id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
d014052673be3872abcdc093805f908701018087 | wikidoc | CCNF | CCNF
G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.
# Function
This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified.
# Discovery and gene/protein characteristics
CCNF gene was first discovered in 1994 by Elledge laboratory while experimenting with Saccharomyces cerevisiae. At the same time, the Frischauf laboratory also identified cyclin F as a new cyclin during their search for new candidate genes for polycystic kidney. CCNF gene has 17 exons and is located at position 16p13.3 on the human chromosome. Its protein, cyclin F, is made up of 786 amino acids and has a predicted molecular weight of 87 kDa. Cyclin F is the main member of the F-box protein family, which has about 40 amino acid motif, forming the F-box.
Cyclin F resembles most to cyclin A in terms of sequence and expression patterns. Moreover, it has additional shared features of cyclins, such as pEST region, protein quantity, localization, cell cycle-regulated mRNA, and ability to influence cell cycle and progression. Cyclin F differs from other cyclins by its ability to monitor and regulate cell cycle without the need for cyclin-dependent kinases (CDKs). Instead, cyclin F forms part of the ubiquitin-proteosome system (UPS) and ubiquitinates or directly interacts with the target substrates through the F-box domain.
# Expression patterns
Cyclin F mRNA is expressed in all human tissues, but at different quantities. It is found most abundantly in the nucleus, and the quantity levels vary during the different stages of cell cycle. Its expression pattern closely resembles the one from cyclin A. Cyclin F levels begin to rise during S phase and reaches its peak during G2.
# Role in DNA synthesis and repair
Cyclin F interacts with other enzymes that are important for DNA synthesis, stability and repair.
## RRM2
RRM2 is a ribonucleotide reductase (RNR), an enzyme responsible for the conversion of ribonucleotides into dNTPs. dNTPs are essential for DNA synthesis during DNA replication and repair. Cyclin F interacts with RRM2 to control the production of dNTPs in the cell to avoid genomic instability and frequency of mutations.
## CP110
Moreover, cyclin F located at the centrosomes are needed to regulate levels of CP110, a protein involved in centrosome duplication. The regulation of CP110 during G2, through ubiquitin mediated proteolysis, helps to prevent mitotic aberrations. by allowing only one centrosome replication per cell cycle.
## NuSAP
NuSAP is a substrate of cyclin F that is involved in cell division. It is a microtubule-associated protein that is required for the spindle assembly process. Its function is to interact with microtubules and chromatin to create stabilization and cross-linking. A lack of NuSAP has been linked with an increase in mutations due to impaired chromosome alignment during metaphase, while an excess of NuSAP leads to mitotic arrest and microtubule bundling. Cyclin F help to control NUSAP abundance and is therefore essential to proper cell division.
Therefore, a defective cyclin F may contribute to hypermutator phenotype and chromosomal instability through RRM2, CP110, and NuSAP pathways.
# Clinical significance
## Neurodegenerative diseases
CCNF mutations have more recently been associated to neurodegenerative diseases such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and co-morbid ALS-FTD. Whole-genome linkage analysis and genome sequencing identified CCNF to be linked to both familial and sporadic ALS patients. In vitro and in vivo studies using ALS-linked mutations in CCNF were also carried out. It was found that certain CCNF mutations caused increased ubiquitination of TDP-43 protein in cells, which is a major feature of ALS and FTD pathology. In zebrafish, mutant CCNF fish showed motor neuron axonopathy and reduced motor response.
## Cancer
Cyclin F has a tumor suppressor role because normal expression is involved in cell cycle regulation by inducing G2 arrest and preventing mitosis. Moreover, cyclin F through RRM2 and CP110 control centrosome duplication and reduce the frequency of genomic mutations. So far, mutations in CCNF and increased RRM2 expression have been identified in several human cancers. | CCNF
G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.[1][2]
# Function
This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified.[2]
# Discovery and gene/protein characteristics
CCNF gene was first discovered in 1994 by Elledge laboratory while experimenting with Saccharomyces cerevisiae.[3] At the same time, the Frischauf laboratory also identified cyclin F as a new cyclin during their search for new candidate genes for polycystic kidney.[4] CCNF gene has 17 exons and is located at position 16p13.3 on the human chromosome.[3] Its protein, cyclin F, is made up of 786 amino acids and has a predicted molecular weight of 87 kDa.[3] Cyclin F is the main member of the F-box protein family, which has about 40 amino acid motif, forming the F-box.[3]
Cyclin F resembles most to cyclin A in terms of sequence and expression patterns.[3] Moreover, it has additional shared features of cyclins, such as pEST region, protein quantity, localization, cell cycle-regulated mRNA, and ability to influence cell cycle and progression.[3] Cyclin F differs from other cyclins by its ability to monitor and regulate cell cycle without the need for cyclin-dependent kinases (CDKs).[5] Instead, cyclin F forms part of the ubiquitin-proteosome system (UPS) and ubiquitinates or directly interacts with the target substrates through the F-box domain.[5]
# Expression patterns
Cyclin F mRNA is expressed in all human tissues, but at different quantities.[3] It is found most abundantly in the nucleus, and the quantity levels vary during the different stages of cell cycle.[3] Its expression pattern closely resembles the one from cyclin A. Cyclin F levels begin to rise during S phase and reaches its peak during G2.[3]
# Role in DNA synthesis and repair
Cyclin F interacts with other enzymes that are important for DNA synthesis, stability and repair.
## RRM2
RRM2 is a ribonucleotide reductase (RNR), an enzyme responsible for the conversion of ribonucleotides into dNTPs. dNTPs are essential for DNA synthesis during DNA replication and repair.[6] Cyclin F interacts with RRM2 to control the production of dNTPs in the cell to avoid genomic instability and frequency of mutations.[7]
## CP110
Moreover, cyclin F located at the centrosomes are needed to regulate levels of CP110, a protein involved in centrosome duplication.[8] The regulation of CP110 during G2, through ubiquitin mediated proteolysis, helps to prevent mitotic aberrations.[8] by allowing only one centrosome replication per cell cycle.
## NuSAP
NuSAP is a substrate of cyclin F that is involved in cell division.[9] It is a microtubule-associated protein that is required for the spindle assembly process.[10] Its function is to interact with microtubules and chromatin to create stabilization and cross-linking.[10] A lack of NuSAP has been linked with an increase in mutations due to impaired chromosome alignment during metaphase, while an excess of NuSAP leads to mitotic arrest and microtubule bundling.[11] Cyclin F help to control NUSAP abundance and is therefore essential to proper cell division.
Therefore, a defective cyclin F may contribute to hypermutator phenotype and chromosomal instability through RRM2, CP110, and NuSAP pathways.
# Clinical significance
## Neurodegenerative diseases
CCNF mutations have more recently been associated to neurodegenerative diseases such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and co-morbid ALS-FTD.[12][13] Whole-genome linkage analysis and genome sequencing identified CCNF to be linked to both familial and sporadic ALS patients.[12] In vitro and in vivo studies using ALS-linked mutations in CCNF were also carried out. It was found that certain CCNF mutations caused increased ubiquitination of TDP-43 protein in cells, which is a major feature of ALS and FTD pathology.[12] In zebrafish, mutant CCNF fish showed motor neuron axonopathy and reduced motor response.[14]
## Cancer
Cyclin F has a tumor suppressor role because normal expression is involved in cell cycle regulation by inducing G2 arrest and preventing mitosis.[15] Moreover, cyclin F through RRM2 and CP110 control centrosome duplication and reduce the frequency of genomic mutations.[5] So far, mutations in CCNF and increased RRM2 expression have been identified in several human cancers.[16] | https://www.wikidoc.org/index.php/CCNF | |
b227c87737d4111638d797675196f233ca8e91c5 | wikidoc | CCR1 | CCR1
C-C chemokine receptor type 1 is a protein that in humans is encoded by the CCR1 gene.
CCR1 has also recently been designated CD191 (cluster of differentiation 191).
# Function
This gene encodes a member of the beta chemokine receptor family, which belongs to G protein-coupled receptors. The ligands of this receptor include CCL3 (or MIP-1 alpha), CCL5 (or RANTES), CCL7 (or MCP-3), and CCL23 (or MPIF-1). Chemokines and their receptors, which mediate signal transduction, are critical for the recruitment of effector immune cells to the site of inflammation. Knockout studies of the mouse homolog suggested the roles of this gene in host protection from inflammatory response, and susceptibility to virus and parasite. This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CXCR1, are found to form a gene cluster on chromosome 3p.
# Interactions
CCR1 has been shown to interact with CCL5. | CCR1
C-C chemokine receptor type 1 is a protein that in humans is encoded by the CCR1 gene.[1]
CCR1 has also recently been designated CD191 (cluster of differentiation 191).
# Function
This gene encodes a member of the beta chemokine receptor family, which belongs to G protein-coupled receptors. The ligands of this receptor include CCL3 (or MIP-1 alpha), CCL5 (or RANTES), CCL7 (or MCP-3), and CCL23 (or MPIF-1). Chemokines and their receptors, which mediate signal transduction, are critical for the recruitment of effector immune cells to the site of inflammation. Knockout studies of the mouse homolog suggested the roles of this gene in host protection from inflammatory response, and susceptibility to virus and parasite. This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CXCR1, are found to form a gene cluster on chromosome 3p.[2]
# Interactions
CCR1 has been shown to interact with CCL5.[3][4] | https://www.wikidoc.org/index.php/CCR1 | |
a6221f2cf997a136cd8a872ba902d001656d5700 | wikidoc | CCR2 | CCR2
C-C chemokine receptor type 2 (CCR2 or CD192 (cluster of differentiation 192) is a protein that in humans is encoded by the CCR2 gene. CCR2 is a chemokine receptor.
# Gene
This CCR2 gene is located in the chemokine receptor gene cluster region. Two alternatively spliced transcript variants are expressed by the gene.
# Function
This gene encodes two isoforms of a receptor for monocyte chemoattractant protein-1 (CCL2), a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The receptors encoded by this gene mediate agonist-dependent calcium mobilization and inhibition of adenylyl cyclase.
# Animal studies
## Alzheimer
CCR2 deficient mice have been shown to develop an accelerated Alzheimer's-like pathology in comparison to wild type mice. This is not the first time that immune function and inflammation have been linked to age-related cognitive decline (i.e. dementia).
## Obesity
Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.
## Myocardial Infarct
CCR2 surface expression on blood monocytes changes in a time-of-day–dependent manner (being higher at the beginning of the active phase) and affects monocytes recruitment in tissues including the heart. As a consequence when an acute ischemic event happens during the active phase, monocytes are more susceptible to invade the heart . An excessive monocytes infiltration generates higher inflammation and increases the risk of heart failure.
