During myelination, caspr associates with contactin in a cis complex,[3] though its precise role in myelination is not yet understood.
# Function
The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. [provided by RefSeq, Jan 2009].
Mutations in CNTNAP1 cause arthrogryposis multiplex congenita .[4] | https://www.wikidoc.org/index.php/CASPR | |
6c8ee61e4415505c120d5b165d6c73ec77170802 | wikidoc | CASS4 | CASS4
Cas scaffolding protein family member 4 is a protein that in humans is encoded by the CASS4 gene.
# History and discovery
CASS4 (Crk associated substrate 4) is the fourth and last described member of the CAS protein family. CASS4 was detected by Singh et al. in 2008 following in silico screening of databases describing expressed sequence tags from an evolutionarily diverse group of organisms, using the CAS-related proteins (p130Cas, NEDD9/HEF1 and EFS) mRNAs as templates. Singh et al. subsequently cloned and characterized the CASS4 gene, originally assigning the name HEPL (HEF1-EFS-p130Cas-like) for similarity to the other three defined CAS genes. The official name was subsequently changed to CASS4 by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC).
# Gene
The chromosomal location of the CASS4 gene is 20q13.31, with genomic coordinates of 20: 56411548-56459340 on the forward strand in GRChB38p2. While its HGNC-approved symbol is CASS4, this gene has multiple synonyms, including "HEF-like protein", "HEF1-Efs-p130Cas-like", HEFL, HEPL and C20orf32 ("chromosome 20 open reading frame 32"). Official IDs assigned to this gene include 15878 (HGNC), 57091 (Entrez Gene) and ENSG00000087589 (Ensembl). In humans four transcript variants are known. The first and second each contain 7 exons and encode the same full-length protein isoform a (786 amino acids, considered the major isoform), the third one contains 6 exons and encodes a shorter isoform b (732 amino acids) and the fourth one contains 5 exons and encodes the shortest isoform c (349 amino acids). Cumulatively, the CASS4 transcripts are most highly expressed in spleen and lung among normal tissues, and are highly expressed in ovarian and leukemia cell lines.
To date, little effort has been applied to the direct study of transcriptional regulation of CASS4. The SABiosciences’ DECODE database, based on the UCSC Bioinformatics Genome Browser, proposes several transcriptional regulators for CASS4 based on its promotor region sequence: NF-κβ, p53, LCR-F1 (NFE2-L1, nuclear factor, erythroid 2-like1), MAX1, C/EBPα, CHOP-10 (C/EBP homologous protein 10), POU3F1 (POU domain, class 3, transcription factor 1, aka Oct-6), Areb6 (ZEB1, Zinc finger E-box binding homeobox 1). These are compatible with regulation relevant to lymphocytes and deregulation in cancer.
# Protein family
In vertebrates, the CAS protein family contains four members: p130Cas/BCAR1, NEDD9/HEF1, EFS and CASS4. There are no paralogous genes for this family in acoelomates, pseudocoelomates, and nematodes, while a single ancestral member is found in Drosophila. Evolutionary divergence of the CAS proteins family members is discussed by Singh et al. in detail.
# Structure
All CAS protein family members have common structural characteristics. CAS proteins have an amino terminal SH3 domain enabling interaction with poly-proline motif-containing proteins such as FAK. Carboxy-terminal to this, they possess an unstructured domain containing multiple SH2 binding site motifs, which when tyrosine-phosphorylated allow interaction with SH2 domain containing proteins. Further to the carboxy-terminus, they have a four-helix bundle rich in serine residues, and a second highly conserved four-helix bundle that has been recognized as functionally and structurally similar to a focal adhesion targeting domain. For the better studied members of the CAS family (BCAR1 and NEDD9), all of these domains have been defined as crucial for recognition and binding by other proteins, reflecting the primary role of CAS family proteins as cell signaling cascades mediators.
Isoform “a” of human CASS4 is considered the predominant species, and at 786 amino acids is the longest one. Amino acid sequence homology of this isoform of human CASS4 with other family members is 26% overall identity and 42% similarity. Using a yeast two-hybrid approach, the CASS4 protein SH3 domain was shown to interact with the FAK C-terminus, despite the lowest overall similarity to other SH3 domains in the CAS group. In addition, human CASS4 has a limited number of candidate SH2-binding sites, estimated at 10, which is similar to EFS (estimated at 9) and in contrast to p130Cas/BCAR1 and NEDD9, which have 20 and 18 respectively. The CASS4 C-terminus has a short region of CAS family homology, but lacks obvious similarity at the level of primary amino acid sequence. It also lacks a YDYVHL sequence at the N-terminal end of the FAT-like carboxy-terminal domain, even though this motif is conserved among the other three CAS family proteins and is an important binding site for the Src SH2 domain. Although this lack of sequence similarity may mean a reduced functionality of the CASS4 protein, molecular modeling analysis performed by Singh and colleagues using p130CAS/BCAR1 structures as templates suggested an almost identical fold between CASS4 and p130CAS/BCAR1 within their SH3 domains, and substantial similarity within 432-591 residues of CASS4 and 449-610 residues of p130Cas/BCAR1 at the level of secondary and tertiary structures. Also, the similar periodicity of α-helices and β-sheets in both CASS4 and p130Cas/BCAR1 provides another confirmation for the idea of well-conserved structures within the family members.
# Function
The exact function of CASS4 and its role in development and human pathologies have been subject to little investigation compared to other family members. The primary study exploring CASS4 function was the initial report by Singh et al., who showed the direct interaction between CASS4 and FAK, and CASS4 regulation of FAK activation, affecting cellular adhesion, migration and motility. Unusually, CASS4 depletion had a bimodal affect, causing some cells to have lower velocity and others to have higher velocity than control cells, suggesting a potential role in maintaining homeostasis. This work also suggested the function of CASS4 may be cell-type specific and dependent upon the presence or absence of expression of other CAS family members. Direct binding has also been identified between CASS4 and CRKL, an SH2- and SH3 domain-containing adaptor protein that has been also shown to interact with another CAS family member, p130Cas/BCAR1, in regulation of cellular motility and migration. Because of the high degree of homology in interaction domains and some identified common partners, CASS4 is likely to share some functions with other CAS family members. These include association with FAK and Src family kinases at focal adhesions to transmit integrin-initiated signals to downstream effectors, which results in cytoskeleton reorganization and changes in motility and invasion.
# Disease association
Altered expression or modification of CASS4 has been proposed as relevant to several human pathologies, typically based on detection of changes in CASS4 in high throughput screening, although the role of CASS4 in the pathology of these conditions has not yet been studied directly. These findings are summarized in Table 1; some examples are provided below.
## Cancer
Many CAS family proteins have altered activity and functional roles in cancer progression and metastasis, with functional roles in influencing cellular adhesion, migration and drug resistance. Changes in CASS4 may also be associated with human malignancies. CASS4 function was linked to non-small cell lung cancer (NSCLC) in a study by Miao et al. that correlated elevated CASS4 expression with lymph node metastasis and high TNM stage. In addition, this study detected a significant difference in cytoplasmic accumulation of CASS4 protein between high (H1299 and BE1) and low (LTE and A549) metastatic potential lung cancer cell lines. These may suggest CASS4 as a possible prognostic marker in clinical management of NSCLC.
## Alzheimer's disease
CASS4 and corresponding SNP - rs7274581 T/C has been identified in a large meta-analysis as a locus for lower susceptibility to Alzheimer's disease (AD). However this SNP was not found predictive in a follow-up study.
In a genome wide association screen (GWAS), CASS4 showed a significant correlation with clinical pathological features of AD such as neurofibrillary tangles and neuritic plaques. Two additional CASS4 SNPs were reported to be associated with AD susceptibility: rs6024870, and rs16979934 T/G. Given the likely conserved CAS-family cytoskeletal function of CASS4, it has been speculated that it may have a role in axonal transport and influence the expression of the amyloid precursor protein (APP) and tau, which are pathologically affected in AD. Several possible mechanisms for CASS4 action in AD have been proposed.
## Immunopathological conditions
An association of CASS4 with atopic asthma has been shown. CASS4 has also been reported to be an eosinophil-associated gene, with expression in sputum cells increased more than 1.5-fold after whole lung allergen challenge. Moreover, the CASS4 mRNA was upregulated in cells collected by bronchoalveolar lavage after segmental broncho-provocation with an allergen. Reciprocally, the CASS4 mRNA was downregulated when this procedure was performed following administration of mepolizumab (a humanized monoclonal anti-IL-5 antibodies which reduces excessive eosinophilia). This suggests CASS4 activity may be associated with immune response in the context of atopic asthma development.
### Cystic fibrosis
CASS4 has been reported to play a modifying role in cystic fibrosis severity, progression and comorbid conditions. The CAS family member NEDD9 has also been shown to interact directly with AURKA (encoding Aurora-A kinase) to regulate cell cycle and ciliary resorption; it is possible that CASS4 may similarly interact with aurora-A kinase.
## Thrombosis
CASS4 signaling may contribute to platelet activation and aggregation. A PKA/PKG phosphorylation site has been identified in CASS4 on residue S305 in the unstructured domain containing SH2-binding motifs; the functional significance of this phosphorylation is currently unknown. Significantly increased phosphorylation on S249 of CASS4, also in the unstructured domain, after platelet stimulation with the oxidized phospholipid KODA-PC (9-keto-12-oxo-10-dodecenoic acid ester of 2-lyso-phosphocholine, a CD36 receptor agonist) versus thrombin treatment, which may implicate CASS4 mediated signaling in platelet hyperreactivity.
# Clinical significance
There are currently no therapeutic approaches targeting CASS4, and in the absence of a catalytic domain and no extracellular moieties, it may be challenging to generate such an agent. However, CASS4 may ultimately be relevant in clinical practice as a possible marker to assess prognosis and outcome in cases of NSCLC (and possibly other types of cancer). At present, its greatest clinical value is likely to be as a predictive variant for severity and onset of Alzheimer's disease and cystic fibrosis.
# Notes | CASS4
Cas scaffolding protein family member 4 is a protein that in humans is encoded by the CASS4 gene.[1]
# History and discovery
CASS4 (Crk associated substrate 4) is the fourth and last described member of the CAS protein family.[2] CASS4 was detected by Singh et al.[3] in 2008 following in silico screening of databases describing expressed sequence tags from an evolutionarily diverse group of organisms, using the CAS-related proteins (p130Cas, NEDD9/HEF1 and EFS) mRNAs as templates. Singh et al. subsequently cloned and characterized the CASS4 gene, originally assigning the name HEPL (HEF1-EFS-p130Cas-like) for similarity to the other three defined CAS genes. The official name was subsequently changed to CASS4 by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC).
# Gene
The chromosomal location of the CASS4 gene is 20q13.31, with genomic coordinates of 20: 56411548-56459340 on the forward strand in GRChB38p2.[4] While its HGNC-approved symbol is CASS4, this gene has multiple synonyms, including "HEF-like protein", "HEF1-Efs-p130Cas-like", HEFL, HEPL and C20orf32 ("chromosome 20 open reading frame 32"). Official IDs assigned to this gene include 15878 (HGNC), 57091 (Entrez Gene) and ENSG00000087589 (Ensembl). In humans four transcript variants are known. The first and second each contain 7 exons and encode the same full-length protein isoform a (786 amino acids, considered the major isoform), the third one contains 6 exons and encodes a shorter isoform b (732 amino acids) and the fourth one contains 5 exons and encodes the shortest isoform c (349 amino acids). Cumulatively, the CASS4 transcripts are most highly expressed in spleen and lung among normal tissues, and are highly expressed in ovarian and leukemia cell lines.[3]
To date, little effort has been applied to the direct study of transcriptional regulation of CASS4. The SABiosciences’ DECODE database, based on the UCSC Bioinformatics Genome Browser,[5] proposes several transcriptional regulators for CASS4 based on its promotor region sequence: NF-κβ, p53, LCR-F1 (NFE2-L1, nuclear factor, erythroid 2-like1), MAX1, C/EBPα, CHOP-10 (C/EBP homologous protein 10), POU3F1 (POU domain, class 3, transcription factor 1, aka Oct-6), Areb6 (ZEB1, Zinc finger E-box binding homeobox 1). These are compatible with regulation relevant to lymphocytes and deregulation in cancer.
# Protein family
In vertebrates, the CAS protein family contains four members: p130Cas/BCAR1, NEDD9/HEF1, EFS and CASS4. There are no paralogous genes for this family in acoelomates, pseudocoelomates, and nematodes, while a single ancestral member is found in Drosophila.[3] Evolutionary divergence of the CAS proteins family members is discussed by Singh et al. in detail.[3]
# Structure
All CAS protein family members have common structural characteristics.[2] CAS proteins have an amino terminal SH3 domain enabling interaction with poly-proline motif-containing proteins such as FAK. Carboxy-terminal to this, they possess an unstructured domain containing multiple SH2 binding site motifs, which when tyrosine-phosphorylated allow interaction with SH2 domain containing proteins. Further to the carboxy-terminus, they have a four-helix bundle rich in serine residues, and a second highly conserved four-helix bundle that has been recognized as functionally and structurally similar to a focal adhesion targeting [FAT] domain.[4] For the better studied members of the CAS family (BCAR1 and NEDD9), all of these domains have been defined as crucial for recognition and binding by other proteins, reflecting the primary role of CAS family proteins as cell signaling cascades mediators.
Isoform “a” of human CASS4 is considered the predominant species, and at 786 amino acids is the longest one.[6] Amino acid sequence homology of this isoform of human CASS4 with other family members is 26% overall identity and 42% similarity.[3] Using a yeast two-hybrid approach, the CASS4 protein SH3 domain was shown to interact with the FAK C-terminus, despite the lowest overall similarity to other SH3 domains in the CAS group. In addition, human CASS4 has a limited number of candidate SH2-binding sites, estimated at 10, which is similar to EFS (estimated at 9) and in contrast to p130Cas/BCAR1 and NEDD9, which have 20 and 18 respectively. The CASS4 C-terminus has a short region of CAS family homology, but lacks obvious similarity at the level of primary amino acid sequence. It also lacks a YDYVHL sequence at the N-terminal end of the FAT-like carboxy-terminal domain, even though this motif is conserved among the other three CAS family proteins and is an important binding site for the Src SH2 domain.[7] Although this lack of sequence similarity may mean a reduced functionality of the CASS4 protein, molecular modeling analysis performed by Singh and colleagues[3] using p130CAS/BCAR1 structures as templates suggested an almost identical fold between CASS4 and p130CAS/BCAR1 within their SH3 domains, and substantial similarity within 432-591 residues of CASS4 and 449-610 residues of p130Cas/BCAR1 at the level of secondary and tertiary structures. Also, the similar periodicity of α-helices and β-sheets in both CASS4 and p130Cas/BCAR1 provides another confirmation for the idea of well-conserved structures within the family members.
# Function
The exact function of CASS4 and its role in development and human pathologies have been subject to little investigation compared to other family members. The primary study exploring CASS4 function was the initial report by Singh et al.,[3] who showed the direct interaction between CASS4 and FAK, and CASS4 regulation of FAK activation, affecting cellular adhesion, migration and motility. Unusually, CASS4 depletion had a bimodal affect, causing some cells to have lower velocity and others to have higher velocity than control cells, suggesting a potential role in maintaining homeostasis. This work also suggested the function of CASS4 may be cell-type specific and dependent upon the presence or absence of expression of other CAS family members.[3] Direct binding has also been identified between CASS4 and CRKL,[8] an SH2- and SH3 domain-containing adaptor protein that has been also shown to interact with another CAS family member, p130Cas/BCAR1, in regulation of cellular motility and migration.[9] Because of the high degree of homology in interaction domains and some identified common partners, CASS4 is likely to share some functions with other CAS family members. These include association with FAK and Src family kinases at focal adhesions to transmit integrin-initiated signals to downstream effectors, which results in cytoskeleton reorganization and changes in motility and invasion.[10]
# Disease association
Altered expression or modification of CASS4 has been proposed as relevant to several human pathologies, typically based on detection of changes in CASS4 in high throughput screening, although the role of CASS4 in the pathology of these conditions has not yet been studied directly. These findings are summarized in Table 1; some examples are provided below.
## Cancer
Many CAS family proteins have altered activity and functional roles in cancer progression and metastasis, with functional roles in influencing cellular adhesion, migration and drug resistance.[22][23] Changes in CASS4 may also be associated with human malignancies. CASS4 function was linked to non-small cell lung cancer (NSCLC) in a study by Miao et al. that correlated elevated CASS4 expression with lymph node metastasis and high TNM stage.[19] In addition, this study detected a significant difference in cytoplasmic accumulation of CASS4 protein between high (H1299 and BE1) and low (LTE and A549) metastatic potential lung cancer cell lines. These may suggest CASS4 as a possible prognostic marker in clinical management of NSCLC.
## Alzheimer's disease
CASS4 and corresponding SNP - rs7274581 T/C has been identified in a large meta-analysis as a locus for lower susceptibility to Alzheimer's disease (AD).[12][24] However this SNP was not found predictive in a follow-up study.[13]
In a genome wide association screen (GWAS), CASS4 showed a significant correlation with clinical pathological features of AD such as neurofibrillary tangles and neuritic plaques.[11] Two additional CASS4 SNPs were reported to be associated with AD susceptibility: rs6024870,[15] and rs16979934 T/G.[16] Given the likely conserved CAS-family cytoskeletal function of CASS4, it has been speculated that it may have a role in axonal transport and influence the expression of the amyloid precursor protein (APP) and tau, which are pathologically affected in AD.[25] Several possible mechanisms for CASS4 action in AD have been proposed.[26]
## Immunopathological conditions
An association of CASS4 with atopic asthma has been shown.[17] CASS4 has also been reported to be an eosinophil-associated gene, with expression in sputum cells increased more than 1.5-fold after whole lung allergen challenge. Moreover, the CASS4 mRNA was upregulated in cells collected by bronchoalveolar lavage after segmental broncho-provocation with an allergen. Reciprocally, the CASS4 mRNA was downregulated when this procedure was performed following administration of mepolizumab (a humanized monoclonal anti-IL-5 antibodies which reduces excessive eosinophilia). This suggests CASS4 activity may be associated with immune response in the context of atopic asthma development.
### Cystic fibrosis
CASS4 has been reported to play a modifying role in cystic fibrosis severity, progression and comorbid conditions.[18] The CAS family member NEDD9 has also been shown to interact directly with AURKA (encoding Aurora-A kinase) to regulate cell cycle[27] and ciliary resorption;[28] it is possible that CASS4 may similarly interact with aurora-A kinase.
## Thrombosis
CASS4 signaling may contribute to platelet activation and aggregation. A PKA/PKG phosphorylation site has been identified in CASS4 on residue S305 in the unstructured domain containing SH2-binding motifs; the functional significance of this phosphorylation is currently unknown.[20] Significantly increased phosphorylation on S249 of CASS4, also in the unstructured domain, after platelet stimulation with the oxidized phospholipid KODA-PC (9-keto-12-oxo-10-dodecenoic acid ester of 2-lyso-phosphocholine, a CD36 receptor agonist) versus thrombin treatment, which may implicate CASS4 mediated signaling in platelet hyperreactivity.[21]
# Clinical significance
There are currently no therapeutic approaches targeting CASS4, and in the absence of a catalytic domain and no extracellular moieties, it may be challenging to generate such an agent. However, CASS4 may ultimately be relevant in clinical practice as a possible marker to assess prognosis and outcome in cases of NSCLC (and possibly other types of cancer). At present, its greatest clinical value is likely to be as a predictive variant for severity and onset of Alzheimer's disease and cystic fibrosis.
# Notes | https://www.wikidoc.org/index.php/CASS4 | |
6b4be5a9a3aa482c5c9dbe5529ddb661bbf6f7e5 | wikidoc | CCBE1 | CCBE1
Collagen and calcium-binding EGF domain-containing protein 1 is a protein that in humans is encoded by the CCBE1 gene.
# Function
CCBE1 is a regulator of the development and growth of the lymphatic system. CCBE1 is necessary for the proteolytic activation of VEGF-C by ADAMTS3, which is the main growth factor for the lymphatic system .
# Clinical significance
Hennekam syndrome type I (a generalized lymphatic dysplasia in humans) is associated with mutations in the CCBE1 gene, and the molecular etiology of the disease has been elucidated. | CCBE1
Collagen and calcium-binding EGF domain-containing protein 1 is a protein that in humans is encoded by the CCBE1 gene.[1][2]
# Function
CCBE1 is a regulator of the development and growth of the lymphatic system. CCBE1 is necessary for the proteolytic activation of VEGF-C by ADAMTS3[3], which is the main growth factor for the lymphatic system [4].
# Clinical significance
Hennekam syndrome type I (a generalized lymphatic dysplasia in humans) is associated with mutations in the CCBE1 gene[5], and the molecular etiology of the disease has been elucidated[3]. | https://www.wikidoc.org/index.php/CCBE1 | |
0d565f74b449608713b9adc26d17e79e26087ab6 | wikidoc | CCDC8 | CCDC8
Coiled-coil domain containing 8 is a protein that in humans is encoded by the CCDC8 gene.
# Function
This gene encodes a coiled coil domain-containing protein. The encoded protein functions as a cofactor required for p53-mediated apoptosis following DNA damage, and may also play a role in growth through interactions with the cytoskeletal adaptor protein obscurin-like 1.
# Clinical relevance
Mutations in this gene have been shown to cause 3-M syndrome. | CCDC8
Coiled-coil domain containing 8 is a protein that in humans is encoded by the CCDC8 gene.[1]
# Function
This gene encodes a coiled coil domain-containing protein. The encoded protein functions as a cofactor required for p53-mediated apoptosis following DNA damage, and may also play a role in growth through interactions with the cytoskeletal adaptor protein obscurin-like 1.
# Clinical relevance
Mutations in this gene have been shown to cause 3-M syndrome.[2] | https://www.wikidoc.org/index.php/CCDC8 | |
31b588a2dfa3584b57fdfc3d07515564b89e86de | wikidoc | CCL11 | CCL11
C-C motif chemokine 11 also known as eosinophil chemotactic protein and eotaxin-1 is a protein that in humans is encoded by the CCL11 gene. This gene is encoded on three exons and is located on chromosome 17.
# Function
CCL11 is a small cytokine belonging to the CC chemokine family. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. The effects of CCL11 are mediated by its binding to a G-protein-linked receptor known as a chemokine receptor. Chemokine receptors for which CCL11 is a ligand include CCR2, CCR3 and CCR5. However, it has been found that eotaxin-1 (CCL11) has high degree selectivity for its receptor, such that they are inactive on neutrophils and monocytes, which do not express CCR3.
# Clinical significance
Increased CCL11 levels in blood plasma are associated with aging in mice and humans. Additionally, it has been demonstrated that exposing young mice to CCL11 or the blood plasma of older mice decreases their neurogenesis and cognitive performance on behavioural tasks thought to be dependent on neurogenesis in the hippocampus.
Higher plasma concentrations of CCL11 have been found in current cannabis users compared to past users and those who had never used. CCL11 has also been found in higher concentrations in people suffering from schizophrenia; cannabis is a known trigger of schizophrenia.
It's also a biomarker for CTE or punch-drunk syndrome.
During periods of bone inflammation, CCL11 and CCR3 are upregulated. This is associated with an increase in osteoclast activity. | CCL11
C-C motif chemokine 11 also known as eosinophil chemotactic protein and eotaxin-1 is a protein that in humans is encoded by the CCL11 gene. This gene is encoded on three exons and is located on chromosome 17.[1][2]
# Function
CCL11 is a small cytokine belonging to the CC chemokine family. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses.[3][4][5] The effects of CCL11 are mediated by its binding to a G-protein-linked receptor known as a chemokine receptor. Chemokine receptors for which CCL11 is a ligand include CCR2,[6] CCR3[1] and CCR5.[6] However, it has been found that eotaxin-1 (CCL11) has high degree selectivity for its receptor, such that they are inactive on neutrophils and monocytes, which do not express CCR3.[7]
# Clinical significance
Increased CCL11 levels in blood plasma are associated with aging in mice and humans.[8] Additionally, it has been demonstrated that exposing young mice to CCL11 or the blood plasma of older mice decreases their neurogenesis and cognitive performance on behavioural tasks thought to be dependent on neurogenesis in the hippocampus.[8]
Higher plasma concentrations of CCL11 have been found in current cannabis users compared to past users and those who had never used. CCL11 has also been found in higher concentrations in people suffering from schizophrenia; cannabis is a known trigger of schizophrenia.[9]
It's also a biomarker for CTE or punch-drunk syndrome.[10]
During periods of bone inflammation, CCL11 and CCR3 are upregulated. This is associated with an increase in osteoclast activity.[11] | https://www.wikidoc.org/index.php/CCL11 | |
35a8b928820d992b4b5cea611dda4c4c9724fe8b | wikidoc | CCL16 | CCL16
Chemokine (C-C motif) ligand 16 (CCL16) is a small cytokine belonging to the CC chemokine family that is known under several pseudonyms, including Liver-expressed chemokine (LEC) and Monotactin-1 (MTN-1). This chemokine is expressed by the liver, thymus, and spleen and is chemoattractive for monocytes and lymphocytes. Cellular expression of CCL16 can be strongly induced in monocytes by IL-10, IFN-γ and bacterial lipopolysaccharide. Its gene is located on chromosome 17, in humans, among a cluster of other CC chemokines. CCL16 elicits its effects on cells by interacting with cell surface chemokine receptors such as CCR1, CCR2, CCR5 and CCR8.
C-C motif chemokine ligand 16 has been found in high levels in the blood plasma of humans.
CCL16 may be useful for trafficking eosinophils. This ligand has been found to have a functional affinity for H4 receptors that are expressed by eosinophils and mast cells.
This chemokine has been shown to suppress rapid proliferation of myeloid progenitor cells. | CCL16
Chemokine (C-C motif) ligand 16 (CCL16) is a small cytokine belonging to the CC chemokine family that is known under several pseudonyms, including Liver-expressed chemokine (LEC) and Monotactin-1 (MTN-1). This chemokine is expressed by the liver, thymus, and spleen and is chemoattractive for monocytes and lymphocytes.[1] Cellular expression of CCL16 can be strongly induced in monocytes by IL-10, IFN-γ and bacterial lipopolysaccharide. Its gene is located on chromosome 17, in humans, among a cluster of other CC chemokines.[2] CCL16 elicits its effects on cells by interacting with cell surface chemokine receptors such as CCR1, CCR2, CCR5 and CCR8.[3][4]
C-C motif chemokine ligand 16 has been found in high levels in the blood plasma of humans.[5]
CCL16 may be useful for trafficking eosinophils. This ligand has been found to have a functional affinity for H4 receptors that are expressed by eosinophils and mast cells.[5]
This chemokine has been shown to suppress rapid proliferation of myeloid progenitor cells.[6] | https://www.wikidoc.org/index.php/CCL16 | |
659468b33a75be1f5bd486178839346013cb525f | wikidoc | CCL18 | CCL18
Chemokine (C-C motif) ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.
CCL18 is produced and secreted mainly by innate immune system, and has effects mainly on the adaptive immune system. It was previously known as Pulmonary and activation-regulated chemokine (PARC), dendritic cell (DC)-chemokine 1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1), and macrophage inflammatory protein-4 (MIP-4).
# Gene and protein structure
The gene of CCL18 is most similar to CCL3. CCL18 is located on chromosome 17, along with many other macrophage inflammatory proteins (MIPs). The gene itself has 3 exons and 2 introns; but, unlike other chemokines, CCL18 includes 2 pseudo-exons (exons that do not appear in the final peptide) in the first intron. Because of these pseudo-exons, it is believed that CCL18 arose as a result of a gene fusion event between CCL3-like protein encoding genes and gained a different function over time due to accumulating mutations. CCL18 is an 89 peptide-long protein, with a 20 peptide signalling sequence (to signal its secretion) at the N’ terminus which is cleaved in the endoplasmic reticulum into a 69 peptide mature protein.
# Sources
CCL18 is produced mainly by antigen-presenting cells of the innate immune system. These cells include dendritic cells, monocytes, and macrophages. Neither T-cells nor B-cells are known to produce CCL18. Its production is upregulated in these cells by IL-10, IL-4, and IL-13, which are cytokines that favour a T-helper 2 type response and are generally involved in humoral immunity or for immunosuppression. The presence of IFN-gamma, a T-helper 1 type response cytokine important for cell-mediated immunity, dampens the production of CCL18. Furthermore, CCL18 is induced by fibroblasts, specifically by induction of collagen produced by fibroblasts, which is important in tissue healing and repair. Finally, CCL18 is constitutively and highly expressed in the lungs, suggesting that CCL18 plays role in maintaining homeostasis.
# Chemotactic functions
Chemokines are classed as a special type of cytokine that is involved in immune cell trafficking. CCL18 in particular has some chemotactic functions for the innate immune system, but its functions are primarily involved with recruitment of the adaptive immune system. CCL18 is involved in attracting naïve T-cells, T-regulatory cells, T-helper 2 cells, both immunosuppressive and immature Dendritic Cells, basophils, and B-cells (naïve and effector). The T-regulatory cells that CCL18 attracts are not classical T-regulatory cells; these cells do not express FoxP3 as most T-regulatory cells do, and instead non-antigen specifically exert their immunosuppressive functions by secreting IL-10. It is thought that these recruited cells maintain homeostasis under healthy conditions.
# Receptor
The classical receptors for chemokines are G-protein coupled receptors (GPCRs), which have 7 transmembrane regions. Following this trend, it was thought that CCL18’s receptor is also probably a GPCR. However, for a long time, the physiological receptor has not been found until very recently. To date, are three receptors that have been proposed for CCL18: PITPNM3, GPR30, and CCR8. PITPNM3 is a CCL18 receptor, but PITPNM3 is only expressed on breast cancer cells and not on T-cells nor B-cells, and PITPNM3-CCL8 binding induces Pyk2 and Src mediated signaling, a cancer related signaling pathway, and subsequent metastasis of breast cancer. GPR30 is also reported to bind to CCL18, but binding of CCL18 does not induce chemotaxis; instead, binding of CCL18 to GPR30 blocks both activation of GPR30 by its natural ligands and reduces the ability of CXCL12-dependant activation of acute lymphocytic leukemia B cells. CCR8 is the most recently discovered receptor for CCL18, and the effects of CCR8-CCL18 interactions appear to be physiological, as CCL18 binding to CCR8 induces chemotaxis of Th2 cells. Furthermore, CCL18 binding is competitive with CCR8’s previously described ligand, CCL1, further suggesting that CCL18 binds physiologically with CCR8.) Further elucidation of the role of CCR8 in CCL18-mediated pathologies would allow for better understanding of CCL18’s function in these diseases.
# Effector functions
CCL18 has a plethora of functions that have been characterized in vitro and in vivo. Strangely, CCL18 seems to play a part in both activation of the immune system and the induction of tolerance and homeostasis at steady-state conditions.
## Immune activation
The production of CCL18 is induced by T-helper 2 type cytokines, namely IL-4 and IL-13. Coupled with the fact that CCL18 is highly expressed in patients with allergic asthma and other hypersensitivity diseases, CCL18 seems to play an important role for generating and maintaining a T-helper 2 (Th2) type response. Furthermore, the addition of CCL18 as an adjuvant for a malaria vaccine have shown efficacy, perhaps by recruiting immune cells to the site of vaccination. Finally, CCL18 is expressed by dendritic cells in the germinal center of inflamed lymph nodes, and recruits naïve B-cells for antigen presentation. Perhaps aberrant CCL18 expression is involved in the generation of chronic Th2 response, leading to asthma or arthritis.
## Immunosuppression
In addition to immune-activating effects, CCL18 also has strong immunosuppressive effects. CCL18 induces immature dendritic cells to differentiate into an immunosuppressive dendritic cell that is capable producing CCL18 which attract T-cells, suppressing effector T-cell function, and generating T-regulatory cells by secreting large amounts of IL-10. Furthermore, exposure to CCL18 by macrophages causes them to mature in the #M2 spectrum, which promotes immunosuppression and healing.
# Involvement in disease
Aberrant CCL18 expression is observed in many diseases, and it is thought that these abnormal expression patterns play a key role in these diseases. This table shows a list of all the diseases that CCL18 is involved in.
## Breast cancer
The most understood disease that CCL18 is involved in is in breast cancer, where CCL18 induces metastasis of breast cancer cells by binding to PITPNM3. Perhaps CCL18, in breast cancers, is acting as an immunosuppressive cytokine by generating T-regulatory cells, generating immunosuppressive dendritic cells and macrophages, and recruiting effector T-cells to these dendritic cells and macrophages to abolish their anti-cancer functions and allowing the cancer to escape the immune system.
## Autoimmunity and hypersensitivity
CCL18 is highly expressed in T-helper 2 mediated hypersensitivity and autoimmune diseases, such as asthma and arthritis. CCL18 is expressed at much higher levels in allergic patients compared to healthy patients and respond aggressively to innocuous antigens. Allergic patients also had higher amounts of activated T-cells in the lungs, suggesting that CCL18 recruitment of these cells is contributing to hypersensitivity. In addition to lung hypersensitivities, these patterns were also observed in dermatitis patients. Furthermore, a similar pattern was also observed in arthritis patients, where CCL18 was expressed at much higher rates by dendritic cells in affected patients. However, in arthritis, perhaps the increased CCL18 is an attempt to suppress effector T-helper 1 cells that are self-reactive. | CCL18
Chemokine (C-C motif) ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.
CCL18 is produced and secreted mainly by innate immune system, and has effects mainly on the adaptive immune system. It was previously known as Pulmonary and activation-regulated chemokine (PARC), dendritic cell (DC)-chemokine 1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1), and macrophage inflammatory protein-4 (MIP-4).
# Gene and protein structure
The gene of CCL18 is most similar to CCL3.[1] CCL18 is located on chromosome 17, along with many other macrophage inflammatory proteins (MIPs). The gene itself has 3 exons and 2 introns; but, unlike other chemokines, CCL18 includes 2 pseudo-exons (exons that do not appear in the final peptide) in the first intron.[2] Because of these pseudo-exons, it is believed that CCL18 arose as a result of a gene fusion event between CCL3-like protein encoding genes and gained a different function over time due to accumulating mutations.[2][3] CCL18 is an 89 peptide-long protein, with a 20 peptide signalling sequence (to signal its secretion) at the N’ terminus which is cleaved in the endoplasmic reticulum into a 69 peptide mature protein.[1]
# Sources
CCL18 is produced mainly by antigen-presenting cells of the innate immune system. These cells include dendritic cells, monocytes, and macrophages.[5][6][7] Neither T-cells nor B-cells are known to produce CCL18.[5] Its production is upregulated in these cells by IL-10, IL-4, and IL-13, which are cytokines that favour a T-helper 2 type response and are generally involved in humoral immunity or for immunosuppression. The presence of IFN-gamma, a T-helper 1 type response cytokine important for cell-mediated immunity, dampens the production of CCL18.[8] Furthermore, CCL18 is induced by fibroblasts, specifically by induction of collagen produced by fibroblasts, which is important in tissue healing and repair.[7] Finally, CCL18 is constitutively and highly expressed in the lungs, suggesting that CCL18 plays role in maintaining homeostasis.
# Chemotactic functions
Chemokines are classed as a special type of cytokine that is involved in immune cell trafficking. CCL18 in particular has some chemotactic functions for the innate immune system, but its functions are primarily involved with recruitment of the adaptive immune system. CCL18 is involved in attracting naïve T-cells,[9] T-regulatory cells,[5][10] T-helper 2 cells,[11] both immunosuppressive and immature Dendritic Cells,[5][8] basophils,[11] and B-cells (naïve and effector).[4] The T-regulatory cells that CCL18 attracts are not classical T-regulatory cells; these cells do not express FoxP3 as most T-regulatory cells do, and instead non-antigen specifically exert their immunosuppressive functions by secreting IL-10.[7] It is thought that these recruited cells maintain homeostasis under healthy conditions.
# Receptor
The classical receptors for chemokines are G-protein coupled receptors (GPCRs), which have 7 transmembrane regions. Following this trend, it was thought that CCL18’s receptor is also probably a GPCR. However, for a long time, the physiological receptor has not been found until very recently. To date, are three receptors that have been proposed for CCL18: PITPNM3, GPR30, and CCR8. PITPNM3 is a CCL18 receptor, but PITPNM3 is only expressed on breast cancer cells and not on T-cells nor B-cells, and PITPNM3-CCL8 binding induces Pyk2 and Src mediated signaling, a cancer related signaling pathway, and subsequent metastasis of breast cancer.[12][13] GPR30 is also reported to bind to CCL18, but binding of CCL18 does not induce chemotaxis; instead, binding of CCL18 to GPR30 blocks both activation of GPR30 by its natural ligands and reduces the ability of CXCL12-dependant activation of acute lymphocytic leukemia B cells.[14] CCR8 is the most recently discovered receptor for CCL18, and the effects of CCR8-CCL18 interactions appear to be physiological, as CCL18 binding to CCR8 induces chemotaxis of Th2 cells.[15] Furthermore, CCL18 binding is competitive with CCR8’s previously described ligand, CCL1, further suggesting that CCL18 binds physiologically with CCR8.[15]) Further elucidation of the role of CCR8 in CCL18-mediated pathologies would allow for better understanding of CCL18’s function in these diseases.
# Effector functions
CCL18 has a plethora of functions that have been characterized in vitro and in vivo. Strangely, CCL18 seems to play a part in both activation of the immune system and the induction of tolerance and homeostasis at steady-state conditions.
## Immune activation
The production of CCL18 is induced by T-helper 2 type cytokines, namely IL-4 and IL-13. Coupled with the fact that CCL18 is highly expressed in patients with allergic asthma[16] and other hypersensitivity diseases,[4] CCL18 seems to play an important role for generating and maintaining a T-helper 2 (Th2) type response. Furthermore, the addition of CCL18 as an adjuvant for a malaria vaccine have shown efficacy, perhaps by recruiting immune cells to the site of vaccination.[17] Finally, CCL18 is expressed by dendritic cells in the germinal center of inflamed lymph nodes, and recruits naïve B-cells for antigen presentation.[18] Perhaps aberrant CCL18 expression is involved in the generation of chronic Th2 response, leading to asthma or arthritis.
## Immunosuppression
In addition to immune-activating effects, CCL18 also has strong immunosuppressive effects. CCL18 induces immature dendritic cells to differentiate into an immunosuppressive dendritic cell that is capable producing CCL18 which attract T-cells, suppressing effector T-cell function, and generating T-regulatory cells by secreting large amounts of IL-10.[8][19] Furthermore, exposure to CCL18 by macrophages causes them to mature in the #M2 spectrum, which promotes immunosuppression and healing.[7]
# Involvement in disease
Aberrant CCL18 expression is observed in many diseases, and it is thought that these abnormal expression patterns play a key role in these diseases.[4] This table shows a list of all the diseases that CCL18 is involved in.
## Breast cancer
The most understood disease that CCL18 is involved in is in breast cancer, where CCL18 induces metastasis of breast cancer cells by binding to PITPNM3.[13] Perhaps CCL18, in breast cancers, is acting as an immunosuppressive cytokine by generating T-regulatory cells, generating immunosuppressive dendritic cells and macrophages, and recruiting effector T-cells to these dendritic cells and macrophages to abolish their anti-cancer functions and allowing the cancer to escape the immune system.
## Autoimmunity and hypersensitivity
CCL18 is highly expressed in T-helper 2 mediated hypersensitivity and autoimmune diseases, such as asthma and arthritis.[11] CCL18 is expressed at much higher levels in allergic patients compared to healthy patients and respond aggressively to innocuous antigens.[11] Allergic patients also had higher amounts of activated T-cells in the lungs, suggesting that CCL18 recruitment of these cells is contributing to hypersensitivity. In addition to lung hypersensitivities, these patterns were also observed in dermatitis patients.[4] Furthermore, a similar pattern was also observed in arthritis patients, where CCL18 was expressed at much higher rates by dendritic cells in affected patients.[20] However, in arthritis, perhaps the increased CCL18 is an attempt to suppress effector T-helper 1 cells that are self-reactive. | https://www.wikidoc.org/index.php/CCL18 | |
cc2dc999fe0cf74cd380b1579306dddc8ed38c84 | wikidoc | CCL19 | CCL19
Chemokine (C-C motif) ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.
This gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene may play a role in normal lymphocyte recirculation and homing. It also plays an important role in trafficking of T cells in thymus, and in T cell and B cell migration to secondary lymphoid organs. It specifically binds to chemokine receptor CCR7.
Chemokine (C-C motif) ligand 19 (CCL19) is a small cytokine belonging to the CC chemokine family that is also known as EBI1 ligand chemokine (ELC) and macrophage inflammatory protein-3-beta (MIP-3-beta). CCL19 is expressed abundantly in thymus and lymph nodes, with moderate levels in trachea and colon and low levels in stomach, small intestine, lung, kidney and spleen. The gene for CCL19 is located on human chromosome 9. This chemokine elicits its effects on its target cells by binding to the chemokine receptor chemokine receptor CCR7. It attracts certain cells of the immune system, including dendritic cells and antigen-engaged B cells, CCR7+ central-memory T-Cells. | CCL19
Chemokine (C-C motif) ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.[1][2]
This gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene may play a role in normal lymphocyte recirculation and homing. It also plays an important role in trafficking of T cells in thymus, and in T cell and B cell migration to secondary lymphoid organs. It specifically binds to chemokine receptor CCR7.[2]
Chemokine (C-C motif) ligand 19 (CCL19) is a small cytokine belonging to the CC chemokine family that is also known as EBI1 ligand chemokine (ELC) and macrophage inflammatory protein-3-beta (MIP-3-beta). CCL19 is expressed abundantly in thymus and lymph nodes, with moderate levels in trachea and colon and low levels in stomach, small intestine, lung, kidney and spleen.[3] The gene for CCL19 is located on human chromosome 9.[4] This chemokine elicits its effects on its target cells by binding to the chemokine receptor chemokine receptor CCR7.[3] It attracts certain cells of the immune system, including dendritic cells and antigen-engaged B cells,[5][6] CCR7+ central-memory T-Cells.[7] | https://www.wikidoc.org/index.php/CCL19 | |
d75abacbce7299b5bb2c92a83a2685481e4da01e | wikidoc | CCL20 | CCL20
Chemokine (C-C motif) ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils. CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.
Gene expression of CCL20 can be induced by microbial factors such as lipopolysaccharide (LPS), and inflammatory cytokines such as tumor necrosis factor and interferon-γ, and down-regulated by IL-10. CCL20 is expressed in several tissues with highest expression observed in peripheral blood lymphocytes, lymph nodes, liver, appendix, and fetal lung and lower levels in thymus, testis, prostate and gut. The gene for CCL20 (scya20) is located on chromosome 2 in humans.
Recent research in an animal model of multiple sclerosis known as experimental autoimmune encephalitis (EAE) demonstrated that regional neural activation can create "gates" for pathogenic CD4+ T cells to enter the CNS by increasing CCL20 expression, especially at L5. Sensory nerve stimulation, elicited by using muscles in the leg or electrical stimulation as in Arima et al., 2012, activates sympathetic neurons whose axons run through the dorsal root ganglia containing cell bodies of the stimulated afferent sensory nerve. Sympathetic neuronal activity activates IL-6 amplifier resulting in increased regional CCL20 expression and subsequent pathogenic CD4+ T cell accumulation at the same spinal cord level. CCL20 expression was observed to be dependent on IL-6 amplifier activation, which is dependent on NF-κB and STAT3 activation. This research provides evidence for a critical role for CCL20 in autoimmune pathogenesis of the central nervous system. | CCL20
Chemokine (C-C motif) ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils.[1] CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.[2]
Gene expression of CCL20 can be induced by microbial factors such as lipopolysaccharide (LPS), and inflammatory cytokines such as tumor necrosis factor and interferon-γ, and down-regulated by IL-10.[3] CCL20 is expressed in several tissues with highest expression observed in peripheral blood lymphocytes, lymph nodes, liver, appendix, and fetal lung and lower levels in thymus, testis, prostate and gut.[1][4] The gene for CCL20 (scya20) is located on chromosome 2 in humans.[5]
Recent research [6] in an animal model of multiple sclerosis known as experimental autoimmune encephalitis (EAE) demonstrated that regional neural activation can create "gates" for pathogenic CD4+ T cells to enter the CNS by increasing CCL20 expression, especially at L5. Sensory nerve stimulation, elicited by using muscles in the leg or electrical stimulation as in Arima et al., 2012, activates sympathetic neurons whose axons run through the dorsal root ganglia containing cell bodies of the stimulated afferent sensory nerve. Sympathetic neuronal activity activates IL-6 amplifier resulting in increased regional CCL20 expression and subsequent pathogenic CD4+ T cell accumulation at the same spinal cord level. CCL20 expression was observed to be dependent on IL-6 amplifier activation, which is dependent on NF-κB and STAT3 activation. This research provides evidence for a critical role for CCL20 in autoimmune pathogenesis of the central nervous system. | https://www.wikidoc.org/index.php/CCL20 | |
d8db52ccd390e1910fc63e78355d535ab7cceed1 | wikidoc | CCL24 | CCL24
Chemokine (C-C motif) ligand 24 (CCL24) also known as myeloid progenitor inhibitory factor 2 (MPIF-2) or eosinophil chemotactic protein 2 (eotaxin-2) is a protein that in humans is encoded by the CCL24 gene. This gene is located on human chromosome 7.
# Function
CCL24 is a small cytokine belonging to the CC chemokine family. CCL24 interacts with chemokine receptor CCR3 to induce chemotaxis in eosinophils. This chemokine is also strongly chemotactic for resting T lymphocytes and slightly chemotactic for neutrophils.
# Clinical significance
Elevated levels of eotaxin-2 has been seen in patients with aspirin-exacerbated respiratory disease (AERD), such as asthma. People with lower plasma levels of eotaxin-2 have not been showing tendency to develop aspirin inducible asthma. | CCL24
Chemokine (C-C motif) ligand 24 (CCL24) also known as myeloid progenitor inhibitory factor 2 (MPIF-2) or eosinophil chemotactic protein 2 (eotaxin-2) is a protein that in humans is encoded by the CCL24 gene.[1] This gene is located on human chromosome 7.[2]
# Function
CCL24 is a small cytokine belonging to the CC chemokine family. CCL24 interacts with chemokine receptor CCR3 to induce chemotaxis in eosinophils.[3] This chemokine is also strongly chemotactic for resting T lymphocytes and slightly chemotactic for neutrophils.[1]
# Clinical significance
Elevated levels of eotaxin-2 has been seen in patients with aspirin-exacerbated respiratory disease (AERD), such as asthma. People with lower plasma levels of eotaxin-2 have not been showing tendency to develop aspirin inducible asthma.[4] | https://www.wikidoc.org/index.php/CCL24 | |
8fd9134bb94a855abeb52fa446e14581a877e7c5 | wikidoc | CCL28 | CCL28
Chemokine (C-C motif) ligand 28 (CCL28), also known as mucosae-associated epithelial chemokine (MEC), CCK1 and SCYA28, is a chemokine. CCL28 regulates the chemotaxis of cells that express the chemokine receptors CCR3 and CCR10.
CCL28 is expressed by columnar epithelial cells in the gut, lung, breast and the salivary glands and drives the mucosal homing of T and B lymphocytes that express CCR10, and the migration of eosinophils expressing CCR3. This chemokine is constitutively expressed in the colon, but its levels can be increased by pro-inflammatory cytokines and certain bacterial products implying a role in effector cell recruitment to sites of epithelial injury. CCL28 has also been implicated in the migration of IgA-expressing cells to the mammary gland, salivary gland, intestine and other mucosal tissues. It has also been shown as a potential antimicrobial agent effective against certain pathogens, such as Gram negative and Gram positive bacteria and the fungus Candida albicans.
Human CCL28 is encoded by an RNA transcript of 373 nucleotides and a gene with four exons. The gene codes for a 127-amino acid CCL28 protein with a 22-amino acid N-terminal signal peptide. It shares 76% nucleic acid identity and 83% amino acid similarity to the equivalent molecule in mouse. Sequence analysis has revealed CCL28 to be most similar to another CC chemokine called CCL27.
# Gene neighbourhood
The gene C5orf34 is found downstream of CCL28 and is a predicted to be in the Polo-like Kinase family. C5orf34 extends from base pair 43,486,701 to base pair 43,515,445. | CCL28
Chemokine (C-C motif) ligand 28 (CCL28), also known as mucosae-associated epithelial chemokine (MEC), CCK1 and SCYA28, is a chemokine. CCL28 regulates the chemotaxis of cells that express the chemokine receptors CCR3 and CCR10.
CCL28 is expressed by columnar epithelial cells in the gut, lung, breast and the salivary glands and drives the mucosal homing of T and B lymphocytes that express CCR10, and the migration of eosinophils expressing CCR3.[1][2][3] This chemokine is constitutively expressed in the colon, but its levels can be increased by pro-inflammatory cytokines and certain bacterial products implying a role in effector cell recruitment to sites of epithelial injury.[4] CCL28 has also been implicated in the migration of IgA-expressing cells to the mammary gland,[5] salivary gland, intestine[6] and other mucosal tissues.[7] It has also been shown as a potential antimicrobial agent effective against certain pathogens, such as Gram negative and Gram positive bacteria and the fungus Candida albicans.[4]
Human CCL28 is encoded by an RNA transcript of 373 nucleotides and a gene with four exons. The gene codes for a 127-amino acid CCL28 protein with a 22-amino acid N-terminal signal peptide. It shares 76% nucleic acid identity and 83% amino acid similarity to the equivalent molecule in mouse.[8][9] Sequence analysis has revealed CCL28 to be most similar to another CC chemokine called CCL27.
# Gene neighbourhood
The gene C5orf34 is found downstream of CCL28 and is a predicted to be in the Polo-like Kinase family. C5orf34 extends from base pair 43,486,701 to base pair 43,515,445.[10] | https://www.wikidoc.org/index.php/CCL28 | |
fd8dd7988a5501999dfe5557f0ef737729bcfd23 | wikidoc | CCR10 | CCR10
C-C chemokine receptor type 10 is a protein that in humans is encoded by the CCR10 gene.
# Function
Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines.
CCR10 is a chemokine receptor. Its ligands are CCL27 and CCL28. This receptor is normally expressed by melanocytes, plasma cells and skin-homing T cells. B16 melanoma cell transduction of CCR10 significantly increases the development of lymph node metastasis in mice after inoculation in the skin, suggesting a role for the receptor in directing metastasis. CCR10-CCL27 interactions are involved in T cell-mediated skin inflammation. | CCR10
C-C chemokine receptor type 10 is a protein that in humans is encoded by the CCR10 gene.[1][2]
# Function
Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines.[2]
CCR10 is a chemokine receptor. Its ligands are CCL27 and CCL28.[3] This receptor is normally expressed by melanocytes,[4] plasma cells and skin-homing T cells. B16 melanoma cell transduction of CCR10 significantly increases the development of lymph node metastasis in mice after inoculation in the skin,[5] suggesting a role for the receptor in directing metastasis. CCR10-CCL27 interactions are involved in T cell-mediated skin inflammation.[6] | https://www.wikidoc.org/index.php/CCR10 | |
a6bc87968f13a782ed600baa9aab2928f6fef047 | wikidoc | ITGAE | ITGAE
Integrin, alpha E (ITGAE) also known as CD103 (cluster of differentiation 103) is an integrin protein that in human is encoded by the ITGAE gene. CD103 binds integrin beta 7 (β7– ITGB7) to form the complete heterodimeric integrin molecule αEβ7, which has no distinct name. The αEβ7 complex is often referred to as "CD103" though this appellation strictly refers only to the αE chain. Note that the β7 subunit can bind with other integrin α chains, such as α4 (CD49d).
# Tissue distribution
CD103 is expressed widely on intraepithelial lymphocyte (IEL) T cells (both αβ T cells and γδ T cells) and on some peripheral regulatory T cells (Tregs). It has also been reported on lamina propria T cells. A subset of dendritic cells in the gut mucosa and mesenteric lymph nodes, known as CD103 dendritic cells, also expresses this marker.
It is useful in identifying hairy cell leukemia which is positive for this marker in contrast to most other hematologic malignancies which are negative for CD103 except enteropathy-associated T cell lymphoma.
# Function
The chief ligand for αEβ7 is E-cadherin, an adhesion molecule (CAM) found on epithelial cells. It is probably important for T cell homing to the intestinal sites.
Tregs are important for decreasing the immune response and appear to play a crucial role in the prevention of autoimmune diseases. Tregs are defined as CD4+/CD25+/Foxp3+ cells. Some CD4+/FoxP3− cells also express CD103 and have been attributed regulatory activity. It is unclear whether the presence of CD103 on Treg cells represents a specialized feature for Treg, or Treg differentiation of IEL T cells. | ITGAE
Integrin, alpha E (ITGAE) also known as CD103 (cluster of differentiation 103) is an integrin protein that in human is encoded by the ITGAE gene.[1][2] CD103 binds integrin beta 7 (β7– ITGB7) to form the complete heterodimeric integrin molecule αEβ7, which has no distinct name. The αEβ7 complex is often referred to as "CD103" though this appellation strictly refers only to the αE chain. Note that the β7 subunit can bind with other integrin α chains, such as α4 (CD49d).
# Tissue distribution
CD103 is expressed widely on intraepithelial lymphocyte (IEL) T cells (both αβ T cells and γδ T cells) and on some peripheral regulatory T cells (Tregs).[3] It has also been reported on lamina propria T cells.[4] A subset of dendritic cells in the gut mucosa and mesenteric lymph nodes, known as CD103 dendritic cells, also expresses this marker.[5]
It is useful in identifying hairy cell leukemia which is positive for this marker in contrast to most other hematologic malignancies which are negative for CD103 except enteropathy-associated T cell lymphoma.[6]
# Function
The chief ligand for αEβ7 is E-cadherin, an adhesion molecule (CAM) found on epithelial cells.[7] It is probably important for T cell homing to the intestinal sites.[8]
Tregs are important for decreasing the immune response and appear to play a crucial role in the prevention of autoimmune diseases. Tregs are defined as CD4+/CD25+/Foxp3+ cells.[9] Some CD4+/FoxP3− cells also express CD103 and have been attributed regulatory activity. It is unclear whether the presence of CD103 on Treg cells represents a specialized feature for Treg, or Treg differentiation of IEL T cells. | https://www.wikidoc.org/index.php/CD103 | |
0616342ed88d6f22bae39ea94627efb57bff0759 | wikidoc | LAMP2 | LAMP2
Lysosome-associated membrane protein 2 (LAMP2) also known as CD107b (Cluster of Differentiation 107b), is a human gene. Its protein, LAMP2, is one of the lysosome-associated membrane glycoproteins.
The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of the gene produces three variants - LAMP-2A, LAMP-2B and LAMP-2C. LAMP-2A is the receptor for chaperone-mediated autophagy. Recently it has been determined that antibodies against LAMP-2 account for a fraction of patients who get a serious kidney disease termed focal necrotizing glomerulonephritis.
LAMP-2B is associated with Danon disease.
# Structure and tissue distribution
The gene for LAMP2 has 9 coding exons and 2 alternate last exons, 9a and 9b. When the last exon is spliced with the alternative exon, it is a variant called LAMP2b, which varies in the last 11 amino acids of its C-terminal sequence: in the luminal domain, the transmembrane domain, and the cytoplasmic tail. The original (LAMP2a) is highly expressed in the placenta, lung, and liver, while LAMP2b is highly expressed in skeletal muscle.
# Function
Lysosomes are cell organelles found in most animal cells. Their main functions center around breaking down materials and debris in the cell. Some of this is done via acid hydrolases that degrade foreign materials and have specialized autolytic functions. These hydrolyses are stored in the lysosomal membrane, which also house lysosomal membrane glycoproteins.
LAMP1 and LAMP2 make up about 50% of lysosomal membrane glycoproteins. (See LAMP1 for more information on both LAMP1 and LAMP2.) Both of these consist of polypeptides of about 40 kD, with the core polypeptide surrounded by 16 to 20 attached N-linked saccharides. The biological functions of these glycoproteins are disputed. They are believed to be significantly involved in operations of the lysosomes, including maintaining integrity, pH and catabolism. Further, some of the functions of LAMP2 are believed to be protecting the lysosomal membrane from proteolytic enzymes that are within the lysosome itself (as in autodigestion), acting as a receptor into the lysosome for proteins, adhesion (when expressed on the outside surface of the plasma membrane) and signal transduction, both inter- and intra-. It also provides protection for the cell from methylating mutagens.
# Role in cancer
LAMP2 has been specifically implicated in tumor cell metastasis. Both LAMP1 and LAMP2 have been found expressed on the surface of cancerous tumors, specifically in cells of highly metastatic cancer such as colon cancer and melanoma. They are rarely found on the plasma membranes of normal cells, and are found more on highly metastatic tumors than on poorly metastatic ones. LAMP2, along with LAMP1, interact with E-selectin and galectins to mediate the adhesion of some cancer cells to the ECM. The two LAMP molecules act as ligands for the cell-adhesion molecules.
It has also been shown that the down-regulation of LAMP2 could both reduce the resistance of breast cancer cells to the paclitaxel and could inhibit cell proliferation in multiple myeloma cells.
Along with other genes such as LC3B, p62 and CTSB, a strong up regulation of LAMP2 was detected in perinecrotic areas of glioblastomas. This suggests autophagy induction in gliomas could be caused by micro-environmental changes.
In a study of glial tumors, the cell membranes of glial and endothelial cells were found to contain LAMP1 and LAMP2, while YKL-40 (a different glycoprotein) was found in the cytoplasm. This suggests that the three glycoproteins are involved in tumor development, specifically in the processes of angiogenesis and tissue remodeling. | LAMP2
Lysosome-associated membrane protein 2 (LAMP2) also known as CD107b (Cluster of Differentiation 107b), is a human gene. Its protein, LAMP2, is one of the lysosome-associated membrane glycoproteins.
The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of the gene produces three variants - LAMP-2A, LAMP-2B and LAMP-2C.[1] LAMP-2A is the receptor for chaperone-mediated autophagy. Recently it has been determined that antibodies against LAMP-2 account for a fraction of patients who get a serious kidney disease termed focal necrotizing glomerulonephritis.
LAMP-2B is associated with Danon disease.
# Structure and tissue distribution
The gene for LAMP2 has 9 coding exons and 2 alternate last exons, 9a and 9b.[2] When the last exon is spliced with the alternative exon, it is a variant called LAMP2b, which varies in the last 11 amino acids of its C-terminal sequence: in the luminal domain, the transmembrane domain, and the cytoplasmic tail. The original (LAMP2a) is highly expressed in the placenta, lung, and liver, while LAMP2b is highly expressed in skeletal muscle.[3]
# Function
Lysosomes are cell organelles found in most animal cells. Their main functions center around breaking down materials and debris in the cell. Some of this is done via acid hydrolases that degrade foreign materials and have specialized autolytic functions. These hydrolyses are stored in the lysosomal membrane, which also house lysosomal membrane glycoproteins.[2]
LAMP1 and LAMP2 make up about 50% of lysosomal membrane glycoproteins. (See LAMP1 for more information on both LAMP1 and LAMP2.) Both of these consist of polypeptides of about 40 kD, with the core polypeptide surrounded by 16 to 20 attached N-linked saccharides.[2] The biological functions of these glycoproteins are disputed.[4] They are believed to be significantly involved in operations of the lysosomes, including maintaining integrity, pH and catabolism. Further, some of the functions of LAMP2 are believed to be protecting the lysosomal membrane from proteolytic enzymes that are within the lysosome itself (as in autodigestion), acting as a receptor into the lysosome for proteins, adhesion (when expressed on the outside surface of the plasma membrane) and signal transduction, both inter- and intra-. It also provides protection for the cell from methylating mutagens.[2]
# Role in cancer
LAMP2 has been specifically implicated in tumor cell metastasis.[5] Both LAMP1 and LAMP2 have been found expressed on the surface of cancerous tumors, specifically in cells of highly metastatic cancer such as colon cancer and melanoma.[4] They are rarely found on the plasma membranes of normal cells, and are found more on highly metastatic tumors than on poorly metastatic ones. LAMP2, along with LAMP1, interact with E-selectin and galectins to mediate the adhesion of some cancer cells to the ECM. The two LAMP molecules act as ligands for the cell-adhesion molecules.
It has also been shown that the down-regulation of LAMP2 could both reduce the resistance of breast cancer cells to the paclitaxel[6] and could inhibit cell proliferation in multiple myeloma cells.[7]
Along with other genes such as LC3B, p62 and CTSB, a strong up regulation of LAMP2 was detected in perinecrotic areas of glioblastomas. This suggests autophagy induction in gliomas could be caused by micro-environmental changes.[8]
In a study of glial tumors, the cell membranes of glial and endothelial cells were found to contain LAMP1 and LAMP2, while YKL-40 (a different glycoprotein) was found in the cytoplasm. This suggests that the three glycoproteins are involved in tumor development, specifically in the processes of angiogenesis and tissue remodeling.[9] | https://www.wikidoc.org/index.php/CD107b | |
bb26d73691024432015974bc60100303c9a2b7d8 | wikidoc | CD11a | CD11a
Integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide), also known as ITGAL, is a human gene which functions in the immune system. It is involved in cellular adhesion and costimulatory signaling. It is the target of the drug efalizumab.
# Function
ITGAL encodes the integrin alpha L chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This I-domain containing alpha integrin combines with the beta 2 chain (ITGB2) to form the integrin lymphocyte function-associated antigen-1 (LFA-1), which is expressed on all leukocytes. LFA-1 plays a central role in leukocyte intercellular adhesion through interactions with its ligands, ICAMs 1-3 (intercellular adhesion molecules 1 through 3), and also functions in lymphocyte costimulatory signaling.
CD11a is one of the two components, along with CD18, which form lymphocyte function-associated antigen-1.
Efalizumab acts as an immunosuppressant by binding to CD11a but was withdrawn in 2009 because it was associated with severe side effects.
# Interactions
CD11a has been shown to interact with ICAM-1. | CD11a
Integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide), also known as ITGAL, is a human gene which functions in the immune system. It is involved in cellular adhesion and costimulatory signaling. It is the target of the drug efalizumab.
# Function
ITGAL encodes the integrin alpha L chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This I-domain containing alpha integrin combines with the beta 2 chain (ITGB2) to form the integrin lymphocyte function-associated antigen-1 (LFA-1), which is expressed on all leukocytes. LFA-1 plays a central role in leukocyte intercellular adhesion through interactions with its ligands, ICAMs 1-3 (intercellular adhesion molecules 1 through 3), and also functions in lymphocyte costimulatory signaling.[1]
CD11a is one of the two components, along with CD18, which form lymphocyte function-associated antigen-1.
Efalizumab acts as an immunosuppressant by binding to CD11a but was withdrawn in 2009 because it was associated with severe side effects.
# Interactions
CD11a has been shown to interact with ICAM-1.[2][3][4] | https://www.wikidoc.org/index.php/CD11a | |
73fbb6bb2dd28d7e47a95b1f2f617cadab51867c | wikidoc | CD11c | CD11c
CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c .
CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This protein combines with the beta 2 chain (ITGB2) to form a leukocyte-specific integrin referred to as inactivated-C3b (iC3b) receptor 4 (CR4). The alpha X beta 2 complex seems to overlap the properties of the alpha M beta 2 integrin in the adherence of neutrophils and monocytes to stimulated endothelium cells, and in the phagocytosis of complement coated particles.
CD11c is a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst; expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell chronic lymphocytic leukemias. | CD11c
CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c .[1][2]
CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This protein combines with the beta 2 chain (ITGB2) to form a leukocyte-specific integrin referred to as inactivated-C3b (iC3b) receptor 4 (CR4). The alpha X beta 2 complex seems to overlap the properties of the alpha M beta 2 integrin in the adherence of neutrophils and monocytes to stimulated endothelium cells, and in the phagocytosis of complement coated particles.[1]
CD11c is a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst; expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell chronic lymphocytic leukemias. | https://www.wikidoc.org/index.php/CD11c | |
4a70b0ae58a7f214110b6e34ccf42e59da89c9fe | wikidoc | CD120 | CD120
CD120 (Cluster of Differentiation 120) can refer to two members of the tumor necrosis factor receptor superfamily: tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).
# Receptor subtypes
There are two variants of the receptor, each encoded by a separate gene:
- CD120a - TNFR1 - TNFR superfamily member 1A
- CD120b - TNFR2 - TNFR superfamily member 1B
TNFR1 is the receptor type responsible for mediation of TNF-alpha induced sickness behavior, and is involved in neurotoxic processes. Elevated levels of TNFR1 has been found in severe mental disorders.
# Signaling pathway | CD120
CD120 (Cluster of Differentiation 120) can refer to two members of the tumor necrosis factor receptor superfamily: tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).[1][2]
# Receptor subtypes
There are two variants of the receptor, each encoded by a separate gene:
- CD120a - TNFR1 - TNFR superfamily member 1A
- CD120b - TNFR2 - TNFR superfamily member 1B
TNFR1 is the receptor type responsible for mediation of TNF-alpha induced sickness behavior,[3] and is involved in neurotoxic processes.[4] Elevated levels of TNFR1 has been found in severe mental disorders.[5]
# Signaling pathway | https://www.wikidoc.org/index.php/CD120 | |
7c6b5909901df543faf22b2f1fa9a410e78139ea | wikidoc | CD133 | CD133
CD133 antigen, also known as prominin-1, is a glycoprotein that in humans is encoded by the PROM1 gene. It is a member of pentaspan transmembrane glycoproteins, which specifically localize to cellular protrusions. When embedded in the cell membrane, the membrane topology of prominin-1 is such that the N-terminus extends into the extracellular space and the C-terminus resides in the intracellular compartment. The protein consists of five transmembrane segments, with the first and second segments and the third and fourth segments connected by intracellular loops while the second and third as well as fourth and fifth transmembrane segments are connected by extracellular loops. While the precise function of CD133 remains unknown, it has been proposed that it acts as an organizer of cell membrane topology.
# Tissue distribution
CD133 is expressed in hematopoietic stem cells, endothelial progenitor cells, glioblastoma, neuronal and glial stem cells, various pediatric brain tumors, as well as adult kidney, mammary glands, trachea, salivary glands, uterus, placenta, digestive tract, testes, and some other cell types.
# Clinical significance
Today CD133 is the most commonly used marker for isolation of cancer stem cell (CSC) population from different tumors, mainly from various gliomas and carcinomas. Initial studies that showed ability of CD133-positive population to efficiently propagate tumor when injected into immune-compromised mice firstly were performed on brain tumors. However, subsequent studies have indicated the difficulty in isolating pure CSC populations. CD133+ melanoma cells are considered a subpopulation of CSC and play a critical role in recurrence. Moreover, CD133+ melanoma cells are immunogenic and can be used as an antimelanoma vaccination. In mice the vaccination with CD133+ melanoma cells mediated strong anti-tumor activity that resulted in the eradication of parental melanoma cells. In addition, it has also been shown that CD133+ melanoma cells preferentially express the RNA helicase DDX3X . As DDX3X also is an immunogenic protein, the same anti-melanoma vaccination strategy can be employed to give therapeutic antitumor immunity in mice. | CD133
CD133 antigen, also known as prominin-1, is a glycoprotein that in humans is encoded by the PROM1 gene.[1][2] It is a member of pentaspan transmembrane glycoproteins, which specifically localize to cellular protrusions. When embedded in the cell membrane, the membrane topology of prominin-1 is such that the N-terminus extends into the extracellular space and the C-terminus resides in the intracellular compartment. The protein consists of five transmembrane segments, with the first and second segments and the third and fourth segments connected by intracellular loops while the second and third as well as fourth and fifth transmembrane segments are connected by extracellular loops.[3] While the precise function of CD133 remains unknown, it has been proposed that it acts as an organizer of cell membrane topology.[4]
# Tissue distribution
CD133 is expressed in hematopoietic stem cells,[5] endothelial progenitor cells,[6] glioblastoma, neuronal and glial stem cells,[7] various pediatric brain tumors,[8] as well as adult kidney, mammary glands, trachea, salivary glands, uterus, placenta, digestive tract, testes, and some other cell types.[9][10][11]
# Clinical significance
Today CD133 is the most commonly used marker for isolation of cancer stem cell (CSC) population from different tumors, mainly from various gliomas and carcinomas.[12] Initial studies that showed ability of CD133-positive population to efficiently propagate tumor when injected into immune-compromised mice firstly were performed on brain tumors.[13][8][14][15] However, subsequent studies have indicated the difficulty in isolating pure CSC populations.[16] CD133+ melanoma cells are considered a subpopulation of CSC and play a critical role in recurrence.[17] Moreover, CD133+ melanoma cells are immunogenic and can be used as an antimelanoma vaccination. In mice the vaccination with CD133+ melanoma cells mediated strong anti-tumor activity that resulted in the eradication of parental melanoma cells.[18] In addition, it has also been shown that CD133+ melanoma cells preferentially express the RNA helicase DDX3X . As DDX3X also is an immunogenic protein, the same anti-melanoma vaccination strategy can be employed to give therapeutic antitumor immunity in mice.[19] | https://www.wikidoc.org/index.php/CD133 | |
b7d320e6693747f4aec649e41942f57e6ffd4223 | wikidoc | CD134 | CD134
Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.
# Function
OX40 has no effect on the proliferative abilities of CD4+ cells for the first three days, however after this time proliferation begins to slow and cells die at a greater rate, due to an inability to maintain a high level of PKB activity and expression of Bcl-2, Bcl-XL and survivin. OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo.
OX40 binds TRAF2, 3 and 5 as well as PI3K by an unknown mechanism. TRAF2 is required for survival via NF-κB and memory cell generation whereas TRAF5 seems to have a more negative or modulatory role, as knockouts have higher levels of cytokines and are more susceptible to Th2-mediated inflammation. TRAF3 may play a critical role in OX40-mediated signal transduction. CTLA-4 is down-regulated following OX40 engagement in vivo and the OX40-specific TRAF3 DN defect was partially overcome by CTLA-4 blockade in vivo. TRAF3 may be linked to OX40-mediated memory T cell expansion and survival, and point to the down-regulation of CTLA-4 as a possible control element to enhance early T cell expansion through OX40 signaling.
# Clinical significance
OX40 has been implicated in the pathologic cytokine storm associated with certain viral infections, including the H5N1 bird flu.
# As a drug or drug target
An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with the cytokine storm (an immune overreaction) while allowing the immune system to fight off the virus successfully.
An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment. Research in mice has included the combination of an agonistic OX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylated CpG oligonucleotide, which as a TLR9 ligand activates expression of OX40 so that it can be affected.
# Interactions
CD134 has been shown to interact with TRAF5 and TRAF2. | CD134
Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.
# Function
OX40 has no effect on the proliferative abilities of CD4+ cells for the first three days, however after this time proliferation begins to slow and cells die at a greater rate, due to an inability to maintain a high level of PKB activity and expression of Bcl-2, Bcl-XL and survivin. OX40L binds to OX40 receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo.
OX40 binds TRAF2, 3 and 5 as well as PI3K by an unknown mechanism. TRAF2 is required for survival via NF-κB and memory cell generation whereas TRAF5 seems to have a more negative or modulatory role, as knockouts have higher levels of cytokines and are more susceptible to Th2-mediated inflammation. TRAF3 may play a critical role in OX40-mediated signal transduction. CTLA-4 is down-regulated following OX40 engagement in vivo and the OX40-specific TRAF3 DN defect was partially overcome by CTLA-4 blockade in vivo. TRAF3 may be linked to OX40-mediated memory T cell expansion and survival, and point to the down-regulation of CTLA-4 as a possible control element to enhance early T cell expansion through OX40 signaling.
# Clinical significance
OX40 has been implicated in the pathologic cytokine storm associated with certain viral infections, including the H5N1 bird flu.[citation needed]
# As a drug or drug target
An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with the cytokine storm (an immune overreaction) while allowing the immune system to fight off the virus successfully.[citation needed]
An anti-OX40 antibody GSK3174998 has started clinical trials as a cancer treatment.[1] Research in mice has included the combination of an agonistic OX40 antibody (clone OX86) injected directly into a tumor in combination with an unmethylated CpG oligonucleotide, which as a TLR9 ligand activates expression of OX40 so that it can be affected.[2]
# Interactions
CD134 has been shown to interact with TRAF5[3] and TRAF2.[4] | https://www.wikidoc.org/index.php/CD134 | |
5b388959558f905bd3358851587b5a5a34a5788e | wikidoc | CD135 | CD135
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).
It is expressed on the surface of many hematopoietic progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.
The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML). High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.
# Structure
FLT3 is composed of five extracellular immunoglobulin-like domains, an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane.
# Function
CD135 is a Class III receptor tyrosine kinase. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L. The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development, but not for the development of other blood cells (myeloid development).
Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:
- TNF-Alpha (Tumor necrosis factor-alpha)
- TGF-Beta (Transforming growth factor-beta)
TGF-Beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.
# Clinical significance
## Cell surface marker
Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) express high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive. (See Lymphopoiesis#Labeling lymphopoiesis)
## Role in cancer
CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer. Mutations of the FLT3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with acute myelogenous leukemia (AML) and are a prognostic indicator associated with adverse disease outcome.
## FLT3 inhibitors
Gilteritinib, a dual FLT3-AXL tyrosine kinase inhibitor is currently in multiple Phase III trials in acute myeloid leukemia (AML). In 2017, gilteritinib gained FDA orphan drug status for AML.
Quizartinib (AC220) had good results in a phase II clinical trial for AML patients with FLT3 mutations. for refractory AML – particularly in patients who went on to have a stem cell transplant.
Midostaurin was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.
Sorafenib has been reported to show significant activity against Flt3-ITD positive acute myelogenous leukemia.
Sunitinib also inhibits Flt3.
Lestaurtinib is in clinical trials.
A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment. | CD135
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).
It is expressed on the surface of many hematopoietic progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.
The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML).[1] High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.
# Structure
FLT3 is composed of five extracellular immunoglobulin-like domains, an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane.[2]
# Function
CD135 is a Class III receptor tyrosine kinase. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L.[3] The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development, but not for the development of other blood cells (myeloid development).
Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:
- TNF-Alpha (Tumor necrosis factor-alpha)
- TGF-Beta (Transforming growth factor-beta)
TGF-Beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.[2]
# Clinical significance
## Cell surface marker
Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. CD135 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) express high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive.[citation needed] (See Lymphopoiesis#Labeling lymphopoiesis)
## Role in cancer
CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.[4] Mutations of the FLT3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with acute myelogenous leukemia (AML) and are a prognostic indicator associated with adverse disease outcome.
## FLT3 inhibitors
Gilteritinib, a dual FLT3-AXL tyrosine kinase inhibitor is currently in multiple Phase III trials in acute myeloid leukemia (AML).[5] In 2017, gilteritinib gained FDA orphan drug status for AML.[6]
Quizartinib (AC220) had good results in a phase II clinical trial for AML patients with FLT3 mutations.[7] for refractory AML – particularly in patients who went on to have a stem cell transplant.[8]
Midostaurin was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.[9] The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.
Sorafenib has been reported to show significant activity against Flt3-ITD positive acute myelogenous leukemia.[10][11]
Sunitinib also inhibits Flt3.
Lestaurtinib is in clinical trials.
A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment.[12] | https://www.wikidoc.org/index.php/CD135 | |
6e764fcc9b8f84e651d2341ac3d35c8cf3b40e98 | wikidoc | CD137 | CD137
CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB and induced by lymphocyte activation (ILA). It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule.
# Expression
CD137 can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, B cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation.
# Specific effects on cells
The best characterized activity of CD137 is its costimulatory activity for activated T cells. Crosslinking of CD137 enhances T cell proliferation, IL-2 secretion, survival and cytolytic activity. Further, it can enhance immune activity to eliminate tumors in mice.
# Interactions
CD137 has been shown to interact with TRAF2.
# As a drug target
## Utomilumab
Utomilumab (PF-05082566) targets this receptor to stimulate a more intense immune system attack on cancers. It is a fully human IgG2 monoclonal antibody. It is in early clinical trials. As of June 2016 5 clinical trials are active. | CD137
CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB and induced by lymphocyte activation (ILA). It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule.
# Expression
CD137 can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, B cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation.
# Specific effects on cells
The best characterized activity of CD137 is its costimulatory activity for activated T cells. Crosslinking of CD137 enhances T cell proliferation, IL-2 secretion, survival and cytolytic activity. Further, it can enhance immune activity to eliminate tumors in mice.
# Interactions
CD137 has been shown to interact with TRAF2.[1][2]
# As a drug target
## Utomilumab
Utomilumab (PF-05082566) targets this receptor to stimulate a more intense immune system attack on cancers.[3] It is a fully human IgG2 monoclonal antibody.[4] It is in early clinical trials.[3] As of June 2016[update] 5 clinical trials are active.[5] | https://www.wikidoc.org/index.php/CD137 | |
6b5635694e5e66692a06c5c135bf0766efe0f6f3 | wikidoc | CD146 | CD146
CD146 (cluster of differentiation 146) also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.
# Function
MCAM functions as a receptor for laminin alpha 4, a matrix molecule that is broadly expressed within the vascular wall. Accordingly, MCAM is highly expressed by cells that are components of the blood vessel wall, including vascular endothelial cells, smooth muscle cells and pericytes. Its function is still poorly understood, but evidence points to it being part of the endothelial junction associated with the actin cytoskeleton. A member of the Immunoglobulin superfamily, it consists of five Ig domains, a transmembrane domain, and a cytoplasmic region. It is expressed on chicken embryonic spleen and thymus, activated human T cells, endothelial progenitors such as angioblasts and mesenchymal stem cells, and strongly expressed on blood vessel endothelium and smooth muscle.
Two isoforms exist (MCAM long (MCAM-1), and MCAM short, or MCAM-s) which differ in the length of their cytoplasmic domain. Activation of these isoforms seems to produce functional differences as well. Natural killer cells transfected with MCAM-1 demonstrate decreased rolling velocity and increased cell adhesion to an endothelial cell monolayer and increased microvilli formation while cells transfected with MCAM-s showed no change in adhesion characteristics. Since these characteristics are important in leukocyte extravasation, MCAM-1 may be an important part of the inflammatory response.