# Clinical significance
In an observational study of gene expression in blood leukocytes in humans, Harries et al. found evidence of a relationship between expression of CCR2 and cognitive function (assessed using the mini-mental state examination, MMSE). Higher CCR2 expression was associated with worse performance on the MMSE assessment of cognitive function. The same study found that CCR2 expression was also associated with cognitive decline over 9-years in a sub-analysis on inflammatory related transcripts only. Harries et al. suggest that CCR2 signaling may have a direct role in human cognition, partly because expression of CCR2 was associated with the ApoE haplotype (previously associated with Alzheimer's disease), but also because CCL2 is expressed at high concentrations in macrophages found in atherosclerotic plaques and in brain microglia. The difference in observations between mice (CCR2 depletion causes cognitive decline) and humans (higher CCR2 associated with lower cognitive function) could be due to increased demand for macrophage activation during cognitive decline, associated with increased β-amyloid deposition (a core feature of Alzheimer's disease progression). | CCR2
C-C chemokine receptor type 2 (CCR2 or CD192 (cluster of differentiation 192) is a protein that in humans is encoded by the CCR2 gene.[1] CCR2 is a chemokine receptor.
# Gene
This CCR2 gene is located in the chemokine receptor gene cluster region. Two alternatively spliced transcript variants are expressed by the gene.[1]
# Function
This gene encodes two isoforms of a receptor for monocyte chemoattractant protein-1 (CCL2), a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The receptors encoded by this gene mediate agonist-dependent calcium mobilization and inhibition of adenylyl cyclase.[1]
# Animal studies
## Alzheimer
CCR2 deficient mice have been shown to develop an accelerated Alzheimer's-like pathology in comparison to wild type mice.[2][3] This is not the first time that immune function and inflammation have been linked to age-related cognitive decline (i.e. dementia).[4]
## Obesity
Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.[5]
## Myocardial Infarct
CCR2 surface expression on blood monocytes changes in a time-of-day–dependent manner (being higher at the beginning of the active phase) and affects monocytes recruitment in tissues including the heart. As a consequence when an acute ischemic event happens during the active phase, monocytes are more susceptible to invade the heart [6]. An excessive monocytes infiltration generates higher inflammation and increases the risk of heart failure.
# Clinical significance
In an observational study of gene expression in blood leukocytes in humans, Harries et al. found evidence of a relationship between expression of CCR2 and cognitive function (assessed using the mini-mental state examination, MMSE).[7] Higher CCR2 expression was associated with worse performance on the MMSE assessment of cognitive function. The same study found that CCR2 expression was also associated with cognitive decline over 9-years in a sub-analysis on inflammatory related transcripts only. Harries et al. suggest that CCR2 signaling may have a direct role in human cognition, partly because expression of CCR2 was associated with the ApoE haplotype (previously associated with Alzheimer's disease), but also because CCL2 is expressed at high concentrations in macrophages found in atherosclerotic plaques and in brain microglia.[2] The difference in observations between mice (CCR2 depletion causes cognitive decline) and humans (higher CCR2 associated with lower cognitive function) could be due to increased demand for macrophage activation during cognitive decline, associated with increased β-amyloid deposition (a core feature of Alzheimer's disease progression). | https://www.wikidoc.org/index.php/CCR2 | |
acad1c5a114ccd698b6c8deca605ddad0949b15f | wikidoc | CCR4 | CCR4
C-C chemokine receptor type 4 is a protein that in humans is encoded by the CCR4 gene. CCR4 has also recently been designated CD194 (cluster of differentiation 194).
The protein encoded by this gene belongs to the G protein-coupled receptor family. It is a receptor for the following CC chemokines:
- CCL2 (MCP-1)
- CCL4 (MIP-1)
- CCL5 (RANTES)
- CCL17 (TARC)
- CCL22 (Macrophage-derived chemokine)
Chemokines are a group of small structurally related proteins that regulate cell trafficking of various types of leukocytes. The 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.
# Clinical significance
CCR4 is often expressed on leukemic cells in cutaneous T-cell lymphoma (CTCL).
## As a drug target
Mogamulizumab is a humanised monoclonal antibody targeted at CCR4 and is an investigational drug for CTCL. | CCR4
C-C chemokine receptor type 4 is a protein that in humans is encoded by the CCR4 gene.[1][2][3] CCR4 has also recently been designated CD194 (cluster of differentiation 194).
The protein encoded by this gene belongs to the G protein-coupled receptor family. It is a receptor for the following CC chemokines:
- CCL2 (MCP-1)
- CCL4 (MIP-1)
- CCL5 (RANTES)
- CCL17 (TARC)[4]
- CCL22 (Macrophage-derived chemokine)[5]
Chemokines are a group of small structurally related proteins that regulate cell trafficking of various types of leukocytes. The 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.[3]
# Clinical significance
CCR4 is often expressed on leukemic cells in cutaneous T-cell lymphoma (CTCL).[6]
## As a drug target
Mogamulizumab is a humanised monoclonal antibody targeted at CCR4 and is an investigational drug for CTCL.[6] | https://www.wikidoc.org/index.php/CCR4 | |
dc9f6455a836a8df43c5ce4d66c8858199baa64c | wikidoc | CCR5 | CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.
# Function
The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins. It is a G protein–coupled receptor which functions as a chemokine receptor in the CC chemokine group.
CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1α and 1β, respectively), and CCL3L1. CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).
CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, microglia and a subpopulation of either breast or prostate cancer cells. The expression of CCR5 is selectively induced during the cancer transformation process and is not expressed in normal breast or prostate epithelial cells. Approximately 50% of human breast cancer expressed CCR5, primarily in triple negative breast cancer. CCR5 inhibitors blocked the migration and metastasis of CCR5 expressing breast and prostate cancer cells, suggesting CCR5 may function as a new therapeutic target. Recent studies suggest that CCR5 is expressed in a subset of cancer cells with characteristics of cancer stem cells which are known to drive therapy resistance and CCR5 inhibitors enhanced cell killing of current chemotherapy. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, functional response of the receptor, and HIV co-receptor activity.
# HIV
HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells. These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell. The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit, and the Gp41 transmembrane subunit. This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of three Gp120-Gp41 hetero-dimers. The Gp120 envelope protein is a chemokine mimic. It lacks the unique structure of a chemokine, however it is still capable of binding to the CCR5 and CXCR4 chemokine receptors. During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell- forming a heterotrimeric complex. The formation of this complex stimulates the release of a fusogenic peptide inducing the fusion of the viral membrane with the membrane of the target host cell. Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein. Co-receptor recognition also include the V1-V2 region of gp120, and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it hasn't been finalized as a proven theory yet, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains
CCR5 is essential for the spread of the R5-strain of the HIV-1 virus. Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function. A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with the associative binding between the Gp120 envelope protein and the HIV co-receptor CCR5. These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007. It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor. A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. However, because there is still another co-receptor available, this indicates that lacking the CCR5 gene doesn't make one immune to the virus; it simply implies that it would be more challenging for the individual to contract it. Also, the virus still has access to the CD4. Unlike CCR5, which the body apparently doesn't really need due to those still living healthy lives even with the lack of/or absence of the gene (as a result of the delta 32 mutation), CD4 is critical in the body's defense system (fighting against infection). Even without the availability of either co-receptors (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail), resulting in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.
# Cancer
Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation. The induction of CCR5 expression promotes cellular invasion, migration and metastasis. The induction of metastasis involves homing to the metastatic site. CCR5 inhibitors have been shown to block lung metastasis of human breast cancer cell lines. In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain. CCR5 inhibitors also reduce the infiltration of tumor associated macrophages. A Phase 1 clinical study of CCR5 inhibitor in heavily pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden.
# CCR5-Δ32
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.
CCR5 Δ32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor. CCR5 is required for M-tropic HIV-1 virus entry. Individuals homozygous (denoted Δ32/Δ32) for CCR5 Δ32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures. Individuals heterozygous (+/Δ32) for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface. Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types. Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment. CCR5 Δ32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.
## Evolutionary history and age of the allele
The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution, which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.
Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion. Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval). A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the Nordic countries and lowest allele frequency in southern Europe. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries. Vikings were later replaced by the Varangians in Russia, which may have contributed to the observed east-to-west cline of allele frequency.
HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa, through exposure to infected blood and body fluids while butchering bushmeat. However, HIV-1 was effectively absent from Europe until the late 1980s. Therefore, given the average age of roughly 1000 years for the CCR5-Δ32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies. Hence, other pathogens have been suggested as agents of positive selection for CCR5 Δ32, including bubonic plague (Yersinia pestis) and smallpox (Variola major).
Other data suggest that the allele frequency experienced negative selection pressure as a result of pathogens that became more widespread during Roman expansion. The idea that negative selection played a role in the allele's low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.
## Evidence for a single mutation
Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once. First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations, suggesting that a single mutation occurred after divergence of Europeans from their African ancestor. Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor. This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele. This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event. Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).
## Positive selection
In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%. Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.
It is estimated that HIV-1 entered the human population in Africa in the early 1900s, symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years. In 1998, Stephens et al. suggested that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 Δ32. This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352. After the Black Death, there were less severe, intermittent, epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent. In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europe’s population. Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents and spread by fleas and only occasionally infecting humans. Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs. Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur. Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 Δ32 to 10% in Europe.
To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox. Plague was modeled according to historical accounts, while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812. Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague. Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human. The authors calculated that if plague were selecting for CCR5 Δ32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.
The hypothesis that smallpox exerted positive selection for CCR5 Δ32 is also biologically plausible, since poxviruses, like HIV, are viruses that enter white blood cells by using chemokine receptors. By contrast, Yersinia pestis is a bacterium with a very different biology.
Although Europeans are the only group to have subpopulations with a high frequency of CCR5 Δ32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia. By contrast, the CCR5 Δ32 mutation is found only in European, West Asian, and North African populations. The anomalously high frequency of CCR5 Δ32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.
## Potential costs
Research has not yet revealed a cost of carrying the CCR5 null mutation that is as dramatic as the benefit conferred in the context of HIV-1 exposure. In general, research suggests that the CCR5 Δ32 mutation protects against diseases caused by certain pathogens but may also play a deleterious role in postinfection inflammatory processes, which can injure tissue and create further pathology. The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 Δ32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus). In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 Δ32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.
This finding in humans confirmed a previously-observed experiment in an animal model of CCR5 Δ32 homozygosity. After infection with West Nile Virus, CCR5 Δ32 mice had markedly increased viral titers in the central nervous system and had increased mortality compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.
CCR5 Δ32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.
## Medical applications
A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals. When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus-resistant cell pool in infected individuals.
This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues. Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either. However, this outcome is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4. After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment. Results reported in 2014 were promising.
Inspired by the first person ever to be cured of HIV, The Berlin Patient, StemCyte began collaborations with Cord blood banks worldwide to systematically screen Umbilical cord blood samples for the CCR5 mutation beginning in 2011.
In November 2018, Jiankui He announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier. He said that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism) and were still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature. | CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[1][2][3][4][5][6]
# Function
The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins.[7][8] It is a G protein–coupled receptor[7] which functions as a chemokine receptor in the CC chemokine group.
CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1α and 1β, respectively), and CCL3L1.[9][10] CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).[9][11][12]
CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, microglia and a subpopulation of either breast or prostate cancer cells.[13][14] The expression of CCR5 is selectively induced during the cancer transformation process and is not expressed in normal breast or prostate epithelial cells. Approximately 50% of human breast cancer expressed CCR5, primarily in triple negative breast cancer. [13] CCR5 inhibitors blocked the migration and metastasis of CCR5 expressing breast and prostate cancer cells, suggesting CCR5 may function as a new therapeutic target. [13][14][15] Recent studies suggest that CCR5 is expressed in a subset of cancer cells with characteristics of cancer stem cells which are known to drive therapy resistance and CCR5 inhibitors enhanced cell killing of current chemotherapy.[16] It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, functional response of the receptor, and HIV co-receptor activity.[17]
# HIV
HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.[18] These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell.[19] The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.[19] The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit, and the Gp41 transmembrane subunit.[19] This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of three Gp120-Gp41 hetero-dimers.[19] The Gp120 envelope protein is a chemokine mimic.[18] It lacks the unique structure of a chemokine, however it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.[18] During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell- forming a heterotrimeric complex.[18] The formation of this complex stimulates the release of a fusogenic peptide inducing the fusion of the viral membrane with the membrane of the target host cell.[18] Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein.[20] Co-receptor recognition also include the V1-V2 region of gp120, and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity.[20] The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[21] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it hasn't been finalized as a proven theory yet, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains [20]
CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.[22] Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function.[23] A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with the associative binding between the Gp120 envelope protein and the HIV co-receptor CCR5.[22] These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007.[22] It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor.[20] A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. However, because there is still another co-receptor available, this indicates that lacking the CCR5 gene doesn't make one immune to the virus; it simply implies that it would be more challenging for the individual to contract it. Also, the virus still has access to the CD4. Unlike CCR5, which the body apparently doesn't really need due to those still living healthy lives even with the lack of/or absence of the gene (as a result of the delta 32 mutation), CD4 is critical in the body's defense system (fighting against infection).[24] Even without the availability of either co-receptors (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail), resulting in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.[25]
# Cancer
Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation. The induction of CCR5 expression promotes cellular invasion, migration and metastasis. The induction of metastasis involves homing to the metastatic site. CCR5 inhibitors have been shown to block lung metastasis of human breast cancer cell lines. [13] In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain. [14] CCR5 inhibitors also reduce the infiltration of tumor associated macrophages. [26] A Phase 1 clinical study of CCR5 inhibitor in heavily pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden. [27]
# CCR5-Δ32
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.[28][29]
CCR5 Δ32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor.[30][31] CCR5 is required for M-tropic HIV-1 virus entry.[32] Individuals homozygous (denoted Δ32/Δ32) for CCR5 Δ32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures.[32] Individuals heterozygous (+/Δ32) for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface.[33] Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types.[30][32][34] Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment.[35] CCR5 Δ32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.
## Evolutionary history and age of the allele
The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,[36] which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.
Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion.[29][37] Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval).[37] A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the Nordic countries and lowest allele frequency in southern Europe. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries.[38] Vikings were later replaced by the Varangians in Russia, which may have contributed to the observed east-to-west cline of allele frequency.[36][38]
HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa,[39] through exposure to infected blood and body fluids while butchering bushmeat.[40] However, HIV-1 was effectively absent from Europe until the late 1980s.[41] Therefore, given the average age of roughly 1000 years for the CCR5-Δ32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies.[36] Hence, other pathogens have been suggested as agents of positive selection for CCR5 Δ32, including bubonic plague (Yersinia pestis) and smallpox (Variola major).
Other data suggest that the allele frequency experienced negative selection pressure as a result of pathogens that became more widespread during Roman expansion.[42] The idea that negative selection played a role in the allele's low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.[43][44]
## Evidence for a single mutation
Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once.[36] First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,[29] suggesting that a single mutation occurred after divergence of Europeans from their African ancestor.[29][30][45] Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor.[37] This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.[37] This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event. Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).[37]
## Positive selection
In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.[29] Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.
It is estimated that HIV-1 entered the human population in Africa in the early 1900s,[39] symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years. In 1998, Stephens et al. suggested that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 Δ32.[29] This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.[46] After the Black Death, there were less severe, intermittent, epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.[46][47][48] In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europe’s population.[46][49] Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents and spread by fleas and only occasionally infecting humans.[50] Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.[51] Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.[50] Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 Δ32 to 10% in Europe.[28]
To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.[28] Plague was modeled according to historical accounts,[52][53] while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.[47] Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.[28] Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.[54][55] The authors calculated that if plague were selecting for CCR5 Δ32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.
The hypothesis that smallpox exerted positive selection for CCR5 Δ32 is also biologically plausible, since poxviruses, like HIV, are viruses that enter white blood cells by using chemokine receptors.[56] By contrast, Yersinia pestis is a bacterium with a very different biology.
Although Europeans are the only group to have subpopulations with a high frequency of CCR5 Δ32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.[55] By contrast, the CCR5 Δ32 mutation is found only in European, West Asian, and North African populations.[57] The anomalously high frequency of CCR5 Δ32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.
## Potential costs
Research has not yet revealed a cost of carrying the CCR5 null mutation that is as dramatic as the benefit conferred in the context of HIV-1 exposure. In general, research suggests that the CCR5 Δ32 mutation protects against diseases caused by certain pathogens but may also play a deleterious role in postinfection inflammatory processes, which can injure tissue and create further pathology.[58] The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 Δ32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus).[59] In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 Δ32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.[60]
This finding in humans confirmed a previously-observed experiment in an animal model of CCR5 Δ32 homozygosity. After infection with West Nile Virus, CCR5 Δ32 mice had markedly increased viral titers in the central nervous system and had increased mortality[61] compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.
CCR5 Δ32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.
## Medical applications
A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals.[62] When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus-resistant cell pool in infected individuals.[62]
This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[2][63] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either.[2] However, this outcome is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[64] After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[3]
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.[65][66] Results reported in 2014 were promising.[6]
Inspired by the first person ever to be cured of HIV, The Berlin Patient, StemCyte began collaborations with Cord blood banks worldwide to systematically screen Umbilical cord blood samples for the CCR5 mutation beginning in 2011.[67] [68][69]
In November 2018, Jiankui He announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier. He said that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism) and were still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature.[70][71] | https://www.wikidoc.org/index.php/CCR5 | |
1f08d10faf32ecd282e419cce593b6b8501613a1 | wikidoc | CCR9 | CCR9
C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene.
CCR9 has also recently been designated CDw199 (cluster of differentiation w199).
The protein encoded by this gene is a member of the beta chemokine receptor family. It is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are key regulators of thymocyte migration and maturation in normal and inflammatory conditions. The specific ligand of this receptor is CCL25. It has been found that this gene is differentially expressed by T lymphocytes of small intestine and colon, suggested a role in thymocyte recruitment and development that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described. | CCR9
C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene.[1][2]
CCR9 has also recently been designated CDw199 (cluster of differentiation w199).
The protein encoded by this gene is a member of the beta chemokine receptor family. It is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are key regulators of thymocyte migration and maturation in normal and inflammatory conditions. The specific ligand of this receptor is CCL25. It has been found that this gene is differentially expressed by T lymphocytes of small intestine and colon, suggested a role in thymocyte recruitment and development that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.[2] | https://www.wikidoc.org/index.php/CCR9 | |
b2f430e27c7014143ce42ab7f899b5369e18fb96 | wikidoc | CD31 | CD31
Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome 17. PECAM-1 plays a key role in removing aged neutrophils from the body.
# Function
PECAM-1 is found on the surface of platelets, monocytes, neutrophils, and some types of T-cells, and makes up a large portion of endothelial cell intercellular junctions. The encoded protein is a member of the immunoglobulin superfamily and is likely involved in leukocyte transmigration, angiogenesis, and integrin activation.
# Tissue distribution
CD31 is normally found on endothelial cells, platelets, macrophages and Kupffer cells, granulocytes, lymphocytes (T cells, B cells, and NK cells), megakaryocytes, and osteoclasts.
CD31 is also expressed in certain tumors, including epithelioid hemangioendothelioma, epithelioid sarcoma-like hemangioendothelioma, other vascular tumors, histiocytic malignancies, and plasmacytomas. It is rarely found in some sarcomas, such as Kaposi's sarcoma, and carcinomas.
## Immunohistochemistry
In immunohistochemistry, CD31 is used primarily to demonstrate the presence of endothelial cells in histological tissue sections. This can help to evaluate the degree of tumor angiogenesis, which can imply a rapidly growing tumor. Malignant endothelial cells also commonly retain the antigen, so that CD31 immunohistochemistry can also be used to demonstrate both angiomas and angiosarcomas. It can also be demonstrated in small lymphocytic and lymphoblastic lymphomas, although more specific markers are available for these conditions. | CD31
Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome 17.[1][2][3][4] PECAM-1 plays a key role in removing aged neutrophils from the body.
# Function
PECAM-1 is found on the surface of platelets, monocytes, neutrophils, and some types of T-cells, and makes up a large portion of endothelial cell intercellular junctions. The encoded protein is a member of the immunoglobulin superfamily and is likely involved in leukocyte transmigration, angiogenesis, and integrin activation.[1]
# Tissue distribution
CD31 is normally found on endothelial cells, platelets, macrophages and Kupffer cells, granulocytes, lymphocytes (T cells, B cells, and NK cells), megakaryocytes, and osteoclasts.
CD31 is also expressed in certain tumors, including epithelioid hemangioendothelioma, epithelioid sarcoma-like hemangioendothelioma, other vascular tumors, histiocytic malignancies, and plasmacytomas. It is rarely found in some sarcomas, such as Kaposi's sarcoma,[5][6] and carcinomas.
## Immunohistochemistry
In immunohistochemistry, CD31 is used primarily to demonstrate the presence of endothelial cells in histological tissue sections. This can help to evaluate the degree of tumor angiogenesis, which can imply a rapidly growing tumor. Malignant endothelial cells also commonly retain the antigen, so that CD31 immunohistochemistry can also be used to demonstrate both angiomas and angiosarcomas. It can also be demonstrated in small lymphocytic and lymphoblastic lymphomas, although more specific markers are available for these conditions.[7] | https://www.wikidoc.org/index.php/CD-31 | |
d0bf9efd12a196d5fa37082aa141c19fa018b604 | wikidoc | CD14 | CD14
CD14 (cluster of differentiation 14) is a human gene.
The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms, one anchored to the membrane by a glycosylphosphatidylinositol tail (mCD14), the other a soluble form (sCD14). Soluble CD14 either appears after shedding of mCD14 (48 kDa) or is directly secreted from intracellular vesicles (56 kDa).