CD146 has been demonstrated to appear on a small subset of T and B lymphocytes in the peripheral blood of healthy individuals. The CD146+ T cells display an immunophenotype consistent with effector memory cells and have a distinct gene profile from the CD146- T cells. CD146 T cells have been shown by Dagur and colleagues to produce IL-17.
CD146 has been seen as a marker for mesenchymal stem cells isolated from multiple adult and fetal organs, and its expression may be linked to multipotency; mesenchymal stem cells with greater differentiation potential express higher levels of CD146 on the cell surface.
# Clinical significance
MCAM inhibits breast cancer progression. | CD146
CD146 (cluster of differentiation 146) also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.[1]
# Function
MCAM functions as a receptor for laminin alpha 4,[2] a matrix molecule that is broadly expressed within the vascular wall. Accordingly, MCAM is highly expressed by cells that are components of the blood vessel wall, including vascular endothelial cells, smooth muscle cells and pericytes. Its function is still poorly understood, but evidence points to it being part of the endothelial junction associated with the actin cytoskeleton. A member of the Immunoglobulin superfamily, it consists of five Ig domains, a transmembrane domain, and a cytoplasmic region. It is expressed on chicken embryonic spleen and thymus, activated human T cells, endothelial progenitors such as angioblasts and mesenchymal stem cells, and strongly expressed on blood vessel endothelium and smooth muscle.
Two isoforms exist (MCAM long (MCAM-1), and MCAM short, or MCAM-s) which differ in the length of their cytoplasmic domain. Activation of these isoforms seems to produce functional differences as well. Natural killer cells transfected with MCAM-1 demonstrate decreased rolling velocity and increased cell adhesion to an endothelial cell monolayer and increased microvilli formation while cells transfected with MCAM-s showed no change in adhesion characteristics. Since these characteristics are important in leukocyte extravasation, MCAM-1 may be an important part of the inflammatory response.
CD146 has been demonstrated to appear on a small subset of T and B lymphocytes in the peripheral blood of healthy individuals. The CD146+ T cells display an immunophenotype consistent with effector memory cells and have a distinct gene profile from the CD146- T cells.[3][4] CD146 T cells have been shown by Dagur and colleagues to produce IL-17.[5]
CD146 has been seen as a marker for mesenchymal stem cells isolated from multiple adult and fetal organs,[6] and its expression may be linked to multipotency; mesenchymal stem cells with greater differentiation potential express higher levels of CD146 on the cell surface.[7]
# Clinical significance
MCAM inhibits breast cancer progression.[8] | https://www.wikidoc.org/index.php/CD146 | |
e3c9225ee409713d3f0bd217665dcd635c0850f3 | wikidoc | CD154 | CD154
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 (protein) on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells). On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.
# History
In 1991, three groups reported discovering CD154. Seth Lederman at Columbia University generated a murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4+ T cells. Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig. Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function. Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts
# Expression
CD40 ligand is primarily expressed on activated CD4+ T lymphocytes but is also found in a soluble form. While CD40L was originally described on T lymphocytes, its expression has since been found on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-haematopoietic cells (smooth muscle cells, endothelial cells, and epithelial cells).
# Specific effects on cells
CD40L plays a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40-expressing immune cells.
## Macrophages
In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T cell, which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroy phagocytosed bacteria and produce more cytokines.
## B cells
B cells can present antigens to a specialized group of helper T cells called TFH cells. If an activated TFH cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40, causing B cell activation. The T cell also produces IL-4, which directly influences B cells. As a result of this stimulation, the B cell can undergo rapid cellular division to form a germinal center where antibody isotype switching and affinity maturation occurs, as well as their differentiation to plasma cells and memory B cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target.
Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited.
## Endothelial cells
Activation of endothelial cells by CD40L (e.g. from activated platelets) leads to reactive oxygen species production, as well as chemokine and cytokine production, and expression of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. This inflammatory reaction in endothelial cells promotes recruitment of leukocytes to lesions and may potentially promote atherogenesis. CD40L has shown to be a potential biomarker for atherosclerotic instability.
# Interactions
CD154 has been shown to interact with RNF128. | CD154
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells[1] and is a member of the TNF superfamily of molecules. It binds to CD40 (protein) on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells).[2] On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication.[3] A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome.[4] Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.
# History
In 1991, three groups reported discovering CD154. Seth Lederman at Columbia University generated a murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4+ T cells.[5] Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.[6] Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.[7] Noelle contested Lederman's patent, but the challenge (called an interference) was rejected on all counts [8]
# Expression
CD40 ligand is primarily expressed on activated CD4+ T lymphocytes but is also found in a soluble form. While CD40L was originally described on T lymphocytes, its expression has since been found on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-haematopoietic cells (smooth muscle cells, endothelial cells, and epithelial cells).[9]
# Specific effects on cells
CD40L plays a central role in costimulation and regulation of the immune response via T cell priming and activation of CD40-expressing immune cells.[10]
## Macrophages
In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T cell, which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroy phagocytosed bacteria and produce more cytokines.
## B cells
B cells can present antigens to a specialized group of helper T cells called TFH cells. If an activated TFH cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40, causing B cell activation.[11] The T cell also produces IL-4, which directly influences B cells. As a result of this stimulation, the B cell can undergo rapid cellular division to form a germinal center where antibody isotype switching and affinity maturation occurs, as well as their differentiation to plasma cells and memory B cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target.
Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited.[12]
## Endothelial cells
Activation of endothelial cells by CD40L (e.g. from activated platelets) leads to reactive oxygen species production, as well as chemokine and cytokine production, and expression of adhesion molecules such as E-selectin, ICAM-1, and VCAM-1. This inflammatory reaction in endothelial cells promotes recruitment of leukocytes to lesions and may potentially promote atherogenesis.[13] CD40L has shown to be a potential biomarker for atherosclerotic instability.[14]
# Interactions
CD154 has been shown to interact with RNF128.[15] | https://www.wikidoc.org/index.php/CD154 | |
a0307acb17120f3a2f088b43ed9aa9afddec46b7 | wikidoc | CD155 | CD155
CD155 (cluster of differentiation 155) also known as the poliovirus receptor is a protein that in humans is encoded by the PVR gene.
# Function
CD155 is a Type I transmembrane glycoprotein in the immunoglobulin superfamily. Commonly known as Poliovirus Receptor (PVR) due to its involvement in the cellular poliovirus infection in primates, CD155's normal cellular function is in the establishment of intercellular adherens junctions between epithelial cells. The role of CD155 in the immune system is unclear, though it may be involved in intestinal humoral immune responses. Subsequent data has also suggested that CD155 may also be used to positively select MHC-independent T cells in the thymus.
The external domain mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1/DYNLT1. The gene is specific to the primate lineage, and serves as a cellular receptor for poliovirus in the first step of poliovirus replication.
# Structure
CD155 is a transmembrane protein with 3 extracellular immunoglobulin-like domains, D1-D3, where D1 is recognized by the virus.
Low resolution structures of CD155 complexed with poliovirus have been obtained using electron microscopy while a high resolution structures of the ectodomain D1 and D2 of CD155 were solved by x-ray crystallography. | CD155
CD155 (cluster of differentiation 155) also known as the poliovirus receptor is a protein that in humans is encoded by the PVR gene.[1][2]
# Function
CD155 is a Type I transmembrane glycoprotein in the immunoglobulin superfamily.[3] Commonly known as Poliovirus Receptor (PVR) due to its involvement in the cellular poliovirus infection in primates, CD155's normal cellular function is in the establishment of intercellular adherens junctions between epithelial cells.[4] The role of CD155 in the immune system is unclear, though it may be involved in intestinal humoral immune responses.[4] Subsequent data has also suggested that CD155 may also be used to positively select MHC-independent T cells in the thymus.
The external domain mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1/DYNLT1. The gene is specific to the primate lineage, and serves as a cellular receptor for poliovirus in the first step of poliovirus replication.[1]
# Structure
CD155 is a transmembrane protein with 3 extracellular immunoglobulin-like domains, D1-D3, where D1 is recognized by the virus.[5]
Low resolution structures of CD155 complexed with poliovirus have been obtained using electron microscopy[6] while a high resolution structures of the ectodomain D1 and D2 of CD155 were solved by x-ray crystallography.[5] | https://www.wikidoc.org/index.php/CD155 | |
44fce36aabe8f6babacba7ed5eaeb6d5a0216d7d | wikidoc | CD160 | CD160
CD160 antigen is a protein that in humans is encoded by the CD160 gene.
CD160 is a 27 kDa glycoprotein which was initially identified with the monoclonal antibody BY55. Its expression is tightly associated with peripheral blood NK cells and CD8 T lymphocytes with cytolytic effector activity. The cDNA sequence of CD160 predicts a cysteine-rich, glycosylphosphatidylinositol-anchored protein of 181 amino acids with a single Ig-like domain weakly homologous to KIR2DL4 molecule. CD160 is expressed at the cell surface as a tightly disulfide-linked multimer. RNA blot analysis revealed CD160 mRNAs of 1.5 and 1.6 kb whose expression was highly restricted to circulating NK and T cells, spleen and small intestine. Within NK cells CD160 is expressed by CD56dimCD16+ cells whereas among circulating T cells its expression is mainly restricted to TCRgd bearing cells and to TCRab+CD8brightCD95+CD56+CD28-CD27-cells. In tissues, CD160 is expressed on all intestinal intraepithelial lymphocytes. CD160 shows a broad specificity for binding to both classical and nonclassical MHC class I molecules.
# Clinical significance
CD160 is a ligand for HVEM, and considered a proposed immune checkpoint inhibitor with anti-cancer activity alongside with anti- PD-1 antibodies. CD160 has also been proposed as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.
# Related gene problems
- TAR syndrome
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | CD160
CD160 antigen is a protein that in humans is encoded by the CD160 gene.[1][2][3]
CD160 is a 27 kDa glycoprotein which was initially identified with the monoclonal antibody BY55. Its expression is tightly associated with peripheral blood NK cells and CD8 T lymphocytes with cytolytic effector activity. The cDNA sequence of CD160 predicts a cysteine-rich, glycosylphosphatidylinositol-anchored protein of 181 amino acids with a single Ig-like domain weakly homologous to KIR2DL4 molecule. CD160 is expressed at the cell surface as a tightly disulfide-linked multimer. RNA blot analysis revealed CD160 mRNAs of 1.5 and 1.6 kb whose expression was highly restricted to circulating NK and T cells, spleen and small intestine. Within NK cells CD160 is expressed by CD56dimCD16+ cells whereas among circulating T cells its expression is mainly restricted to TCRgd bearing cells and to TCRab+CD8brightCD95+CD56+CD28-CD27-cells. In tissues, CD160 is expressed on all intestinal intraepithelial lymphocytes. CD160 shows a broad specificity for binding to both classical and nonclassical MHC class I molecules.[3]
# Clinical significance
CD160 is a ligand for HVEM, and considered a proposed immune checkpoint inhibitor with anti-cancer activity alongside with anti- PD-1 antibodies.[4] CD160 has also been proposed as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.[5]
# Related gene problems
- TAR syndrome[6]
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | https://www.wikidoc.org/index.php/CD160 | |
43ad0597d64c43b790cdcd83441fc1f5b30d273a | wikidoc | CD163 | CD163
CD163 (Cluster of Differentiation 163) is a protein that in humans is encoded by the CD163 gene. CD163 is the high affinity scavenger receptor for the hemoglobin-haptoglobin complex and in the absence of haptoglobin - with lower affinity - for hemoglobin alone. It also is a marker of cells from the monocyte/macrophage lineage. CD163 functions as innate immune sensor for gram-positive and gram-negative bacteria. The receptor was discovered in 1987.
# Structure
The molecular size is 130 kDa. The receptor belongs to the scavenger receptor cysteine rich family type B and consists of a 1048 amino acid residues extracellular domain, a single transmembrane segment and a cytoplasmic tail with several splice variants.
# Clinical significance
A soluble form of the receptor exists in plasma, and cerebrospinal fluid., commonly denoted sCD163. It is generated by ectodomain shedding of the membrane bound receptor, which may represent a form of modulation of CD163 function. sCD163 shedding occurs as a result of enzymatic cleavage by ADAM17. sCD163 is upregulated in a large range of inflammatory diseases including liver cirrhosis, type 2 diabetes, macrophage activation syndrome, Gaucher's disease, sepsis, HIV infection, rheumatoid arthritis and Hodgkin Lymphoma. sCD163 is also upregulated in cerebrospinal fluid after subarachnoid haemorrhage.
# Differences between mouse and human
Differences between mice and humans in CD163 biology are important to note since preclinical studies are frequently conducted in mice. sCD163 shedding occurs in humans but not mice, due to the emergence of an Arg-Ser-Ser-Arg sequence in humans, essential for enzymatic cleavage by ADAM17. Human CD163, but mouse CD163, exhibits a strikingly higher affinity to hemoglobin-haptoglobin complex compared to hemoglobin alone.
# Animal studies
Pigs with a section of the CD163 gene removed showed complete resistance to the virus that causes Porcine Reproductive and Respiratory Syndrome.
# Interactions
CD163 has been shown to interact with CSNK2B. | CD163
CD163 (Cluster of Differentiation 163) is a protein that in humans is encoded by the CD163 gene.[1] CD163 is the high affinity scavenger receptor for the hemoglobin-haptoglobin complex[2] and in the absence of haptoglobin - with lower affinity - for hemoglobin alone.[3] It also is a marker of cells from the monocyte/macrophage lineage.[4] CD163 functions as innate immune sensor for gram-positive and gram-negative bacteria.[5][6] The receptor was discovered in 1987.[7]
# Structure
The molecular size is 130 kDa. The receptor belongs to the scavenger receptor cysteine rich family type B and consists of a 1048 amino acid residues extracellular domain, a single transmembrane segment and a cytoplasmic tail with several splice variants.
# Clinical significance
A soluble form of the receptor exists in plasma, and cerebrospinal fluid.,[8] commonly denoted sCD163. It is generated by ectodomain shedding of the membrane bound receptor, which may represent a form of modulation of CD163 function.[9] sCD163 shedding occurs as a result of enzymatic cleavage by ADAM17.[10] sCD163 is upregulated in a large range of inflammatory diseases including liver cirrhosis, type 2 diabetes, macrophage activation syndrome, Gaucher's disease, sepsis, HIV infection, rheumatoid arthritis and Hodgkin Lymphoma.[11][12] sCD163 is also upregulated in cerebrospinal fluid after subarachnoid haemorrhage.[8]
# Differences between mouse and human
Differences between mice and humans in CD163 biology are important to note since preclinical studies are frequently conducted in mice. sCD163 shedding occurs in humans but not mice, due to the emergence of an Arg-Ser-Ser-Arg sequence in humans, essential for enzymatic cleavage by ADAM17.[13] Human CD163, but mouse CD163, exhibits a strikingly higher affinity to hemoglobin-haptoglobin complex compared to hemoglobin alone.[14]
# Animal studies
Pigs with a section of the CD163 gene removed showed complete resistance to the virus that causes Porcine Reproductive and Respiratory Syndrome.[15]
# Interactions
CD163 has been shown to interact with CSNK2B.[16] | https://www.wikidoc.org/index.php/CD163 | |
a29dc64e817d1f66304616d141fd8af749c75141 | wikidoc | CD226 | CD226
CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1') or DNAM-1 (DNAX Accessory Molecule-1) is a protein that in humans is encoded by the CD226 gene which is located on chromosome 18q22.3.
# Structure and function
CD226 is a ~65 kDa glycoprotein expressed on the surface of natural killer cells, platelets, monocytes and a subset of T cells. It is a member of the immunoglobulin superfamily containing 2 Ig-like domains of the V-set.
CD226 mediates cellular adhesion to other cells bearing its ligands, CD112 and CD155, and cross-linking CD226 with antibodies causes cellular activation. | CD226
CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1')[1] or DNAM-1 (DNAX Accessory Molecule-1)[1] is a protein that in humans is encoded by the CD226 gene which is located on chromosome 18q22.3.[2]
# Structure and function
CD226 is a ~65 kDa glycoprotein expressed on the surface of natural killer cells, platelets, monocytes and a subset of T cells. It is a member of the immunoglobulin superfamily containing 2 Ig-like domains of the V-set.[3]
CD226 mediates cellular adhesion to other cells bearing its ligands, CD112 and CD155,[3][4] and cross-linking CD226 with antibodies causes cellular activation.[2] | https://www.wikidoc.org/index.php/CD226 | |
dc1348fb7cbd40afcff4b9b4c4cd87a75df03734 | wikidoc | CD244 | CD244
CD244 (Cluster of Differentiation 244) is a human protein encoded by the CD244 gene. It is also known as Natural Killer Cell Receptor 2B4
This gene encodes a cell surface receptor expressed on natural killer cells (NK cells) (and some T cells) mediating non-major histocompatibility complex (MHC) restricted killing. The interaction between NK-cell and target cells via this receptor is thought to modulate NK-cell cytolytic activity. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.
CD244 can also be expressed on non-lymphocytes such as eosinophils, mast cells and dendritic cells. | CD244
CD244 (Cluster of Differentiation 244) is a human protein encoded by the CD244 gene.[1] It is also known as Natural Killer Cell Receptor 2B4[2]
This gene encodes a cell surface receptor expressed on natural killer cells (NK cells) (and some T cells) mediating non-major histocompatibility complex (MHC) restricted killing. The interaction between NK-cell and target cells via this receptor is thought to modulate NK-cell cytolytic activity. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[3]
CD244 can also be expressed on non-lymphocytes such as eosinophils, mast cells and dendritic cells.[4] | https://www.wikidoc.org/index.php/CD244 | |
182ff67ff68841a232136757e829ac091d03398a | wikidoc | CD247 | CD247
T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the CD247 gene.
# Genomics
The gene is located on the long arm of chromosome 1 at location 1q22-q25 on the Crick (negative) strand. The gene is 87,896 bases in length. The encoded protein is 164 amino acids long with a predicted weight of 18.696 kiloDaltons.
# Function
T-cell receptor zeta (ζ), together with T-cell receptor alpha/beta and gamma/delta heterodimers and CD3-gamma, -delta, and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Interactions
CD247 has been shown to interact with Janus kinase 3 and Protein unc-119 homolog. | CD247
T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the CD247 gene.[1]
# Genomics
The gene is located on the long arm of chromosome 1 at location 1q22-q25 on the Crick (negative) strand. The gene is 87,896 bases in length. The encoded protein is 164 amino acids long with a predicted weight of 18.696 kiloDaltons.
# Function
T-cell receptor zeta (ζ), together with T-cell receptor alpha/beta and gamma/delta heterodimers and CD3-gamma, -delta, and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]
# Interactions
CD247 has been shown to interact with Janus kinase 3[3] and Protein unc-119 homolog.[4] | https://www.wikidoc.org/index.php/CD247 | |
4d8aea8895b778550530cad209d6f5b6b6ff73dd | wikidoc | CD248 | CD248
Endosialin is a protein that in humans is encoded by the CD248 gene.
Endosialin is a member of the “Group XIV”, a novel family of C-type lectin transmembrane receptors which play a role not only in cell–cell adhesion processes but also in host defence. This family comprise two other members, CD93 and Thrombomodulin which are better characterized.
The function of endosialin remains elusive, but its expression has been associated with angiogenesis in the embryo and uterus and in tumor development and growth. | CD248
Endosialin is a protein that in humans is encoded by the CD248 gene.[1][2][3]
Endosialin is a member of the “Group XIV”, a novel family of C-type lectin transmembrane receptors which play a role not only in cell–cell adhesion processes but also in host defence. This family comprise two other members, CD93 and Thrombomodulin which are better characterized.
The function of endosialin remains elusive, but its expression has been associated with angiogenesis in the embryo and uterus and in tumor development and growth.[4] | https://www.wikidoc.org/index.php/CD248 | |
c50ad12ff8ff4be56917af254a533cc7b0fa687e | wikidoc | CD276 | CD276
CD276 (Cluster of Differentiation 276) is a human protein encoded by the CD276 gene.
# Function
Costimulatory B7 molecules (e.g., B7-1, or CD80; MIM 112203) signal through CD28 (MIM 186760) family molecules such as CD28, CTLA4 (MIM 123890), and ICOS (MIM 604558).
CD276 (aka B7-H3), an immune checkpoint molecule, is expressed by some solid tumours and is the target of anticancer candidates such as MGA271. | CD276
CD276 (Cluster of Differentiation 276) is a human protein encoded by the CD276 gene.[1]
# Function
Costimulatory B7 molecules (e.g., B7-1, or CD80; MIM 112203) signal through CD28 (MIM 186760) family molecules such as CD28, CTLA4 (MIM 123890), and ICOS (MIM 604558).[supplied by OMIM][1]
CD276 (aka B7-H3), an immune checkpoint molecule, is expressed by some solid tumours and is the target of anticancer candidates such as MGA271.[2] | https://www.wikidoc.org/index.php/CD276 | |
5ebc138720d5b267063e2d0e8946dd829fae4aad | wikidoc | CD278 | CD278
Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene.
CD278 or ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. It is thought to be important for Th2 cells in particular.
# Function
The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.
# Knockout phenotype
Compared to wild-type naïve T cells, ICOS-/- T cells activated with plate-bound anti-CD3 have reduced proliferation and IL-2 secretion. The defect in proliferation can be rescued by addition of IL-2 to the culture, suggesting the proliferative defect is due either to ICOS-mediated IL-2 secretion or the activation of similar signaling pathways between ICOS and IL-2. In terms of Th1 and Th2 cytokine secretion, ICOS-/- CD4+ T cell activated in vitro reduced IL-4 secretion, while maintaining similar IFN-g secretion. Similarly, CD4+ T cells purified from ICOS-/- mice immunized with the protein keyhole limpet hemocyanin (KLH) in alum or complete Freund's Adjuvant have attenuated IL-4 secretion, but similar IFN-g and IL-5 secretion when recalled with KLH.
These data are similar to an airway hypersensitivity model showing similar IL-5 secretion, but reduced IL-4 secretion in response to sensitization with Ova protein, indicating a defect in Th2 cytokine secretion, but not a defect in Th1 differentiation as both IL-4 and IL-5 are Th2-associated cytokines. In agreement with reduced Th2 responses, ICOS-/- mice expressed reduced germinal center formation and IgG1 and IgE antibody titers in response to immunization.
# Combination therapy
Ipilimumab patients expressed increased ICOS+ T cells in tumor tissues and blood. The increase served as a pharmacodynamic biomarker of anti-CTLA-4 treatment. In wild-type C57BL/6 mice, anti-CTLA-4 treatment resulted in tumor rejection in 80 to 90% of subjects, but in gene-targeted mice that were deficient for either ICOS or its ligand (ICOSLG), the efficacy was less than 50%. An agonistic stimulus for the ICOS pathway during anti-CTLA-4 therapy resulted in an increase in efficacy that was about four to five times as large as that of control treatments. As of 2015 antibodies for ICOS were not available for clinical testing. | CD278
Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene.[1][2][3]
CD278 or ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. It is thought to be important for Th2 cells in particular.[4][5]
# Function
The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses and regulation of cell proliferation.[3]
# Knockout phenotype
Compared to wild-type naïve T cells, ICOS-/- T cells activated with plate-bound anti-CD3 have reduced proliferation and IL-2 secretion.[6] The defect in proliferation can be rescued by addition of IL-2 to the culture, suggesting the proliferative defect is due either to ICOS-mediated IL-2 secretion or the activation of similar signaling pathways between ICOS and IL-2. In terms of Th1 and Th2 cytokine secretion, ICOS-/- CD4+ T cell activated in vitro reduced IL-4 secretion, while maintaining similar IFN-g secretion. Similarly, CD4+ T cells purified from ICOS-/- mice immunized with the protein keyhole limpet hemocyanin (KLH) in alum or complete Freund's Adjuvant have attenuated IL-4 secretion, but similar IFN-g and IL-5 secretion when recalled with KLH.
These data are similar to an airway hypersensitivity model showing similar IL-5 secretion, but reduced IL-4 secretion in response to sensitization with Ova protein, indicating a defect in Th2 cytokine secretion, but not a defect in Th1 differentiation as both IL-4 and IL-5 are Th2-associated cytokines. In agreement with reduced Th2 responses, ICOS-/- mice expressed reduced germinal center formation and IgG1 and IgE antibody titers in response to immunization.
# Combination therapy
Ipilimumab patients expressed increased ICOS+ T cells in tumor tissues and blood. The increase served as a pharmacodynamic biomarker of anti-CTLA-4 treatment. In wild-type C57BL/6 mice, anti-CTLA-4 treatment resulted in tumor rejection in 80 to 90% of subjects, but in gene-targeted mice that were deficient for either ICOS or its ligand (ICOSLG), the efficacy was less than 50%. An agonistic stimulus for the ICOS pathway during anti-CTLA-4 therapy resulted in an increase in efficacy that was about four to five times as large as that of control treatments. As of 2015 antibodies for ICOS were not available for clinical testing.[7] | https://www.wikidoc.org/index.php/CD278 | |
40c7b3e67a123b9825b521ba714e33786f847042 | wikidoc | CD49b | CD49b
Integrin alpha-2 or CD49b (cluster of differentiation 49b) is a protein which in humans is encoded by the CD49b gene.
The CD49b protein is an integrin alpha subunit. It makes up half of the α2β1 integrin duplex. Integrins are heterodimeric integral membrane glycoproteins composed of a distinct alpha chain and a common beta chain. They are found on a wide variety of cell types including, T cells (the NKT cells), NK cells, fibroblasts and platelets. Integrins are involved in cell adhesion and also participate in cell-surface mediated signalling.
Expression of CD49b in conjunction with LAG-3 has been used to identify type 1 regulatory (Tr1) cells.
DX5 is a monoclonal antibody which binds to CD49b.
# Interactions
CD49b has been shown to interact with MMP1. | CD49b
Integrin alpha-2 or CD49b (cluster of differentiation 49b) is a protein which in humans is encoded by the CD49b gene.
The CD49b protein is an integrin alpha subunit. It makes up half of the α2β1 integrin duplex. Integrins are heterodimeric integral membrane glycoproteins composed of a distinct alpha chain and a common beta chain. They are found on a wide variety of cell types including, T cells (the NKT cells), NK cells, fibroblasts and platelets. Integrins are involved in cell adhesion and also participate in cell-surface mediated signalling.[1]
Expression of CD49b in conjunction with LAG-3 has been used to identify type 1 regulatory (Tr1) cells.[2]
DX5 is a monoclonal antibody which binds to CD49b.[3]
# Interactions
CD49b has been shown to interact with MMP1.[4][5] | https://www.wikidoc.org/index.php/CD49b | |
a00bb7a9524dcb99c975ccb7d42f8be9f6ac55b8 | wikidoc | CD49c | CD49c
Integrin alpha-3 is a protein that in humans is encoded by the ITGA3 gene.
ITGA3 is an integrin alpha subunit. Together with beta-1 subunit, it makes up half of the α3β1 integrin duplex that plays a role in neural migration and corticogenesis, acted upon by such factors as netrin-1 and reelin.
ITGA3 encodes the integrin alpha 3 chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha chain 3 undergoes post-translational cleavage in the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that interacts with many extracellular matrix proteins.
# Alternative names
The alpha 3 beta 1 integrin is known variously as: very late (activation) antigen 3 ('VLA-3'), very common antigen 2 ('VCA-2'), extracellular matrix receptor 1 ('ECMR1'), and galactoprotein b3 ('GAPB3').
# Interactions
CD49c has been shown to interact with:
- CD9
- FHL2,
- LGALS8, and
- TSPAN4. | CD49c
Integrin alpha-3 is a protein that in humans is encoded by the ITGA3 gene.[1][2]
ITGA3 is an integrin alpha subunit. Together with beta-1 subunit, it makes up half of the α3β1 integrin duplex that plays a role in neural migration and corticogenesis, acted upon by such factors as netrin-1 and reelin.
ITGA3 encodes the integrin alpha 3 chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha chain 3 undergoes post-translational cleavage in the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that interacts with many extracellular matrix proteins.
# Alternative names
The alpha 3 beta 1 integrin is known variously as: very late (activation) antigen 3 ('VLA-3'), very common antigen 2 ('VCA-2'), extracellular matrix receptor 1 ('ECMR1'), and galactoprotein b3 ('GAPB3').[3]
# Interactions
CD49c has been shown to interact with:
- CD9[4][5]
- FHL2,[6]
- LGALS8,[7] and
- TSPAN4.[8] | https://www.wikidoc.org/index.php/CD49c | |
c75f86ad541ae27ea27f0c06cf2247fec9680e96 | wikidoc | CD79A | CD79A
Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.
The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.
It is associated with agammaglobulinemia-3.
# Gene
The mouse CD79A gene, then called mb-1, was cloned in the late 1980s, followed by the discovery of human CD79A in the early 1990s. It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms.
CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark. The occurrence of CD79A thus coincides with the evolution of B cell receptors with greater diversity generated by recombination of multiple V, D, and J elements in bony fish contrasting the single V, D and J elements found in shark.
# Structure
CD79a is a membrane protein with an extracellular immunoglobulin domain, a single span transmembrane region and a short cytoplasmic domain. The cytoplasmic domain contains multiple phosphorylation sites including a conserved dual phosphotyrosine binding motif, termed immunotyrosine-based activation motif (ITAM). The larger CD79a isoform contains an insert in position 88-127 of human CD79a resulting in a complete immunoglobulin domain, whereas the smaller isoform has only a truncated Ig-like domain. CD79a has several cysteine residues, one of which forms covalent bonds with CD79b.
# Function
CD79a plays multiple and diverse roles in B cell development and function. The CD79a/b heterodimer associates non-covalently with the immunoglobulin heavy chain through its transmembrane region, thus forming the BCR along with the immunoglobulin light chain and the pre-BCR when associated with the surrogate light chain in developing B cells. Association of the CD79a/b heterodimer with the immunoglobulin heavy chain is required for surface expression of the BCR and BCR induced calcium flux and protein tyrosine phosphorylation. Genetic deletion of the transmembrane exon of CD79A results in loss of CD79a protein and a complete block of B cell development at the pro to pre B cell transition. Similarly, humans with homozygous splice variants in CD79A predicted to result in loss of the transmembrane region and a truncated or absent protein display agammaglobulinemia and no peripheral B cells.
The CD79a ITAM tyrosines (human CD79a Tyr188 and Tyr199, mouse CD79a Tyr182 and Tyr193) phosphorylated in response to BCR crosslinking, are critical for binding of Src-homology 2 domain-containing kinases such as spleen tyrosine kinase (Syk) and signal transduction by CD79a. In vivo, the CD79a ITAM tyrosines synergize with the CD79b ITAM tyrosines to mediate the transition from the pro to the pre B cell stage as suggested by the analysis of mice with targeted mutations of the CD79a and CD79b ITAM. Loss of only one of the two functional CD79a/b ITAMs resulted in impaired B cell development but B cell functions such as the T cell independent type II response and BCR mediated calcium flux in the available B cells were intact. However, the presence of both the CD79a and CD79b ITAM tyrosines were required for normal T cell dependent antibody responses. The CD79a cytoplasmic domain further contains a non-ITAM tyrosine distal of the CD79a ITAM (human CD79a Tyr210, mouse CD79a Tyr204) that can bind BLNK and Nck once phosphorylated, and is critical for BCR mediated B cell proliferation and B1 cell development. CD79a ITAM tyrosine phosphorylation and signaling is negatively regulated by serine and threonine residues in direct proximity of the ITAM (human CD79a Ser197, Ser203, Thr209; mouse CD79a Ser191, Ser197, Thr203), and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.
# Diagnostic relevance
The CD79a protein is present on the surface of B-cells throughout their life cycle, and is absent on all other healthy cells, making it a highly reliable marker for B-cells in immunohistochemistry. The protein remains present when B-cells transform into active plasma cells, and is also present in virtually all B-cell neoplasms, including B-cell lymphomas, plasmacytomas, and myelomas. It is also present in abnormal lymphocytes associated with some cases of Hodgkins disease. Because even on B-cell precursors, it can be used to stain a wider range of cells than can the alternative B-cell marker CD20, but the latter is more commonly retained on mature B-cell lymphomas, so that the two are often used together in immunohistochemistry panels. | CD79A
Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.[1]
The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.[2]
It is associated with agammaglobulinemia-3.[3]
# Gene
The mouse CD79A gene, then called mb-1, was cloned in the late 1980s,[4] followed by the discovery of human CD79A in the early 1990s.[5][6] It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms.[1]
CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark.[7] The occurrence of CD79A thus coincides with the evolution of B cell receptors with greater diversity generated by recombination of multiple V, D, and J elements in bony fish contrasting the single V, D and J elements found in shark.[8]
# Structure
CD79a is a membrane protein with an extracellular immunoglobulin domain, a single span transmembrane region and a short cytoplasmic domain.[1] The cytoplasmic domain contains multiple phosphorylation sites including a conserved dual phosphotyrosine binding motif, termed immunotyrosine-based activation motif (ITAM).[9][10] The larger CD79a isoform contains an insert in position 88-127 of human CD79a resulting in a complete immunoglobulin domain, whereas the smaller isoform has only a truncated Ig-like domain.[1] CD79a has several cysteine residues, one of which forms covalent bonds with CD79b.[11]
# Function
CD79a plays multiple and diverse roles in B cell development and function. The CD79a/b heterodimer associates non-covalently with the immunoglobulin heavy chain through its transmembrane region, thus forming the BCR along with the immunoglobulin light chain and the pre-BCR when associated with the surrogate light chain in developing B cells. Association of the CD79a/b heterodimer with the immunoglobulin heavy chain is required for surface expression of the BCR and BCR induced calcium flux and protein tyrosine phosphorylation.[citation needed] Genetic deletion of the transmembrane exon of CD79A results in loss of CD79a protein and a complete block of B cell development at the pro to pre B cell transition.[12] Similarly, humans with homozygous splice variants in CD79A predicted to result in loss of the transmembrane region and a truncated or absent protein display agammaglobulinemia and no peripheral B cells.[3][13][14]
The CD79a ITAM tyrosines (human CD79a Tyr188 and Tyr199, mouse CD79a Tyr182 and Tyr193) phosphorylated in response to BCR crosslinking, are critical for binding of Src-homology 2 domain-containing kinases such as spleen tyrosine kinase (Syk) and signal transduction by CD79a.[15][16] In vivo, the CD79a ITAM tyrosines synergize with the CD79b ITAM tyrosines to mediate the transition from the pro to the pre B cell stage as suggested by the analysis of mice with targeted mutations of the CD79a and CD79b ITAM.[17][18] Loss of only one of the two functional CD79a/b ITAMs resulted in impaired B cell development but B cell functions such as the T cell independent type II response and BCR mediated calcium flux in the available B cells were intact. However, the presence of both the CD79a and CD79b ITAM tyrosines were required for normal T cell dependent antibody responses.[17][19] The CD79a cytoplasmic domain further contains a non-ITAM tyrosine distal of the CD79a ITAM (human CD79a Tyr210, mouse CD79a Tyr204) that can bind BLNK and Nck once phosphorylated,[20][21][22] and is critical for BCR mediated B cell proliferation and B1 cell development.[23] CD79a ITAM tyrosine phosphorylation and signaling is negatively regulated by serine and threonine residues in direct proximity of the ITAM (human CD79a Ser197, Ser203, Thr209; mouse CD79a Ser191, Ser197, Thr203),[24][25] and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.[18]
# Diagnostic relevance
The CD79a protein is present on the surface of B-cells throughout their life cycle, and is absent on all other healthy cells, making it a highly reliable marker for B-cells in immunohistochemistry. The protein remains present when B-cells transform into active plasma cells, and is also present in virtually all B-cell neoplasms, including B-cell lymphomas, plasmacytomas, and myelomas. It is also present in abnormal lymphocytes associated with some cases of Hodgkins disease. Because even on B-cell precursors, it can be used to stain a wider range of cells than can the alternative B-cell marker CD20, but the latter is more commonly retained on mature B-cell lymphomas, so that the two are often used together in immunohistochemistry panels.[2] | https://www.wikidoc.org/index.php/CD79A | |
6ff3993d4f404267c5557656f57d5a82e42982d9 | wikidoc | CDC20 | CDC20
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.
CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes: nuclear movement prior to anaphase, and chromosome separation.
# Discovery
Cdc20, along with a handful of other Cdc proteins, was discovered in the early 1970s when Hartwell and colleagues made cell-division cycle mutants that failed to complete major events in the cell cycle in the yeast strain S. cerevisiae. Hartwell found mutants that did not enter anaphase and thus could not complete mitosis; this phenotype could be traced back to the CDC20 gene. However, even after the biochemistry of the protein was eventually elucidated, the molecular role of Cdc20 remained elusive until the discovery of the APC/C in 1995.
# Structure
Cdc20 is a protein related to the beta subunit of heterotrimeric G proteins. Near its C-terminus it contains seven WD40 repeats, which are multiple short, structural motifs of around 40 amino acids that often play a role in binding with larger protein complexes. In the case of Cdc20, they arrange into a seven-bladed beta propeller. The human Cdc20 is about 499 amino acids long, and contains at least four phosphorylation sites near the N-terminus. In between these phosphorylation sites, which play regulatory roles, are the C-box, the KEN-box, the Mad2-interacting motif, and the Cry box. The KEN-box, as well as the Cry box, are important recognition and degradation sequences for the APC/CCdh1 complex (see below).
# Interactions
CDC20 has been shown to interact with:
- ANAPC7
- BUB1B,
- CDC16,
- CDC27,
- Cyclin A1,
- FBXO5,
- HDAC1,
- HDAC2, and
- MAD2L1.
However, the most important interaction of Cdc20 is with the Anaphase Promoting Complex. The APC/C is a large E3 ubiquitin ligase, which triggers the metaphase to anaphase transition by marking select proteins for degradation. The two main targets of the APC/C are the S/M cyclins and the protein securin. S/M cyclins activate cyclin-dependent kinases (Cdks), which have a vast array of downstream effects that work to guide the cell through mitosis. They must be degraded for cells to exit mitosis. Securin is a protein that inhibits separase, which in turn inhibits cohesin, a protein that holds sister chromatids together. Therefore, in order for anaphase to progress, securin must be inhibited so that cohesin can be cleaved by separase. These processes are dependent on both the APC/C and Cdc20: When Cdks phosphorylate the APC/C, Cdc20 can bind and activate it, allowing both the degradation of Cdks and the cleavage of cohesin. APC/C activity is dependent on Cdc20 (and Cdh1), because Cdc20 often binds the APC/C substrates directly. In fact, it is thought that Cdc20 and Cdh1 (see below) are receptors for the KEN-box and D-box motifs on substrates. However, these sequences are normally not sufficient for ubiquitination and degradation; much remains to be learned about how Cdc20 binds its substrate.
# Regulation
The APC/CCdc20 complex regulates itself so that it is present during the appropriate times of the cell cycle. In order for Cdc20 to bind the APC/C, specific APC/C subunits must be phosphorylated by Cdk1 (among other Cdks). Therefore, when cdk activity is high in mitosis, and the cell must prepare to enter anaphase and exit mitosis, the APC/CCdc20 complex is activated. Once active, APC/CCdc20 promotes the degradation of Cdks by inactivating S/M cyclins. Cdk degradation brings about lower rates of APC/C phosphorylation and thus lower rates of Cdc20 binding. In this way, the APC/CCdc20 complex inactivates itself by the end of mitosis. However, because the cell does not immediately enter the cell cycle, Cdks can not immediately be reactivated. Multiple different mechanisms inhibit Cdks in G1: Cdk inhibitor proteins are expressed, and cyclin gene expression is down-regulated. Importantly, cyclin accumulation is also prevented by Cdh1.
# Cdh1
Cdc20-homologue 1 (Cdh1) plays a complementary role to Cdc20 in cell cycle progression. During the time of APC/CCdc20 activity, Cdh1 is phosphorylated and cannot bind to the APC/C. After metaphase, however, S/M-Cdks are inactivated by APC/CCdc20, and Cdh1 can exist in a non-phosphorylated state and bind the APC/C. This enables the APC/C to continue to degrade S/M cyclins (and thus S/M Cdks) until they are needed again in the next S-phase.
How can S/M cyclins reappear to shepherd the cell into mitosis? The APC/CCdc20 does not recognize G1/S cyclins. Their concentration rises during G1, activating G1/S Cdks, which in turn phosphorylate Cdh1 and gradually relieve the inhibition on S/M cyclins.
# Spindle assembly checkpoint
Cdc20 is also a part of, and regulated by, the Spindle Assembly Checkpoint (SAC). This checkpoint ensures that anaphase proceeds only when the centromeres of all sister chromatids lined up on the metaphase plate are properly attached to microtubules. The checkpoint is held active by any unattached centromere; only when all centromeres are attached will anaphase commence. The APC/CCdc20 is an important target of the SAC, which consists of several different proteins, including Mad2, Mad3(BubR1), and Bub3. In fact, these three proteins, together with Cdc20, likely form the mitotic checkpoint complex (MCC), which inhibits APC/CCdc20 so that anaphase cannot begin prematurely. Moreover, Bub1 phosphorylates and thus inhibits Cdc20 directly, while in yeast Mad2 and Mad3, when bound to Cdc20, trigger its autoubiquitiniation. (For more information see Spindle Checkpoint.) | CDC20
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene[1][2] in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.
CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes: nuclear movement prior to anaphase, and chromosome separation.[3]
# Discovery
Cdc20, along with a handful of other Cdc proteins, was discovered in the early 1970s when Hartwell and colleagues made cell-division cycle mutants that failed to complete major events in the cell cycle in the yeast strain S. cerevisiae.[4] Hartwell found mutants that did not enter anaphase and thus could not complete mitosis; this phenotype could be traced back to the CDC20 gene.[5] However, even after the biochemistry of the protein was eventually elucidated, the molecular role of Cdc20 remained elusive until the discovery of the APC/C in 1995.[6][7]
# Structure
Cdc20 is a protein related to the beta subunit of heterotrimeric G proteins. Near its C-terminus it contains seven WD40 repeats, which are multiple short, structural motifs of around 40 amino acids that often play a role in binding with larger protein complexes. In the case of Cdc20, they arrange into a seven-bladed beta propeller. The human Cdc20 is about 499 amino acids long, and contains at least four phosphorylation sites near the N-terminus. In between these phosphorylation sites, which play regulatory roles, are the C-box, the KEN-box, the Mad2-interacting motif, and the Cry box. The KEN-box, as well as the Cry box, are important recognition and degradation sequences for the APC/CCdh1 complex (see below).
# Interactions
CDC20 has been shown to interact with:
- ANAPC7[8][9]
- BUB1B,[9][10][11][12][13][14]
- CDC16,[8][9][12][15]
- CDC27,[8][9][12][15][16][17][18]
- Cyclin A1,[19]
- FBXO5,[20]
- HDAC1,[21]
- HDAC2,[21] and
- MAD2L1.[9][12][14][15][16][17][22][23][24][25][26][27]
However, the most important interaction of Cdc20 is with the Anaphase Promoting Complex. The APC/C is a large E3 ubiquitin ligase, which triggers the metaphase to anaphase transition by marking select proteins for degradation. The two main targets of the APC/C are the S/M cyclins and the protein securin. S/M cyclins activate cyclin-dependent kinases (Cdks), which have a vast array of downstream effects that work to guide the cell through mitosis. They must be degraded for cells to exit mitosis. Securin is a protein that inhibits separase, which in turn inhibits cohesin, a protein that holds sister chromatids together. Therefore, in order for anaphase to progress, securin must be inhibited so that cohesin can be cleaved by separase. These processes are dependent on both the APC/C and Cdc20: When Cdks phosphorylate the APC/C, Cdc20 can bind and activate it, allowing both the degradation of Cdks and the cleavage of cohesin. APC/C activity is dependent on Cdc20 (and Cdh1), because Cdc20 often binds the APC/C substrates directly.[28] In fact, it is thought that Cdc20 and Cdh1 (see below) are receptors for the KEN-box and D-box motifs on substrates.[29] However, these sequences are normally not sufficient for ubiquitination and degradation; much remains to be learned about how Cdc20 binds its substrate.
# Regulation
The APC/CCdc20 complex regulates itself so that it is present during the appropriate times of the cell cycle. In order for Cdc20 to bind the APC/C, specific APC/C subunits must be phosphorylated by Cdk1 (among other Cdks). Therefore, when cdk activity is high in mitosis, and the cell must prepare to enter anaphase and exit mitosis, the APC/CCdc20 complex is activated. Once active, APC/CCdc20 promotes the degradation of Cdks by inactivating S/M cyclins. Cdk degradation brings about lower rates of APC/C phosphorylation and thus lower rates of Cdc20 binding. In this way, the APC/CCdc20 complex inactivates itself by the end of mitosis.[30] However, because the cell does not immediately enter the cell cycle, Cdks can not immediately be reactivated. Multiple different mechanisms inhibit Cdks in G1: Cdk inhibitor proteins are expressed, and cyclin gene expression is down-regulated. Importantly, cyclin accumulation is also prevented by Cdh1.[30]
# Cdh1
Cdc20-homologue 1 (Cdh1) plays a complementary role to Cdc20 in cell cycle progression. During the time of APC/CCdc20 activity, Cdh1 is phosphorylated and cannot bind to the APC/C. After metaphase, however, S/M-Cdks are inactivated by APC/CCdc20, and Cdh1 can exist in a non-phosphorylated state and bind the APC/C. This enables the APC/C to continue to degrade S/M cyclins (and thus S/M Cdks) until they are needed again in the next S-phase.
How can S/M cyclins reappear to shepherd the cell into mitosis? The APC/CCdc20 does not recognize G1/S cyclins. Their concentration rises during G1, activating G1/S Cdks, which in turn phosphorylate Cdh1 and gradually relieve the inhibition on S/M cyclins.[30]
# Spindle assembly checkpoint
Cdc20 is also a part of, and regulated by, the Spindle Assembly Checkpoint (SAC). This checkpoint ensures that anaphase proceeds only when the centromeres of all sister chromatids lined up on the metaphase plate are properly attached to microtubules. The checkpoint is held active by any unattached centromere; only when all centromeres are attached will anaphase commence. The APC/CCdc20 is an important target of the SAC, which consists of several different proteins, including Mad2, Mad3(BubR1), and Bub3. In fact, these three proteins, together with Cdc20, likely form the mitotic checkpoint complex (MCC), which inhibits APC/CCdc20 so that anaphase cannot begin prematurely. Moreover, Bub1 phosphorylates and thus inhibits Cdc20 directly, while in yeast Mad2 and Mad3, when bound to Cdc20, trigger its autoubiquitiniation.[31] (For more information see Spindle Checkpoint.) | https://www.wikidoc.org/index.php/CDC20 | |
ce6394642aff4577c1164d1f0dfd99160977c411 | wikidoc | CDC34 | CDC34
CDC34 is a gene encoding a protein product that has ubiquitin conjugating activity. CDC34 was originally discovered by work in baker's yeast as a gene that has a role in the cell division cycle. Cdc34 in yeast targets numerous substrates (Sic1, Far1, Cln1, Cln2) for ubiquitin mediated degradation.
Ubiquitin-conjugating enzyme E2 R1 is a protein that in humans is encoded by the CDC34 gene.
The protein encoded by this gene is a member of the ubiquitin-conjugating enzyme family. Ubiquitin-conjugating enzyme catalyzes the covalent attachment of ubiquitin to other proteins. This protein is a part of the large multiprotein complex, which is required for ubiquitin-mediated degradation of cell cycle G1 regulators, and for the initiation of DNA replication.
# Interactions
CDC34 has been shown to interact with CSNK2B, BTRC and CDK9. | CDC34
CDC34 is a gene encoding a protein product that has ubiquitin conjugating activity. CDC34 was originally discovered by work in baker's yeast as a gene that has a role in the cell division cycle. Cdc34 in yeast targets numerous substrates (Sic1, Far1, Cln1, Cln2) for ubiquitin mediated degradation.
Ubiquitin-conjugating enzyme E2 R1 is a protein that in humans is encoded by the CDC34 gene.[1][2][3]
The protein encoded by this gene is a member of the ubiquitin-conjugating enzyme family. Ubiquitin-conjugating enzyme catalyzes the covalent attachment of ubiquitin to other proteins. This protein is a part of the large multiprotein complex, which is required for ubiquitin-mediated degradation of cell cycle G1 regulators, and for the initiation of DNA replication.[3]
# Interactions
CDC34 has been shown to interact with CSNK2B,[4] BTRC[5][6] and CDK9.[7] | https://www.wikidoc.org/index.php/CDC34 | |
92dd85c960a88bcce0d8b0c3b64d9a52c1056575 | wikidoc | CDC37 | CDC37
Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.
The protein encoded by this gene is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a molecular chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.
# Interactions
CDC37 has been shown to interact with:
- CDK4,
- HSP90AA1
- IKBKG,
- IKK2, and
- STK11.
# Domain architecture
CDC37 consists of three structural domains. The N-terminal domain binds to protein kinases. The central domain is the Hsp90 chaperone (heat shock protein 90) binding domain. The function of the C-terminal domain is unclear. | CDC37
Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.[1][2]
The protein encoded by this gene is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a molecular chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.[3]
# Interactions
CDC37 has been shown to interact with:
- CDK4,[1][2][4][5]
- HSP90AA1[6][7]
- IKBKG,[8][9]
- IKK2,[9] and
- STK11.[10]
# Domain architecture
CDC37 consists of three structural domains. The N-terminal domain binds to protein kinases.[11] The central domain is the Hsp90 chaperone (heat shock protein 90) binding domain.[12] The function of the C-terminal domain is unclear. | https://www.wikidoc.org/index.php/CDC37 | |
b4acd341d5965d3bca6f2fd0a7f8c9e67cbb7db4 | wikidoc | CDC42 | CDC42
Cell division control protein 42 homolog, also known as Cdc42, is a protein involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.
# Function
Human Cdc42 is a small GTPase of the Rho family, which regulates signaling pathways that control diverse cellular functions including cell morphology, cell migration, endocytosis and cell cycle progression. Rho GTPases are central to dynamic actin cytoskeletal assembly and rearrangement that are the basis of cell-cell adhesion and migration. Activated Cdc42 activates by conformational changes p21-activated kinases PAK1 and PAK2, which in turn initiate actin reorganization and regulate cell adhesion, migration, and invasion.
# Structure
Cdc42 is a homodimer with A and B chains. Its total length is 191 amino acids and its theoretical weight is 21.33 KDa. Its sequence domains include a P-loop containing nucleoside triphosphate hydrolase and a small GTP-binding protein domain.
Cdc42 cycles between an active GTP-bound state and an inactive GDP-bound state. This process is regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase.
# Role in cancer
Recently, Cdc42 has been shown to actively assist in cancer progression. Several studies have established the basis for this and hypothesized about the underlying mechanisms.
Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB. It has been hypothesized that targeting Cdc42 in conjunction with chemotherapy may be an effective cancer treatment strategy.
In one study studying the role of Cdc42 in cervical cancer, immunohistochemistry was used to detect Cdc42 expression in three types of tissues: normal cervical tissues, cervical intraepithelial neoplasia (CIN) I or below, CIN II or above, and cervical cancer tissues. Cdc42 expression was gradually increased showing significant difference and was significantly higher in HeLa cells than in regular cells. The migration ability of HeLa cells transfected with Cdc42 was higher than that of non-transfected cells. It was proposed that the overexpression of Cdc42 can promote filopodia formation in HeLa cells. Cdc42 overexpression significantly improved the ability of cervical cancer cells to migrate, possibly due to improved pseudopodia formation.
Another study found that Cdc42 drives the process of initiating a metastatic tumor in a new tissue by promoting the expression of β1 integrin, an adhesion receptor known to be involved in metastasis. Levels of β1 integrin were reduced in Cdc42-deficient cells. β1 integrin is important for adhesion to the extracellular matrix, and could be important for the initial attachment to endothelial cells as well. Knocking down β1 integrin inhibited cancer cell migration, whereas overexpressing the integrin in Cdc42-deficient cells restored endothelial invasion. Cdc42 promoted β1 integrin expression by activating a transcription factor called SRF. A continually active form of the transcription factor was also capable of restoring endothelial insertion to cancer cells lacking Cdc42.
Normal cancer cells and Cdc42-deficient cancer cells have also been compared in vivo. When both types of cells were injected into mouse tail veins, control cells spread out more on the vessel endothelium within minutes, suggesting that Cdc42 assists in cell migration. After six weeks, the control cells had generated more metastases than the Cdc42-deficient cells. Invading cancer cells send out protrusions that reach down between neighboring endothelial cells to contact the underlying basement membrane. The cancer cells then spread out on this extracellular matrix so that the endothelial cells retract, and allow the invaders to insert themselves between them. In the absence of Cdc42, cancer cells failed to spread out on the basement membrane, and Cdc42-deficient cells showed reduced adhesion to extracellular matrix-coated coverslips. Cdc42 therefore promotes the attachment of cancer cells to both endothelial cells and the underlying basement membrane during transendothelial migration.
The small molecular inhibitor AZA197 has been used to inhibit Cdc42 in the treatment of KRAS mutant colorectal cancers. There was evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion. In mice, systemic AZA197 treatment in vivo reduced primary tumor growth and prolonged survival. Therapy targeting Rho GTPase Cdc42 signaling pathways may be effective for treatment of patients with advanced colon cancer overexpressing Cdc42, and particularly those with KRAS-mutant disease.
# Interactions
CDC42 has been shown to interact with:
- ARHGAP1,
- ARHGDIA,
- BAIAP2,
- BNIP2,
- BNIPL,
- CDC42EP2,
- CDC42EP3,
- ERRFI1,
- GDI1,
- IQGAP1,
- IQGAP2,
- ITSN1,
- MAP3K10,
- MAP3K11,
- PAK1,
- PAK2,
- PAK4.
- PAK7,
- PARD6A,
- PARD6B,
- Phospholipase D1,
- RICS
- TRIP10,
- WASL,
- Wiskott-Aldrich syndrome protein, | CDC42
Cell division control protein 42 homolog, also known as Cdc42, is a protein involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.
# Function
Human Cdc42 is a small GTPase of the Rho family, which regulates signaling pathways that control diverse cellular functions including cell morphology, cell migration, endocytosis and cell cycle progression.[1] Rho GTPases are central to dynamic actin cytoskeletal assembly and rearrangement that are the basis of cell-cell adhesion and migration. Activated Cdc42 activates by conformational changes[2] p21-activated kinases PAK1 and PAK2, which in turn initiate actin reorganization and regulate cell adhesion, migration, and invasion.[3]
# Structure
Cdc42 is a homodimer with A and B chains.[4] Its total length is 191 amino acids and its theoretical weight is 21.33 KDa.[4] Its sequence domains include a P-loop containing nucleoside triphosphate hydrolase and a small GTP-binding protein domain.[4]
Cdc42 cycles between an active GTP-bound state and an inactive GDP-bound state. This process is regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase.[5]
# Role in cancer
Recently, Cdc42 has been shown to actively assist in cancer progression. Several studies have established the basis for this and hypothesized about the underlying mechanisms.
Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer.[6] Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB.[6] It has been hypothesized that targeting Cdc42 in conjunction with chemotherapy may be an effective cancer treatment strategy.
In one study studying the role of Cdc42 in cervical cancer, immunohistochemistry was used to detect Cdc42 expression in three types of tissues: normal cervical tissues, cervical intraepithelial neoplasia (CIN) I or below, CIN II or above, and cervical cancer tissues.[7] Cdc42 expression was gradually increased showing significant difference and was significantly higher in HeLa cells than in regular cells. The migration ability of HeLa cells transfected with Cdc42 was higher than that of non-transfected cells.[7] It was proposed that the overexpression of Cdc42 can promote filopodia formation in HeLa cells. Cdc42 overexpression significantly improved the ability of cervical cancer cells to migrate, possibly due to improved pseudopodia formation.[7]
Another study found that Cdc42 drives the process of initiating a metastatic tumor in a new tissue by promoting the expression of β1 integrin, an adhesion receptor known to be involved in metastasis.[8] Levels of β1 integrin were reduced in Cdc42-deficient cells. β1 integrin is important for adhesion to the extracellular matrix, and could be important for the initial attachment to endothelial cells as well. Knocking down β1 integrin inhibited cancer cell migration, whereas overexpressing the integrin in Cdc42-deficient cells restored endothelial invasion.[8] Cdc42 promoted β1 integrin expression by activating a transcription factor called SRF. A continually active form of the transcription factor was also capable of restoring endothelial insertion to cancer cells lacking Cdc42.
Normal cancer cells and Cdc42-deficient cancer cells have also been compared in vivo. When both types of cells were injected into mouse tail veins, control cells spread out more on the vessel endothelium within minutes, suggesting that Cdc42 assists in cell migration.[8] After six weeks, the control cells had generated more metastases than the Cdc42-deficient cells. Invading cancer cells send out protrusions that reach down between neighboring endothelial cells to contact the underlying basement membrane. The cancer cells then spread out on this extracellular matrix so that the endothelial cells retract, and allow the invaders to insert themselves between them.[8] In the absence of Cdc42, cancer cells failed to spread out on the basement membrane, and Cdc42-deficient cells showed reduced adhesion to extracellular matrix-coated coverslips.[8] Cdc42 therefore promotes the attachment of cancer cells to both endothelial cells and the underlying basement membrane during transendothelial migration.
The small molecular inhibitor AZA197 has been used to inhibit Cdc42 in the treatment of KRAS mutant colorectal cancers.[9] There was evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion.[9] In mice, systemic AZA197 treatment in vivo reduced primary tumor growth and prolonged survival.[9] Therapy targeting Rho GTPase Cdc42 signaling pathways may be effective for treatment of patients with advanced colon cancer overexpressing Cdc42, and particularly those with KRAS-mutant disease.
# Interactions
CDC42 has been shown to interact with:
- ARHGAP1,[10][11][12][13]
- ARHGDIA,[14][15]
- BAIAP2,[16][17][18]
- BNIP2,[12][19][20]
- BNIPL,[21]
- CDC42EP2,[22][23]
- CDC42EP3,[22][24]
- ERRFI1,[25]
- GDI1,[26]
- IQGAP1,[13][27][28][29][30]
- IQGAP2,[31]
- ITSN1,[32][33]
- MAP3K10,[10]
- MAP3K11,[10][34]
- PAK1,[13][35]
- PAK2,[13][36][37]
- PAK4.[14][37][38]
- PAK7,[38][39]
- PARD6A,[40][41][42]
- PARD6B,[40][41][43]
- Phospholipase D1,[44]
- RICS[45][46][47]
- TRIP10,[48][49]
- WASL,[50][51]
- Wiskott-Aldrich syndrome protein,[49][52][53][54] | https://www.wikidoc.org/index.php/CDC42 | |
e95b2b44a83f93f1e76034fde396991780c502de | wikidoc | CDC73 | CDC73
Cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae), also known as CDC73 and parafibromin, is a protein which in humans is encoded by the CDC73 gene.
# Function
Parafibromin, LEO1, PAF1, and CTR9 form the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A and with a histone methyltransferase complex.
# Clinical significance
Mutations in the CDC73 gene are associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinomas. | CDC73
Cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae), also known as CDC73 and parafibromin, is a protein which in humans is encoded by the CDC73 gene.[1][2][3]
# Function
Parafibromin, LEO1, PAF1, and CTR9 form the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A and with a histone methyltransferase complex.[4]
# Clinical significance
Mutations in the CDC73 gene are associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT)[3] and parathyroid carcinomas.[5][6] | https://www.wikidoc.org/index.php/CDC73 | |
71ac6136c8544b06cf0658f4cd081237684db50e | wikidoc | CDCA5 | CDCA5
Sororin is a protein that in humans is encoded by the CDCA5 gene.
# Function
Sororin is required for stable binding of cohesin to chromatin and for sister chromatid cohesion in interphase.
# Clinical significance
Transactivation of Sororin and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation. | CDCA5
Sororin is a protein that in humans is encoded by the CDCA5 gene.[1][2][3]
# Function
Sororin is required for stable binding of cohesin to chromatin and for sister chromatid cohesion in interphase.[4]
# Clinical significance
Transactivation of Sororin and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation.[5] | https://www.wikidoc.org/index.php/CDCA5 | |
df17a4eb54f3a74321bda0342ef60e06f8bdfd4d | wikidoc | CDCA8 | CDCA8
Borealin is a protein that in humans is encoded by the CDCA8 gene.
# Function
CDCA8 is a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle.
# Interactions
CDCA8 has been shown to interact with INCENP, Survivin and Aurora B kinase. | CDCA8
Borealin is a protein that in humans is encoded by the CDCA8 gene.[1][2][3]
# Function
CDCA8 is a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle.[3][4]
# Interactions
CDCA8 has been shown to interact with INCENP,[4] Survivin[2][4] and Aurora B kinase.[2][4] | https://www.wikidoc.org/index.php/CDCA8 | |
2d45736d486403e7b49dae15285998d580a89cbb | wikidoc | CDCP1 | CDCP1
CUB domain-containing protein 1 (CDCP1) is a protein that in humans is encoded by the CDCP1 gene. CDCP1 has also been designated as CD318 (cluster of differentiation 318) and Trask (Transmembrane and associated with src kinases). Alternatively spliced transcript variants encoding distinct isoforms have been reported.
# Function
CDCP1/Trask is not important for the development of the mouse. Adult mice lacking CDCP1 do not exhibit gross morphologic, reproductive or behavioral abnormalities compared with wild-type mice, and histologic examination of multiple organ systems has shown no significant pathology and no observed histologic differences. CDCP1 is a ligand for CD6, a receptor molecule expressed on certain T-cells and may play a role in their migration and chemotaxis. As such CDCP1 may contribute to autoimmune diseases such as encephalomyelitis, multiple sclerosis and inflammatory arthritis.
CDCP1 is a 140 kD transmembrane glycoprotein with a large extracellular domain (ECD) containing two CUB domains, and a smaller intracellular domain (ICD). CDCP1 is cleaved by serine proteases at the extracellular domain next to Arg368 to generate a truncated molecule of 80 kDa size. Different cell lines express different amounts of p140 and p80, depending on the activity of endogenous serine proteases. In vivo, CDCP1 is not cleaved during normal physiological circumstances, but its cleavage can be induced during tumorigenesis or tissue injury.
The intracellular domain of CDCP1 contains five tyrosine residues - Y707, Y734, Y743, Y762 and Y806. Phosphorylation of CDCP1 is exclusively mediated by Src kinases and depends on the adherence state of the cells. The tyrosine phosphorylation of CDCP1 in cultured cells occurs when cells are induced to detach by trypsin or EDTA, or seen spontaneously during mitotic detachment. The loss of anchorage or cellular detachment is associated with the phosphorylation of CDCP1 as well as the concomitant dephosphorylation of focal adhesion proteins, consistent with the dismantling of focal adhesions. Contrary, during cellular attachment CDCP1 is dephosphorylated, allowing the phosphorylation of focal adhesion proteins. The anti-adhesion and anti-migratory functions of CDCP1 are mediated through negative regulation on integrin receptors.
# Clinical significance
The phosphorylation of CDCP1 is seen in many cancers, including some pre-invasive cancers as well as in invasive tumors and in tumor metastases. | CDCP1
CUB domain-containing protein 1 (CDCP1) is a protein that in humans is encoded by the CDCP1 gene.[1][2] CDCP1 has also been designated as CD318 (cluster of differentiation 318) and Trask (Transmembrane and associated with src kinases). Alternatively spliced transcript variants encoding distinct isoforms have been reported.[2]
# Function
CDCP1/Trask is not important for the development of the mouse.[3] Adult mice lacking CDCP1 do not exhibit gross morphologic, reproductive or behavioral abnormalities compared with wild-type mice, and histologic examination of multiple organ systems has shown no significant pathology and no observed histologic differences.[3] CDCP1 is a ligand for CD6, a receptor molecule expressed on certain T-cells and may play a role in their migration and chemotaxis. As such CDCP1 may contribute to autoimmune diseases such as encephalomyelitis, multiple sclerosis and inflammatory arthritis.[4]
CDCP1 is a 140 kD transmembrane glycoprotein with a large extracellular domain (ECD) containing two CUB domains, and a smaller intracellular domain (ICD). CDCP1 is cleaved by serine proteases at the extracellular domain next to Arg368 to generate a truncated molecule of 80 kDa size.[5] Different cell lines express different amounts of p140 and p80, depending on the activity of endogenous serine proteases. In vivo, CDCP1 is not cleaved during normal physiological circumstances, but its cleavage can be induced during tumorigenesis or tissue injury.[3]
The intracellular domain of CDCP1 contains five tyrosine residues - Y707, Y734, Y743, Y762 and Y806. Phosphorylation of CDCP1 is exclusively mediated by Src kinases and depends on the adherence state of the cells.[6][7] The tyrosine phosphorylation of CDCP1 in cultured cells occurs when cells are induced to detach by trypsin or EDTA, or seen spontaneously during mitotic detachment. The loss of anchorage or cellular detachment is associated with the phosphorylation of CDCP1 as well as the concomitant dephosphorylation of focal adhesion proteins, consistent with the dismantling of focal adhesions.[7] Contrary, during cellular attachment CDCP1 is dephosphorylated, allowing the phosphorylation of focal adhesion proteins. The anti-adhesion and anti-migratory functions of CDCP1 are mediated through negative regulation on integrin receptors.[8]
# Clinical significance
The phosphorylation of CDCP1 is seen in many cancers, including some pre-invasive cancers as well as in invasive tumors and in tumor metastases.[9] | https://www.wikidoc.org/index.php/CDCP1 | |
4161ab82806396b64ef9ee3005db972e9db4b7fb | wikidoc | CDCa1 | CDCa1
CDCa1 is a protein product of the human genome. The gene that codes for this protein is found on chromosome 1, from 150,076,963-150,079,657. The gene contains 2 exons and encodes 353 amino acids. Synonyms for CDCa1 are "hypothetical protein LOC100191040" and NP_001129475. CDCa1 contains a conserved metal binding domain that is a known as Protein kinase C conserved region 2, subgroup 1. This motif is known to be a member of the C2 superfamily, which is present in phospholipases, protein kinases C, and synaptotagmins. The amino acid sequence of CDCa1 can be accessed at Prior to any post translational modification, CDCa1 has a molecular weight of 37.6 kdal. Although scientists have not yet determined where CDCa1 functions within the cell, CDCa1 has a predicted isoelectric point of 11.636 which severely limits the places in which it can be effective. In addition, CDCa1 does not contain any predicted transmembrane domains or any predicted signal peptides.
# Expression
According to the National Center for Biotechnology Information, CDCa1 has only been found to be expressed in adult individuals with some form of cancer. CDCa1 is not ubiquitously expressed, and thus far scientists have only found CDCa1 expressed in the tissues of the brain, intestine, and mammary gland.
# Evolutionary conservation
There are 52 known mammalian orthologs for CDCa1, found in at least 10 species including Pan troglodytes, Ornithorhynchus anatinus, and Sus scrofa. There are a total of 38 completely conserved residues across these 10 species, corresponding to 10.76% conservation. Within vertebrates conservation remains high at 33 residues, corresponding to 9.3%. However, outside of vertebrates, conservation drops to a maximum of 1.98%, or 3 residues. | CDCa1
CDCa1 is a protein product of the human genome. The gene that codes for this protein is found on chromosome 1, from 150,076,963-150,079,657. The gene contains 2 exons and encodes 353 amino acids. Synonyms for CDCa1 are "hypothetical protein LOC100191040"[1] and NP_001129475. CDCa1 contains a conserved metal binding domain that is a known as Protein kinase C conserved region 2, subgroup 1. This motif is known to be a member of the C2 superfamily, which is present in phospholipases, protein kinases C, and synaptotagmins.[2] The amino acid sequence of CDCa1 can be accessed at [2] Prior to any post translational modification, CDCa1 has a molecular weight of 37.6 kdal.[3] Although scientists have not yet determined where CDCa1 functions within the cell, CDCa1 has a predicted isoelectric point of 11.636 which severely limits the places in which it can be effective. In addition, CDCa1 does not contain any predicted transmembrane domains or any predicted signal peptides.
# Expression
According to the National Center for Biotechnology Information, CDCa1 has only been found to be expressed in adult individuals with some form of cancer.[4] CDCa1 is not ubiquitously expressed, and thus far scientists have only found CDCa1 expressed in the tissues of the brain, intestine, and mammary gland.
# Evolutionary conservation
There are 52 known mammalian orthologs for CDCa1,[5] found in at least 10 species including Pan troglodytes, Ornithorhynchus anatinus, and Sus scrofa. There are a total of 38 completely conserved residues across these 10 species, corresponding to 10.76% conservation. Within vertebrates conservation remains high at 33 residues, corresponding to 9.3%. However, outside of vertebrates, conservation drops to a maximum of 1.98%, or 3 residues.[6] | https://www.wikidoc.org/index.php/CDCa1 | |
87dec77254fd12b0d33f7ef7d9efebb6a08aa5ff | wikidoc | CDEPT | CDEPT
# Overview
Clostridial-directed enzyme prodrug therapy (CDEPT) is the use of Clostridia to convert prodrugs into active drug agents. It is comparable to a more popular strategy, called ADEPT.
# The CDEPT strategy
Perhaps the most challenging issue in cancer treatment is how to reduce the side effects of the injected anti-cancer agents, which are of a high cytotoxicity potential. A widely used solution is to use enzymes which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT) is one of the possible approaches.
Solid tumors, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood and oxygen supply. Therefore, clostridia can grow in tumor and destroy it specifically. (Originally, Parker and co-workers showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumour lysis. Soon after, it was shown that a direct injection is not necessary, and that tumour colonization was readily obtained after intravenous administration of spores).
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression plasmid converts a prodrug into an active drug form within the tumor. While the prodrug is the inactive form and can be administrated to the blood, the products of the prodrug cleavage are highly cytotoxic and show their effect only in the vicinity of tumor cells.
Difficulties in the engineering of clostridial strains have restricted the application of other enzyme prodrug systems. So far, two enzymes have been applied in CDEPT: cytosine deaminase and nitroreductase. It has been recently suggested that β-lactamases, which are naturally found in Clostridia, can facilitate the application of the method significantly. | CDEPT
# Overview
Clostridial-directed enzyme prodrug therapy (CDEPT) is the use of Clostridia to convert prodrugs into active drug agents. It is comparable to a more popular strategy, called ADEPT.[1]
# The CDEPT strategy
Perhaps the most challenging issue in cancer treatment is how to reduce the side effects of the injected anti-cancer agents, which are of a high cytotoxicity potential. A widely used solution is to use enzymes which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT)[2] is one of the possible approaches.
Solid tumors, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood and oxygen supply.[3] Therefore, clostridia can grow in tumor and destroy it specifically.[4] (Originally, Parker and co-workers[5] showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumour lysis. Soon after, it was shown that a direct injection is not necessary, and that tumour colonization was readily obtained after intravenous administration of spores[6]).
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression plasmid converts a prodrug into an active drug form within the tumor. While the prodrug is the inactive form and can be administrated to the blood, the products of the prodrug cleavage are highly cytotoxic and show their effect only in the vicinity of tumor cells.
Difficulties in the engineering of clostridial strains have restricted the application of other enzyme prodrug systems. So far, two enzymes have been applied in CDEPT: cytosine deaminase and nitroreductase.[7] It has been recently suggested that β-lactamases, which are naturally found in Clostridia, can facilitate the application of the method significantly.[8] | https://www.wikidoc.org/index.php/CDEPT | |
b751eed37a0dc17ceeecc418b9a9e0a950aa3d4b | wikidoc | CDH11 | CDH11
Cadherin-11 is a protein that in humans is encoded by the CDH11 gene.
# Function
This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance. The mammalian CDH-11 homologues are termed calsyntenin.
# Relevance to cancer
CDH11 is overexpressed in 15% of breast cancers and seems essential to tumour progression in some other cancer types.
# Drug interactions
Arthritis drug celecoxib binds to CDH11.
# Interactions
CDH11 has been shown to interact with CDH2. | CDH11
Cadherin-11 is a protein that in humans is encoded by the CDH11 gene.[1][2]
# Function
This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance.[2] The mammalian CDH-11 homologues are termed calsyntenin.[3]
# Relevance to cancer
CDH11 is overexpressed in 15% of breast cancers and seems essential to tumour progression in some other cancer types.[4][5]
# Drug interactions
Arthritis drug celecoxib binds to CDH11.[4][5]
# Interactions
CDH11 has been shown to interact with CDH2.[6] | https://www.wikidoc.org/index.php/CDH11 | |
c8bfe2344b58d50dbdae30a08b2c5a9ffe9fbeb5 | wikidoc | CDH23 | CDH23
Cadherin-23 is a protein that in humans is encoded by the CDH23 gene.
# Function
This gene is a member of the cadherin superfamily, genes encoding calcium dependent cell-cell adhesion glycoproteins. The protein encoded by this gene is a large, single-pass transmembrane protein composed of an extracellular domain containing 27 repeats that show significant homology to the cadherin ectodomain. Expressed in the neurosensory epithelium, the protein is thought to be involved in stereocilia organization and hair bundle formation. Specifically, it is thought to interact with protocadherin 15 to form tip-link filaments.
# Clinical significance
The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this novel cadherin-like gene.
The gene is associated with kidney function decline.
# Interactions
CDH23 has been shown to interact with USH1C. | CDH23
Cadherin-23 is a protein that in humans is encoded by the CDH23 gene.[1][2][3]
# Function
This gene is a member of the cadherin superfamily, genes encoding calcium dependent cell-cell adhesion glycoproteins. The protein encoded by this gene is a large, single-pass transmembrane protein composed of an extracellular domain containing 27 repeats that show significant homology to the cadherin ectodomain. Expressed in the neurosensory epithelium, the protein is thought to be involved in stereocilia organization and hair bundle formation. Specifically, it is thought to interact with protocadherin 15 to form tip-link filaments.[4]
# Clinical significance
The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this novel cadherin-like gene.[3][5]
The gene is associated with kidney function decline.[6]
# Interactions
CDH23 has been shown to interact with USH1C.[7][8] | https://www.wikidoc.org/index.php/CDH23 | |
605424153bd4f1a2a8bc942b02377f7876b58c31 | wikidoc | CDKL5 | CDKL5
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development with mutations causing deficiencies in the protein level. It regulates neuronal morphology through cytoplasmic signaling and controlling gene expression. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.
# Mutations
CDKL5 Deficiency had been thought of as a variant of Rett's Syndrome due to some similarities in the clinical presentation, but it is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate to Rett Syndrome rather than a variant of it. While CDKL5 is primarily associated with girls, it has been seen in boys as well. This disorder includes many of the features of classic Rett syndrome (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements), but also causes recurrent seizures beginning in infancy. Some CDKL5 mutations change a single protein building block (amino acid) in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctional version of the protein.
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by this study, published in April 2016, which concluded 'There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics'. At one time, mutations in the CDKL5 gene were said to cause a disorder called X-linked infantile spasm syndrome (ISSX) or West syndrome. but this research established CDKL5 disorder as a distinct clinical entity.
# Animal studies
GSK3β inhibitors in Cdkl5 knockout (Cdkl5 -/Y) mice rescues hippocampal development and learning. Likewise, IGF-1 treatment in CDKL5 null mice restores synaptic deficits.
# Therapeutics
There are currently no approved drugs to treat CDKL5 Deficiency, save for Anti-Epileptic Drugs (AEDs) to treat the epileptic seizures. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients.
A clinical trial of Ataluren for nonsense mutations in CDKL5 and Dravet Syndrome has been announced. This same drug was approved by the UK's National Institute for Health and Care Excellence (NICE) for use in treating nonsense mutations in Duchenne muscular dystrophy. Finally a CDKL5 protein replacement therapy is in development.
# Location
The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22. More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome. | CDKL5
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development with mutations causing deficiencies in the protein level. It regulates neuronal morphology through cytoplasmic signaling and controlling gene expression.[1] The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.[2]
# Mutations
CDKL5 Deficiency had been thought of as a variant of Rett's Syndrome due to some similarities in the clinical presentation,[3] but it is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate to Rett Syndrome rather than a variant of it.[4] While CDKL5 is primarily associated with girls, it has been seen in boys as well.[5] This disorder includes many of the features of classic Rett syndrome (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements), but also causes recurrent seizures beginning in infancy. Some CDKL5 mutations change a single protein building block (amino acid) in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctional version of the protein.
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by this study, published in April 2016, which concluded 'There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics'.[6] At one time, mutations in the CDKL5 gene were said to cause a disorder called X-linked infantile spasm syndrome (ISSX)[7][8] or West syndrome.[9][10] but this research established CDKL5 disorder as a distinct clinical entity.
# Animal studies
GSK3β inhibitors in Cdkl5 knockout (Cdkl5 -/Y) mice rescues hippocampal development and learning.[11] Likewise, IGF-1 treatment in CDKL5 null mice restores synaptic deficits.[12]
# Therapeutics
There are currently no approved drugs to treat CDKL5 Deficiency, save for Anti-Epileptic Drugs (AEDs) to treat the epileptic seizures. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients.[13]
A clinical trial of Ataluren for nonsense mutations in CDKL5 and Dravet Syndrome has been announced.[14] This same drug was approved by the UK's National Institute for Health and Care Excellence (NICE) for use in treating nonsense mutations in Duchenne muscular dystrophy.[15] Finally a CDKL5 protein replacement therapy is in development.[16]
# Location
The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22.[17] More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.[2] | https://www.wikidoc.org/index.php/CDKL5 | |
ec3271ad2bc2ad2fee419e3788d887e9bea1fa4a | wikidoc | CDKN3 | CDKN3
Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.
The protein encoded by this gene belongs to the dual specificity protein phosphatase family. It was identified as a cyclin-dependent kinase inhibitor, and has been shown to interact with, and dephosphorylate CDK2 kinase, thus prevent the activation of CDK2 kinase. This gene was reported to be deleted, mutated, or overexpressed in several kinds of cancers.