The x-ray crystal structure of human CD14 (4GLP.pdb) reveals a monomeric, bent solenoid structure containing a hydrophobic amino-terminal pocket.
CD14 was the first described pattern recognition receptor.
# Function
CD14 acts as a co-receptor (along with the Toll-like receptor TLR 4 and MD-2) for the detection of bacterial lipopolysaccharide (LPS). CD14 can bind LPS only in the presence of lipopolysaccharide-binding protein (LBP).
Although LPS is considered its main ligand, CD14 also recognizes other pathogen-associated molecular patterns such as lipoteichoic acid.
# Tissue distribution
CD14 is expressed mainly by macrophages and (at 10-times lesser extent) by neutrophils. It is also expressed by dendritic cells. The soluble form of the receptor (sCD14) is secreted by the liver and monocytes and is sufficient in low concentrations to confer LPS-responsiveness to cells not expressing CD14. mCD14 and sCD14 are also present on enterocytes. sCD14 is also present in human milk, where it is believed to regulate microbial growth in the infant gut.
# Differentiation
CD14+ monocytes can differentiate into a host of different cells, including dendritic cells, a differentiation pathway encouraged by cytokines, including GM-CSF and IL-4.
# Interactions
CD14 has been shown to interact with lipopolysaccharide-binding protein. | CD14
CD14 (cluster of differentiation 14) is a human gene.[1][2]
The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms, one anchored to the membrane by a glycosylphosphatidylinositol tail (mCD14), the other a soluble form (sCD14). Soluble CD14 either appears after shedding of mCD14 (48 kDa) or is directly secreted from intracellular vesicles (56 kDa).[3]
The x-ray crystal structure of human CD14 (4GLP.pdb) reveals a monomeric, bent solenoid structure containing a hydrophobic amino-terminal pocket.[4]
CD14 was the first described pattern recognition receptor.
# Function
CD14 acts as a co-receptor (along with the Toll-like receptor TLR 4 and MD-2) for the detection of bacterial lipopolysaccharide (LPS).[5][6] CD14 can bind LPS only in the presence of lipopolysaccharide-binding protein (LBP).
Although LPS is considered its main ligand, CD14 also recognizes other pathogen-associated molecular patterns such as lipoteichoic acid.[7]
# Tissue distribution
CD14 is expressed mainly by macrophages and (at 10-times lesser extent) by neutrophils. It is also expressed by dendritic cells. The soluble form of the receptor (sCD14) is secreted by the liver and monocytes and is sufficient in low concentrations to confer LPS-responsiveness to cells not expressing CD14. mCD14 and sCD14 are also present on enterocytes.[8] sCD14 is also present in human milk, where it is believed to regulate microbial growth in the infant gut.
# Differentiation
CD14+ monocytes can differentiate into a host of different cells, including dendritic cells, a differentiation pathway encouraged by cytokines, including GM-CSF and IL-4.
# Interactions
CD14 has been shown to interact with lipopolysaccharide-binding protein.[9][10] | https://www.wikidoc.org/index.php/CD14 | |
44906b56fbaa646a761b50c3365671802d5f3f2b | wikidoc | CD16 | CD16
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophil polymorphonuclear leukocytes, monocytes and macrophages. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.
# Function
CD16 is the type III Fcγ receptor. In humans, it exists in two different forms: FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which have 96% sequence similarity in the extracellular immunoglobulin binding regions. While FcγRIIIa is expressed on mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcγRIIIb is only expressed on neutrophils. In addition, FcγRIIIb is the only Fc receptor anchored to the cell membrane by a glycosyl-phosphatidylinositol (GPI) linker, and also plays a significant role in triggering calcium mobilization and neutrophil degranulation. FcγRIIIa and FcγRIIIb together are able to activate degranulation, phagocytosis, and oxidative burst, which allows neutrophils to clear opsonized pathogens.
# Mechanism and regulation
These receptors bind to the Fc portion of IgG antibodies, which then activates antibody-dependent cell-mediated cytotoxicity (ADCC) in human NK cells. CD16 is required for ADCC processes carried out by human monocytes. In humans, monocytes expressing CD16 have a variety of ADCC capabilities in the presence of specific antibodies, and can kill primary leukemic cells, cancer cell lines, and cells infected with hepatitis B virus. In addition, CD16 is able to mediate the direct killing of some virally infected and cancer cells without antibodies.
After binding to ligands such as the conserved section of IgG antibodies, CD16 on human NK cells induce gene transcription of surface activation molecules such as IL-2-R (CD25) and inflammatory cytokines such as IFN-gamma and TNF. This CD16-induced expression of cytokine mRNA in NK cells is mediated by the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of various cytokines. The upregulated expression of specific cytokine genes occurs via a CsA-sensitive and calcium-dependent mechanism.
# Structure
The crystal structures of FcεRIα, FcγRIIa, FcγRIIb and FcγRIII have been experimentally determined. These structures revealed a conserved immunoglobulin-like (Ig-like) structure. In addition, the structures demonstrated a common feature in all known Ig superfamily Fc receptors: the acute hinge angle between the N- and C-terminal Ig domains. Specifically, the structure of CD16 (FcγRIIIb) consists of two immunoglobulin-like domains, with an interdomain hinge angle of around 50°. The receptor’s Fc binding region also carries a net positive charge, which complements the negatively-charged receptor binding regions on Fc.
# Clinical significance
CD16 plays a significant role in early activation of natural killer (NK) cells following vaccination. In addition, CD16 downregulation represents a possible way to moderate NK cell responses and maintain immune homeostasis in both T cell and antibody-dependent signaling pathways. In a normal, healthy individual, cross-linking of CD16 (FcγRIII) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) in NK cells. However, this pathway can also be targeted in cancerous or diseased cells by immunotherapy. After influenza vaccination, CD16 downregulation was associated with significant upregulation of influenza-specific plasma antibodies, and positively correlated with degranulation of NK cells.
CD16 is often used as an additional marker to reliably identify different subsets of human immune cells. Several other CD molecules, such as CD11b and CD33, are traditionally used as markers for human myeloid-derived suppressor cells (MDSCs). However, since these markers are also expressed on NK cells and all other cells derived from myelocytes, other markers are required, such as CD14 and CD15. Neutrophils are found to be CD14low and CD15high, whereas monocytes are CD14high and CD15low. While these two markers are sufficient to differentiate between neutrophils and monocytes, eosinophils have a similar CD15 expression to neutrophils. Therefore, CD16 is used as a further marker to identify neutrophils: mature neutrophils are CD16high, while eosinophils and monocytes are both CD16low. CD16 allows for distinction between these two types of granulocytes. Additionally, CD16 expression varies between the different stages of neutrophil development: neutrophil progenitors that have differentiation capacity are CD16low, with increasing expression of CD16 in metamyelocytes, banded, and mature neutrophils, respectively.
# As a drug target
With its expression on neutrophils, CD16 represents a possible target in cancer immunotherapy. Margetuximab, an Fc-optimized monoclonal antibody that recognizes the human epidermal growth factor receptor 2 (HER2) expressed on tumor cells in breast, bladder, and other solid tumor cancers, targets CD16A in preference to CD16B. In addition, CD16 could play a role in antibody-targeting cancer therapies. Bispecific antibody fragments, such as anti-CD19/CD16, allow the targeting of immunotherapeutic drugs to the cancer cell. Anti-CD19/CD16 diabodies have been shown to enhance the natural killer cell response to B-cell lymphomas. Furthermore, targeting extrinsic factors such as FasL or TRAIL to the tumor cell surface triggers death receptors, inducing apoptosis by both autocrine and paracrine processes. | CD16
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophil polymorphonuclear leukocytes, monocytes and macrophages.[1] CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction.[2] The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC).[3] It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.
# Function
CD16 is the type III Fcγ receptor. In humans, it exists in two different forms: FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which have 96% sequence similarity in the extracellular immunoglobulin binding regions.[4] While FcγRIIIa is expressed on mast cells, macrophages, and natural killer cells as a transmembrane receptor, FcγRIIIb is only expressed on neutrophils.[4] In addition, FcγRIIIb is the only Fc receptor anchored to the cell membrane by a glycosyl-phosphatidylinositol (GPI) linker, and also plays a significant role in triggering calcium mobilization and neutrophil degranulation. FcγRIIIa and FcγRIIIb together are able to activate degranulation, phagocytosis, and oxidative burst, which allows neutrophils to clear opsonized pathogens.[4]
# Mechanism and regulation
These receptors bind to the Fc portion of IgG antibodies, which then activates antibody-dependent cell-mediated cytotoxicity (ADCC) in human NK cells. CD16 is required for ADCC processes carried out by human monocytes.[5] In humans, monocytes expressing CD16 have a variety of ADCC capabilities in the presence of specific antibodies, and can kill primary leukemic cells, cancer cell lines, and cells infected with hepatitis B virus.[5] In addition, CD16 is able to mediate the direct killing of some virally infected and cancer cells without antibodies.[3]
After binding to ligands such as the conserved section of IgG antibodies, CD16 on human NK cells induce gene transcription of surface activation molecules such as IL-2-R (CD25) and inflammatory cytokines such as IFN-gamma and TNF.[6] This CD16-induced expression of cytokine mRNA in NK cells is mediated by the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of various cytokines. The upregulated expression of specific cytokine genes occurs via a CsA-sensitive and calcium-dependent mechanism.[7]
# Structure
The crystal structures of FcεRIα, FcγRIIa, FcγRIIb and FcγRIII have been experimentally determined. These structures revealed a conserved immunoglobulin-like (Ig-like) structure.[8] In addition, the structures demonstrated a common feature in all known Ig superfamily Fc receptors: the acute hinge angle between the N- and C-terminal Ig domains. Specifically, the structure of CD16 (FcγRIIIb) consists of two immunoglobulin-like domains, with an interdomain hinge angle of around 50°.[4] The receptor’s Fc binding region also carries a net positive charge, which complements the negatively-charged receptor binding regions on Fc.[4]
# Clinical significance
CD16 plays a significant role in early activation of natural killer (NK) cells following vaccination. In addition, CD16 downregulation represents a possible way to moderate NK cell responses and maintain immune homeostasis in both T cell and antibody-dependent signaling pathways.[9] In a normal, healthy individual, cross-linking of CD16 (FcγRIII) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) in NK cells. However, this pathway can also be targeted in cancerous or diseased cells by immunotherapy. After influenza vaccination, CD16 downregulation was associated with significant upregulation of influenza-specific plasma antibodies, and positively correlated with degranulation of NK cells.[9]
CD16 is often used as an additional marker to reliably identify different subsets of human immune cells.[10] Several other CD molecules, such as CD11b and CD33, are traditionally used as markers for human myeloid-derived suppressor cells (MDSCs).[10] However, since these markers are also expressed on NK cells and all other cells derived from myelocytes, other markers are required, such as CD14 and CD15. Neutrophils are found to be CD14low and CD15high, whereas monocytes are CD14high and CD15low.[11] While these two markers are sufficient to differentiate between neutrophils and monocytes, eosinophils have a similar CD15 expression to neutrophils. Therefore, CD16 is used as a further marker to identify neutrophils: mature neutrophils are CD16high, while eosinophils and monocytes are both CD16low. CD16 allows for distinction between these two types of granulocytes. Additionally, CD16 expression varies between the different stages of neutrophil development: neutrophil progenitors that have differentiation capacity are CD16low, with increasing expression of CD16 in metamyelocytes, banded, and mature neutrophils, respectively.[12]
# As a drug target
With its expression on neutrophils, CD16 represents a possible target in cancer immunotherapy. Margetuximab, an Fc-optimized monoclonal antibody that recognizes the human epidermal growth factor receptor 2 (HER2) expressed on tumor cells in breast, bladder, and other solid tumor cancers, targets CD16A in preference to CD16B.[13] In addition, CD16 could play a role in antibody-targeting cancer therapies. Bispecific antibody fragments, such as anti-CD19/CD16, allow the targeting of immunotherapeutic drugs to the cancer cell. Anti-CD19/CD16 diabodies have been shown to enhance the natural killer cell response to B-cell lymphomas.[14] Furthermore, targeting extrinsic factors such as FasL or TRAIL to the tumor cell surface triggers death receptors, inducing apoptosis by both autocrine and paracrine processes. | https://www.wikidoc.org/index.php/CD16 | |
28e6e25dfcdf60cc0310c3eb3e6987d429b075a1 | wikidoc | CD18 | CD18
Integrin beta-2 (CD18) is a protein that in humans is encoded by the ITGB2 gene.