# Interactions
CDKN3 has been shown to interact with Cyclin-dependent kinase 2, Cdk1 and MS4A3. | CDKN3
Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.[1][2][3]
The protein encoded by this gene belongs to the dual specificity protein phosphatase family. It was identified as a cyclin-dependent kinase inhibitor, and has been shown to interact with, and dephosphorylate CDK2 kinase, thus prevent the activation of CDK2 kinase. This gene was reported to be deleted, mutated, or overexpressed in several kinds of cancers.[3]
# Interactions
CDKN3 has been shown to interact with Cyclin-dependent kinase 2,[4][5][6] Cdk1[1][5] and MS4A3.[7] | https://www.wikidoc.org/index.php/CDKN3 | |
c062f39a8f1636222a078b11b8ef65f83f5971d3 | wikidoc | CEBPA | CEBPA
CCAAT/enhancer-binding protein alpha is a protein encoded by the CEBPA gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.
# Function
The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and gene enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as c-Jun. The encoded protein is a key regulator of adipogenesis (the process of forming new fat cells) and the accumulation of lipids in those cells, as well as in the metabolism of glucose and lipids in the liver. The protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing cultured cells to stop dividing. In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal acute myeloid leukemia.
# Common mutations
There are two major categories which CEBPA mutations can be categorized into. One category of mutations prevent CCAAT/enhancer-binding protein alpha DNA binding by altering its COOH-terminal basic leucine zipper domain. The other category of mutations disrupt the translation of the CCAAT/enhancer-binding protein alpha NH2 terminus. CEBPA mutations, which result in diminished CCAAT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents.
# Interactions
CEBPA has been shown to interact with Cyclin-dependent kinase 2 and Cyclin-dependent kinase 4.
# Clinical significance
It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients.
## Significance in acute myeloid leukemia
Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the hematopoiesis of granulocytes. It has been shown that suppression of CEBPA expression and blocking of CCAAT/enhancer-binding protein alpha stops the differentiation of myeloid progenitors. For this reason, CCAAT/enhancer-binding protein alpha's role during granulocyte differentiation and CEBPA's role as a tumor suppressor gene is critically important in the prognosis of acute myeloid leukemia.
## Prognostic significance of CEBPA mutations
CCAAT/enhancer-binding protein alpha, the transcription factor that is encoded by CEBPA, is very important in the differentiation of immature granulocytes. Mutation of the CEBPA gene has been shown to play a crucial role in leukemogenesis and prognosis in acute myeloid leukemia patients. In recent studies CEBPA mutations were found in between 7% and 15% of patients with acute myeloid leukemia. The three different types of mutations seen in these AML patients include germ-line N-terminal mutation, N-terminal frameshift mutation, and C-terminal mutation. These mutations are most frequently found in acute myeloid leukemia M1 or acute myeloid leukemia M2. Many reports link CEBPA mutations with a favorable outcome in acute myeloid leukemia. This is because these mutations are likely to induce differentiation arrest in these patients. Patients with CEBPA mutations have longer remission duration and survival time than those without the mutations. Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease.
## Significance in solid tumors
Recently it has been shown that epigenetic modification of the distal promoter region of CEBPA has resulted in downregulation of CEBPA expression in pancreatic cancer cells, lung cancer, and head and neck squamous cell carcinoma.
## Methylation of CEBPA as a prognostic biomarker in AML patients
A recent study has found that higher levels of CEBPA methylation are directly proportionate with treatment response. The complete response rate increased proportionately with the level of CEBPA methylation. For this reason it has been proposed that methylation of CEBPA could be a very useful biomarker in acute myeloid leukemia prognosis. | CEBPA
CCAAT/enhancer-binding protein alpha is a protein encoded by the CEBPA gene in humans.[1][2] CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells.[3] For details on the CCAAT structural motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.
# Function
The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and gene enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as c-Jun. The encoded protein is a key regulator of adipogenesis (the process of forming new fat cells) and the accumulation of lipids in those cells, as well as in the metabolism of glucose and lipids in the liver.[4] The protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing cultured cells to stop dividing.[5] In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal acute myeloid leukemia.[6]
# Common mutations
There are two major categories which CEBPA mutations can be categorized into. One category of mutations prevent CCAAT/enhancer-binding protein alpha DNA binding by altering its COOH-terminal basic leucine zipper domain. The other category of mutations disrupt the translation of the CCAAT/enhancer-binding protein alpha NH2 terminus. CEBPA mutations, which result in diminished CCAAT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents.[7]
# Interactions
CEBPA has been shown to interact with Cyclin-dependent kinase 2[8] and Cyclin-dependent kinase 4.[8]
# Clinical significance
It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients.[9]
## Significance in acute myeloid leukemia
Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the hematopoiesis of granulocytes. It has been shown that suppression of CEBPA expression and blocking of CCAAT/enhancer-binding protein alpha stops the differentiation of myeloid progenitors. For this reason, CCAAT/enhancer-binding protein alpha's role during granulocyte differentiation and CEBPA's role as a tumor suppressor gene is critically important in the prognosis of acute myeloid leukemia.[10]
## Prognostic significance of CEBPA mutations
CCAAT/enhancer-binding protein alpha, the transcription factor that is encoded by CEBPA, is very important in the differentiation of immature granulocytes. Mutation of the CEBPA gene has been shown to play a crucial role in leukemogenesis and prognosis in acute myeloid leukemia patients. In recent studies CEBPA mutations were found in between 7% and 15% of patients with acute myeloid leukemia. The three different types of mutations seen in these AML patients include germ-line N-terminal mutation, N-terminal frameshift mutation, and C-terminal mutation. These mutations are most frequently found in acute myeloid leukemia M1 or acute myeloid leukemia M2. Many reports link CEBPA mutations with a favorable outcome in acute myeloid leukemia. This is because these mutations are likely to induce differentiation arrest in these patients. Patients with CEBPA mutations have longer remission duration and survival time than those without the mutations.[7] Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease.[11]
## Significance in solid tumors
Recently it has been shown that epigenetic modification of the distal promoter region of CEBPA has resulted in downregulation of CEBPA expression in pancreatic cancer cells, lung cancer, and head and neck squamous cell carcinoma.[12][13]
## Methylation of CEBPA as a prognostic biomarker in AML patients
A recent study has found that higher levels of CEBPA methylation are directly proportionate with treatment response. The complete response rate increased proportionately with the level of CEBPA methylation. For this reason it has been proposed that methylation of CEBPA could be a very useful biomarker in acute myeloid leukemia prognosis.[14] | https://www.wikidoc.org/index.php/CEBPA | |
acd9434da22cfedfe8e25847e0aeb2f182162b07 | wikidoc | CEBPB | CEBPB
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
# Function
The protein encoded by this intronless gene is a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related proteins CEBP-alpha, CEBP-delta, and CEBP-gamma. The encoded protein is important in the regulation of genes involved in immune and inflammatory responses and has been shown to bind to the IL-1 response element in the IL-6 gene, as well as to regulatory regions of several acute-phase and cytokine genes. In addition, the encoded protein can bind the promoter and upstream element and stimulate the expression of the collagen type I gene.
CEBP-beta is critical for normal macrophage functioning, an important immune cell sub-type; mice unable to express CEBP-beta have macrophages that cannot differentiate (specialize) and thus are unable to perform all their biological functions - including macrophage-mediated muscle repair. Observational work has shown that expression of CEBP-beta in blood leukocytes is positively associated with muscle strength in humans, emphasizing the importance of the immune system, and particularly macrophages, in the maintenance of muscle function.
Function of CEBPB gene can be effectively examined by siRNA knockdown based on an independent validation.
# Target genes
CEBPB is capable of increasing the expression of several target genes. Among them, some have specific role in the nervous system such as the preprotachykinin-1 gene, giving rise to substance P and neurokinin A and the choline acetyltransferase responsible for the biosynthesis of the important neurotransmitter acetylcholine.
Other targets include genes coding for cytokines such as IL-6, IL-4, IL-5, and TNF-alpha.
Genes coding for transporter proteins that confer multidrug resistance to the cells have also been found to be activated by CEBPB. Such genes include ABCC2 and ABCB1.
# Interactions
CEBPB has been shown to interact with:
- CREB1,
- CRSP3
- DNA damage-inducible transcript 3,
- EP300,
- Estrogen receptor alpha,
- Glucocorticoid receptor,
- HMGA1,
- HSF1,
- Nucleolar phosphoprotein p130,
- RELA,
- Serum response factor,
- SMARCA2,
- Sp1 transcription factor,
- TRIM28, and
- Zif268. | CEBPB
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.[1][2]
# Function
The protein encoded by this intronless gene is a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related proteins CEBP-alpha, CEBP-delta, and CEBP-gamma. The encoded protein is important in the regulation of genes involved in immune and inflammatory responses and has been shown to bind to the IL-1 response element in the IL-6 gene, as well as to regulatory regions of several acute-phase and cytokine genes. In addition, the encoded protein can bind the promoter and upstream element and stimulate the expression of the collagen type I gene.[3]
CEBP-beta is critical for normal macrophage functioning, an important immune cell sub-type; mice unable to express CEBP-beta have macrophages that cannot differentiate (specialize) and thus are unable to perform all their biological functions - including macrophage-mediated muscle repair.[4] Observational work has shown that expression of CEBP-beta in blood leukocytes is positively associated with muscle strength in humans,[5] emphasizing the importance of the immune system, and particularly macrophages, in the maintenance of muscle function.
Function of CEBPB gene can be effectively examined by siRNA knockdown based on an independent validation.[6]
# Target genes
CEBPB is capable of increasing the expression of several target genes. Among them, some have specific role in the nervous system such as the preprotachykinin-1 gene, giving rise to substance P and neurokinin A[7] and the choline acetyltransferase responsible for the biosynthesis of the important neurotransmitter acetylcholine.[8]
Other targets include genes coding for cytokines such as IL-6,[9] IL-4,[10] IL-5,[11] and TNF-alpha.[12]
Genes coding for transporter proteins that confer multidrug resistance to the cells have also been found to be activated by CEBPB. Such genes include ABCC2[13] and ABCB1.[14]
# Interactions
CEBPB has been shown to interact with:
- CREB1,[15]
- CRSP3[16]
- DNA damage-inducible transcript 3,[17][18]
- EP300,[19]
- Estrogen receptor alpha,[20][21]
- Glucocorticoid receptor,[20]
- HMGA1,[22]
- HSF1,[23]
- Nucleolar phosphoprotein p130,[24]
- RELA,[25][26]
- Serum response factor,[27][28]
- SMARCA2,[29]
- Sp1 transcription factor,[22][30]
- TRIM28,[31][32] and
- Zif268.[33] | https://www.wikidoc.org/index.php/CEBPB | |
1a34a4d65c19931b339be2812ae1cb0cfd7a6331 | wikidoc | CEBPD | CEBPD
CCAAT/enhancer-binding protein delta is a protein that in humans is encoded by the CEBPD gene.
# Function
The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related protein CEBP-alpha. The encoded protein is important in the regulation of genes involved in immune and inflammatory responses, and may be involved in the regulation of genes associated with activation and/or differentiation of macrophages.
# Functions
CEBPD is involved in regulation of apoptosis and cell proliferation. It probably acts as tumor suppressor.
One study in mice showed that CEBPD prevents development of tubular injury and tubulointerstitial fibrogenesis during the progression of chronic obstructive nephropathy.
Function of CEBPD gene can be effectively examined by siRNA knockdown based on an independent validation.
# Interactions
CEBPD has been shown to interact with Mothers against decapentaplegic homolog 3. | CEBPD
CCAAT/enhancer-binding protein delta is a protein that in humans is encoded by the CEBPD gene.[1][2]
# Function
The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related protein CEBP-alpha. The encoded protein is important in the regulation of genes involved in immune and inflammatory responses, and may be involved in the regulation of genes associated with activation and/or differentiation of macrophages.[3]
# Functions
CEBPD is involved in regulation of apoptosis and cell proliferation. It probably acts as tumor suppressor.[4]
One study in mice showed that CEBPD prevents development of tubular injury and tubulointerstitial fibrogenesis during the progression of chronic obstructive nephropathy.[5]
Function of CEBPD gene can be effectively examined by siRNA knockdown based on an independent validation.[6]
# Interactions
CEBPD has been shown to interact with Mothers against decapentaplegic homolog 3.[7] | https://www.wikidoc.org/index.php/CEBPD | |
3ebfbea15be28b08375d51246605dce89464e107 | wikidoc | CENPA | CENPA
Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene.
# Function
Centromeres are the chromosomal domains that specify the mitotic behavior of chromosomes. The CENPA gene encodes a centromere protein which contains a histone H3 related histone fold domain that is required for targeting to the centromere. CENPA is proposed to be a component of a modified nucleosome or nucleosome-like structure in which it replaces 1 or both copies of conventional histone H3 in the (H3-H4)2 tetrameric core of the nucleosome particle. Alternative splicing results in multiple transcript variants encoding distinct isoforms.
In higher eukaryotes, the recruitment of CENP-A nucleosomes to existing centromeres is an epigenetic process, independent of the underlying DNA sequence. In S. pombe, de novo recruitment of the CENP-A to the centromere is believed to be controlled by "centromeric" heterochromatin surrounding the centromere, and by an RNAi mechanism. The RNAi is cut to form siRNA; this complexes with the protein Chp1, which then binds the centromeric heterochromatin. This helps recruit other proteins, ultimately resulting in a protein complex that forms cohesin between two sister chromatids at the centromeric heterochromatin. This cohesin is believed to be essential in replacing the centromere H3 with CENP-A. CENP-A is one of the epigenetic changes that is believed to distinguish centromeric DNA from other DNA. Once the CENP-A has been added, the centromere becomes self-propagating, and the surrounding heterochromatin/RNAi mechanism is no longer necessary. | CENPA
Centromere protein A, also known as CENPA, is a protein which in humans is encoded by the CENPA gene.[1]
# Function
Centromeres are the chromosomal domains that specify the mitotic behavior of chromosomes. The CENPA gene encodes a centromere protein which contains a histone H3 related histone fold domain that is required for targeting to the centromere. CENPA is proposed to be a component of a modified nucleosome or nucleosome-like structure in which it replaces 1 or both copies of conventional histone H3 in the (H3-H4)2 tetrameric core of the nucleosome particle. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[1]
In higher eukaryotes, the recruitment of CENP-A nucleosomes to existing centromeres is an epigenetic process, independent of the underlying DNA sequence. In S. pombe, de novo recruitment of the CENP-A to the centromere is believed to be controlled by "centromeric" heterochromatin surrounding the centromere, and by an RNAi mechanism. The RNAi is cut to form siRNA; this complexes with the protein Chp1, which then binds the centromeric heterochromatin. This helps recruit other proteins, ultimately resulting in a protein complex that forms cohesin between two sister chromatids at the centromeric heterochromatin. This cohesin is believed to be essential in replacing the centromere H3 with CENP-A. CENP-A is one of the epigenetic changes that is believed to distinguish centromeric DNA from other DNA.[2] Once the CENP-A has been added, the centromere becomes self-propagating, and the surrounding heterochromatin/RNAi mechanism is no longer necessary.[3] | https://www.wikidoc.org/index.php/CENPA | |
861000498ef4a79db816b87020f761e283f73078 | wikidoc | CENPH | CENPH
Centromere protein H is a protein that in humans is encoded by the CENPH gene.
# Function
Centromere and kinetochore proteins play a critical role in centromere structure, kinetochore formation, and sister chromatid separation. The protein encoded by this gene colocalizes with inner kinetochore plate proteins CENP-A and CENP-C in both interphase and metaphase. CENP-H is required for the localisation of CENP-C, but not CENP-A, to the centromere. However, it may be involved in the incorporation of newly synthesised CENP-A into centromeres via its interaction with the CENP-A/CENP-HI complex. CENP-H localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex. CENP-H contains a coiled-coil structure and a nuclear localisation signal.
Studies show that CENP-H may be associated with certain human cancers.
CENP-H shows sequence similarity to the Schizosaccharomyces pombe kinetochore protein Fta3 which is a subunit of the Sim4 complex. This complex is required for loading the DASH complex onto the kinetochore via interaction with dad1. Fta2, Fta3 and Fta4 associate with the central core and inner repeat region of the centromere.
# Other Protein Interactions
CENPH has also been shown to interact with KIAA0090. The significance of this interaction is unclear. | CENPH
Centromere protein H is a protein that in humans is encoded by the CENPH gene.[1][2][3]
# Function
Centromere and kinetochore proteins play a critical role in centromere structure, kinetochore formation, and sister chromatid separation. The protein encoded by this gene colocalizes with inner kinetochore plate proteins CENP-A and CENP-C in both interphase and metaphase. CENP-H is required for the localisation of CENP-C, but not CENP-A, to the centromere. However, it may be involved in the incorporation of newly synthesised CENP-A into centromeres via its interaction with the CENP-A/CENP-HI complex.[4] CENP-H localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex.[5] CENP-H contains a coiled-coil structure and a nuclear localisation signal.[5]
Studies show that CENP-H may be associated with certain human cancers.[6][7]
CENP-H shows sequence similarity to the Schizosaccharomyces pombe kinetochore protein Fta3 which is a subunit of the Sim4 complex. This complex is required for loading the DASH complex onto the kinetochore via interaction with dad1. Fta2, Fta3 and Fta4 associate with the central core and inner repeat region of the centromere.[8]
# Other Protein Interactions
CENPH has also been shown to interact with KIAA0090.[9] The significance of this interaction is unclear. | https://www.wikidoc.org/index.php/CENPH | |
1bd64a43a89b56b379ad20c63700dffb9229a68f | wikidoc | CENPJ | CENPJ
Centromere protein J is a protein that in humans is encoded by the CENPJ gene. It is also known as centrosomal P4.1-associated protein (CPAP).
During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with Seckel syndrome and primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and mental retardation.
The Drosophila ortholog, sas-4, has been shown to be a scaffold for a cytoplasmic complex of Cnn, Asl, CP-190, tubulin and D-PLP (similar to the human proteins PCNT and AKAP9). These complexes are then anchored at the centriole to begin formation of the centrosome.
# Model organisms
Model organisms have been used in the study of CENPJ function. A conditional knockout mouse line, called Cenpjtm1a(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 five tests were carried out on mutant mice and thirteen significant abnormalities were observed. Homozygous mutants were subviable, had a decreased body weight, abnormal open field, body composition, X-ray imaging, peripheral blood lymphocytes and indirect calorimetry parameters, abnormal head, genitalia and tail morphology, an impaired glucose tolerance, hypoalbuminemia, a 1.5 fold increase in micronuclei, a reduction in dentate gyrus length and abnormal corneal epithelium and endothelium.
A more detailed analysis revealed this mutant to model a number of aspects of Seckel syndrome (type 4). The authors concluded that, "increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism" that is characteristic of the disorder.
# Interactions
CENPJ has been shown to interact with EPB41. | CENPJ
Centromere protein J is a protein that in humans is encoded by the CENPJ gene.[1][2] It is also known as centrosomal P4.1-associated protein (CPAP).
During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with Seckel syndrome and primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and mental retardation.[2][3][4]
The Drosophila ortholog, sas-4, has been shown to be a scaffold for a cytoplasmic complex of Cnn, Asl, CP-190, tubulin and D-PLP (similar to the human proteins PCNT and AKAP9). These complexes are then anchored at the centriole to begin formation of the centrosome.[5]
# Model organisms
Model organisms have been used in the study of CENPJ function. A conditional knockout mouse line, called Cenpjtm1a(EUCOMM)Wtsi[19][20] 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.[21][22][23]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[17][24] Twenty five tests were carried out on mutant mice and thirteen significant abnormalities were observed. Homozygous mutants were subviable, had a decreased body weight, abnormal open field, body composition, X-ray imaging, peripheral blood lymphocytes and indirect calorimetry parameters, abnormal head, genitalia and tail morphology, an impaired glucose tolerance, hypoalbuminemia, a 1.5 fold increase in micronuclei, a reduction in dentate gyrus length and abnormal corneal epithelium and endothelium.[17]
A more detailed analysis revealed this mutant to model a number of aspects of Seckel syndrome (type 4). The authors concluded that, "increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism" that is characteristic of the disorder.[25]
# Interactions
CENPJ has been shown to interact with EPB41.[1] | https://www.wikidoc.org/index.php/CENPJ | |
bc3b2563fd069ed27e8319575e083f424908e38f | wikidoc | CEP63 | CEP63
Centrosomal protein of 63 kDa is a protein that in humans is encoded by the CEP63 gene. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined.
# Function
This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Recent computational analysis revealed pathogenic property of L61P point mutation in CEP63 protein that affected its native structural conformation.
# Interactions
CEP63 has been shown to interact with DISC1, CEP152 and CDK1. | CEP63
Centrosomal protein of 63 kDa is a protein that in humans is encoded by the CEP63 gene.[1][2] Several alternatively spliced transcript variants have been found, but their biological validity has not been determined.
# Function
This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells.[2] Recent computational analysis revealed pathogenic property of L61P point mutation in CEP63 protein that affected its native structural conformation.[3]
# Interactions
CEP63 has been shown to interact with DISC1,[4] CEP152 and CDK1.[3] | https://www.wikidoc.org/index.php/CEP63 | |
e1e410fdaf2ad5ada4549d3be2597e8e726be3c5 | wikidoc | CHD1L | CHD1L
Chromodomain-helicase-DNA-binding protein 1-like (ALC1) is an enzyme that in humans is encoded by the CHD1L gene. It has been implicated in chromatin remodeling and DNA relaxation process required for DNA replication, repair and transcription. The ALC1 comprises ATPase domain and macro domain. On the basis of homology within the ATPase domain, ALC1 belongs to Snf2 family.
# Function
## In development
CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during developmental reprogramming. The CHD1L macro-domain interacts with the PAR moiety of PARylated-PARP1 to facilitate early-stage reprogramming and pluripotency in stem cells. It appears that CHD1L expression is vital for early events in embryonic development.
## In DNA repair
To allow the critical cellular process of DNA repair, the chromatin must be remodeled at sites of damage. CHD1L (ALC1) a chromatin remodeling protein, acts very early in DNA repair. Chromatin relaxation occurs rapidly at the site of a DNA damage. This process is initiated by PARP1 protein that starts to appear at DNA damage in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs. Next the chromatin remodeler CHD1L (ALC1) quickly attaches to the product of PARP1, and completes arrival at the DNA damage within 10 seconds of the damage. About half of the maximum chromatin relaxation, due to action of CHD1L (ALC1), occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds. MRE11 is involved in homologous recombinational repair. CHD1L (ALC1) is also required for repair of UV-damaged chromatin through nucleotide excision repair.
# Related gene problems
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome
With 1q21.1 deletion syndrome a disturbance occurs, which leads to increased DNA breaks. The role of CHD1L is similar to that of helicase with the Werner syndrome | CHD1L
Chromodomain-helicase-DNA-binding protein 1-like (ALC1) is an enzyme that in humans is encoded by the CHD1L gene.[1][2] It has been implicated in chromatin remodeling and DNA relaxation process required for DNA replication, repair and transcription. The ALC1 comprises ATPase domain and macro domain. On the basis of homology within the ATPase domain, ALC1 belongs to Snf2 family[3].
# Function
## In development
CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during developmental reprogramming. The CHD1L macro-domain interacts with the PAR moiety of PARylated-PARP1 to facilitate early-stage reprogramming and pluripotency in stem cells.[4] It appears that CHD1L expression is vital for early events in embryonic development. [5]
## In DNA repair
To allow the critical cellular process of DNA repair, the chromatin must be remodeled at sites of damage. CHD1L (ALC1) a chromatin remodeling protein, acts very early in DNA repair. Chromatin relaxation occurs rapidly at the site of a DNA damage.[6] This process is initiated by PARP1 protein that starts to appear at DNA damage in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs.[7] Next the chromatin remodeler CHD1L (ALC1) quickly attaches to the product of PARP1, and completes arrival at the DNA damage within 10 seconds of the damage.[6] About half of the maximum chromatin relaxation, due to action of CHD1L (ALC1), occurs by 10 seconds.[6] This then allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds.[7] MRE11 is involved in homologous recombinational repair. CHD1L (ALC1) is also required for repair of UV-damaged chromatin through nucleotide excision repair.[8]
# Related gene problems
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome
With 1q21.1 deletion syndrome a disturbance occurs, which leads to increased DNA breaks. The role of CHD1L is similar to that of helicase with the Werner syndrome[9] | https://www.wikidoc.org/index.php/CHD1L | |
677a3a6f0997632feab6032ec619975c57b1c6ef | wikidoc | CHEK1 | CHEK1
Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.
# Discovery
In 1993, Beach and associates initially identified Chk1 as a serine/threonine kinase which regulates the G2/M phase transition in fission yeast. Constitutive expression of Chk1 in fission yeast was shown to induce cell cycle arrest. The same gene called Rad27 was identified in budding yeast by Carr and associates. In 1997, homologs were identified in more complex organisms including the fruit fly, human and mouse. Through these findings, it is apparent Chk1 is highly conserved from yeast to humans.
# Structure
Human Chk1 is located on chromosome 11 on the cytogenic band 11q22-23. Chk1 has a N-terminal kinase domain, a linker region, a regulatory SQ/TQ domain and a C-terminal domain. Chk1 contains four Ser/Gln residues. Chk 1 activation occurs primarily through the phosphorylation of the conserved sites, Ser-317, Ser-345 and less often at Ser-366.
# Function
Checkpoint kinases (Chks) are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. Chk1 is a central component of genome surveillance pathways and is a key regulator of the cell cycle and cell survival. Chk1 is required for the initiation of DNA damage checkpoints and has recently been shown to play a role in the normal (unperturbed) cell cycle. Chk1 impacts various stages of the cell cycle including the S phase, G2/M transition and M phase.
In addition to mediating cell cycle checkpoints, Chk1 also contributes to DNA repair processes, gene transcription, embryo development, cellular responses to HIV infection and somatic cell viability.
## S phase
Chk1 is essential for the maintenance of genomic integrity. Chk1 monitors DNA replication in unperturbed cell cycles and responds to genotoxic stress if present. Chk1 recognizes DNA strand instability during replication and can stall DNA replication in order to allow time for DNA repair mechanisms to restore the genome. Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating various repair factors. Furthermore, Chk1 has been associated with three particular aspects of the S-phase, which includes the regulation of late origin firing, controlling the elongation process and maintenance of DNA replication fork stability.
## G2/M transition
In response to DNA damage, Chk1 is an important signal transducer for G2/M checkpoint activation. Activation of Chk1 holds the cell in the G2 phase until ready to enter the mitotic phase. This delay allows time for DNA to repair or cell death to occur if DNA damage is irreversible. Chk1 must inactivate in order for the cell to transition from the G2 phase into mitosis, Chk1 expression levels are mediated by regulatory proteins.
## M phase
Chk1 has a regulatory role in the spindle checkpoint however the relationship is less clear as compared to checkpoints in other cell cycle stages. During this phase the Chk1 activating element of ssDNA can not be generated suggesting an alternate form of activation. Studies on Chk1 deficient chicken lymphoma cells have shown increased levels of genomic instability and failure to arrest during the spindle checkpoint phase in mitosis. Furthermore, haploinsufficient mammary epithelial cells illustrated misaligned chromosomes and abnormal segregation. These studies suggest Chk1 depletion can lead to defects in the spindle checkpoint resulting in mitotic abnormalities.
# Interactions
DNA damage induces the activation of Chk1 which facilitates the initiation of the DNA damage response (DDR) and cell cycle checkpoints. The DNA damage response is a network of signaling pathways that leads to activation of checkpoints, DNA repair and apoptosis to inhibit damaged cells from progressing through the cell cycle.
## Chk1 activation
Chk1 is regulated by ATR through phosphorylation, forming the ATR-Chk1 pathway. This pathway recognizes single strand DNA (ssDNA) which can be a result of UV-induced damage, replication stress and inter-strand cross linking. Often ssDNA can be a result of abnormal replication during S phase through the uncoupling of replication enzymes helicase and DNA polymerase. These ssDNA structures attract ATR and eventually activates the checkpoint pathway.
However, activation of Chk1 is not solely dependent on ATR, intermediate proteins involved in DNA replication are often necessary. Regulatory proteins such as replication protein A, Claspin, Tim/Tipin, Rad 17, TopBP1 may be involved to facilitate Chk1 activation. Additional protein interactions are involved to induce maximal phosphorylation of Chk1. Chk1 activation can also be ATR-independent through interactions with other protein kinases such as PKB/AKT, MAPKAPK and p90/RSK.
Also, Chk1 has been shown to be activated by the Scc1 subunit of the protein cohesin, in zygotes.
## Cell cycle arrest
Chk1 interacts with many downstream effectors to induce cell cycle arrest. In response to DNA damage, Chk1 primarily phosphorylates Cdc25 which results in its proteasomal degradation. The degradation has an inhibitory effect on the formation of cyclin-dependent kinase complexes, which are key drivers of the cell cycle. Through targeting Cdc25, cell cycle arrest can occur at multiple time points including the G1/S transition, S phase and G2/M transition. Furthermore, Chk1 can target Cdc25 indirectly through phosphorylating Nek11.
WEE1 kinase and PLK1 are also targeted by Chk1 to induce cell cycle arrest. Phosphorylation of WEE1 kinase inhibits cdk1 which results in cell cycle arrest at the G2 phase.
Chk1 has a role in the spindle checkpoint during mitosis thus interacts with spindle assembly proteins Aurora A kinase and Aurora B kinase.
## DNA repair
Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating repair factors such as proliferating cell nuclear antigen (PCNA), FANCE, Rad51 and TLK. Chk1 facilitates replication fork stabilization during DNA replication and repair however more research is necessary to define the underlying interactions.
# Clinical relevance
Chk1 has a central role in coordinating the DNA damage response and therefore is an area of great interest in oncology and the development of cancer therapeutics. Initially Chk1 was thought to function as a tumor suppressor due to the regulatory role it serves amongst cells with DNA damage. However, there has been no evidence of homozygous loss of function mutants for Chk1 in human tumors. Instead, Chk1 has been shown to be overexpressed in a numerous tumors including breast, colon, liver, gastric and nasopharyngeal carcinoma. There is a positive correlation with Chk1 expression and tumor grade and disease recurrence suggesting Chk1 may promote tumor growth. Chk1 is essential for cell survival and through high levels of expressions in tumors the function may be inducing tumor cell proliferation. Further, a study has demonstrated that targeting CHK1 reactivates the tumour suppressive activity of protein phosphtase 2A (PP2A) complex in cancer cells. Studies have shown complete loss of Chk1 suppresses chemically induce carcinogenesis however Chk1 haploinsufficiency results in tumor progression.
Due to the possibility of Chk1 involvement in tumor promotion, the kinase and related signaling molecules may be potentially effective therapeutic targets. Cancer therapies utilize DNA damaging therapies such as chemotherapies and ionizing radiation to inhibit tumor cell proliferation and induce cell cycle arrest. Tumor cells with increased levels of Chk1 acquire survival advantages due to the ability to tolerate a higher level of DNA damage. Therefore, Chk1 may contribute to chemotherapy resistance. In order to optimize chemotherapies, Chk1 must be inhibited to reduce the survival advantage. Chk1 gene can be effectively silenced by siRNA knockdown for further analysis based on an independent validation. By inhibiting Chk1, cancer cells lose the ability to repair damaged DNA which allows chemotherapeutic agents to work more effectively. Combining DNA damaging therapies such as chemotherapy or radiation treatment with Chk1 inhibition enhances targeted cell death and provides synthetic lethality. Many cancers rely on Chk1 mediated cell cycle arrest heavily especially if cancers are deficient in p53. Approximately 50% of cancers possess p53 mutations illustrating the dependence that many cancers may have on the Chk1 pathway. Inhibition of Chk1 allows selective targeting of p53 mutant cells as Chk1 levels are more likely to highly expressed in tumor cells with p53 deficiencies. Even though this method of inhibition is highly targeted, recent research has shown Chk1 also has a role in the normal cell cycle. Therefore, off-target effects and toxicity associated with combination therapies using CHk1 inhibitors must be considered during development of novel therapies.
# Meiosis
During meiosis in human and mouse, CHEK1 protein kinase is important for integrating DNA damage repair with cell cycle arrest. CHEK1 is expressed in the testes and associates with meiotic synaptonemal complexes during the zygonema and pachynema stages. CHEK1 likely acts as an integrator for ATM and ATR signals and may be involved in monitoring meiotic recombination. In mouse oocytes CHEK1 appears to be indispensable for prophase I arrest and to function at the G2/M checkpoint. | CHEK1
Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene.[1][2] Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response.[3] Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.
# Discovery
In 1993, Beach and associates initially identified Chk1 as a serine/threonine kinase which regulates the G2/M phase transition in fission yeast.[4] Constitutive expression of Chk1 in fission yeast was shown to induce cell cycle arrest. The same gene called Rad27 was identified in budding yeast by Carr and associates. In 1997, homologs were identified in more complex organisms including the fruit fly, human and mouse.[5] Through these findings, it is apparent Chk1 is highly conserved from yeast to humans.[1]
# Structure
Human Chk1 is located on chromosome 11 on the cytogenic band 11q22-23. Chk1 has a N-terminal kinase domain, a linker region, a regulatory SQ/TQ domain and a C-terminal domain.[5] Chk1 contains four Ser/Gln residues.[4] Chk 1 activation occurs primarily through the phosphorylation of the conserved sites, Ser-317, Ser-345 and less often at Ser-366.[4][6]
# Function
Checkpoint kinases (Chks) are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. Chk1 is a central component of genome surveillance pathways and is a key regulator of the cell cycle and cell survival. Chk1 is required for the initiation of DNA damage checkpoints and has recently been shown to play a role in the normal (unperturbed) cell cycle.[5] Chk1 impacts various stages of the cell cycle including the S phase, G2/M transition and M phase.[4]
In addition to mediating cell cycle checkpoints, Chk1 also contributes to DNA repair processes, gene transcription, embryo development, cellular responses to HIV infection and somatic cell viability.[4]
## S phase
Chk1 is essential for the maintenance of genomic integrity. Chk1 monitors DNA replication in unperturbed cell cycles and responds to genotoxic stress if present.[5] Chk1 recognizes DNA strand instability during replication and can stall DNA replication in order to allow time for DNA repair mechanisms to restore the genome.[4] Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating various repair factors. Furthermore, Chk1 has been associated with three particular aspects of the S-phase, which includes the regulation of late origin firing, controlling the elongation process and maintenance of DNA replication fork stability.[4]
## G2/M transition
In response to DNA damage, Chk1 is an important signal transducer for G2/M checkpoint activation. Activation of Chk1 holds the cell in the G2 phase until ready to enter the mitotic phase. This delay allows time for DNA to repair or cell death to occur if DNA damage is irreversible.[7] Chk1 must inactivate in order for the cell to transition from the G2 phase into mitosis, Chk1 expression levels are mediated by regulatory proteins.
## M phase
Chk1 has a regulatory role in the spindle checkpoint however the relationship is less clear as compared to checkpoints in other cell cycle stages. During this phase the Chk1 activating element of ssDNA can not be generated suggesting an alternate form of activation. Studies on Chk1 deficient chicken lymphoma cells have shown increased levels of genomic instability and failure to arrest during the spindle checkpoint phase in mitosis.[4] Furthermore, haploinsufficient mammary epithelial cells illustrated misaligned chromosomes and abnormal segregation. These studies suggest Chk1 depletion can lead to defects in the spindle checkpoint resulting in mitotic abnormalities.
# Interactions
DNA damage induces the activation of Chk1 which facilitates the initiation of the DNA damage response (DDR) and cell cycle checkpoints. The DNA damage response is a network of signaling pathways that leads to activation of checkpoints, DNA repair and apoptosis to inhibit damaged cells from progressing through the cell cycle.
## Chk1 activation
Chk1 is regulated by ATR through phosphorylation, forming the ATR-Chk1 pathway. This pathway recognizes single strand DNA (ssDNA) which can be a result of UV-induced damage, replication stress and inter-strand cross linking.[4][5] Often ssDNA can be a result of abnormal replication during S phase through the uncoupling of replication enzymes helicase and DNA polymerase.[4] These ssDNA structures attract ATR and eventually activates the checkpoint pathway.
However, activation of Chk1 is not solely dependent on ATR, intermediate proteins involved in DNA replication are often necessary. Regulatory proteins such as replication protein A, Claspin, Tim/Tipin, Rad 17, TopBP1 may be involved to facilitate Chk1 activation. Additional protein interactions are involved to induce maximal phosphorylation of Chk1. Chk1 activation can also be ATR-independent through interactions with other protein kinases such as PKB/AKT, MAPKAPK and p90/RSK.[4]
Also, Chk1 has been shown to be activated by the Scc1 subunit of the protein cohesin, in zygotes.[8]
## Cell cycle arrest
Chk1 interacts with many downstream effectors to induce cell cycle arrest. In response to DNA damage, Chk1 primarily phosphorylates Cdc25 which results in its proteasomal degradation.[5] The degradation has an inhibitory effect on the formation of cyclin-dependent kinase complexes, which are key drivers of the cell cycle.[9] Through targeting Cdc25, cell cycle arrest can occur at multiple time points including the G1/S transition, S phase and G2/M transition.[4] Furthermore, Chk1 can target Cdc25 indirectly through phosphorylating Nek11.
WEE1 kinase and PLK1 are also targeted by Chk1 to induce cell cycle arrest. Phosphorylation of WEE1 kinase inhibits cdk1 which results in cell cycle arrest at the G2 phase.[4]
Chk1 has a role in the spindle checkpoint during mitosis thus interacts with spindle assembly proteins Aurora A kinase and Aurora B kinase.[5]
## DNA repair
Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating repair factors such as proliferating cell nuclear antigen (PCNA), FANCE, Rad51 and TLK.[4] Chk1 facilitates replication fork stabilization during DNA replication and repair however more research is necessary to define the underlying interactions.[5]
# Clinical relevance
Chk1 has a central role in coordinating the DNA damage response and therefore is an area of great interest in oncology and the development of cancer therapeutics.[10] Initially Chk1 was thought to function as a tumor suppressor due to the regulatory role it serves amongst cells with DNA damage. However, there has been no evidence of homozygous loss of function mutants for Chk1 in human tumors.[4] Instead, Chk1 has been shown to be overexpressed in a numerous tumors including breast, colon, liver, gastric and nasopharyngeal carcinoma.[4] There is a positive correlation with Chk1 expression and tumor grade and disease recurrence suggesting Chk1 may promote tumor growth.[4][5][10] Chk1 is essential for cell survival and through high levels of expressions in tumors the function may be inducing tumor cell proliferation. Further, a study has demonstrated that targeting CHK1 reactivates the tumour suppressive activity of protein phosphtase 2A (PP2A) complex in cancer cells.[11] Studies have shown complete loss of Chk1 suppresses chemically induce carcinogenesis however Chk1 haploinsufficiency results in tumor progression.[5]
Due to the possibility of Chk1 involvement in tumor promotion, the kinase and related signaling molecules may be potentially effective therapeutic targets. Cancer therapies utilize DNA damaging therapies such as chemotherapies and ionizing radiation to inhibit tumor cell proliferation and induce cell cycle arrest.[12] Tumor cells with increased levels of Chk1 acquire survival advantages due to the ability to tolerate a higher level of DNA damage. Therefore, Chk1 may contribute to chemotherapy resistance.[13] In order to optimize chemotherapies, Chk1 must be inhibited to reduce the survival advantage.[3] Chk1 gene can be effectively silenced by siRNA knockdown for further analysis based on an independent validation.[14] By inhibiting Chk1, cancer cells lose the ability to repair damaged DNA which allows chemotherapeutic agents to work more effectively. Combining DNA damaging therapies such as chemotherapy or radiation treatment with Chk1 inhibition enhances targeted cell death and provides synthetic lethality.[15] Many cancers rely on Chk1 mediated cell cycle arrest heavily especially if cancers are deficient in p53.[16] Approximately 50% of cancers possess p53 mutations illustrating the dependence that many cancers may have on the Chk1 pathway.[17][18][19] Inhibition of Chk1 allows selective targeting of p53 mutant cells as Chk1 levels are more likely to highly expressed in tumor cells with p53 deficiencies.[10][20] Even though this method of inhibition is highly targeted, recent research has shown Chk1 also has a role in the normal cell cycle.[21] Therefore, off-target effects and toxicity associated with combination therapies using CHk1 inhibitors must be considered during development of novel therapies.[22]
# Meiosis
During meiosis in human and mouse, CHEK1 protein kinase is important for integrating DNA damage repair with cell cycle arrest.[23] CHEK1 is expressed in the testes and associates with meiotic synaptonemal complexes during the zygonema and pachynema stages.[23] CHEK1 likely acts as an integrator for ATM and ATR signals and may be involved in monitoring meiotic recombination.[23] In mouse oocytes CHEK1 appears to be indispensable for prophase I arrest and to function at the G2/M checkpoint.[24] | https://www.wikidoc.org/index.php/CHEK1 | |
b82c2fbde7dfc525887c8cf5a127ff0ad882c8f4 | wikidoc | CHEK2 | CHEK2
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.
# Gene location
The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1. Its location on chromosome 22 stretches from base pair 28,687,742 to base pair 28,741,904.
# Protein structure
The CHK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 amino acids and the following domains:
- N-terminal SQ/TQ cluster doman (SCD)
- Central forkhead-associated (FHA) domain
- C-terminal serine/threonine kinase domain (KD)
The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage. The most notable and frequently phosphorylated site being Thr68.
CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD phosphorylation causes CHK2 dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form the dimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates.
# Function and mechanism
The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates cell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.
When DNA undergoes a double-strand break, CHK2 is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2. Once activated, CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). Thus, CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into mitosis. Furthermore, the CHK2 protein interacts with several other proteins including p53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1. Furthermore, CHK2 is known to phosphorylate the cell-cycle transcription factor E2F1 and the promyelocytic leukemia protein (PML) involved in apoptosis (programmed cell death).
# Association with cancer
The CHK2 protein plays a critical role in the DNA damage checkpoint. Thus, mutations to the CHEK2 gene have been labeled as causes to a wide range of cancers.
In 1999, genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.
Bell et al. (1999) discovered three CHEK2 germline mutations among four Li–Fraumeni syndrome (LFS) and 18 Li–Fraumeni-like (LFL) families. Since the time of this discovery, two of the three variants (a deletion in the kinase domain in exon 10 and a missense mutation in the FHA domain in exon 3) have been linked to inherited susceptibility to breast as well as other cancers.
Beyond initial speculations, screening of LFS and LFL patients has revealed no or very rare individual missense variants in the CHEK2 gene. Additionally, the deletion in the kinase domain on exon 10 has been found rare among LFS/LFL patients. The evidence from these studies has suggests that CHEK2 is not a predisposition gene to Li–Fraumeni syndrome.
## Breast cancer
Inherited mutations in the CHEK2 gene have been linked to certain cases of breast cancer. Most notably, the deletion of a single DNA nucleotide at position 1100 in exon 10 (1100delC) produces a nonfunctional version of the CHK2 protein, truncated at the kinase domain. The loss of normal CHK2 protein function leads to unregulated cell division, accumulated damage to DNA and in many cases, tumor development. The CHEK2*1100del mutation is most commonly seen in individuals of Eastern and Northern European descent. Within these populations the CHEK2*1100delC mutation is seen in 1 out of 100 to 1 out of 200 individuals. However, in North America the frequency drops to 1 out of 333 to 1 out of 500. The mutation is almost absent in Spain and India. Studies show that a CHEK2 1100delC corresponds to a two-fold increased risk of breast cancer and a 10-fold increased risk of breast cancer in males.
A CHEK2 mutation known as the I157T variant to the FHA domain in exon 3 has also been linked to breast cancer but at a lower risk than the CHEK2*1100delC mutation. The estimated fraction of breast cancer attributed to this variant is reported to be around 1.2% in the US.
Two more CHEK2 gene mutations, CHEK2*S428F, an amino-acid substitution to the kinase domain in exon 11 and CHEK2*P85L, an amino-acid substitution in the N-terminal region (exon 1) have been found in the Ashkenazi Jewish population.
## Other cancers
Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. Studies link the mutation to cases of prostate, lung, colon, kidney, and thyroid cancers. Links have also been drawn to certain brain tumors and osteosarcoma.
Unlike BRCA1 and BRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk for ovarian cancer.
# Meiosis
CHEK2 regulates cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development. Although CHEK2 is a down stream effector of the ATM kinase that responds primarily to double-strand breaks it can also be activated by ATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mice, CHEK2 is essential for DNA damage surveillance in female meiosis. The response of oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates p53 and p63 proteins.
In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and apoptosis. The Drosophila CHEK2 ortholog mnk and the p53 ortholog dp53 are required for much of the cell death observed in early oogenesis when oocyte selection and meiotic recombination occur.
# Interactions
CHEK2 has been shown to interact with:
- BRCA1
- GINS2
- MDC1
- MSH2
- MUS81
- PLK1
- PLK3 | CHEK2
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.[1]
# Gene location
The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1. Its location on chromosome 22 stretches from base pair 28,687,742 to base pair 28,741,904.[1]
# Protein structure
The CHK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 amino acids and the following domains:
- N-terminal SQ/TQ cluster doman (SCD)
- Central forkhead-associated (FHA) domain
- C-terminal serine/threonine kinase domain (KD)
The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage. The most notable and frequently phosphorylated site being Thr68.[2]
CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD phosphorylation causes CHK2 dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form the dimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates.[2]
# Function and mechanism
The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates cell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.[1]
When DNA undergoes a double-strand break, CHK2 is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2.[2] Once activated, CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). Thus, CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into mitosis. Furthermore, the CHK2 protein interacts with several other proteins including p53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1. Furthermore, CHK2 is known to phosphorylate the cell-cycle transcription factor E2F1 and the promyelocytic leukemia protein (PML) involved in apoptosis (programmed cell death).[2]
# Association with cancer
The CHK2 protein plays a critical role in the DNA damage checkpoint. Thus, mutations to the CHEK2 gene have been labeled as causes to a wide range of cancers.
In 1999, genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.[3]
Bell et al. (1999) discovered three CHEK2 germline mutations among four Li–Fraumeni syndrome (LFS) and 18 Li–Fraumeni-like (LFL) families. Since the time of this discovery, two of the three variants (a deletion in the kinase domain in exon 10 and a missense mutation in the FHA domain in exon 3) have been linked to inherited susceptibility to breast as well as other cancers.[4]
Beyond initial speculations, screening of LFS and LFL patients has revealed no or very rare individual missense variants in the CHEK2 gene. Additionally, the deletion in the kinase domain on exon 10 has been found rare among LFS/LFL patients. The evidence from these studies has suggests that CHEK2 is not a predisposition gene to Li–Fraumeni syndrome.[4]
## Breast cancer
Inherited mutations in the CHEK2 gene have been linked to certain cases of breast cancer. Most notably, the deletion of a single DNA nucleotide at position 1100 in exon 10 (1100delC) produces a nonfunctional version of the CHK2 protein, truncated at the kinase domain. The loss of normal CHK2 protein function leads to unregulated cell division, accumulated damage to DNA and in many cases, tumor development.[1] The CHEK2*1100del mutation is most commonly seen in individuals of Eastern and Northern European descent. Within these populations the CHEK2*1100delC mutation is seen in 1 out of 100 to 1 out of 200 individuals. However, in North America the frequency drops to 1 out of 333 to 1 out of 500. The mutation is almost absent in Spain and India.[5] Studies show that a CHEK2 1100delC corresponds to a two-fold increased risk of breast cancer and a 10-fold increased risk of breast cancer in males.[6]
A CHEK2 mutation known as the I157T variant to the FHA domain in exon 3 has also been linked to breast cancer but at a lower risk than the CHEK2*1100delC mutation. The estimated fraction of breast cancer attributed to this variant is reported to be around 1.2% in the US.[4]
Two more CHEK2 gene mutations, CHEK2*S428F, an amino-acid substitution to the kinase domain in exon 11 and CHEK2*P85L, an amino-acid substitution in the N-terminal region (exon 1) have been found in the Ashkenazi Jewish population.[5]
## Other cancers
Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. Studies link the mutation to cases of prostate, lung, colon, kidney, and thyroid cancers. Links have also been drawn to certain brain tumors and osteosarcoma.[1]
Unlike BRCA1 and BRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk for ovarian cancer.[6]
# Meiosis
CHEK2 regulates cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development.[7] Although CHEK2 is a down stream effector of the ATM kinase that responds primarily to double-strand breaks it can also be activated by ATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mice, CHEK2 is essential for DNA damage surveillance in female meiosis. The response of oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates p53 and p63 proteins.[8]
In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and apoptosis. The Drosophila CHEK2 ortholog mnk and the p53 ortholog dp53 are required for much of the cell death observed in early oogenesis when oocyte selection and meiotic recombination occur.[9]
# Interactions
CHEK2 has been shown to interact with:
- BRCA1[10][11]
- GINS2[12]
- MDC1[13]
- MSH2[14][15]
- MUS81[16]
- PLK1[17]
- PLK3[18] | https://www.wikidoc.org/index.php/CHEK2 | |
907f2abee36de44947728cff6934e96746b47249 | wikidoc | CHHIP | CHHIP
# Overview
CHHIP stands for Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer, a treatment protocol currently undergoing clinical trials for the treatment of prostate cancer using external beam radiotherapy.
# Protocol Details
The main arm of the protocol prescribes 74 Gy to the prostate, with optional additional volumes around the prostate (such as the seminal vesicles and nodes prescribed to 71 Gy and 59 Gy. Each target with a prescribed dose must receive at least 95% of that dose to at least 99% of its volume and the dose to the 'hottest' 1% of the volume must be recorded.
There are various limits on doses delivered to healthy tissues:
Rectal dose constraints:
- No more than 68% dose (50 Gy) to 60% of the rectum
- No more than 81% (60 Gy) to 50%
- No more than 88% (65 Gy) to 30%
- No more than 95% (70 Gy) to 15%
- No more than 100% (74 Gy) to 5%
Femoral head constraints:
- No more than 50% of volume to receive more than 68% dose (50 Gy)
Bladder constraints:
- No more than 68% dose (50 Gy) to 50 % of the volume
- No more than 81% (60 Gy) to 25%
- No more than 100% (74 Gy) to 5%
Bowel constraints:
- No more than 68% dose (50 Gy) to 17 cc of the bowel
Additional targets:
- No more than 68% dose (50 Gy) to 50% of the urethral bulb
- No more than 81% (60 Gy) to 10% of the urethral bulb
- No more than 41% dose (30 Gy) to 80% of the rectum
- No more than 54% (40 Gy) to 70% of the rectum
The protocol has three arms, comparing conventional 2-Gray-per-fraction treatments against hypofractionated 3-Gray-per-fraction. One arm of the trial is the control group, receiving the standard 74 Gy in 37 fractions. The second arm prescribes 60 Gy in 20 fractions and the third prescribes 57 Gy in 19 fractions. The dose constraints for the hypofractionated arms of the trial are dose-scaled equivalents of those determined for the 74 Gy arm.
# Eligibility
Inclusion Criteria
a) Histologically confirmed, previously untreated locally confined adenocarcinoma of the prostate
b) All clinical T categories
Exclusion criteria
a) Patients with T3 cancers with Gleason Sum=8 cancers are ineligible
b) Prior pelvic radiotherapy or radical prostatectomy
c) Previous androgen deprivation
d) Life expectancy <10 years
e) Previous active malignancy within the last five years other than basal cell carcinoma
f) Co-morbid conditions likely to impact on the advisability of radical radiotherapy (e.g. previously inflammatory bowel disease, previous colorectal surgery, significant bladder instability or urinary incontinence)
g) Full anticoagulation with e.g. Warfarin or Heparin
h) Hip prosthesis or fixation which would interfere with standard radiation beam configuration
# Trial
The trial is being run and co-ordinated by Prof David Dearnaley at the Institute of cancer Research, Surrey.
The trial aims to recruit over 2162 patients. As of May 2007, 671 patients had been recruited onto the trial, an accrual of 30%. The trial will close in 2015. | CHHIP
# Overview
CHHIP stands for Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer, a treatment protocol currently undergoing clinical trials for the treatment of prostate cancer using external beam radiotherapy.
# Protocol Details
The main arm of the protocol prescribes 74 Gy to the prostate, with optional additional volumes around the prostate (such as the seminal vesicles and nodes prescribed to 71 Gy and 59 Gy. Each target with a prescribed dose must receive at least 95% of that dose to at least 99% of its volume and the dose to the 'hottest' 1% of the volume must be recorded.
There are various limits on doses delivered to healthy tissues:
Rectal dose constraints:
- No more than 68% dose (50 Gy) to 60% of the rectum
- No more than 81% (60 Gy) to 50%
- No more than 88% (65 Gy) to 30%
- No more than 95% (70 Gy) to 15%
- No more than 100% (74 Gy) to 5%
Femoral head constraints:
- No more than 50% of volume to receive more than 68% dose (50 Gy)
Bladder constraints:
- No more than 68% dose (50 Gy) to 50 % of the volume
- No more than 81% (60 Gy) to 25%
- No more than 100% (74 Gy) to 5%
Bowel constraints:
- No more than 68% dose (50 Gy) to 17 cc of the bowel
Additional targets:
- No more than 68% dose (50 Gy) to 50% of the urethral bulb
- No more than 81% (60 Gy) to 10% of the urethral bulb
- No more than 41% dose (30 Gy) to 80% of the rectum
- No more than 54% (40 Gy) to 70% of the rectum
The protocol has three arms, comparing conventional 2-Gray-per-fraction treatments against hypofractionated 3-Gray-per-fraction. One arm of the trial is the control group, receiving the standard 74 Gy in 37 fractions. The second arm prescribes 60 Gy in 20 fractions and the third prescribes 57 Gy in 19 fractions. The dose constraints for the hypofractionated arms of the trial are dose-scaled equivalents of those determined for the 74 Gy arm.
# Eligibility
Inclusion Criteria
a) Histologically confirmed, previously untreated locally confined adenocarcinoma of the prostate
b) All clinical T categories
Exclusion criteria
a) Patients with T3 cancers with Gleason Sum=8 cancers are ineligible
b) Prior pelvic radiotherapy or radical prostatectomy
c) Previous androgen deprivation
d) Life expectancy <10 years
e) Previous active malignancy within the last five years other than basal cell carcinoma
f) Co-morbid conditions likely to impact on the advisability of radical radiotherapy (e.g. previously inflammatory bowel disease, previous colorectal surgery, significant bladder instability or urinary incontinence)
g) Full anticoagulation with e.g. Warfarin or Heparin
h) Hip prosthesis or fixation which would interfere with standard radiation beam configuration
# Trial
The trial is being run and co-ordinated by Prof David Dearnaley at the Institute of cancer Research, Surrey.
The trial aims to recruit over 2162 patients. As of May 2007, 671 patients had been recruited onto the trial, an accrual of 30%. The trial will close in 2015. | https://www.wikidoc.org/index.php/CHHIP | |
37fd6c9a3f48fa05ab8cad7b38a08422d4746ba0 | wikidoc | CHODL | CHODL
Chondrolectin is a protein that in humans is encoded by the CHODL gene. Mouse chondrolectin is encoded by Chodl.
# Structure
Chondrolectin is a type I membrane protein with a carbohydrate recognition domain characteristic of C-type lectins in its extracellular portion. In other proteins, this domain is involved in endocytosis of glycoproteins and exogenous sugar-bearing pathogens. This protein has been shown to localise to the perinucleus.
# Function
The exact function of chondrolectin is unknown but it has been show to be a marker of fast motor neurons in mice, and is involved in motor neuron development and growth in zebrafish (danio rerio). Furthermore, human chondrolectin has been shown to localise to motor neurons within the spinal cord.
# Clinical significance
Chondrolectin is alternatively spliced in the spinal cord of mouse models of the neuromuscular disease, spinal muscular atrophy (SMA), which predominantly affects lower motor neurons. Increased levels of chondrolectin in a zebrafish model of SMA results in significant improvements in disease-related motor neuron defects. | CHODL
Chondrolectin is a protein that in humans is encoded by the CHODL gene.[1][2] Mouse chondrolectin is encoded by Chodl.[3]
# Structure
Chondrolectin is a type I membrane protein with a carbohydrate recognition domain characteristic of C-type lectins in its extracellular portion.[1][3] In other proteins, this domain is involved in endocytosis of glycoproteins and exogenous sugar-bearing pathogens.[4] This protein has been shown to localise to the perinucleus.[1][5][6]
# Function
The exact function of chondrolectin is unknown but it has been show to be a marker of fast motor neurons in mice,[6] and is involved in motor neuron development and growth in zebrafish (danio rerio).[7] Furthermore, human chondrolectin has been shown to localise to motor neurons within the spinal cord.[8]
# Clinical significance
Chondrolectin is alternatively spliced in the spinal cord of mouse models[9] of the neuromuscular disease, spinal muscular atrophy (SMA), which predominantly affects lower motor neurons.[8] Increased levels of chondrolectin in a zebrafish model of SMA results in significant improvements in disease-related motor neuron defects.[10] | https://www.wikidoc.org/index.php/CHODL | |
a6962a35040a6fc106e2490c0d782c99e89276ec | wikidoc | CHRND | CHRND
Acetylcholine receptor subunit delta is a protein that in humans is encoded by the CHRND gene.
# Function
The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
# Interactions
CHRND has been shown to interact with Cholinergic receptor, nicotinic, alpha 1. | CHRND
Acetylcholine receptor subunit delta is a protein that in humans is encoded by the CHRND gene.[1]
# Function
The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.[1]
# Interactions
CHRND has been shown to interact with Cholinergic receptor, nicotinic, alpha 1.[2][3] | https://www.wikidoc.org/index.php/CHRND | |
65b70e855b1b91bea9b6d62fbc34359284590783 | wikidoc | CHRNE | CHRNE
Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.
Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The achetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome.
# Role in health and disease
Congenital myasthenic syndrome (CMS) is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). The majority of mutations causing CMS are found in the AChR subunits genes.
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult AChR subunits. Mutations of the AChR often result in endplate deficiency. The most common AChR gene mutation that underlies CMS is the mutation of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an arginine (Arg) into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS. | CHRNE
Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the CHRNE gene.[1][2]
Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The achetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome.[2]
# Role in health and disease
Congenital myasthenic syndrome (CMS) is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in the acetylcholine receptor (AChR). The majority of mutations causing CMS are found in the AChR subunits genes.[3]
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult AChR subunits. Mutations of the AChR often result in endplate deficiency. The most common AChR gene mutation that underlies CMS is the mutation of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR.[4] One type of mutation of the epsilon subunit of the AChR introduces an arginine (Arg) into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.[5] | https://www.wikidoc.org/index.php/CHRNE | |
aa51a0360fb3c11ab8ab076ba06b76567de8ac20 | wikidoc | CIITA | CIITA
CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator. Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and cannot effectively fight infection. Chromosomal rearrangement of CIITA is involved in the pathogenesis of Hodgkin lymphoma and primary mediastinal B cell lymphoma.
# Function
CIITA mRNA can only be detected in human leukocyte antigen (HLA) system class II-positive cell lines and tissues. This highly restricted tissue distribution suggests that expression of HLA class II genes is to a large extent under the control of CIITA. However CIITA does not appear to directly bind to DNA. Instead CIITA functions through activation of the transcription factor RFX5. Hence CIITA is classified as a transcriptional coactivator.
The CIITA protein contains an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus, the protein acts as a positive regulator of class II major histocompatibility complex gene transcription, and is often referred to as the "master control factor" for the expression of these genes.
# Interactions
CIITA has been shown to interact with:
- MAPK1,
- Nuclear receptor coactivator 1,
- RFX5,
- RFXANK,
- XPO1, and
- ZXDC. | CIITA
CIITA is a human gene which encodes a protein called the class II, major histocompatibility complex, transactivator.[1] Mutations in this gene are responsible for the bare lymphocyte syndrome in which the immune system is severely compromised and cannot effectively fight infection.[1] Chromosomal rearrangement of CIITA is involved in the pathogenesis of Hodgkin lymphoma and primary mediastinal B cell lymphoma.[2]
# Function
CIITA mRNA can only be detected in human leukocyte antigen (HLA) system class II-positive cell lines and tissues. This highly restricted tissue distribution suggests that expression of HLA class II genes is to a large extent under the control of CIITA.[3] However CIITA does not appear to directly bind to DNA.[3] Instead CIITA functions through activation of the transcription factor RFX5.[4] Hence CIITA is classified as a transcriptional coactivator.
The CIITA protein contains an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain.[5] The protein uses GTP binding to facilitate its own transport into the nucleus.[6] Once in the nucleus, the protein acts as a positive regulator of class II major histocompatibility complex gene transcription, and is often referred to as the "master control factor" for the expression of these genes.[7][8]
# Interactions
CIITA has been shown to interact with:
- MAPK1,[9]
- Nuclear receptor coactivator 1,[10]
- RFX5,[4][11]
- RFXANK,[11][12]
- XPO1,[9][13] and
- ZXDC.[14][15] | https://www.wikidoc.org/index.php/CIITA | |
34781966ed12c1b782b7178838570578543042a3 | wikidoc | CKAP2 | CKAP2
Cytoskeleton-associated protein 2 is a protein that in humans is encoded by the CKAP2 gene.
Human CKAP2 gene, the cDNA of which is known as LB1, is a cytoskeleton-associated protein involved in mitotic progression. Its high transcriptional activity has been observed in the testes, thymus, and diffuse B-cell lymphomas. The gene codes for a protein of 683 residues, which lacks a homology to known amino acid sequences. On evidence of immunofluorescence analysis, the CKAP2 product is a cytoplasmic protein associated with cytoskeletal fibrils.
The CKAP2 gene is in chromosome 13q14. Rearrangements of this region result in various tumors. Thus deletions have been detected in multiple myeloma, prostate cancer, head-and-neck squamous-cell carcinoma, B-cell prolymphocytic leukemia, non-Hodgkin lymphoma, and in more than half cases of B-cell chronic lymphocytic leukemia. | CKAP2
Cytoskeleton-associated protein 2 is a protein that in humans is encoded by the CKAP2 gene.[1][2]
Human CKAP2 gene, the cDNA of which is known as LB1, is a cytoskeleton-associated protein involved in mitotic progression. Its high transcriptional activity has been observed in the testes, thymus, and diffuse B-cell lymphomas. The gene codes for a protein of 683 residues, which lacks a homology to known amino acid sequences. On evidence of immunofluorescence analysis, the CKAP2 product is a cytoplasmic protein associated with cytoskeletal fibrils.
The CKAP2 gene is in chromosome 13q14. Rearrangements of this region result in various tumors. Thus deletions have been detected in multiple myeloma, prostate cancer, head-and-neck squamous-cell carcinoma, B-cell prolymphocytic leukemia, non-Hodgkin lymphoma, and in more than half cases of B-cell chronic lymphocytic leukemia. | https://www.wikidoc.org/index.php/CKAP2 | |
38350d0efb410661d1b403cfe0fbdc69b2962d18 | wikidoc | CKAP4 | CKAP4
Cytoskeleton-associated protein 4 is a protein that in humans is encoded by the CKAP4 gene.
CKAP4 also historically known as CLIMP-63 (cytoskeleton-linking membrane protein 63), or just p63 (during the 90’s) is an abundant type II transmembrane protein residing predominantly in the endoplasmic reticulum (ER) of eukaryotic cells and encoded in higher vertebrates by the gene CKAP4.
# Discovery
CLIMP-63 was discovered in the early 90’s as the most S-palmitoylated protein during mitosis , Nevertheless, the effect of this modification to date remains unclear. CLIMP-63 was extensively studied during the 90’s by the group of Hans-Peter Hauri (University of Basel, CH) which has characterized CLIMP-63’s life in the ER. More recently, different groups have also reported CLIMP-63’s presence at the plasma membrane acting as a ligand-activated receptor. CLIMP-63 has also now been described as a marker in different cancers.
# Localization, molecular functions and regulation
CLIMP-63’s cellular distribution has been assessed (and re-assessed) several times in the last two decades. The protein includes a cytosolic segment composed of positively charged amino acid (2–23) which might act as a preponderant motif for folding and ER localization. Furthermore, CLIMP-63 was one of the first discovered ER-shaping proteins. and is mostly known for participating in the generation and maintenance of the ER sheets This is thought to occur after dimerization of CLIMP-63’s luminal COILED-COIL domains in cis (two CLIMP-63 proteins of the same ER membrane layer) and/or trans (between two different ER membrane layers, across the ER lumen). Multimerization might in addition limit CLIMP-63’s diffusion out of ER-sheets.
CLIMP-63 was also shown to bind microtubules through its cytoplasmic disordered tail which might help anchoring the ER-sheets to the cytoskeleton. This is regulated by phosphorylation of at least three serine residues of CLIMP-63’s cytosolic tail (S3, S17 and S19) as phosphorylation interferes with CLIMP-63’s microtubule binding capacity.
In addition, CLIMP-63 can undergo another post-translational modification, S-palmitoylation, on cysteine 100 of its cytoplasmic domain. So far only the palmitoyl-acyltransferase ZDHHC2 has been identified as a potential regulator of CLIMP-63’s palmitoylation but as ZDHHC2 resides mostly at the plasma membrane, supplementary investigations are needed. The consequence of S-palmitoylation remain to be investigated but could play a role in the cell cycle as CLIMP-63’s palmitoylation was reported to strongly increase during mitosis.
Finally, CLIMP-63 has been shown by different groups to serve as a cell surface receptor for various extracellular ligands, in particular for surfactant protein A (SP-A) in lungs alveoli , tissue plasminogen activator (tPA) in vascular smooth muscle cells and for anti-proliferative factor (APF) in bladder epithelial cells of patients with interstitial cystitis disorder.
# Diseases
More recently, CLIMP-63 has been related to different types of cancer prognosis. Upregulation of CLIMP-63 is observed in cholangio-cellular and hepatocellular carcinoma and it correlates with lymph node metastasis appearance. | CKAP4
Cytoskeleton-associated protein 4 is a protein that in humans is encoded by the CKAP4 gene.[1][2]
CKAP4 also historically known as CLIMP-63 (cytoskeleton-linking membrane protein 63), or just p63 (during the 90’s) is an abundant type II transmembrane protein residing predominantly in the endoplasmic reticulum (ER) of eukaryotic cells and encoded in higher vertebrates by the gene CKAP4.[3][4][5][6][7]
# Discovery
CLIMP-63 was discovered in the early 90’s as the most S-palmitoylated protein during mitosis [8][9], Nevertheless, the effect of this modification to date remains unclear. CLIMP-63 was extensively studied during the 90’s by the group of Hans-Peter Hauri (University of Basel, CH) which has characterized CLIMP-63’s life in the ER. More recently, different groups have also reported CLIMP-63’s presence at the plasma membrane acting as a ligand-activated receptor.[10][11][12] CLIMP-63 has also now been described as a marker in different cancers.[13]
# Localization, molecular functions and regulation
CLIMP-63’s cellular distribution has been assessed (and re-assessed) several times in the last two decades. The protein includes a cytosolic segment composed of positively charged amino acid (2–23) which might act as a preponderant motif for folding and ER localization.[14][15] Furthermore, CLIMP-63 was one of the first discovered ER-shaping proteins.[16] and is mostly known for participating in the generation and maintenance of the ER sheets [16][17] This is thought to occur after dimerization of CLIMP-63’s luminal COILED-COIL domains in cis (two CLIMP-63 proteins of the same ER membrane layer) and/or trans (between two different ER membrane layers, across the ER lumen).[16] Multimerization might in addition limit CLIMP-63’s diffusion out of ER-sheets.[18]
CLIMP-63 was also shown to bind microtubules through its cytoplasmic disordered tail which might help anchoring the ER-sheets to the cytoskeleton. This is regulated by phosphorylation of at least three serine residues of CLIMP-63’s cytosolic tail (S3, S17 and S19) as phosphorylation interferes with CLIMP-63’s microtubule binding capacity.[19]
In addition, CLIMP-63 can undergo another post-translational modification, S-palmitoylation, on cysteine 100 of its cytoplasmic domain. So far only the palmitoyl-acyltransferase ZDHHC2 has been identified as a potential regulator of CLIMP-63’s palmitoylation but as ZDHHC2 resides mostly at the plasma membrane, supplementary investigations are needed.[20][21] The consequence of S-palmitoylation remain to be investigated but could play a role in the cell cycle as CLIMP-63’s palmitoylation was reported to strongly increase during mitosis.[8]
Finally, CLIMP-63 has been shown by different groups to serve as a cell surface receptor for various extracellular ligands, in particular for surfactant protein A (SP-A) in lungs alveoli [11], tissue plasminogen activator (tPA) in vascular smooth muscle cells [10] and for anti-proliferative factor (APF) in bladder epithelial cells of patients with interstitial cystitis disorder.[12]
# Diseases
More recently, CLIMP-63 has been related to different types of cancer prognosis. Upregulation of CLIMP-63 is observed in cholangio-cellular and hepatocellular carcinoma and it correlates with lymph node metastasis appearance.[13][22] | https://www.wikidoc.org/index.php/CKAP4 | |
b33e262e6ffccdf589e093879482a8977fa766b5 | wikidoc | CKMT2 | CKMT2
Creatine kinase S-type, mitochondrial is an enzyme that in humans is encoded by the CKMT2 gene.
Mitochondrial creatine kinase (MtCK) is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. The "energy-rich" gamma-phosphate group of ATP that is generated by oxidative phosphorylation inside mitochondria is trans-phosphorylated to creatine (Cr) to give phospho-creatine (PCr), which then is exported from the mitochondria into the cytosol, where it is made available to cytosolic creatine kinases (CK) for in situ regeneration of the ATP that has been used for cellular work. Cr then is returning to the mitochondria where it stimulates mitochondrial respiration and again is charged-up by mitochondrial ATP via MtCK. This process is termed the PCr/Cr-shuttle or circuit.
MtCK belongs to the creatine kinase (CK) isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Sarcomeric mitochondrial creatine kinase has 80% homology with the coding exons of ubiquitous mitochondrial creatine kinase. This gene contains sequences homologous to several motifs that are shared among some nuclear genes encoding mitochondrial proteins and thus may be essential for the coordinated activation of these genes during mitochondrial biogenesis. | CKMT2
Creatine kinase S-type, mitochondrial is an enzyme that in humans is encoded by the CKMT2 gene.[1][2]
Mitochondrial creatine kinase (MtCK) is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. The "energy-rich" gamma-phosphate group of ATP that is generated by oxidative phosphorylation inside mitochondria is trans-phosphorylated to creatine (Cr) to give phospho-creatine (PCr), which then is exported from the mitochondria into the cytosol, where it is made available to cytosolic creatine kinases (CK) for in situ regeneration of the ATP that has been used for cellular work. Cr then is returning to the mitochondria where it stimulates mitochondrial respiration and again is charged-up by mitochondrial ATP via MtCK. This process is termed the PCr/Cr-shuttle or circuit.
MtCK belongs to the creatine kinase (CK) isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Sarcomeric mitochondrial creatine kinase has 80% homology with the coding exons of ubiquitous mitochondrial creatine kinase. This gene contains sequences homologous to several motifs that are shared among some nuclear genes encoding mitochondrial proteins and thus may be essential for the coordinated activation of these genes during mitochondrial biogenesis.[2] | https://www.wikidoc.org/index.php/CKMT2 | |
e37efe2b8c04cb82935841add9f81cc42b5735aa | wikidoc | CKS1B | CKS1B
Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.
# Function
The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein.
CKS1B and CKS2 proteins have demonstrated principal roles in cell cycle regulation. Defined originally as suppressors of mutations in both fission and budding yeast Cdk1 genes, Cks molecules interact with Cdk1, Cdk2 and Cdk3. These Cdk-dependent enzyme complexes in cell cycle regulation frequently consist of Cdk molecules bound to a catalytic Cdk subunit, i.e. Cks and a regulatory cyclin subunit, such as a G1 cyclin, controlling Cdk function by directing cyclin-cdk complex activity toward specific and significant substrates. Malfunctions of cdk-dependent associations lead to defects into the entry of mitosis for cells.
Cks1 in the Cdk-independent pathway involves the recognition of substrates p27Kip1 and p21cip1 by directly associating with E3 SCFSkp2 when stimulated by certainmitogenic signals, such as TGF-β.
# Clinical significance
Cks1-depleted breast cancer cells not only exhibit slowed G(1) progression, but also accumulate in G(2)-M due to blocked mitotic entry. Cdk1 expression, which is crucial for M phase entry, is drastically diminished by Cks1 depletion, and that restoration of cdk1 reduces G(2)-M accumulation in Cks1-depleted cells.
# Interactions
CKS1B has been shown to interact with SKP2 and CDKN1B. | CKS1B
Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.[1][2]
# Function
The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein.[2]
CKS1B and CKS2 proteins have demonstrated principal roles in cell cycle regulation. Defined originally as suppressors of mutations in both fission and budding yeast Cdk1 genes, Cks molecules interact with Cdk1, Cdk2 and Cdk3. These Cdk-dependent enzyme complexes in cell cycle regulation frequently consist of Cdk molecules bound to a catalytic Cdk subunit, i.e. Cks and a regulatory cyclin subunit, such as a G1 cyclin, controlling Cdk function by directing cyclin-cdk complex activity toward specific and significant substrates. Malfunctions of cdk-dependent associations lead to defects into the entry of mitosis for cells.[3]
Cks1 in the Cdk-independent pathway involves the recognition of substrates p27Kip1 and p21cip1 by directly associating with E3 SCFSkp2 when stimulated by certainmitogenic signals, such as TGF-β.[4]
# Clinical significance
Cks1-depleted breast cancer cells not only exhibit slowed G(1) progression, but also accumulate in G(2)-M due to blocked mitotic entry. Cdk1 expression, which is crucial for M phase entry, is drastically diminished by Cks1 depletion, and that restoration of cdk1 reduces G(2)-M accumulation in Cks1-depleted cells.[5]
# Interactions
CKS1B has been shown to interact with SKP2[6][7][8][9] and CDKN1B.[6][7] | https://www.wikidoc.org/index.php/CKS1B | |
f40ed29cdc161cbe70a249a6ed6b96470c225236 | wikidoc | CLCF1 | CLCF1
Cardiotrophin-like cytokine factor 1 (CLCF1), also known as Novel Neurotrophin-1 (NNT-1) or B cell-stimulating factor-3 (BSF-3), is a protein that in humans is encoded by the CLCF1 gene.
# Function
CLCF1 induces tyrosine phosphorylation of the IL-6 receptor common subunit glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and the transcription factor STAT3. It has been implicated in the induction of IL-1 (via induction of corticosterone and IL-6) and serum amyloid A, and in B cell hyperplasia. This cytokine is capable of B cell activation via gp130 receptor stimulation.
# Structure
CLCF1 is a cytokine belonging to the interleukin-6 (IL6) family. It is a secreted protein, found predominantly in lymph nodes and spleen, and contains 225 amino acids with a molecular mass of 22 kDa in its mature form. IL6 family members share similarity in gene structure and have a 4-helix bundle in their protein structure. CLCF1 is closely related to other proteins called cardiotrophin-1 and ciliary neurotrophic factor. | CLCF1
Cardiotrophin-like cytokine factor 1 (CLCF1), also known as Novel Neurotrophin-1 (NNT-1) or B cell-stimulating factor-3 (BSF-3), is a protein that in humans is encoded by the CLCF1 gene.[1]
# Function
CLCF1 induces tyrosine phosphorylation of the IL-6 receptor common subunit glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and the transcription factor STAT3. It has been implicated in the induction of IL-1 (via induction of corticosterone and IL-6) and serum amyloid A, and in B cell hyperplasia. This cytokine is capable of B cell activation via gp130 receptor stimulation.[2]
# Structure
CLCF1 is a cytokine belonging to the interleukin-6 (IL6) family. It is a secreted protein, found predominantly in lymph nodes and spleen, and contains 225 amino acids with a molecular mass of 22 kDa in its mature form. IL6 family members share similarity in gene structure and have a 4-helix bundle in their protein structure. CLCF1 is closely related to other proteins called cardiotrophin-1 and ciliary neurotrophic factor. | https://www.wikidoc.org/index.php/CLCF1 | |
5bb2c583b13613518ab1ae55df9792d061c8439e | wikidoc | CLCN1 | CLCN1
The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).
Chloride channel protein, skeletal muscle (CLCN1) is a protein that in humans is encoded by the CLCN1 gene. Mutations in this protein cause congenital myotonia.
CLCN1 is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contraction and relaxation are controlled by the flow of ions into and out of muscle cells. CLCN1 forms an ion channel that controls the flow of negatively charged chloride ions into these cells. The main function of this channel is to stabilize the cells' electrical charge, enabling muscles to contract normally.
In people with congenital myotonia due to a mutation in CLCN1, the ion channel admits too few chloride ions into the cell. This shortage of chloride ions causes prolonged muscle contractions, which are the hallmark of myotonia. | CLCN1
The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).[1]
Chloride channel protein, skeletal muscle (CLCN1) is a protein that in humans is encoded by the CLCN1 gene.[2] Mutations in this protein cause congenital myotonia.
CLCN1 is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contraction and relaxation are controlled by the flow of ions into and out of muscle cells. CLCN1 forms an ion channel that controls the flow of negatively charged chloride ions into these cells. The main function of this channel is to stabilize the cells' electrical charge, enabling muscles to contract normally.
In people with congenital myotonia due to a mutation in CLCN1, the ion channel admits too few chloride ions into the cell. This shortage of chloride ions causes prolonged muscle contractions, which are the hallmark of myotonia. | https://www.wikidoc.org/index.php/CLCN1 | |
1df4c61cd5456e166238f1925da7f6a6c7c708f8 | wikidoc | CLCN4 | CLCN4
H(+)/Cl(-) exchange transporter 4 is a protein that in humans is encoded by the CLCN4 gene.
# Function
The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders.