It is the beta subunit of four different structures:
- LFA-1 (paired with CD11a)
- Macrophage-1 antigen (paired with CD11b)
- Integrin alphaXbeta2 (paired with CD11c)
- Integrin alphaDbeta2 (paired with CD11d)
# Function
The ITGB2 protein product is the integrin beta chain beta 2. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. For example, beta 2 combines with the alpha L chain to form the integrin LFA-1, and combines with the alpha M chain to form the integrin Mac-1. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling.
# Clinical significance
In humans lack of CD18 causes Leukocyte Adhesion Deficiency, a disease defined by a lack of leukocyte extravasation from blood into tissues. The beta 2 integrins have also been found in a soluble form. The soluble beta 2 integrins are ligand binding and plasma levels are inversely associated with disease activity in the autoimmune disease spondyloarthritis.
# Interactions
CD18 has been shown to interact with:
- FHL2,
- GNB2L1,
- ICAM-1, and
- PSCD1. | CD18
Integrin beta-2 (CD18) is a protein that in humans is encoded by the ITGB2 gene.
It is the beta subunit of four different structures:
- LFA-1 (paired with CD11a)
- Macrophage-1 antigen (paired with CD11b)
- Integrin alphaXbeta2 (paired with CD11c)
- Integrin alphaDbeta2 (paired with CD11d)
# Function
The ITGB2 protein product is the integrin beta chain beta 2. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. For example, beta 2 combines with the alpha L chain to form the integrin LFA-1, and combines with the alpha M chain to form the integrin Mac-1. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling.[1]
# Clinical significance
In humans lack of CD18 causes Leukocyte Adhesion Deficiency, a disease defined by a lack of leukocyte extravasation from blood into tissues. The beta 2 integrins have also been found in a soluble form.[2] The soluble beta 2 integrins are ligand binding and plasma levels are inversely associated with disease activity in the autoimmune disease spondyloarthritis.[3]
# Interactions
CD18 has been shown to interact with:
- FHL2,[4]
- GNB2L1,[5]
- ICAM-1,[6][7][8] and
- PSCD1.[9][10] | https://www.wikidoc.org/index.php/CD18 | |
793b1e8914883141dd6fa7109f1fb52fb239a402 | wikidoc | CD19 | CD19
B-lymphocyte antigen CD19, also known as CD19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells, except for plasma cells, and in follicular dendritic cells. CD19 plays two major roles in human B cells. It acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane and it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.
# Structure
In humans, CD19 is encoded by the 7.41 kilobase CD19 gene located on the short arm of chromosome 16. It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids. Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.
CD19 is a 95 kd Type I transmembrane glycoprotein in the immunoglobulin superfamily (IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species. The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites. The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus. Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19. Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.
# Expression
CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell lymphopoiesis, CD19 surface expression starts during immunoglobulin (Ig) gene rearrangement, which coincides during B lineage commitment from hematopoietic stem cell. Throughout development, the surface density of CD19 is highly regulated. CD19 expression in mature B cells is three fold higher than that in immature B cells. CD19 is expressed on all normal, mitogen-stimulated, and malignant B cells, excluding plasma cells. CD19 expression is even maintained in B lineage cells that undergo neoplastic transformation. Because of its ubiquity on all B cells, it can function as a B cell marker and a target for immunotherapies targeting neoplastic lymphocytes.
# Function
## Role in development & survival
Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development. These decisions are tightly regulated through BCR interactions and signaling. The presence of a functional BCR is necessary during antigen-dependent differentiation and for continued survival in the peripheral immune system. Essential to the functionality of a BCR is the presence of CD19. Experiments using CD19 knockout mice found that CD19 is essential for B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells. Analysis of mixed bone marrow chimeras suggest that prior to an initial antigen encounter, CD19 promotes the survival of naive recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment. Ultimately, CD19 expression is integral to the propagation of BCR-induced survival signals and the maintenance of homeostasis through tonic signaling.
## BCR-independent
Paired box transcription factor 5 (PAX5) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked. Part of B cell differentiation is controlling c-MYC protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the PI3K-AKT-GSK3β axis. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 knockdown mice. CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase (PI3K) and later downstream, the activation of protein kinase B (Akt). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC. CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion in vitro and in vivo.
## CD19/CD21 complex
On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21, a complement receptor, CD81, a tetraspanin membrane protein (TAPA-1), and CD225. The CD19/CD21 complex arises from C3d binding to CD21; however, CD19 does not require CD21 for signal transduction. CD81, attached to CD19, is a part of the tetraspanin web, acts as a chaperone protein, and provides docking sites for molecules in various different signal transduction pathways.
## BCR-dependent
While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation. Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, MHC class II mediated signaling.
Activated spleen tyrosine kinase (Syk) leads to phosphorylation of the scaffold protein, BLNK, which provides multiple sites for tyrosine phosphorylation and recruits SH2-containing enzymes and adaptor proteins that can form various multiprotein signaling complexes. In this way, CD19 can modulate the threshold for B cell activation. This is important during primary immune response, prior to affinity maturation, amplifying the response of low affinity BCRs to low concentrations of antigen.
# Interactions
CD19 has been shown to interact with:
- CD81
- CD82
- Complement receptor 2
- VAV2
# In disease
## Autoimmunity & immunodeficiency
Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production. Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation. These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory. Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched memory B cells with high terminal differentiation potential in patients with Down Syndrome. CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.
Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak T cell dependent humoral response, that in turn leads to an overall impaired humoral immune response. Additionally CD19 plays a role in modulating MHC Class II expression and signaling, which can be affected by mutations. CD19 deficient B cells exhibit selective growth disadvantage; therefore, it is rare for CD19 to be absent in neoplastic B cells, as it is essential for development.
## Cancer
Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably B cell lymphomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). The majority of B cell malignancies express normal to high levels of CD19. The most current experimental anti-CD19 immunotoxins in development work by exploiting the widespread presence of CD19 on B cells, with expression highly conserved in most neoplastic B cells, to direct treatment specifically towards B-cell cancers. However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the MYC oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than initially suspected.
CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CARs) have been utilized for their antitumor abilities in patients with CD19+ lymphoma and leukemia, first against Non-Hodgkins Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013. CAR-19 T cells are genetically modified T cells that express a targeting moiety on their surface that confers T cell receptor (TCR) specificity towards CD19+ cells. CD19 activates the TCR signaling cascade that leads to proliferation, cytokine production, and ultimately lysis of the target cells, which in this case are CD19+ B cells. CAR-19 T cells are more effective than anti-CD19 immunotoxins because they can proliferate and remain in the body for a longer period of time. This comes with a caveat since now CD19− immune escape facilitated by splice variants, point mutations, and lineage switching can form as a major form of therapeutic resistance for patients with ALL. | CD19
B-lymphocyte antigen CD19, also known as CD19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19.[1][2] In humans, CD19 is expressed in all B lineage cells, except for plasma cells, and in follicular dendritic cells.[3][4] CD19 plays two major roles in human B cells. It acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane and it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.[4]
# Structure
In humans, CD19 is encoded by the 7.41 kilobase CD19 gene located on the short arm of chromosome 16.[5][6] It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.[6] Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.[5]
CD19 is a 95 kd Type I transmembrane glycoprotein in the immunoglobulin superfamily (IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species.[5][7][8][9] The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.[8][10] The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus.[5][8] Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.[11] Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.[5][12]
# Expression
CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell lymphopoiesis, CD19 surface expression starts during immunoglobulin (Ig) gene rearrangement, which coincides during B lineage commitment from hematopoietic stem cell.[4] Throughout development, the surface density of CD19 is highly regulated.[5] CD19 expression in mature B cells is three fold higher than that in immature B cells.[5] CD19 is expressed on all normal, mitogen-stimulated, and malignant B cells, excluding plasma cells. CD19 expression is even maintained in B lineage cells that undergo neoplastic transformation.[3][12] Because of its ubiquity on all B cells, it can function as a B cell marker and a target for immunotherapies targeting neoplastic lymphocytes.[4][5]
# Function
## Role in development & survival
Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development.[13] These decisions are tightly regulated through BCR interactions and signaling. The presence of a functional BCR is necessary during antigen-dependent differentiation and for continued survival in the peripheral immune system.[8] Essential to the functionality of a BCR is the presence of CD19.[14] Experiments using CD19 knockout mice found that CD19 is essential for B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells.[8][15][16] Analysis of mixed bone marrow chimeras suggest that prior to an initial antigen encounter, CD19 promotes the survival of naive recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment.[17] Ultimately, CD19 expression is integral to the propagation of BCR-induced survival signals and the maintenance of homeostasis through tonic signaling.