# Clinical significance
Mutations in this gene have been linked to cases of early onset epilepsy | CLCN4
H(+)/Cl(-) exchange transporter 4 is a protein that in humans is encoded by the CLCN4 gene.[1][2]
# Function
The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders.[2]
# Clinical significance
Mutations in this gene have been linked to cases of early onset epilepsy[3] | https://www.wikidoc.org/index.php/CLCN4 | |
438b8bd675fea6567ce2317e2262675a1f6817b6 | wikidoc | CLDN2 | CLDN2
Claudin-2 is a protein that in humans is encoded by the CLDN2 gene. It belongs to the group of claudins.
Members of the claudin protein family, such as CLDN2, are expressed in an organ-specific manner and regulate the tissue-specific physiologic properties of tight junctions (Sakaguchi et al., 2002).
# Function
Claudin-2 is expressed in cation-leaky epithelia such as that of the kidney proximal tubule. Mice that are deficient in claudin-2 have reduced reabsorption of Na+ in the proximal tubule, consistent with a role in paracellular transport.
Similar results have been obtained with cultured cells, as overexpression in claudin-2 lacking cells leads to increase of permeability for small cations.
Furthermore, claudin-2 has been shown to form paracellular channels for water. | CLDN2
Claudin-2 is a protein that in humans is encoded by the CLDN2 gene.[1][2] It belongs to the group of claudins.
Members of the claudin protein family, such as CLDN2, are expressed in an organ-specific manner and regulate the tissue-specific physiologic properties of tight junctions (Sakaguchi et al., 2002).[supplied by OMIM][2]
# Function
Claudin-2 is expressed in cation-leaky epithelia such as that of the kidney proximal tubule.[3] Mice that are deficient in claudin-2 have reduced reabsorption of Na+ in the proximal tubule, consistent with a role in paracellular transport.
Similar results have been obtained with cultured cells, as overexpression in claudin-2 lacking cells leads to increase of permeability for small cations.[4]
Furthermore, claudin-2 has been shown to form paracellular channels for water.[5] | https://www.wikidoc.org/index.php/CLDN2 | |
65bb5a71facb256755bbf428c6a27de51d2c3b3f | wikidoc | CLIC4 | CLIC4
Chloride intracellular channel 4, also known as CLIC4, is a eukaryotic gene.
Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits an intracellular vesicular pattern in PANC-1 cells (pancreatic cancer cells).
# Binding partners
CLIC4 binds to dynamin I, α-tubulin, β-actin, creatine kinase and two 14-3-3 isoforms. | CLIC4
Chloride intracellular channel 4, also known as CLIC4, is a eukaryotic gene.[1]
Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits an intracellular vesicular pattern in PANC-1 cells (pancreatic cancer cells).[1]
# Binding partners
CLIC4 binds to dynamin I, α-tubulin, β-actin, creatine kinase and two 14-3-3 isoforms.[2] | https://www.wikidoc.org/index.php/CLIC4 | |
ec13dee9b56dfd7fec995c2741de53473b7fd279 | wikidoc | CLIC5 | CLIC5
Chloride intracellular channel protein 5 is a protein that in humans is encoded by the CLIC5 gene.
# Expression and localization
CLIC5 exists in two alternative splice variants, a smaller CLIC5A and larger CLIC5B protein.
CLIC5A is expressed chiefly in the renal glomerulus, specifically in podocytes. Within the cell, CLIC5A is localized to the plasma membrane and the cytosol, and associates and is regulated by the actin cytoskeleton. CLIC5A can form ion channels in vitro and its channel activity is regulated by actin, though measurement of its chloride conductance in vitro suggests that CLIC5A is equally selective for cations and anions.
# Function
Although chloride intracellular channel (CLIC) proteins were thought to be involved in ion transport in subcellular compartments, their actual functions suggest their role in diverse cellular and physiological functions including apoptosis and angiogenesis in CLIC1.
CLIC5A, through its interactions with the small GTPase Rac1, induces the phosphorylation of ezrin-moeisin-radixin (ERM) proteins and localized production of the phosphoinositide phosphatidylinositol-4,5-bisphosphate. These two events activate ezrin, enabling it to couple transmembrane proteins to the actin cytoskeleton, which could represent a mechanism by which podocyte foot processes form to enable renal filtration.
# Clinical relevance
CLIC5A deficiency in mouse models potentiates glomerular injury in hypertension. In these mice, podocyte foot processes were also more sparse and disperse than in wild-type mice. | CLIC5
Chloride intracellular channel protein 5 is a protein that in humans is encoded by the CLIC5 gene.[1][2]
# Expression and localization
CLIC5 exists in two alternative splice variants, a smaller CLIC5A and larger CLIC5B protein.
CLIC5A is expressed chiefly in the renal glomerulus, specifically in podocytes. Within the cell, CLIC5A is localized to the plasma membrane and the cytosol, and associates and is regulated by the actin cytoskeleton.[2] CLIC5A can form ion channels in vitro and its channel activity is regulated by actin, though measurement of its chloride conductance in vitro suggests that CLIC5A is equally selective for cations and anions.
# Function
Although chloride intracellular channel (CLIC) proteins were thought to be involved in ion transport in subcellular compartments, their actual functions suggest their role in diverse cellular and physiological functions including apoptosis and angiogenesis in CLIC1.
CLIC5A, through its interactions with the small GTPase Rac1, induces the phosphorylation of ezrin-moeisin-radixin (ERM) proteins and localized production of the phosphoinositide phosphatidylinositol-4,5-bisphosphate.[3] These two events activate ezrin, enabling it to couple transmembrane proteins to the actin cytoskeleton, which could represent a mechanism by which podocyte foot processes form to enable renal filtration.[4]
# Clinical relevance
CLIC5A deficiency in mouse models potentiates glomerular injury in hypertension. In these mice, podocyte foot processes were also more sparse and disperse than in wild-type mice.[4] | https://www.wikidoc.org/index.php/CLIC5 | |
20b098d8b0b2c9b5dcaecf2a268a6cefad31d7b9 | wikidoc | CLOCK | CLOCK
Clock (Circadian Locomotor Output Cycles Kaput) is a gene encoding a basic helix-loop-helix-PAS transcription factor (CLOCK) that is believed to affect both the persistence and period of circadian rhythms.
Research shows that the CLOCK gene plays a major role as an activator of downstream elements in the pathway critical to the generation of circadian rhythms.
# Discovery
The Clock gene was first identified in 1994 by Dr. Joseph Takahashi and his colleagues. Takahashi used forward mutagenesis screening of mice treated with N-ethyl-N-nitrosourea to create and identify mutations in key genes that broadly affect circadian activity. The Clock mutants discovered through the screen displayed an abnormally long period of daily activity. This trait proved to be heritable. Mice bred to be heterozygous showed longer periods of 24.4 hours compared to the control 23.3 hour period. Mice homozygous for the mutation showed 27.3 hour periods, but eventually lost all circadian rhythmicity after several days in constant darkness. That showed that "intact Clock genes" are necessary for normal mammalian circadian function.
# Function
CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker. In Drosophila, newly synthesized CLOCK (CLK) is hypophosphorylated in the cytoplasm before entering the nucleus. Once in the nuclei, CLK is localized in nuclear foci and is later redistributed homogeneously. CYCLE (CYC) (also known as dBMAL for the BMAL1 ortholog in mammals) dimerizes with CLK via their respective PAS domains. This dimer then recruits co-activator CREB-binding protein (CBP) and is further phosphorylated. Once phosphorylated, this CLK-CYC complex binds to the E-box elements of the promoters of period (per) and timeless (tim) via its bHLH domain, causing the stimulation of gene expression of per and tim. A large molar excess of period (PER) and timeless (TIM) proteins causes formation of the PER-TIM heterodimer which prevents the CLK-CYC heterodimer from binding to the E-boxes of per and tim, essentially blocking per and tim transcription. CLK is hyperphosphorylated when doubletime (DBT) kinase interacts with the CLK-CYC complex in a PER reliant manner, destabilizing both CLK and PER, leading to the degradation of both proteins.
Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again. This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.
A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome (cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry. The heterodimer CLOCK:BMAL1 functions similarly to other transcriptional activator complexes; CLOCK:BMAL1 interacts with the E-box regulatory elements. PER and CRY proteins accumulate and dimerize during subjective night, and translocate into the nucleus to interact with the CLOCK:BMAL1 complex, directly inhibiting their own expression. This research has been conducted and validated through chrystallographic analysis.
CLOCK exhibits histone acetyl transferase (HAT) activity, which is enhanced by dimerization with BMAL1. Dr. Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants.
## Role in other feedback loops
The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzyme SIRT1 also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps by deacetylation of Bmal1 and surrounding histones. However, SIRT1’s role is still controversial and it may also have a role in deacetylating PER protein, targeting it for degradation.
The CLOCK-BMAL dimer acts as a positive limb of a feedback loop. The binding of CLOCK-BMAL to an E-box promoter element activates transcription of clock genes such as per1, 2, and 3 and tim in mice. It has been shown in mice that CLOCK-BMAL also activates the Nicotinamide phosphoribosyltransferase gene (also called Nampt), part of a separate feedback loop. This feedback loops creates a metabolic oscillator. The CLOCK-BMAL dimer activates transcription of the Nampt gene, which codes for the NAMPT protein. NAMPT is part of a series of enzymatic reactions that covert niacin (also called nicotinamide) to NAD. SIRT1, which requires NAD for its enzymatic activity, then uses increased NAD levels to suppress BMAL1 through deacetylation. This suppression results in less transcription of the NAMPT, less NAMPT protein, less NAD made, and therefore less SIRT1 and less suppression of the CLOCK-BMAL dimer. This dimer can again positively activate the Nampt gene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements. The key role that Clock plays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks.
# Mutants
Clock mutant organisms can either possess a null mutation or an antimorphic allele at the Clock locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by Clock.
## Drosophila
In Drosophila, a mutant form of Clock (Jrk) was identified by Allada, Hall, and Rosbash in 1998. The team used forward genetics to identify non-circadian rhythms in mutant flies. Jrk results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of 24.8 hours, while the other half become arrhythmic. Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects. The similar sequence between Jrk and its mouse homolog suggests common circadian rhythm components were present in both Drosophila and mice ancestors. A recessive allele of Clock leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms.
## Mice
The mouse homolog to the Jrk mutant is the ClockΔ19 mutant that possesses a deletion in exon 19 of the Clock gene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate per transcription. In constant darkness, ClockΔ19 mice heterozygous for the Clock mutant allele exhibit lengthened circadian periods, while ClockΔ19/Δ19 mice homozygous for the allele become arrhythmic. In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level.
Clock -/- null mutant mice, in which Clock has been knocked out, display completely normal circadian rhythms. The discovery of a null Clock mutant with a wild-type phenotype directly challenged the widely accepted premise that Clock is necessary for normal circadian function. Furthermore, it suggested that the CLOCK-BMAL1 dimer need not exist to modulate other elements of the circadian pathway. Neuronal PAS domain containing protein 2 (NPAS2, a CLOCK paralog) can substitute for CLOCK in these Clock-null mice. Mice with one NPAS2 allele showed shorter periods at first, but eventual arrhythmic behavior.
# Observed effects
In humans, a polymorphism in Clock, rs6832769, may be related to the personality trait agreeableness. Another single nucleotide polymorphism (SNP) in Clock, 3111C, has been associated with diurnal preference. This SNP is also associated with increased insomnia, difficulty losing weight, and recurrence of major depressive episodes in patients with bipolar disorder.
In mice, Clock has been implicated in sleep disorders, metabolism, pregnancy, and mood disorders. Clock mutant mice sleep less than normal mice each day. The mice also display altered levels of plasma glucose and rhythms in food intake. These mutants develop metabolic syndrome symptoms over time. Furthermore, Clock mutants demonstrate disrupted estrous cycles and increased rates of full-term pregnancy failure. Mutant Clock has also been linked to bipolar disorder-like symptoms in mice, including mania and euphoria. Clock mutant mice also exhibit increased excitability of dopamine neurons in reward centers of the brain. These results have led Dr. Colleen McClung to propose using Clock mutant mice as a model for human mood and behavior disorders.
The CLOCK-BMAL dimer has also been shown to activate reverse-erb receptor alpha (Rev-ErbA alpha) and retinoic acid orphan receptor alpha (ROR-alpha). REV-ERBα and RORα regulate Bmal by binding to retinoic acid-related orphan receptor response elements (ROREs) in its promoter.
Variations in the epigenetics of the Clock gene may lead to an increased risk of breast cancer. It was found that in women with breast cancer, there was significantly less methylation of the Clock promoter region. It was also noted that this effect was greater in women with estrogen and progesterone receptor-negative tumors.
The CLOCK gene may also be a target for somatic mutations in microsatellite unstable colorectal cancers. Approximately half of putative novel microsatellite instability target genes responsible for colorectal cancer contained CLOCK mutations. Nascent research in the expression of circadian genes in adipose tissue suggests that suppression of the CLOCK gene may causally correlate not only with obesity, but also with type 2 diabetes, with quantitative physical responses to circadian food intake as potential inputs to the clock system. | CLOCK
Clock (Circadian Locomotor Output Cycles Kaput) is a gene encoding a basic helix-loop-helix-PAS transcription factor (CLOCK) that is believed to affect both the persistence and period of circadian rhythms.
Research shows that the CLOCK gene plays a major role as an activator of downstream elements in the pathway critical to the generation of circadian rhythms.[1]
# Discovery
The Clock gene was first identified in 1994 by Dr. Joseph Takahashi and his colleagues. Takahashi used forward mutagenesis screening of mice treated with N-ethyl-N-nitrosourea to create and identify mutations in key genes that broadly affect circadian activity.[2] The Clock mutants discovered through the screen displayed an abnormally long period of daily activity. This trait proved to be heritable. Mice bred to be heterozygous showed longer periods of 24.4 hours compared to the control 23.3 hour period. Mice homozygous for the mutation showed 27.3 hour periods, but eventually lost all circadian rhythmicity after several days in constant darkness.[3] That showed that "intact Clock genes" are necessary for normal mammalian circadian function[how?].
# Function
CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.[4] In Drosophila, newly synthesized CLOCK (CLK) is hypophosphorylated in the cytoplasm before entering the nucleus. Once in the nuclei, CLK is localized in nuclear foci and is later redistributed homogeneously. CYCLE (CYC) (also known as dBMAL for the BMAL1 ortholog in mammals) dimerizes with CLK via their respective PAS domains. This dimer then recruits co-activator CREB-binding protein (CBP) and is further phosphorylated.[5] Once phosphorylated, this CLK-CYC complex binds to the E-box elements of the promoters of period (per) and timeless (tim) via its bHLH domain, causing the stimulation of gene expression of per and tim. A large molar excess of period (PER) and timeless (TIM) proteins causes formation of the PER-TIM heterodimer which prevents the CLK-CYC heterodimer from binding to the E-boxes of per and tim, essentially blocking per and tim transcription.[1][6] CLK is hyperphosphorylated when doubletime (DBT) kinase interacts with the CLK-CYC complex in a PER reliant manner, destabilizing both CLK and PER, leading to the degradation of both proteins.[6]
Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again.[6] This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.[5]
A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome (cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry.[7] The heterodimer CLOCK:BMAL1 functions similarly to other transcriptional activator complexes; CLOCK:BMAL1 interacts with the E-box regulatory elements. PER and CRY proteins accumulate and dimerize during subjective night, and translocate into the nucleus to interact with the CLOCK:BMAL1 complex, directly inhibiting their own expression. This research has been conducted and validated through chrystallographic analysis.[8]
CLOCK exhibits histone acetyl transferase (HAT) activity, which is enhanced by dimerization with BMAL1.[9] Dr. Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants.[9]
## Role in other feedback loops
The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzyme SIRT1 also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps by deacetylation of Bmal1 and surrounding histones.[10] However, SIRT1’s role is still controversial and it may also have a role in deacetylating PER protein, targeting it for degradation.[11]
The CLOCK-BMAL dimer acts as a positive limb of a feedback loop. The binding of CLOCK-BMAL to an E-box promoter element activates transcription of clock genes such as per1, 2, and 3 and tim in mice. It has been shown in mice that CLOCK-BMAL also activates the Nicotinamide phosphoribosyltransferase gene (also called Nampt), part of a separate feedback loop. This feedback loops creates a metabolic oscillator. The CLOCK-BMAL dimer activates transcription of the Nampt gene, which codes for the NAMPT protein. NAMPT is part of a series of enzymatic reactions that covert niacin (also called nicotinamide) to NAD. SIRT1, which requires NAD for its enzymatic activity, then uses increased NAD levels to suppress BMAL1 through deacetylation. This suppression results in less transcription of the NAMPT, less NAMPT protein, less NAD made, and therefore less SIRT1 and less suppression of the CLOCK-BMAL dimer. This dimer can again positively activate the Nampt gene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements. The key role that Clock plays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks.[12]
# Mutants
Clock mutant organisms can either possess a null mutation or an antimorphic allele at the Clock locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by Clock.[13]
## Drosophila
In Drosophila, a mutant form of Clock (Jrk) was identified by Allada, Hall, and Rosbash in 1998. The team used forward genetics to identify non-circadian rhythms in mutant flies. Jrk results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of 24.8 hours, while the other half become arrhythmic. Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects.[14] The similar sequence between Jrk and its mouse homolog suggests common circadian rhythm components were present in both Drosophila and mice ancestors. A recessive allele of Clock leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms.[15]
## Mice
The mouse homolog to the Jrk mutant is the ClockΔ19 mutant that possesses a deletion in exon 19 of the Clock gene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate per transcription. In constant darkness, ClockΔ19 mice heterozygous for the Clock mutant allele exhibit lengthened circadian periods, while ClockΔ19/Δ19 mice homozygous for the allele become arrhythmic.[3] In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level.[16]
Clock -/- null mutant mice, in which Clock has been knocked out, display completely normal circadian rhythms. The discovery of a null Clock mutant with a wild-type phenotype directly challenged the widely accepted premise that Clock is necessary for normal circadian function. Furthermore, it suggested that the CLOCK-BMAL1 dimer need not exist to modulate other elements of the circadian pathway.[17] Neuronal PAS domain containing protein 2 (NPAS2, a CLOCK paralog[18]) can substitute for CLOCK in these Clock-null mice. Mice with one NPAS2 allele showed shorter periods at first, but eventual arrhythmic behavior.[19]
# Observed effects
In humans, a polymorphism in Clock, rs6832769, may be related to the personality trait agreeableness.[20] Another single nucleotide polymorphism (SNP) in Clock, 3111C, has been associated with diurnal preference.[21] This SNP is also associated with increased insomnia,[22] difficulty losing weight,[23] and recurrence of major depressive episodes in patients with bipolar disorder.[24]
In mice, Clock has been implicated in sleep disorders, metabolism, pregnancy, and mood disorders. Clock mutant mice sleep less than normal mice each day.[25] The mice also display altered levels of plasma glucose and rhythms in food intake.[26] These mutants develop metabolic syndrome symptoms over time.[27] Furthermore, Clock mutants demonstrate disrupted estrous cycles and increased rates of full-term pregnancy failure.[28] Mutant Clock has also been linked to bipolar disorder-like symptoms in mice, including mania and euphoria.[29] Clock mutant mice also exhibit increased excitability of dopamine neurons in reward centers of the brain.[30] These results have led Dr. Colleen McClung to propose using Clock mutant mice as a model for human mood and behavior disorders.
The CLOCK-BMAL dimer has also been shown to activate reverse-erb receptor alpha (Rev-ErbA alpha) and retinoic acid orphan receptor alpha (ROR-alpha). REV-ERBα and RORα regulate Bmal by binding to retinoic acid-related orphan receptor response elements (ROREs) in its promoter.[31][32]
Variations in the epigenetics of the Clock gene may lead to an increased risk of breast cancer.[33] It was found that in women with breast cancer, there was significantly less methylation of the Clock promoter region. It was also noted that this effect was greater in women with estrogen and progesterone receptor-negative tumors.[34]
The CLOCK gene may also be a target for somatic mutations in microsatellite unstable colorectal cancers. Approximately half of putative novel microsatellite instability target genes responsible for colorectal cancer contained CLOCK mutations.[35] Nascent research in the expression of circadian genes in adipose tissue suggests that suppression of the CLOCK gene may causally correlate not only with obesity, but also with type 2 diabetes,[36] with quantitative physical responses to circadian food intake as potential inputs to the clock system.[37] | https://www.wikidoc.org/index.php/CLOCK | |
68bfa9d009d6b1e49074840e4640bde190ca41ff | wikidoc | CNDP1 | CNDP1
Beta-Ala-His dipeptidase is an enzyme that in humans is encoded by the CNDP1 gene.
This gene encodes a member of the M20 metalloprotease family. The encoded protein is specifically expressed in the brain, is a homodimeric dipeptidase which was identified as human carnosinase. This gene contains trinucleotide (CTG) repeat length polymorphism in the coding region.
The metabolic disorder Carnosinemia may be caused by mutations in this gene. | CNDP1
Beta-Ala-His dipeptidase is an enzyme that in humans is encoded by the CNDP1 gene.[1][2]
This gene encodes a member of the M20 metalloprotease family. The encoded protein is specifically expressed in the brain, is a homodimeric dipeptidase which was identified as human carnosinase. This gene contains trinucleotide (CTG) repeat length polymorphism in the coding region.[2]
The metabolic disorder Carnosinemia may be caused by mutations in this gene. | https://www.wikidoc.org/index.php/CNDP1 | |
4d5634666e3c47d5ade88ccd8663d3b3362476ad | wikidoc | COPII | COPII
COPII is a coatomer, a type of vesicle coat protein that transports proteins from the rough endoplasmic reticulum to the Golgi apparatus. This process is termed anterograde transport, in contrast to the retrograde transport associated with the COPI protein. The name "COPII" refers to the specific coat protein complex that initiates the budding process. The coat consists of large protein subcomplexes that are made of four different protein subunits.
# Coat proteins
There are two protein heterodimers that form the coat complex. These proteins are
- Sec23p/Sec24p Heterodimer
- Sec13p/Sec31p Heterotetramer
These proteins alone are not able to cause the budding of the vesicle or direct the vesicle to the correct target membrane. SNARE, cargo, and other proteins are also needed for these processes to occur. The CopII protein does, however, cause the binding that forms vesicle coat, and thereby causes the release from the ER. The exact process of how the vesicle is brought to a particular location, or how that location is determined is not yet known.
# Budding process
The GTPase Sar1p is a protein that hydrolyzes GTP and acts like a molecular "switch" that flips between an activated and membrane embedded GTP-bound form, and inactive and soluble GDP-bound form. Inactive GDP-bound Sar1p is attracted to the cytosolic side of the endoplasmic reticulum. Sec12, a transmembrane protein found in the ER acts as a Guanine nucleotide exchange factor by stimulating the release of GDP to allow the binding of GTP. Now in a GTP bound state, Sar1p undergoes a conformational change which exposes a hydrophobic tail that can be inserted into the lipid bilayer, binding it to the membrane. Membrane-bound Sar1p recruits the Sec23p/24p complex to form what is collectively known as the pre-budding complex. The pre-budding complex recruits the long, flexible Sec13p/31p complex. Sec13p/31p complexes polymerizes on the cytosolic side of the membrane to form a convex mesh structure. The assembling mesh causes the membrane to bulge outward until a vesicle buds off. Some proteins are found to be responsible for selectively packaging cargos into COPII vesicles. For example, Erv29p in Saccharomyces cerevisiae is found to be necessary for packaging glycosylated pro-α-factor.
# Conformational changes
CopII has three specific binding sites that can each be complexed. The adjacent picture (Sed5) uses the Sec22 t-SNARE complex to bind. This site is more strongly bound, and therefore is more favored. (Embo)
- Conformation of the CopII protein complexed with the snare protein Bet1 (PDB: 1PCX).
Conformation of the CopII protein complexed with the snare protein Bet1 (PDB: 1PCX).
- Conformation of the CopII protein that is complexed with the snare protein Sed5 (PDB: 1PD0).
Conformation of the CopII protein that is complexed with the snare protein Sed5 (PDB: 1PD0). | COPII
COPII is a coatomer, a type of vesicle coat protein that transports proteins from the rough endoplasmic reticulum to the Golgi apparatus.[2][3] This process is termed anterograde transport, in contrast to the retrograde transport associated with the COPI protein. The name "COPII" refers to the specific coat protein complex that initiates the budding process. The coat consists of large protein subcomplexes that are made of four different protein subunits.
# Coat proteins
There are two protein heterodimers that form the coat complex. These proteins are
- Sec23p/Sec24p Heterodimer
- Sec13p/Sec31p Heterotetramer
These proteins alone are not able to cause the budding of the vesicle or direct the vesicle to the correct target membrane. SNARE, cargo, and other proteins are also needed for these processes to occur. The CopII protein does, however, cause the binding that forms vesicle coat, and thereby causes the release from the ER. The exact process of how the vesicle is brought to a particular location, or how that location is determined is not yet known.
# Budding process
The GTPase Sar1p is a protein that hydrolyzes GTP and acts like a molecular "switch" that flips between an activated and membrane embedded GTP-bound form, and inactive and soluble GDP-bound form.[4] Inactive GDP-bound Sar1p is attracted to the cytosolic side of the endoplasmic reticulum. Sec12, a transmembrane protein found in the ER acts as a Guanine nucleotide exchange factor by stimulating the release of GDP to allow the binding of GTP. Now in a GTP bound state, Sar1p undergoes a conformational change which exposes a hydrophobic tail that can be inserted into the lipid bilayer, binding it to the membrane. Membrane-bound Sar1p recruits the Sec23p/24p complex to form what is collectively known as the pre-budding complex. The pre-budding complex recruits the long, flexible Sec13p/31p complex. Sec13p/31p complexes polymerizes on the cytosolic side of the membrane to form a convex mesh structure. The assembling mesh causes the membrane to bulge outward until a vesicle buds off. Some proteins are found to be responsible for selectively packaging cargos into COPII vesicles. For example, Erv29p in Saccharomyces cerevisiae is found to be necessary for packaging glycosylated pro-α-factor.[5]
# Conformational changes
CopII has three specific binding sites that can each be complexed. The adjacent picture (Sed5) uses the Sec22 t-SNARE complex to bind. This site is more strongly bound, and therefore is more favored. (Embo)
- Conformation of the CopII protein complexed with the snare protein Bet1 (PDB: 1PCX).[6]
Conformation of the CopII protein complexed with the snare protein Bet1 (PDB: 1PCX).[6]
- Conformation of the CopII protein that is complexed with the snare protein Sed5 (PDB: 1PD0).[6]
Conformation of the CopII protein that is complexed with the snare protein Sed5 (PDB: 1PD0).[6] | https://www.wikidoc.org/index.php/COPII | |
8f063eadef27d497cd8a4db20284dde0a2fe85f5 | wikidoc | CORIN | CORIN
Corin, also called atrial natriuretic peptide-converting enzyme, is a protein that in humans is encoded by the CORIN gene.
# Protein
Human corin, a polypeptide of 1042 amino acids, consists of an N-terminal cytoplasmic domain, a transmembrane domain and an extracellular region with two frizzled-like domains, eight LDL receptor-like domains, a scavenger receptor-like domain and a C-terminal trypsin-like serine protease domain. Corin is synthesized as a zymogen that is activated by PCSK6.
Corin exhibits a trypsin-like catalytic activity favoring basic residues at the P1 position.
Human corin contains 19 N-glycosylation sites. N-glycans promote corin expression on the cell surface and protect corin from metalloproteinase-mediated shedding.
# Function
Corin converts the atrial natriuretic peptide (ANP) precursor, pro-ANP, to mature ANP, a cardiac hormone that regulates salt-water balance and blood pressure. In mice, corin deficiency prevents pro-ANP processing and causes salt-sensitive hypertension.
Corin may also function as a pro-brain-type natriuretic peptide convertase.
Corin-mediated ANP production in the pregnant uterus promotes spiral artery remodeling and trophoblast invasion. CORIN mutations have been reported in patients with preeclampsia.
In mice, corin functions in the dermal papilla to regulate coat color in an Agouti-dependent pathway.
# Variants and mutations
Variants encoded by alternative exons were reported in human and mouse corin. A variant allele (T555I/Q568P) was found in African Americans with hypertension and cardiac hypertrophy. The amino acid substitutions impaired corin activity. An insertion variant in exon 1 alters the cytoplasmic tail. This variant appeared more frequently in hypertensive patients. CORIN mutations were found in patients with hypertension. | CORIN
Corin, also called atrial natriuretic peptide-converting enzyme, is a protein that in humans is encoded by the CORIN gene.[1][2]
# Protein
Human corin, a polypeptide of 1042 amino acids, consists of an N-terminal cytoplasmic domain, a transmembrane domain and an extracellular region with two frizzled-like domains, eight LDL receptor-like domains, a scavenger receptor-like domain and a C-terminal trypsin-like serine protease domain.[1][3] Corin is synthesized as a zymogen that is activated by PCSK6.[4]
Corin exhibits a trypsin-like catalytic activity favoring basic residues at the P1 position.[5]
Human corin contains 19 N-glycosylation sites.[1] N-glycans promote corin expression on the cell surface and protect corin from metalloproteinase-mediated shedding.[6][7][8]
# Function
Corin converts the atrial natriuretic peptide (ANP) precursor, pro-ANP, to mature ANP, a cardiac hormone that regulates salt-water balance and blood pressure.[9] In mice, corin deficiency prevents pro-ANP processing and causes salt-sensitive hypertension.[10][11]
Corin may also function as a pro-brain-type natriuretic peptide convertase.[9][12][13]
Corin-mediated ANP production in the pregnant uterus promotes spiral artery remodeling and trophoblast invasion.[14] CORIN mutations have been reported in patients with preeclampsia.[14][15]
In mice, corin functions in the dermal papilla to regulate coat color in an Agouti-dependent pathway.[16]
# Variants and mutations
Variants encoded by alternative exons were reported in human and mouse corin.[17] A variant allele (T555I/Q568P) was found in African Americans with hypertension and cardiac hypertrophy.[18][19] The amino acid substitutions impaired corin activity.[20][21] An insertion variant in exon 1 alters the cytoplasmic tail.[22] This variant appeared more frequently in hypertensive patients. CORIN mutations were found in patients with hypertension.[14][15][23] | https://www.wikidoc.org/index.php/CORIN | |
b83137a2fb08c1123f2b326e168def112a8228a6 | wikidoc | CORO6 | CORO6
Coronin-6 also known as coronin-like protein E (Clipin-E) is a protein that in humans is encoded by the CORO6 gene.
Coronin-6 is belongs to coronin family which is an actin binding protein. Human CORO6 gene is located on chromosome 17 on the cytogenetic band 17 p11.2. Gene CORO6 is well conserved across domain of eukaryotic organisms from animal to fungi.
# Expression
## EST profile
Based on the EST profile, CORO6 expressed in high level at the larynx, nerve and muscle. CORO6 has also been shown to be expressed in high levels in the breast (mammary gland) tumor. During the human development stage,the higher level of CORO6 expressed at blastocyst and adult.
## Transcript Variant
Alternative mRNAs are shown aligned from 5' to 3' on a virtual genome where introns have been shrunk to a minimal length. Exon size is proportional to length, intron height reflects the number of cDNAs supporting each intron. Introns of the same color are identical, of different colors are different. 'Good proteins' are pink, partial or not-good proteins are yellow, uORFs are green. 5' cap or3' poly A flags show completeness of the transcript . CORO6 contains 21 distinct gt-ag introns. Transcription produces 10 alternatively spliced mRNA. There are 3 probable alternative promoters, and validated alternative polyadenylation sites.
# Structure
CORO6 protein sequence contains WD-40 repeats. WD40 domain is a structural motif found in Eukaryotes and cover variety of functions, such as adaptor or regulatory modules in signal transduction, pre-mRNA processing and cytoskeletal assembly. It usually terminating at WD dipeptide at its C-terminus and is about 40 residues long, so called WD40.
The structure of CORO6 is predicted by using Phyre2 program. It is similar to the crystal structure of murine coronin-1. 390 residues ( 83% of CORO6 protein sequence) have been modelled with 100.0% confidence by the single highest scoring template. Image coloured by rainbow N → C terminus
# Homology
## Paralogs
Human proteins which are the paralogs to CORO6,
CORO1A,
CORO1B,
CORO1C,
CORO2A,
CORO2B,
CORO7
The table compared Homo sapiens protein CORO6 to its paralogs
By comparing its paralogs we found that CORO1A and CORO1B are most related to CORO6.
## Orthologs
CORO6 is highly conserved throughout the organisms from vertebrate to fungus, the organisms listed in the table are some representatives.
# Clinical significance
There are several clinical studies about that have been performed by using microarray indicating that CORO6 is positively related to allergic nasal epithelium response to house dust mite allergen in vitro.
# Model organisms
Model organisms have been used in the study of CORO6 function. A conditional knockout mouse line called Coro6tm1e(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | CORO6
Coronin-6 also known as coronin-like protein E (Clipin-E) is a protein that in humans is encoded by the CORO6 gene.
Coronin-6 is belongs to coronin family which is an actin binding protein.[1][2] Human CORO6 gene is located on chromosome 17 on the cytogenetic band 17 p11.2.[3] Gene CORO6 is well conserved across domain of eukaryotic organisms from animal to fungi.[4]
# Expression
## EST profile
Based on the EST profile, CORO6 expressed in high level at the larynx, nerve and muscle. CORO6 has also been shown to be expressed in high levels in the breast (mammary gland) tumor. During the human development stage,the higher level of CORO6 expressed at blastocyst and adult.[5]
## Transcript Variant
Alternative mRNAs are shown aligned from 5' to 3' on a virtual genome where introns have been shrunk to a minimal length. Exon size is proportional to length, intron height reflects the number of cDNAs supporting each intron. Introns of the same color are identical, of different colors are different. 'Good proteins' are pink, partial or not-good proteins are yellow, uORFs are green. 5' cap or3' poly A flags show completeness of the transcript . CORO6 contains 21 distinct gt-ag introns. Transcription produces 10 alternatively spliced mRNA. There are 3 probable alternative promoters, and validated alternative polyadenylation sites.[6]
# Structure
CORO6 protein sequence contains WD-40 repeats. WD40 domain is a structural motif found in Eukaryotes and cover variety of functions, such as adaptor or regulatory modules in signal transduction, pre-mRNA processing and cytoskeletal assembly. It usually terminating at WD dipeptide at its C-terminus and is about 40 residues long, so called WD40.[7]
The structure of CORO6 is predicted by using Phyre2 program. It is similar to the crystal structure of murine coronin-1. 390 residues ( 83% of CORO6 protein sequence) have been modelled with 100.0% confidence by the single highest scoring template. Image coloured by rainbow N → C terminus
# Homology
## Paralogs
Human proteins which are the paralogs to CORO6,
CORO1A,
CORO1B,
CORO1C,
CORO2A,
CORO2B,
CORO7
The table compared Homo sapiens protein CORO6 to its paralogs
By comparing its paralogs we found that CORO1A and CORO1B are most related to CORO6.
## Orthologs
CORO6 is highly conserved throughout the organisms from vertebrate to fungus, the organisms listed in the table are some representatives.
# Clinical significance
There are several clinical studies about that have been performed by using microarray indicating that CORO6 is positively related to allergic nasal epithelium response to house dust mite allergen in vitro.[8]
# Model organisms
Model organisms have been used in the study of CORO6 function. A conditional knockout mouse line called Coro6tm1e(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[9] Male and female animals underwent a standardized phenotypic screen[10] to determine the effects of deletion.[11][12][13][14] Additional screens performed: - In-depth immunological phenotyping[15] | https://www.wikidoc.org/index.php/CORO6 | |
186f75418c40747f95b48526be9836d1c2cdfc1e | wikidoc | COTL1 | COTL1
Coactosin-like protein (COTL1 or CLP) is a protein that in humans is encoded by the COTL1 gene.
# Function
This gene encodes one of the numerous actin-binding proteins which regulate the actin cytoskeleton. This protein binds F-actin, and also interacts with and thereby stabilizes 5-lipoxygenase (ALOX5). Although this gene has been reported to map to chromosome 17 in the Smith-Magenis syndrome region, the best alignments for this gene are to chromosome 16. The Smith-Magenis syndrome region is the site of two related pseudogenes.
# Interactions
COTL1 has been shown to interact with ALOX5. ALOX5 is the first committed enzyme in the metabolism of arachidonic acid to an array of biologically important cell signaling agents: a) the pro-inflammatory mediator, leukotriene B4 (LTB4); b) the airways constrictors, LTC4, LTD4, and LTE4; c) the 5-hydroxyeicosatetraenoic acid family of pro-inflammatory and pro-allergic reactions mediators, 5-HETE and 5-oxo-eicosatetraenoic acid. ALOX5 also contributes to the metabolism of arachidonic acid and other polyunsaturated fatty acids to agents which act block inflammation and allergic reactions, the specialized pro-resolving mediators of the lipoxin and resolvin subclasses. Based on in vitro studies, COTL1 serves to stabilize ALOX5, acting as a chaperone or scaffold, to avert the enzyme's inactivation and thereby to promote its metabolic activity. | COTL1
Coactosin-like protein (COTL1 or CLP) is a protein that in humans is encoded by the COTL1 gene.[1][2][3][4]
# Function
This gene encodes one of the numerous actin-binding proteins which regulate the actin cytoskeleton. This protein binds F-actin, and also interacts with and thereby stabilizes 5-lipoxygenase (ALOX5). Although this gene has been reported to map to chromosome 17 in the Smith-Magenis syndrome region, the best alignments for this gene are to chromosome 16. The Smith-Magenis syndrome region is the site of two related pseudogenes.[4]
# Interactions
COTL1 has been shown to interact with ALOX5.[5] ALOX5 is the first committed enzyme in the metabolism of arachidonic acid to an array of biologically important cell signaling agents: a) the pro-inflammatory mediator, leukotriene B4 (LTB4); b) the airways constrictors, LTC4, LTD4, and LTE4; c) the 5-hydroxyeicosatetraenoic acid family of pro-inflammatory and pro-allergic reactions mediators, 5-HETE and 5-oxo-eicosatetraenoic acid. ALOX5 also contributes to the metabolism of arachidonic acid and other polyunsaturated fatty acids to agents which act block inflammation and allergic reactions, the specialized pro-resolving mediators of the lipoxin and resolvin subclasses. Based on in vitro studies, COTL1 serves to stabilize ALOX5, acting as a chaperone or scaffold, to avert the enzyme's inactivation and thereby to promote its metabolic activity.[6] | https://www.wikidoc.org/index.php/COTL1 | |
0991f11e93a0cf2f241332da29eea7ef90241c15 | wikidoc | PTGS1 | PTGS1
Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene. In humans it is one of two cyclooxygenases.
# History
Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was isolated more than 40 years ago and cloned in 1988.
# Gene and isozymes
There are two isozymes of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible COX-2, which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant cytokines and growth factors. This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis. A splice variant of COX-1 termed COX-3 was identified in the CNS of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.