## BCR-independent
Paired box transcription factor 5 (PAX5) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked.[17][18][19] Part of B cell differentiation is controlling c-MYC protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the PI3K-AKT-GSK3β axis. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 knockdown mice.[17] CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase (PI3K) and later downstream, the activation of protein kinase B (Akt). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC.[17][20] CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion in vitro and in vivo.[17][20]
## CD19/CD21 complex
On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21, a complement receptor, CD81, a tetraspanin membrane protein (TAPA-1), and CD225.[5][17] The CD19/CD21 complex arises from C3d binding to CD21; however, CD19 does not require CD21 for signal transduction. CD81, attached to CD19, is a part of the tetraspanin web, acts as a chaperone protein, and provides docking sites for molecules in various different signal transduction pathways.[5]
## BCR-dependent
While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation.[21] Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, MHC class II mediated signaling.[5]
Activated spleen tyrosine kinase (Syk) leads to phosphorylation of the scaffold protein, BLNK, which provides multiple sites for tyrosine phosphorylation and recruits SH2-containing enzymes and adaptor proteins that can form various multiprotein signaling complexes. In this way, CD19 can modulate the threshold for B cell activation. This is important during primary immune response, prior to affinity maturation, amplifying the response of low affinity BCRs to low concentrations of antigen.[5][21]
# Interactions
CD19 has been shown to interact with:
- CD81
- CD82
- Complement receptor 2
- VAV2
# In disease
## Autoimmunity & immunodeficiency
Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production.[22][23] Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.[24] These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory.[25] Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched memory B cells with high terminal differentiation potential in patients with Down Syndrome.[26] CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.[7][10][27]
Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak T cell dependent humoral response, that in turn leads to an overall impaired humoral immune response.[15][16] Additionally CD19 plays a role in modulating MHC Class II expression and signaling, which can be affected by mutations. CD19 deficient B cells exhibit selective growth disadvantage; therefore, it is rare for CD19 to be absent in neoplastic B cells, as it is essential for development.[17]
## Cancer
Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably B cell lymphomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).[4] The majority of B cell malignancies express normal to high levels of CD19. The most current experimental anti-CD19 immunotoxins in development work by exploiting the widespread presence of CD19 on B cells, with expression highly conserved in most neoplastic B cells, to direct treatment specifically towards B-cell cancers.[7][28] However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the MYC oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than initially suspected.[17][20]
CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CARs) have been utilized for their antitumor abilities in patients with CD19+ lymphoma and leukemia, first against Non-Hodgkins Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013.[4][29][30][31] CAR-19 T cells are genetically modified T cells that express a targeting moiety on their surface that confers T cell receptor (TCR) specificity towards CD19+ cells. CD19 activates the TCR signaling cascade that leads to proliferation, cytokine production, and ultimately lysis of the target cells, which in this case are CD19+ B cells. CAR-19 T cells are more effective than anti-CD19 immunotoxins because they can proliferate and remain in the body for a longer period of time. This comes with a caveat since now CD19− immune escape facilitated by splice variants, point mutations, and lineage switching can form as a major form of therapeutic resistance for patients with ALL.[32] | https://www.wikidoc.org/index.php/CD19 | |
b2b24e84a410250a167bbed064e15ab131de68ac | wikidoc | CD1D | CD1D
CD1D is the human gene that encodes the protein CD1d, a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.
# Biological significance
CD1d-presented lipid antigens activate a special class of T cells, known as natural killer T (NKT) cells, through the interaction with the T-cell receptor present on NKT membranes. When activated, NKT cells rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and interleukin 4 production.
# Nomenclature
CD1d is also known as R3G1
# Ligands
Some of the known ligands for CD1d are:
- α-galactosylceramide (α-GalCer), a compound originally derived from the marine sponge Agelas mauritanius with no physiological role but great research utility.
- α-glucuronyl- and α-galacturonyl- ceramides, a family of compounds of microbial origin which can be found, for example, on the cell wall of Sphingomonas, a ubiquitous Gram-negative bacterium. The related β-D-glucopyranosylceramide is accumulated in antigen-presenting cells after infection, where it serves to activate invariant NKTs (iNKTs), a special kind of NKT.
- iGb3, a self antigen which has been implied in iNKT selection.
- HS44, a synthetic amino cyclitolic ceramide analogue which has less contact with the TCR, activating iNKTs in a more constrained way than α-GalCer (specially in relation to Th2 cytokines production) and thus being more interesting for therapeutic use.
# CD1d tetramers
CD1d tetramers are protein constructs composed of four CD1d molecules joined together and usually fluorescently labelled, used to identify NKT cells or other CD1d-reactive cells. In particular, type I NKT cells and some type II NKT cells are stained by them. A differentiation of these two types can be obtained in human by using an antibody against the TCR Vα24 chain, which is specific of type I NKT cells.
Although they are the most widely used of CD1d oligomers, sometimes CD1d dimers (two units) or pentamers (five units) are used instead. | CD1D
CD1D is the human gene that encodes the protein CD1d,[1] a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.
# Biological significance
CD1d-presented lipid antigens activate a special class of T cells, known as natural killer T (NKT) cells, through the interaction with the T-cell receptor present on NKT membranes.[1] When activated, NKT cells rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and interleukin 4 production.
# Nomenclature
CD1d is also known as R3G1
# Ligands
Some of the known ligands for CD1d are:
- α-galactosylceramide (α-GalCer), a compound originally derived from the marine sponge Agelas mauritanius[2] with no physiological role but great research utility.
- α-glucuronyl- and α-galacturonyl- ceramides, a family of compounds of microbial origin which can be found, for example, on the cell wall of Sphingomonas, a ubiquitous Gram-negative bacterium.[3] The related β-D-glucopyranosylceramide is accumulated in antigen-presenting cells after infection, where it serves to activate invariant NKTs (iNKTs), a special kind of NKT.
- iGb3, a self antigen which has been implied in iNKT selection.[4]
- HS44, a synthetic amino cyclitolic ceramide analogue which has less contact with the TCR, activating iNKTs in a more constrained way than α-GalCer (specially in relation to Th2 cytokines production) and thus being more interesting for therapeutic use.[5]
# CD1d tetramers
CD1d tetramers are protein constructs composed of four CD1d molecules joined together and usually fluorescently labelled, used to identify NKT cells or other CD1d-reactive cells. In particular, type I NKT cells and some type II NKT cells are stained by them. A differentiation of these two types can be obtained in human by using an antibody against the TCR Vα24 chain, which is specific of type I NKT cells.[6]
Although they are the most widely used of CD1d oligomers, sometimes CD1d dimers (two units) or pentamers (five units) are used instead.[6] | https://www.wikidoc.org/index.php/CD1D | |
cff44ee6b4b333b6c18e4d5f550ca6ae771a2d14 | wikidoc | CD20 | CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.
In humans CD20 is encoded by the MS4A1 gene.
This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule that plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants that encode the same protein.
# Function
The protein has no known natural ligand and its function is to enable optimal B-cell immune response, specifically against T-independent antigens. It is suspected that it acts as a calcium channel in the cell membrane.
# Expression
CD20 is expressed on all stages of B cell development except the first and last; it is present from late pro-B cells through memory cells, but not on either early pro-B cells or plasma blasts and plasma cells. It is found on B-cell lymphomas, hairy cell leukemia, B-cell chronic lymphocytic leukemia, and melanoma cancer stem cells.
Immunohistochemistry can be used to determine the presence of CD20 on cells in histological tissue sections. Because CD20 remains present on the cells of most B-cell neoplasms, and is absent on otherwise similar appearing T-cell neoplasms, it can be very useful in diagnosing conditions such as B-cell lymphomas and leukaemias. However, the presence or absence of CD20 in such tumours is not relevant to prognosis, with the progression of the disease being much the same in either case. CD20 positive cells are also sometimes found in cases of Hodgkins disease, myeloma, and thymoma.
Antibody FMC7 (Flinder Medical Centre) appears to recognise a conformational variant of CD20 also known as the FMC7 antigen.
# Clinical significance
CD20 is the target of the monoclonal antibodies rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab, which are all active agents in the treatment of all B cell lymphomas, leukemias, and B cell-mediated autoimmune diseases.
The anti-CD20 mAB ofatumumab (Genmab) was approved by FDA in October 2009 for chronic lymphocytic leukemia.
The anti-CD20 mAB obinutuzumab (Gazyva) was approved by FDA in November 2013 for chronic lymphocytic leukemia.
Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include :
- Obinutuzumab for systemic lupus erythematosus,
- Rituximab for myalgic encephalomyelitis
- Ocaratuzumab for follicular lymphoma and rheumatoid arthritis,
- Ocrelizumab for multiple sclerosis (rheumatoid arthritis discontinued in 2010),
- TRU-015 (by Trubion), (discontinued in 2010)
- IMMU-106 (veltuzumab). for non-Hodgkin's lymphoma or (2015) immune thrombocytopenia.
# B cells, CD20, and diabetes mellitus
A link between the immune system's B cells and diabetes mellitus has been determined. In cases of obesity, the presence of fatty tissues surrounding the body's major organ systems results in cell necrosis and insulin desensitivity along the boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. An inflammation response that mobilizes both T and B cells results in the creation of antibodies against these cells, causing them to become less responsive to insulin by an as-yet unknown mechanism and promoting hypertension, hypertriglyceridemia, and arteriosclerosis, hallmarks of the metabolic syndrome. Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin desensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes the body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as an autoimmune disease rather than a purely metabolic one and focus treatment for it on immune system modulation. | CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.[1]
In humans CD20 is encoded by the MS4A1 gene.[2][3]
This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule that plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants that encode the same protein.[3]
# Function
The protein has no known natural ligand[4] and its function is to enable optimal B-cell immune response, specifically against T-independent antigens.[5] It is suspected that it acts as a calcium channel in the cell membrane.
# Expression
CD20 is expressed on all stages of B cell development except the first and last; it is present from late pro-B cells through memory cells, but not on either early pro-B cells or plasma blasts and plasma cells.[6][7] It is found on B-cell lymphomas, hairy cell leukemia, B-cell chronic lymphocytic leukemia, and melanoma cancer stem cells.[8]
Immunohistochemistry can be used to determine the presence of CD20 on cells in histological tissue sections. Because CD20 remains present on the cells of most B-cell neoplasms, and is absent on otherwise similar appearing T-cell neoplasms, it can be very useful in diagnosing conditions such as B-cell lymphomas and leukaemias. However, the presence or absence of CD20 in such tumours is not relevant to prognosis, with the progression of the disease being much the same in either case. CD20 positive cells are also sometimes found in cases of Hodgkins disease, myeloma, and thymoma.[9]
Antibody FMC7 (Flinder Medical Centre) appears to recognise a conformational variant of CD20[10][11] also known as the FMC7 antigen.[12]
# Clinical significance
CD20 is the target of the monoclonal antibodies rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab, which are all active agents in the treatment of all B cell lymphomas, leukemias, and B cell-mediated autoimmune diseases.
The anti-CD20 mAB ofatumumab (Genmab) was approved by FDA in October 2009 for chronic lymphocytic leukemia.
The anti-CD20 mAB obinutuzumab (Gazyva) was approved by FDA in November 2013 for chronic lymphocytic leukemia.
Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include :
- Obinutuzumab for systemic lupus erythematosus,
- Rituximab for myalgic encephalomyelitis
- Ocaratuzumab for follicular lymphoma and rheumatoid arthritis,
- Ocrelizumab for multiple sclerosis (rheumatoid arthritis discontinued in 2010),
- TRU-015 (by Trubion), (discontinued in 2010[13])
- IMMU-106 (veltuzumab).[14] for non-Hodgkin's lymphoma or (2015) immune thrombocytopenia.