# Function
Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase (dioxygenase) and hydroperoxidase (peroxidase) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such as linoleic acid and eicosapentaenoic acid. Metabolism of arachidonic acid forms a labile intermediate peroxide, PGG2, which is reduced to the corresponding alcohol, PGH2, by the enzyme’s hydroperoxidase activity.
While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as well as a small amount of 11(R)-HETE. The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, the lipoxins. In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of 12-Hydroxyheptadecatrienoic acids viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus Malonyldialdehyde. and can be metabolized by CYP2S1 to 12-HHT (see 12-Hydroxyheptadecatrienoic acid). These alternate metabolites of COX-1 may contribute to its activities.
COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content. COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.
# Clinical significance
COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Thromboxane A2, the major product of COX-1 in platelets, induces platelet aggregation. The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events. | PTGS1
Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene.[1][2] In humans it is one of two cyclooxygenases.
# History
Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was isolated more than 40 years ago and cloned in 1988.[3][4]
# Gene and isozymes
There are two isozymes of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible COX-2, which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant cytokines and growth factors.[5] This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis. A splice variant of COX-1 termed COX-3 was identified in the CNS of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.[6]
# Function
Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase (dioxygenase) and hydroperoxidase (peroxidase) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such as linoleic acid and eicosapentaenoic acid. Metabolism of arachidonic acid forms a labile intermediate peroxide, PGG2, which is reduced to the corresponding alcohol, PGH2, by the enzyme’s hydroperoxidase activity.
While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as well as a small amount of 11(R)-HETE.[7] The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, the lipoxins.[8] In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of 12-Hydroxyheptadecatrienoic acids viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus Malonyldialdehyde.[9][10][11] and can be metabolized by CYP2S1 to 12-HHT[12][13] (see 12-Hydroxyheptadecatrienoic acid). These alternate metabolites of COX-1 may contribute to its activities.
COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content.[14][15] COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.
# Clinical significance
COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Thromboxane A2, the major product of COX-1 in platelets, induces platelet aggregation.[16][17] The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events. | https://www.wikidoc.org/index.php/COX-1 | |
2069c0b8a5752748f6a9b34254247005c2350389 | wikidoc | COX10 | COX10
Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene. Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion.
# Structure
The COX10 gene is located on the p arm of chromosome 17 in position 12 and spans 139,277 base pairs. The gene produces a 48.9 kDa protein composed of 443 amino acids. This gene has an unusually long 3' untranslated region measuring 1426 base pairs, compared to a 1329 base pair open reading frame. The COX10 gene has 7 exons totaling 135 kilobases in length. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. There are hydrophilic loops between transmembrane domains II/III and VI/VII. This protein is considered a constituent of the mitochondrial inner membrane.
# Function
The protein encoded by COX10 is an assembly factor essential to COX synthesis, participating in the first step of the mitochondrial heme A biosynthetic pathway. It catalyzes the farnesylation of the vinyl group at position C2 of protoheme (heme B) and converts it to heme O.
# Clinical Significance
Mutations in the COX10 gene can result in numerous clinical phenotypes, from tubulopathy and leukodystrophy to Leigh syndrome to fatal infantile cardiomyopathy to a French Canadian form of Leigh Syndrome. A wide variety of symptoms encompassing the entire range of COX deficiency symptoms have been reported, including ataxia, hypotonia, ptosis, lactic acidosis, proximal tubulopathy, anemia, myopathy, hypertrophic cardiomyopathy, sensorineural hearing loss, and leukodystrophy.
In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion.
# Interactions
This protein interacts with FAM136A. | COX10
Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene.[1][2] Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion.[2]
# Structure
The COX10 gene is located on the p arm of chromosome 17 in position 12 and spans 139,277 base pairs.[2] The gene produces a 48.9 kDa protein composed of 443 amino acids.[3][4] This gene has an unusually long 3' untranslated region measuring 1426 base pairs, compared to a 1329 base pair open reading frame.[5] The COX10 gene has 7 exons totaling 135 kilobases in length.[6] This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane.[2] There are hydrophilic loops between transmembrane domains II/III and VI/VII.[7] This protein is considered a constituent of the mitochondrial inner membrane.[8]
# Function
The protein encoded by COX10 is an assembly factor essential to COX synthesis, participating in the first step of the mitochondrial heme A biosynthetic pathway. It catalyzes the farnesylation of the vinyl group at position C2 of protoheme (heme B) and converts it to heme O.[6][7]
# Clinical Significance
Mutations in the COX10 gene can result in numerous clinical phenotypes, from tubulopathy and leukodystrophy to Leigh syndrome to fatal infantile cardiomyopathy to a French Canadian form of Leigh Syndrome. A wide variety of symptoms encompassing the entire range of COX deficiency symptoms have been reported, including ataxia, hypotonia, ptosis, lactic acidosis, proximal tubulopathy, anemia, myopathy, hypertrophic cardiomyopathy, sensorineural hearing loss, and leukodystrophy.[7][9]
In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion.[2]
# Interactions
This protein interacts with FAM136A.[10] | https://www.wikidoc.org/index.php/COX10 | |
2cf9342d5df831d5cc2f8b8b608ea811ce2e664b | wikidoc | COX14 | COX14
Cytochrome c oxidase assembly factor COX14 is a protein that in humans is encoded by the COX14 gene. This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.
# Structure
The COX14 gene is located on the q arm of chromosome 12 at position 13.12 and it spans 8,476 base pairs. The COX14 gene produces a 6.6 kDa protein composed of 57 amino acids. COX14 is a component of the enzyme MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, and the structure contains a central transmembrane domain.
# Function
The COX14 gene encodes for a core protein component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, which is required for the proper regulation of complex IV assembly. Complex IV of the mitochondrial respiratory chain is essential in catalyzing the oxidation of cytochrome c by molecular oxygen. COX14 has been shown to contribute to the early stages of complex IV assembly by coelution with COX1 and COX4 for nucleation of the assembly. The protein participates in the coupling synthesis of COX1 followed by an assembly of nascent subunits into the holoenzyme complex IV. The knockdown of the protein COX14 involving small interfering RNA in regular human fibroblast has been shown to result in a complex IV defect with reduced activity.
# Clinical significance
Variants of COX14 have been associated with the mitochonrdial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain which catalyzes the oxidation of cytochrome c utilizing molecular oxygen. The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation.
A mutation in the homozygous missense mutation c.88G>A in the COX14 gene has resulted in the dysfunction of complex IV assembly and an unstable nascent enzyme complex.
# Interactions
Like COA3, COX14 is a key component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. In addition, it has interactions with proteins such as COX17, COX1, LMNA, COA3, SPPL2B, and others. | COX14
Cytochrome c oxidase assembly factor COX14 is a protein that in humans is encoded by the COX14 gene. This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.[1]
# Structure
The COX14 gene is located on the q arm of chromosome 12 at position 13.12 and it spans 8,476 base pairs.[1] The COX14 gene produces a 6.6 kDa protein composed of 57 amino acids.[2][3] COX14 is a component of the enzyme MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, and the structure contains a central transmembrane domain.[4]
# Function
The COX14 gene encodes for a core protein component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, which is required for the proper regulation of complex IV assembly. Complex IV of the mitochondrial respiratory chain is essential in catalyzing the oxidation of cytochrome c by molecular oxygen. COX14 has been shown to contribute to the early stages of complex IV assembly by coelution with COX1 and COX4 for nucleation of the assembly. The protein participates in the coupling synthesis of COX1 followed by an assembly of nascent subunits into the holoenzyme complex IV.[5][6][4] The knockdown of the protein COX14 involving small interfering RNA in regular human fibroblast has been shown to result in a complex IV defect with reduced activity.[4]
# Clinical significance
Variants of COX14 have been associated with the mitochonrdial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain which catalyzes the oxidation of cytochrome c utilizing molecular oxygen.[7][5][6] The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation.[8]
A mutation in the homozygous missense mutation c.88G>A in the COX14 gene has resulted in the dysfunction of complex IV assembly and an unstable nascent enzyme complex.[4]
# Interactions
Like COA3, COX14 is a key component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex.[9] In addition, it has interactions with proteins such as COX17, COX1, LMNA, COA3, SPPL2B, and others.[10][5] | https://www.wikidoc.org/index.php/COX14 | |
c1542f68f62cfbcd2647d864719ae1618ab5480a | wikidoc | COX15 | COX15
Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. COX15 is also part of a three-component mono-oxygenase (ferredoxin, ferredoxin reductase, and COX15) that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.
# Structure
## Gene
The COX15 gene lies on the chromosome location of 10q24 and consists of nine exons. Two splice variants formed by alternative splicing at exon 9, COX15.1 and COX15.2, differ in the C-terminal domain of the protein and the 39-UTR of the transcript. But the functional significance of the different isoforms is still unknown.
## Protein
The COX15 protein localizes to the inner mitochondrial membrane and has several predicted transmembrane domains. Four conserved histidine residues are proven to be critical for COX15 activity. Both COX15 multimerization and enzymatic activity would be impaired if the 20-residue linker region connecting the two conserved domains of COX15 is removed.
# Function
COX15 is one of the cytochrome c oxidase (COX) assembly factors identified in yeast, playing a key role in the biosynthetic pathway of mitochondrial heme A, the prosthetic group of cytochrome a and a3. COX15 in yeast mediates hydroxylation of the methyl group at the C-8 position of the heme O molecule to form heme A. A deletion of COX15 results in undetectable levels of heme A but detectable levels of heme O. Similar findings are observed in patients with COX15 deletion mutants, suggesting a similar functional role for COX15 in mammalian mitochondria and a similar pathogenesis for the COX deficiency. In complex IV of the respiratory chain, heme A is required for the proper folding of the Cox 1 subunit and subsequent assembly. A deficiency in the formation of heme A and functional COX would lead to impaired electron transport and oxidative phosphorylation. COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX.
# Clinical significance
COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, in highly energy-demanding organs and tissues, such as brain and retinal tissue, with mutations in COX15, different clinical phenotypes are presented, such as early onset, fatal hypertrophic cardiomyopathy, Leigh syndrome, and encephalopathy. Signs and symptoms of these diseases that can manifest include lactic acidosis, ataxia, hypotonia, seizures, respiratory distress, psychomotor retardation, vision loss, eye movement abnormalities, dysphagia, and central nervous system lesions. A sequence variation in COX15 has also been reported to associate with determining the genetic risk for Alzheimer’s disease development.
# Interactions
COX15 associates with Shy1 in distinct complexes, C-terminal epitope tagging of COX15 selectively affects its association to cytochrome c oxidase assembly intermediates (COA complexes). COX15 also forms complexes with maturing COX1, the heme-receiving subunit of COX, in the absence of Shy1. COX15 is positively regulated by intracellular heme levels via Huntingtin-associated protein 1. | COX15
Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene.[1][2] This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis.[3] COX15 is also part of a three-component mono-oxygenase (ferredoxin, ferredoxin reductase, and COX15) that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule.[3] Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.[4][5][6]
# Structure
## Gene
The COX15 gene lies on the chromosome location of 10q24 and consists of nine exons. Two splice variants formed by alternative splicing at exon 9, COX15.1 and COX15.2, differ in the C-terminal domain of the protein and the 39-UTR of the transcript. But the functional significance of the different isoforms is still unknown.[1]
## Protein
The COX15 protein localizes to the inner mitochondrial membrane and has several predicted transmembrane domains.[1][7] Four conserved histidine residues are proven to be critical for COX15 activity. Both COX15 multimerization and enzymatic activity would be impaired if the 20-residue linker region connecting the two conserved domains of COX15 is removed.[8]
# Function
COX15 is one of the cytochrome c oxidase (COX) assembly factors identified in yeast, playing a key role in the biosynthetic pathway of mitochondrial heme A, the prosthetic group of cytochrome a and a3. COX15 in yeast mediates hydroxylation of the methyl group at the C-8 position of the heme O molecule to form heme A. A deletion of COX15 results in undetectable levels of heme A but detectable levels of heme O. Similar findings are observed in patients with COX15 deletion mutants, suggesting a similar functional role for COX15 in mammalian mitochondria and a similar pathogenesis for the COX deficiency.[4] In complex IV of the respiratory chain, heme A is required for the proper folding of the Cox 1 subunit and subsequent assembly. A deficiency in the formation of heme A and functional COX would lead to impaired electron transport and oxidative phosphorylation.[9] COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX.[8]
# Clinical significance
COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, in highly energy-demanding organs and tissues, such as brain and retinal tissue, with mutations in COX15, different clinical phenotypes are presented, such as early onset, fatal hypertrophic cardiomyopathy,[4] Leigh syndrome, [6] and encephalopathy.[10] Signs and symptoms of these diseases that can manifest include lactic acidosis, ataxia, hypotonia, seizures, respiratory distress, psychomotor retardation, vision loss, eye movement abnormalities, dysphagia, and central nervous system lesions.[11][12] A sequence variation in COX15 has also been reported to associate with determining the genetic risk for Alzheimer’s disease development.[13]
# Interactions
COX15 associates with Shy1 in distinct complexes, C-terminal epitope tagging of COX15 selectively affects its association to cytochrome c oxidase assembly intermediates (COA complexes). COX15 also forms complexes with maturing COX1, the heme-receiving subunit of COX, in the absence of Shy1.[14] COX15 is positively regulated by intracellular heme levels via Huntingtin-associated protein 1.[15] | https://www.wikidoc.org/index.php/COX15 | |
4261710dcd143c1f2d58fcde4de0db8213d1df5c | wikidoc | COX20 | COX20
Cytochrome c oxidase assembly factor COX20 is a protein that in humans is encoded by the COX20 gene.This gene encodes a protein that plays a role in the assembly of cytochrome c oxidase, an important component of the respiratory pathway. Mutations in this gene can cause mitochondrial complex IV deficiency. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants.
# Structure
The COX20 gene is located on the q arm of chromosome 1 at position 44 and it spans 9,757 base pairs. The COX20 gene produces a 13.3 kDa protein composed of 118 amino acids. It contains two transmembrane helices and localizes to the mitochondrial membrane.
# Function
The COX20 gene encodes for a protein required for the assembly of cytochrome c oxidase(complex IV). Complex IV is the terminal complex of the mitochondrial respiratory chain which is required for catalyzing the oxidation of cytochrome c by molecular oxygen. COX20 is known to act as a chaperone protein during the early stages of COX2 (cytochrome c oxidase subunit II) maturation which leads to the stabilization of the protein. By presenting COX2 to the metallochaperones SCO1 and SCO2, they help facilitate the incorporation of the mature COX2 into the complex IV holoenzyme assembly. However, it has been known that COX20 has no influence on transcription or translation of COX2 or any other genes. The knockdown of the protein COX20 has been shown to result in reduced respiratory capacity and the accumulation of respiratory chain intermediates]].
# Clinical significance
Variants of COX20 have been associated with the mitochonrdial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain which catalyzes the oxidation of cytochrome c utilizing molecular oxygen. The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. A homozygous mutation of c.154A-C in the COX20 gene has been found to result in reduced COX20, cytochrome c oxidase, and decreased activity. Other mutations have included a homozygous T52P.
# Interactions
COX20 has co-complex interactions with proteins such as TMEM177, COX2, SCO1, COA6, and others in a COX2 and COX18 dependent manner. | COX20
Cytochrome c oxidase assembly factor COX20 is a protein that in humans is encoded by the COX20 gene.This gene encodes a protein that plays a role in the assembly of cytochrome c oxidase, an important component of the respiratory pathway. Mutations in this gene can cause mitochondrial complex IV deficiency. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants.[1]
# Structure
The COX20 gene is located on the q arm of chromosome 1 at position 44 and it spans 9,757 base pairs.[1] The COX20 gene produces a 13.3 kDa protein composed of 118 amino acids.[2][3] It contains two transmembrane helices and localizes to the mitochondrial membrane.[1]
# Function
The COX20 gene encodes for a protein required for the assembly of cytochrome c oxidase(complex IV). Complex IV is the terminal complex of the mitochondrial respiratory chain which is required for catalyzing the oxidation of cytochrome c by molecular oxygen.[4] COX20 is known to act as a chaperone protein during the early stages of COX2 (cytochrome c oxidase subunit II) maturation which leads to the stabilization of the protein. By presenting COX2 to the metallochaperones SCO1 and SCO2, they help facilitate the incorporation of the mature COX2 into the complex IV holoenzyme assembly.[4][5][6] However, it has been known that COX20 has no influence on transcription or translation of COX2 or any other genes.[4] The knockdown of the protein COX20 has been shown to result in reduced respiratory capacity and the accumulation of respiratory chain intermediates]].[7]
# Clinical significance
Variants of COX20 have been associated with the mitochonrdial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain which catalyzes the oxidation of cytochrome c utilizing molecular oxygen.[8] The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation.[9][5][6] A homozygous mutation of c.154A-C in the COX20 gene has been found to result in reduced COX20, cytochrome c oxidase, and decreased activity.[4] Other mutations have included a homozygous T52P.[10]
# Interactions
COX20 has co-complex interactions with proteins such as TMEM177, COX2, SCO1, COA6, and others in a COX2 and COX18 dependent manner.[11][5][6] | https://www.wikidoc.org/index.php/COX20 | |
b2000a5ea43375c6388d461554f18ba143be366c | wikidoc | COX5A | COX5A
Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.
# Structure
The COX5A gene, located on the q arm of chromosome 15 in position 24.1, is made up of 5 exons and is 17,880 base pairs in length. The COX5A protein weighs 17 kDa and is composed of 150 amino acids. The protein is a subunit of Complex IV, which consists of 13 mitochondrial- and nuclear-encoded subunits.
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.
Summary reaction:
# Clinical significance
COX5A (this gene) and COX5B are involved in the regulation of cancer cell metabolism by Bcl-2. COX5A interacts specifically with Bcl-2, but not with other members of the Bcl-2 family, such as Bcl-xL, Bax or Bak.
The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples. | COX5A
Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.[1]
# Structure
The COX5A gene, located on the q arm of chromosome 15 in position 24.1, is made up of 5 exons and is 17,880 base pairs in length.[1] The COX5A protein weighs 17 kDa and is composed of 150 amino acids.[2][3] The protein is a subunit of Complex IV, which consists of 13 mitochondrial- and nuclear-encoded subunits.[1]
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.[1]
Summary reaction:
# Clinical significance
COX5A (this gene) and COX5B are involved in the regulation of cancer cell metabolism by Bcl-2. COX5A interacts specifically with Bcl-2, but not with other members of the Bcl-2 family, such as Bcl-xL, Bax or Bak.[5]
The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples.[6] | https://www.wikidoc.org/index.php/COX5A | |
424db27a47bfe062fdbc08919e9a3f46ac5c7665 | wikidoc | COX5B | COX5B
Cytochrome c oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. In humans, cytochrome c oxidase subunit 5B is encoded by the COX5B gene.
# Structure
The enzyme weighs 14 kDa and is composed of 129 amino acids. The protein is a subunit of Complex IV, which consists of 13 mitochondrial- and nuclear-encoded subunits. The sequence of subunit Vb is well conserved and includes three conserved cysteines that coordinate the zinc ion. Two of these cysteines are clustered in the C-terminal section of the subunit.
# Gene
The COX5B gene, located on the q arm of chromosome 2 in position 11.2, is made up of 4 exons and is 2,137 base pairs in length.
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.
Summary reaction:
# Clinical significance
COX5A and COX5B are involved in the regulation of cancer cell metabolism by Bcl-2.
The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples.
# Interactions
COX5B has been shown to interact with Androgen receptor. | COX5B
Cytochrome c oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.[2] In humans, cytochrome c oxidase subunit 5B is encoded by the COX5B gene.
# Structure
The enzyme weighs 14 kDa and is composed of 129 amino acids.[3][4] The protein is a subunit of Complex IV, which consists of 13 mitochondrial- and nuclear-encoded subunits.[2] The sequence of subunit Vb is well conserved and includes three conserved cysteines that coordinate the zinc ion.[5][6] Two of these cysteines are clustered in the C-terminal section of the subunit.
# Gene
The COX5B gene, located on the q arm of chromosome 2 in position 11.2, is made up of 4 exons and is 2,137 base pairs in length.[2]
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive ATP synthesis via protonmotive force. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.[2]
Summary reaction:
# Clinical significance
COX5A and COX5B are involved in the regulation of cancer cell metabolism by Bcl-2.[8]
The Trans-activator of transcription protein (Tat) of human immunodeficiency virus (HIV) inhibits cytochrome c oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples.[9]
# Interactions
COX5B has been shown to interact with Androgen receptor.[10] | https://www.wikidoc.org/index.php/COX5B | |
8e4412bc298d01bd622d84a25b7deb4c9beac357 | wikidoc | COX7B | COX7B
Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene. COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase (complex IV) is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.
# Structure
COX7B is located on the q arm of the X chromosome in position 21.1 and has 3 exons. The COX7B gene produces a 9.2 kDa protein composed of 80 amino acids. COX7B is one of the nuclear-encoded polypeptide chains of cytochrome c oxidase (COX), a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The protein encoded by COX7B belongs to the cytochrome c oxidase VIIb family. COX7B has a 24 amino acid transit peptide domain from positions 1-24, an 8 amino acid topological mitochondrial matrix domain from positions 25-32, a helical, 27 amino acid transmembrane domain from positions 33-59, and a 21 amino acid topological intermembrane domain from positions 60-80. COX7B may also have several pseudogenes on chromosomes 1, 2, 20 and 22.
# Function
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. The mitochondrially-encoded subunits of COX function in electron transfer, while the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. The COX7B nuclear gene encodes subunit 7B, which is located on the inner mitochondrial membrane in association with several other proteins encompassing the COX complex. It is found in all tissues and has been shown to be highly similar to bovine COX VIIb protein. COX7B is believed to be important for COX assembly and activity, the function of mitochondrial respiratory chain, and the proper development of the central nervous system in vertebrates.
# Model organisms
Oryzias latices (also known as medaka) is a Japanese rice fish that has been used as a model organism in COX7B studies. By using a morpholino knockdown technique, COX7B has been shown to be indispensable for COX assembly, COX activity, and mitochondrial respiration. Additionally, the down-regulation of an ortholog of COX7B has suggested that there may be an association between COX7B disfunction and microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Work with Oryzias latices could also indicate an evolutionary conserved role for the mitochondrial respiratory chain complexes in central nervous system development.
# Clinical significance
Mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies. This disorder is a distinct form of aplasia cutis congenita presenting as multiple linear skin defects on the face and neck associated with poor growth and short stature, microcephaly, and facial dysmorphism. Additional clinical features include intellectual disability, nail dystrophy, cardiac abnormalities, diaphragmatic hernia, genitourinary abnormalities, pale optic discs and altered visual-evoked potentials, agenesis of the corpus callosum, and other central nervous system abnormalities. The COX7B mutations associated with disease include c.196delC, a heterozygous mutation leading to a frameshift in exon 3, c.41-2A>G, a heterozygous splice mutation in a novel acceptor site in intron 1, and c.55C>T, a heterozygous nonsense mutation in exon 2. Additionally, experiments with Oryzias latices suggest COX7B may be associated with microphthalmia with linear skin lesions (MLS), an X-linked, dominant, male-lethal mitochondrial disorder.
# Interactions
COX7B has been shown to have 6 binary protein-protein interactions including 3 co-complex interactions. GNMT, MYB, MT-CO1, HSCB, and SLC25A13 have all been found to interact with COX7B. | COX7B
Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene.[1] COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase (complex IV) is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain.[2] Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.[3]
# Structure
COX7B is located on the q arm of the X chromosome in position 21.1 and has 3 exons.[2] The COX7B gene produces a 9.2 kDa protein composed of 80 amino acids.[4][5] COX7B is one of the nuclear-encoded polypeptide chains of cytochrome c oxidase (COX), a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The protein encoded by COX7B belongs to the cytochrome c oxidase VIIb family. COX7B has a 24 amino acid transit peptide domain from positions 1-24, an 8 amino acid topological mitochondrial matrix domain from positions 25-32, a helical, 27 amino acid transmembrane domain from positions 33-59, and a 21 amino acid topological intermembrane domain from positions 60-80.[6][7][8][3] COX7B may also have several pseudogenes on chromosomes 1, 2, 20 and 22.[2]
# Function
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. The mitochondrially-encoded subunits of COX function in electron transfer, while the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. The COX7B nuclear gene encodes subunit 7B, which is located on the inner mitochondrial membrane in association with several other proteins encompassing the COX complex. It is found in all tissues and has been shown to be highly similar to bovine COX VIIb protein.[2] COX7B is believed to be important for COX assembly and activity, the function of mitochondrial respiratory chain, and the proper development of the central nervous system in vertebrates.[3][6][7]
# Model organisms
Oryzias latices (also known as medaka) is a Japanese rice fish that has been used as a model organism in COX7B studies. By using a morpholino knockdown technique, COX7B has been shown to be indispensable for COX assembly, COX activity, and mitochondrial respiration. Additionally, the down-regulation of an ortholog of COX7B has suggested that there may be an association between COX7B disfunction and microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Work with Oryzias latices could also indicate an evolutionary conserved role for the mitochondrial respiratory chain complexes in central nervous system development.[3]
# Clinical significance
Mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies. This disorder is a distinct form of aplasia cutis congenita presenting as multiple linear skin defects on the face and neck associated with poor growth and short stature, microcephaly, and facial dysmorphism. Additional clinical features include intellectual disability, nail dystrophy, cardiac abnormalities, diaphragmatic hernia, genitourinary abnormalities, pale optic discs and altered visual-evoked potentials, agenesis of the corpus callosum, and other central nervous system abnormalities.[6][7] The COX7B mutations associated with disease include c.196delC, a heterozygous mutation leading to a frameshift in exon 3, c.41-2A>G, a heterozygous splice mutation in a novel acceptor site in intron 1, and c.55C>T, a heterozygous nonsense mutation in exon 2. Additionally, experiments with Oryzias latices suggest COX7B may be associated with microphthalmia with linear skin lesions (MLS), an X-linked, dominant, male-lethal mitochondrial disorder.[3]
# Interactions
COX7B has been shown to have 6 binary protein-protein interactions including 3 co-complex interactions. GNMT, MYB, MT-CO1, HSCB, and SLC25A13 have all been found to interact with COX7B.[9] | https://www.wikidoc.org/index.php/COX7B | |
37f71148cef8b3fc93aea9db801ae786e6cc2a3a | wikidoc | COX8A | COX8A
Cytochrome c oxidase subunit 8A (COX8A) is a protein that in humans is encoded by the COX8A gene. Cytochrome c oxidase 8A is a subunit of the cytochrome c oxidase complex, also known as Complex IV. Mutations in the COX8A gene have been associated with complex IV deficiency with Leigh syndrome and epilepsy.
# Structure
COX8A is a 7.6 kDa protein composed of 69 amino acids. This gene encodes the nuclear-encoded subunit 8A of the human mitochondrial respiratory chain enzyme complex cytochrome c oxidase. The complex consists of 13 mitochondrial- and nuclear-encoded subunits.
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.
# Clinical significance
COX8A is a subunit of cytochrome c oxidase and its function is important for the efficacy of complex IV. Mutations in COX8A can affect complex IV of the electron transport chain, resulting in complex IV deficiency. This disorder can have a wide range of clinical manifestations including Leigh syndrome, leukodystrophy, and severe epilepsy.
# Interactions
COX8A has been shown to have 19 binary protein-protein interactions including 7 co-complex interactions. COX8A appears to interact with NPM1, MAGEA4, EDDM3B, BATF, AMBP, CREB1, and NCOR1. | COX8A
Cytochrome c oxidase subunit 8A (COX8A) is a protein that in humans is encoded by the COX8A gene.[1] Cytochrome c oxidase 8A is a subunit of the cytochrome c oxidase complex, also known as Complex IV. Mutations in the COX8A gene have been associated with complex IV deficiency with Leigh syndrome and epilepsy.[2]
# Structure
COX8A is a 7.6 kDa protein composed of 69 amino acids.[3][4] This gene encodes the nuclear-encoded subunit 8A of the human mitochondrial respiratory chain enzyme complex cytochrome c oxidase. The complex consists of 13 mitochondrial- and nuclear-encoded subunits.[1]
# Function
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex.[1]
# Clinical significance
COX8A is a subunit of cytochrome c oxidase and its function is important for the efficacy of complex IV. Mutations in COX8A can affect complex IV of the electron transport chain, resulting in complex IV deficiency. This disorder can have a wide range of clinical manifestations including Leigh syndrome, leukodystrophy, and severe epilepsy.[2]
# Interactions
COX8A has been shown to have 19 binary protein-protein interactions including 7 co-complex interactions. COX8A appears to interact with NPM1, MAGEA4, EDDM3B, BATF, AMBP, CREB1, and NCOR1.[5] | https://www.wikidoc.org/index.php/COX8A | |
c3c1f2eea9e45e19906d2000e9a0f390f276c9ca | wikidoc | CRADD | CRADD
Death domain-containing protein CRADD is a protein that in humans is encoded by the CRADD gene.
# Function
The protein encoded by this gene is a death domain (CARD/DD)-containing protein and has been shown to induce cell apoptosis. Through its CARD domain, this protein interacts with, and thus recruits, caspase 2/ICH1 to the cell death signal transduction complex that includes tumor necrosis factor receptor 1 (TNFR1A), RIPK1/RIP kinase, and numbers of other CARD domain-containing proteins.
# Interactions
CRADD has been shown to interact with RIPK1 and Caspase 2. | CRADD
Death domain-containing protein CRADD is a protein that in humans is encoded by the CRADD gene.[1][2][3]
# Function
The protein encoded by this gene is a death domain (CARD/DD)-containing protein and has been shown to induce cell apoptosis. Through its CARD domain, this protein interacts with, and thus recruits, caspase 2/ICH1 to the cell death signal transduction complex that includes tumor necrosis factor receptor 1 (TNFR1A), RIPK1/RIP kinase, and numbers of other CARD domain-containing proteins.[3]
# Interactions
CRADD has been shown to interact with RIPK1[1][2] and Caspase 2.[1][4][5] | https://www.wikidoc.org/index.php/CRADD | |
142ed5b25685a93638c694f1de9f3c168b88e989 | wikidoc | CRIM1 | CRIM1
Cysteine-rich motor neuron 1 protein is a protein that in humans is encoded by the CRIM1 gene.
# Function
Motor neurons are among the earliest neurons to appear after the commencement of cell patterning and the beginning of cell differentiation. Differentiation occurs in a ventral-to-dorsal gradient and is mediated, at least in part, by the concentration of ventrally expressed sonic hedgehog protein (SHH; MIM 600725). Dorsally expressed factors, such as members of the bone morphogenic protein (e.g., BMP4; MIM 112262) and transforming growth factor-beta (e.g., TGFB1; MIM 190180) families, can repress the induction of these neurons. CRIM1 may interact with growth factors implicated in motor neuron differentiation and survival.
# Clinical significance
Loss of Crim1 function as demonstrated by the Crim1 KST264 hypomorph mice resulted in onset of chronic kidney disease with accompanying pathology including papillary hypoplasia, functional urinary tract obstruction, ectopic collagen accumulation within the endothelium and tubulointerstitial fibrosis which was in part attributed by (endothelial) epithelial–mesenchymal transition. | CRIM1
Cysteine-rich motor neuron 1 protein is a protein that in humans is encoded by the CRIM1 gene.[1][2]
# Function
Motor neurons are among the earliest neurons to appear after the commencement of cell patterning and the beginning of cell differentiation. Differentiation occurs in a ventral-to-dorsal gradient and is mediated, at least in part, by the concentration of ventrally expressed sonic hedgehog protein (SHH; MIM 600725). Dorsally expressed factors, such as members of the bone morphogenic protein (e.g., BMP4; MIM 112262) and transforming growth factor-beta (e.g., TGFB1; MIM 190180) families, can repress the induction of these neurons. CRIM1 may interact with growth factors implicated in motor neuron differentiation and survival.[1][2]
# Clinical significance
Loss of Crim1 function as demonstrated by the Crim1 KST264 hypomorph mice resulted in onset of chronic kidney disease with accompanying pathology including papillary hypoplasia, functional urinary tract obstruction, ectopic collagen accumulation within the endothelium and tubulointerstitial fibrosis which was in part attributed by (endothelial) epithelial–mesenchymal transition.[3][4] | https://www.wikidoc.org/index.php/CRIM1 | |
f13534485e234196a101afa2f5e6533c52d06d27 | wikidoc | CRLF1 | CRLF1
Cytokine receptor-like factor 1 is a protein that in humans is encoded by the CRLF1 gene.
# Function
This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells.
# Clinical significance
Mutations in this gene are associated with two conditions, both rare:
- Cold-induced sweating syndrome, characterized by profuse hyperhidrosis in cold environmental temperature and characteristic craniofacial and skeletal features)
- Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions, abnormal function of the autonomic nervous system and craniofacial and skeletal manifestations such as thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip and a small mouth.
It is unknown whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions.
Other characteristic features in CRLF1 mutation include marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a nose with hypoplastic nares, malar hypoplasia and prognathism. | CRLF1
Cytokine receptor-like factor 1 is a protein that in humans is encoded by the CRLF1 gene.[1][2]
# Function
This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells.[2]
# Clinical significance
Mutations in this gene are associated with two conditions, both rare:
- Cold-induced sweating syndrome, characterized by profuse hyperhidrosis in cold environmental temperature and characteristic craniofacial and skeletal features)[3][4]
- Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions, abnormal function of the autonomic nervous system and craniofacial and skeletal manifestations such as thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip and a small mouth.[3]
It is unknown whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions.[3]
Other characteristic features in CRLF1 mutation include marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a nose with hypoplastic nares, malar hypoplasia and prognathism.[3] | https://www.wikidoc.org/index.php/CRLF1 | |
8ab6bbedf14f1fc88a161b6bd8a8fc428395f9e5 | wikidoc | CRMP1 | CRMP1
Collapsin response mediator protein 1, encoded by the CRMP1 gene, is a human protein of the CRMP family.
This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants.
CRMP1 mediates reelin signaling in cortical neuronal migration. Mice deficient in CRMP1 exhibit impaired long-term potentiation and impaired spatial learning and memory.
CRMP1 gene overlaps with another gene called EVC.
# Interactions
CRMP1 has been shown to interact with DPYSL2. | CRMP1
Collapsin response mediator protein 1, encoded by the CRMP1 gene, is a human protein of the CRMP family.[1]
This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants.[1]
CRMP1 mediates reelin signaling in cortical neuronal migration.[2] Mice deficient in CRMP1 exhibit impaired long-term potentiation and impaired spatial learning and memory.[3]
CRMP1 gene overlaps with another gene called EVC.[4]
# Interactions
CRMP1 has been shown to interact with DPYSL2.[5] | https://www.wikidoc.org/index.php/CRMP1 | |
b6c89c1e48693c9ba61a5338c4a98e2f7599f91d | wikidoc | CRSP3 | CRSP3
Mediator of RNA polymerase II transcription subunit 23 is an enzyme that in humans is encoded by the MED23 gene.
# Function
The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.
# Interactions
CRSP3 has been shown to interact with Estrogen receptor alpha, CEBPB and Cyclin-dependent kinase 8. | CRSP3
Mediator of RNA polymerase II transcription subunit 23 is an enzyme that in humans is encoded by the MED23 gene.[1][2]
# Function
The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene.[2]
# Interactions
CRSP3 has been shown to interact with Estrogen receptor alpha,[3] CEBPB[4] and Cyclin-dependent kinase 8.[3][5] | https://www.wikidoc.org/index.php/CRSP3 | |
98d2af4b25fabc406a48aca45daefc6787012a73 | wikidoc | CRTC1 | CRTC1
CREB-regulated transcription coactivator 1 (CRTC1), previously referred to as TORC1 (Transducer Of Regulated CREB activity 1), is a protein that in humans is encoded by the CRTC1 gene. It is expressed in a limited number of tissues that include fetal brain and liver and adult heart, skeletal muscles, liver and salivary glands and various regions of the adult central nervous system.
# Clinical significance
Production of CRTC1 is blocked in Alzheimer's disease.
TORC1 might be the target protein in ketamin induced anti-depressent effect via NMDA-antagonisation.
The TORC1 inhibitor drugs dactolisib and everolimus, are being investigated to determine if they can boost the immunity of elderly patients. | CRTC1
CREB-regulated transcription coactivator 1 (CRTC1), previously referred to as TORC1 (Transducer Of Regulated CREB activity 1), is a protein that in humans is encoded by the CRTC1 gene.[1][2][3][4] It is expressed in a limited number of tissues that include fetal brain and liver and adult heart, skeletal muscles, liver and salivary glands[5] and various regions of the adult central nervous system.[6]
# Clinical significance
Production of CRTC1 is blocked in Alzheimer's disease.[7]
TORC1 might be the target protein in ketamin induced anti-depressent effect via NMDA-antagonisation.
The TORC1 inhibitor drugs dactolisib and everolimus, are being investigated to determine if they can boost the immunity of elderly patients.[8] | https://www.wikidoc.org/index.php/CRTC1 | |
875f1f37b491ec18271814c9da92c98aa1f8ebc4 | wikidoc | CRYAA | CRYAA
Alpha-crystallin A chain is a protein that in humans is encoded by the CRYAA gene.
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (sHSP also known as the HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC).
# Interactions
CRYAA has been shown to interact with CRYBB2, Hsp27, CRYGC and CRYAB. | CRYAA
Alpha-crystallin A chain is a protein that in humans is encoded by the CRYAA gene.[1]
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (sHSP also known as the HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC).[1]
# Interactions
CRYAA has been shown to interact with CRYBB2,[2] Hsp27,[2] CRYGC[2] and CRYAB.[2] | https://www.wikidoc.org/index.php/CRYAA | |
ee512614663ed7c998bc1bf1e86518ff4ef46bab | wikidoc | CRYGC | CRYGC
Crystallin, gamma C, also known as CRYGC, is a protein which in humans is encoded by the CRYGC gene.
# Function
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation.
# Interactions
CRYGC has been shown to interact with CRYBB2, CRYAA and CRYAB. | CRYGC
Crystallin, gamma C, also known as CRYGC, is a protein which in humans is encoded by the CRYGC gene.[1][2]
# Function
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation.[2]
# Interactions
CRYGC has been shown to interact with CRYBB2,[3] CRYAA[3] and CRYAB.[3] | https://www.wikidoc.org/index.php/CRYGC | |
adadb027d12ddee1c358670db120bd70801a3ef0 | wikidoc | CRYGS | CRYGS
Gamma-crystallin S is a protein that in humans is encoded by the CRYGS gene.
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins.
Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. This gene encodes a protein initially considered to be a beta-crystallin but the encoded protein is monomeric and has greater sequence similarity to other gamma-crystallins. This gene encodes the most significant gamma-crystallin in adult eye lens tissue.
Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. | CRYGS
Gamma-crystallin S is a protein that in humans is encoded by the CRYGS gene.[1]
Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins.
Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. This gene encodes a protein initially considered to be a beta-crystallin but the encoded protein is monomeric and has greater sequence similarity to other gamma-crystallins. This gene encodes the most significant gamma-crystallin in adult eye lens tissue.
Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation.[1] | https://www.wikidoc.org/index.php/CRYGS |
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