# B cells, CD20, and diabetes mellitus
A link between the immune system's B cells and diabetes mellitus has been determined.[15] In cases of obesity, the presence of fatty tissues surrounding the body's major organ systems results in cell necrosis and insulin desensitivity along the boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. An inflammation response that mobilizes both T and B cells results in the creation of antibodies against these cells, causing them to become less responsive to insulin by an as-yet unknown mechanism and promoting hypertension, hypertriglyceridemia, and arteriosclerosis, hallmarks of the metabolic syndrome. Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin desensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes the body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as an autoimmune disease rather than a purely metabolic one and focus treatment for it on immune system modulation.[15] | https://www.wikidoc.org/index.php/CD20 | |
e76daad7ea37d9ef5f8240c1486e5d2e7ea2bf67 | wikidoc | CD22 | CD22
CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.
CD22 is a sugar binding transmembrane protein, which specifically binds sialic acid with an immunoglobulin (Ig) domain located at its N-terminus. The presence of Ig domains makes CD22 a member of the immunoglobulin superfamily. CD22 functions as an inhibitory receptor for B cell receptor (BCR) signaling. It is also involved in the B cell trafficking to Peyer's patches in mice.
An immunotoxin, BL22, that targets this receptor is being tested at the NIH.
# Interactions
CD22 has been shown to interact with Grb2, PTPN6, LYN, SHC1 and INPP5D. | CD22
CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins.[1] It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.[2]
CD22 is a sugar binding transmembrane protein, which specifically binds sialic acid with an immunoglobulin (Ig) domain located at its N-terminus. The presence of Ig domains makes CD22 a member of the immunoglobulin superfamily. CD22 functions as an inhibitory receptor for B cell receptor (BCR) signaling. It is also involved in the B cell trafficking to Peyer's patches in mice.[3]
An immunotoxin, BL22, that targets this receptor is being tested at the NIH.[4]
# Interactions
CD22 has been shown to interact with Grb2,[5][6] PTPN6,[6][7][8][9][10] LYN,[5][8] SHC1[5] and INPP5D.[5] | https://www.wikidoc.org/index.php/CD22 | |
372c606f8ff32f8c5831c8fc18d2da491e041a82 | wikidoc | CD23 | CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin. It is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets.
There are two forms of CD23: CD23a and CD23b. CD23a is present on follicular B cells, whereas CD23b requires IL-4 to be expressed on T-cells, monocytes, Langerhans cells, eosinophils, and macrophages.
# Function
CD23 is known to have a role of transportation in antibody feedback regulation. Antigens which enter the blood stream can be captured by antigen specific IgE antibodies. The IgE immune complexes that are formed bind to CD23 molecules on B cells, and are transported to the B cell follicles of the spleen. The antigen is then transferred from CD23+ B cells to CD11c+ antigen presenting cells. The CD11c+ cells in turn present the antigen to CD4+ T cells, which can lead to an enhanced antibody response.
# Clinical significance
The allergen responsible in dust mite allergy Der p 1 is known to cleave CD23 from a cells surface. As CD23 is soluble, it can move freely and interact with cells in plasma. Recent studies have shown that increased levels of soluble CD23 cause the recruitment of non-sensitised B-cells in the presentation of antigen peptides to allergen-specific B-cells, therefore increasing the production of allergen specific IgE. IgE, in turn, is known to upregulate the cellular expression of CD23 and Fc epsilon RI (high-affinity IgE receptor).
In flow cytometry, CD23 is helpful in the differentiation of chronic lymphocytic leukemia (CD23-positive) from mantle cell lymphoma (CD23-negative). CD23 can also be demonstrated in germinal centre B-cells using immunohistochemistry, but it is not present in the resting cells of the surrounding mantle zone. Lymphomas arising from the mantle zone are generally negative for CD23, but most B-cell chronic lymphomocytic leukaemias and low-grade B-cell lymphomas are positive, allowing immunohistochemistry to distinguish these conditions, which otherwise have a similar appearance. Reed–Sternberg cells are usually positive for CD23. | CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin. It is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets.
There are two forms of CD23: CD23a and CD23b. CD23a is present on follicular B cells, whereas CD23b requires IL-4 to be expressed on T-cells, monocytes, Langerhans cells, eosinophils, and macrophages.[1]
# Function
CD23 is known to have a role of transportation in antibody feedback regulation. Antigens which enter the blood stream can be captured by antigen specific IgE antibodies. The IgE immune complexes that are formed bind to CD23 molecules on B cells, and are transported to the B cell follicles of the spleen. The antigen is then transferred from CD23+ B cells to CD11c+ antigen presenting cells. The CD11c+ cells in turn present the antigen to CD4+ T cells, which can lead to an enhanced antibody response.[2]
# Clinical significance
The allergen responsible in dust mite allergy Der p 1 is known to cleave CD23 from a cells surface. As CD23 is soluble, it can move freely and interact with cells in plasma. Recent studies have shown that increased levels of soluble CD23 cause the recruitment of non-sensitised B-cells in the presentation of antigen peptides to allergen-specific B-cells, therefore increasing the production of allergen specific IgE. IgE, in turn, is known to upregulate the cellular expression of CD23 and Fc epsilon RI (high-affinity IgE receptor).
In flow cytometry, CD23 is helpful in the differentiation of chronic lymphocytic leukemia (CD23-positive) from mantle cell lymphoma (CD23-negative).[3] CD23 can also be demonstrated in germinal centre B-cells using immunohistochemistry, but it is not present in the resting cells of the surrounding mantle zone. Lymphomas arising from the mantle zone are generally negative for CD23, but most B-cell chronic lymphomocytic leukaemias and low-grade B-cell lymphomas are positive, allowing immunohistochemistry to distinguish these conditions, which otherwise have a similar appearance. Reed–Sternberg cells are usually positive for CD23.[4] | https://www.wikidoc.org/index.php/CD23 | |
999424e8532b76d3dd8dc5678f241aef1bfa95f0 | wikidoc | CD27 | CD27
CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule.
# Function
The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. This receptor transduces signals that lead to the activation of NF-κB and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA), a proapoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor.
# Clinical significance
## As a drug target
Varlilumab is an antibody that binds to CD27 and is an experimental cancer treatment.
# Interactions
CD27 has been shown to interact with SIVA1, TRAF2 and TRAF3. | CD27
CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule.
# Function
The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. This receptor transduces signals that lead to the activation of NF-κB and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA), a proapoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor.[1]
# Clinical significance
## As a drug target
Varlilumab is an antibody that binds to CD27 and is an experimental cancer treatment.
# Interactions
CD27 has been shown to interact with SIVA1,[2] TRAF2[3][4] and TRAF3.[3][4] | https://www.wikidoc.org/index.php/CD27 | |
82200734bb1be595caf47e8b22c4f199c7925f8d | wikidoc | CD28 | CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins (IL-6 in particular).
CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins. When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen-presenting cells (APCs). The CD86 expression on antigen-presenting cells is constitutive (expression is independent of environmental factors).
CD28 is the only B7 receptor constitutively expressed on naive T cells. Association of the TCR of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic.
# Signaling
CD28 possesses an intracellular domain with several residues that are critical for its effective signaling. The YMNM motif beginning at tyrosine 170 in particular is critical for the recruitment of SH2-domain containing proteins, especially PI3K, Grb2 and Gads. The Y170 residue is important for the induction of Bcl-xL via mTOR and enhancement of IL-2 transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2 and Gads and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2 and Gads are unable to compensate for the loss of PI3K. IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a PI3K-independent second phase which is dependent on formation of an immune synapse, which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.
CD28 also contains two proline-rich motifs that are able to bind SH3-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck and lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-xL. Phosphorylation of a tyrosine within the PYAP motif (Y191 in the mature human CD28) forms a high affinity-binding site for the SH2 domain of the src kinase Lck which in turn binds to the serine kinase PKC-θ.
# Structure
The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of Oxford.
# As a drug target
The drug TGN1412, which was produced by the German biotech company TeGenero, and unexpectedly caused multiple organ failure in trials, is a superagonist of CD28. Unfortunately, it is often ignored that the same receptors also exist on cells other than lymphocytes. CD28 has also been found to stimulate eosinophil granulocytes where its ligation with anti-CD28 leads to the release of IL-2, IL4, IL-13 and IFN-γ.
# Interactions
CD28 has been shown to interact with:
- GRAP2,
- Grb2, and
- PIK3R1. | CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins (IL-6 in particular).
CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins. When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen-presenting cells (APCs). The CD86 expression on antigen-presenting cells is constitutive (expression is independent of environmental factors).
CD28 is the only B7 receptor constitutively expressed on naive T cells. Association of the TCR of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic.
# Signaling
CD28 possesses an intracellular domain with several residues that are critical for its effective signaling. The YMNM motif beginning at tyrosine 170 in particular is critical for the recruitment of SH2-domain containing proteins, especially PI3K,[1] Grb2[2] and Gads. The Y170 residue is important for the induction of Bcl-xL via mTOR and enhancement of IL-2 transcription via PKCθ, but has no effect on proliferation and results a slight reduction in IL-2 production. The N172 residue (as part of the YMNM) is important for the binding of Grb2 and Gads and seems to be able to induce IL-2 mRNA stability but not NF-κB translocation. The induction of NF-κB seems to be much more dependent on the binding of Gads to both the YMNM and the two proline-rich motifs within the molecule. However, mutation of the final amino acid of the motif, M173, which is unable to bind PI3K but is able to bind Grb2 and Gads, gives little NF-κB or IL-2, suggesting that those Grb2 and Gads are unable to compensate for the loss of PI3K. IL-2 transcription appears to have two stages; a Y170-dependent, PI3K-dependent initial phase which allows transcription and a PI3K-independent second phase which is dependent on formation of an immune synapse, which results in enhancement of IL-2 mRNA stability. Both are required for full production of IL-2.
CD28 also contains two proline-rich motifs that are able to bind SH3-containing proteins. Itk and Tec are able to bind to the N-terminal of these two motifs which immediately succeeds the Y170 YMNM; Lck binds the C-terminal. Both Itk and Lck are able to phosphorylate the tyrosine residues which then allow binding of SH2 containing proteins to CD28. Binding of Tec to CD28 enhances IL-2 production, dependent on binding of its SH3 and PH domains to CD28 and PIP3 respectively. The C-terminal proline-rich motif in CD28 is important for bringing Lck and lipid rafts into the immune synapse via filamin-A. Mutation of the two prolines within the C-terminal motif results in reduced proliferation and IL-2 production but normal induction of Bcl-xL. Phosphorylation of a tyrosine within the PYAP motif (Y191 in the mature human CD28) forms a high affinity-binding site for the SH2 domain of the src kinase Lck which in turn binds to the serine kinase PKC-θ.[3]
# Structure
The first structure of CD28 was obtained in 2005 by the T-cell biology group at the University of Oxford.[4]
# As a drug target
The drug TGN1412, which was produced by the German biotech company TeGenero, and unexpectedly caused multiple organ failure in trials, is a superagonist of CD28. Unfortunately, it is often ignored that the same receptors also exist on cells other than lymphocytes. CD28 has also been found to stimulate eosinophil granulocytes where its ligation with anti-CD28 leads to the release of IL-2, IL4, IL-13 and IFN-γ.[5][6]
# Interactions
CD28 has been shown to interact with:
- GRAP2,[7]
- Grb2,[8][9] and
- PIK3R1.[10] | https://www.wikidoc.org/index.php/CD28 | |
fb73af441e76809557d965aa7064c1ad7514a94f | wikidoc | CD29 | CD29
Integrin beta-1 also known as CD29 is a protein that in humans is encoded by the ITGB1 gene. CD29 is an integrin unit associated with very late antigen receptors. It is known to conjoin with alpha-3 subunit to create α3β1 complex that reacts to such molecules as netrin-1 and reelin. In cardiac muscle and skeletal muscle, the integrin beta-1D isoform is specifically expressed, and localizes to costameres, where it aids in the lateral force transmission from the Z-discs to the extracellular matrix. Abnormal levels of integrin beta-1D have been found in limb girdle muscular dystrophy and polyneuropathy.
# Structure
Integrin beta-1 can exist as different isoforms via alternative splicing. Six alternatively spliced variants have been found for this gene which encode five proteins with alternate C-termini. Integrin receptors exist as heterodimers, and greater than 20 different integrin heterodimeric receptors have been described. All integrins, alpha and beta forms, have large extracellular and short intracellular domains. The cytoplasmic domain of integrin beta-1 binds to the actin cytoskeleton. Integrin beta-1 is the most abundant beta-integrin expressed and associates with at least 10 different integrin-alpha subunits.
# Function
Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells. Integrins link the actin cytoskeleton with the extracellular matrix and they transmit signals bidirectionally between the extracellular matrix and cytoplasmic domains.
Beta-integrins are primarily responsible for targeting integrin dimers to the appropriate subcellular locations, which in adhesive cells is mainly focal adhesions. Integrin beta-1 mutants lose the ability to target to sites of focal adhesions.
Three novel isoforms of integrin beta-1 have been identified, termed beta-1B, beta-1C and beta-1D. Integrin beta-1B is transcribed when the proximal 26 amino acids of the cytoplasmic domain in exon 6 are retained and then succeeded by a 12 amino acid stretch from an adjacent intronic region. The integrin beta-1B isoform appears to act as a dominant negative in that it inhibits cell adhesion. A second integrin beta-1 isoform, termed beta-1C, was described to have an additional 48 amino acids appended to the 26 amino acids in the cytoplasmic domain; the function of this isoform was an inhibitory one on DNA synthesis in the G1 phase of the cell cycle. The third isoform, termed beta-1D, is a striated muscle-specific isoform, which replaces the canonical beta-1A isoform in cardiac and skeletal muscle cells. This isoform is produced from splicing into a novel additional exon between exons 6 and 7. The cytoplasmic domain of integrin beta-1D replaces the distal 21 amino acids (present in integrin beta-1A) with an alternative stretch of 24 amino acids (13 unique).
Integrin beta-1D appears to be developmentally regulated during myofibrilogenesis, appearing immediately following the fusion of myoblasts in C2C12 cell with rising levels throughout myofibrillar differentiation. Integrin beta-1D is specifically localized to costameres and intercalated discs of cardiac muscle and costameres, myotendinous junctions and neuromuscular junctions of skeletal muscle, and it appears to function in general like other integrins, as the clustering of beta-1D integrins on the surface of CHO cells resulted in tyrosine phosphorylation of pp125FAK and induced mitogen-activated protein kinase activation.
# Clinical significance
In patients with limb girdle muscular dystrophy, type 2C, beta-1D integrin has been shown to be severely reduced in skeletal muscle biopsies, coordinate with a reduction in alpha 7B-integrin and filamin 2.
In patients with sensitive-motor polyneuropathy, levels of integrin alpha-7B, integrin beta-1D and agrin were significantly reduced nearly to undetectable levels; and this corresponded with lower mRNA levels.
# Interactions
CD29 has been shown to interact with
- ACTN1;
- CD46,
- CD9,
- FHL2,
- Filamin,
- FLNB,
- CD81,
- GNB2L1,
- ITGB1BP1,
- LGALS8,
- MAP4K4,
- NME1,
- PKC alpha,
- TLN1,
- TSPAN4, and
- YWHAB. | CD29
Integrin beta-1 also known as CD29 is a protein that in humans is encoded by the ITGB1 gene.[1] CD29 is an integrin unit associated with very late antigen receptors. It is known to conjoin with alpha-3 subunit to create α3β1 complex that reacts to such molecules as netrin-1 and reelin. In cardiac muscle and skeletal muscle, the integrin beta-1D isoform is specifically expressed, and localizes to costameres, where it aids in the lateral force transmission from the Z-discs to the extracellular matrix. Abnormal levels of integrin beta-1D have been found in limb girdle muscular dystrophy and polyneuropathy.
# Structure
Integrin beta-1 can exist as different isoforms via alternative splicing. Six alternatively spliced variants have been found for this gene which encode five proteins with alternate C-termini.[2] Integrin receptors exist as heterodimers, and greater than 20 different integrin heterodimeric receptors have been described. All integrins, alpha and beta forms, have large extracellular and short intracellular domains.[3] The cytoplasmic domain of integrin beta-1 binds to the actin cytoskeleton.[4] Integrin beta-1 is the most abundant beta-integrin expressed and associates with at least 10 different integrin-alpha subunits.[3]
# Function
Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells.[3] Integrins link the actin cytoskeleton with the extracellular matrix and they transmit signals bidirectionally between the extracellular matrix and cytoplasmic domains.[5][6]
Beta-integrins are primarily responsible for targeting integrin dimers to the appropriate subcellular locations, which in adhesive cells is mainly focal adhesions.[4][7] Integrin beta-1 mutants lose the ability to target to sites of focal adhesions.[8][9]
Three novel isoforms of integrin beta-1 have been identified, termed beta-1B, beta-1C and beta-1D. Integrin beta-1B is transcribed when the proximal 26 amino acids of the cytoplasmic domain in exon 6 are retained and then succeeded by a 12 amino acid stretch from an adjacent intronic region.[10] The integrin beta-1B isoform appears to act as a dominant negative in that it inhibits cell adhesion.[11] A second integrin beta-1 isoform, termed beta-1C, was described to have an additional 48 amino acids appended to the 26 amino acids in the cytoplasmic domain;[12] the function of this isoform was an inhibitory one on DNA synthesis in the G1 phase of the cell cycle.[13] The third isoform, termed beta-1D, is a striated muscle-specific isoform, which replaces the canonical beta-1A isoform in cardiac and skeletal muscle cells. This isoform is produced from splicing into a novel additional exon between exons 6 and 7. The cytoplasmic domain of integrin beta-1D replaces the distal 21 amino acids (present in integrin beta-1A) with an alternative stretch of 24 amino acids (13 unique).[14][15]
Integrin beta-1D appears to be developmentally regulated during myofibrilogenesis,[15] appearing immediately following the fusion of myoblasts in C2C12 cell with rising levels throughout myofibrillar differentiation.[16] Integrin beta-1D is specifically localized to costameres and intercalated discs of cardiac muscle and costameres, myotendinous junctions and neuromuscular junctions of skeletal muscle, and it appears to function in general like other integrins, as the clustering of beta-1D integrins on the surface of CHO cells resulted in tyrosine phosphorylation of pp125FAK and induced mitogen-activated protein kinase activation.[16]
# Clinical significance
In patients with limb girdle muscular dystrophy, type 2C, beta-1D integrin has been shown to be severely reduced in skeletal muscle biopsies, coordinate with a reduction in alpha 7B-integrin and filamin 2.[17]
In patients with sensitive-motor polyneuropathy, levels of integrin alpha-7B, integrin beta-1D and agrin were significantly reduced nearly to undetectable levels; and this corresponded with lower mRNA levels.[18]
# Interactions
CD29 has been shown to interact with
- ACTN1;[19][20]
- CD46,[21]
- CD9,[22][23]
- FHL2,[24]
- Filamin,[25][26]
- FLNB,[25]
- CD81,[23][27]
- GNB2L1,[28][29]
- ITGB1BP1,[30][31]
- LGALS8,[32]
- MAP4K4,[33]
- NME1,[34]
- PKC alpha,[28][35]
- TLN1,[36][37]
- TSPAN4,[38] and
- YWHAB.[39] | https://www.wikidoc.org/index.php/CD29 | |
4be63c4b1673f9909f7ce63eabd3d4b1ba888a68 | wikidoc | CD30 | CD30
CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.
# Function
This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. It is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
# Clinical significance
CD30 is associated with anaplastic large cell lymphoma. It is expressed in embryonal carcinoma but not in seminoma and is thus a useful marker in distinguishing between these germ cell tumors. CD30 and CD15 are also expressed on Reed-Sternberg cells typical for Hodgkin's lymphoma.
# Cancer treatment
CD30 is the target of the FDA approved therapeutic brentuximab vedotin (Adcetris). It is approved for use in:
- Hodgkin lymphoma (HL) (brentuximab vedotin) after failure of autologous stem cell transplant (ASCT)
- HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens
- Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen
- Primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy
# Interactions
CD30 has been shown to interact with TRAF5, TRAF1, TRAF2 and TRAF3. | CD30
CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.
# Function
This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. It is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[1]
# Clinical significance
CD30 is associated with anaplastic large cell lymphoma. It is expressed in embryonal carcinoma but not in seminoma and is thus a useful marker in distinguishing between these germ cell tumors.[2] CD30 and CD15 are also expressed on Reed-Sternberg cells typical for Hodgkin's lymphoma.[3]
# Cancer treatment
CD30 is the target of the FDA approved therapeutic brentuximab vedotin (Adcetris). It is approved for use in:
- Hodgkin lymphoma (HL) (brentuximab vedotin) after failure of autologous stem cell transplant (ASCT)
- HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens
- Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen[4]
- Primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy[5]
# Interactions
CD30 has been shown to interact with TRAF5,[6] TRAF1,[7] TRAF2[6][7] and TRAF3.[7] | https://www.wikidoc.org/index.php/CD30 | |
f06990c7cd54b16496cac501ba6b603c855864d4 | wikidoc | CD33 | CD33
CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.
It binds sialic acids, therefore is a member of the SIGLEC family of lectins.
# Structure
The extracellular portion of this receptor contains two immunoglobulin domains (one IgV and one IgC2 domain), placing CD33 within the immunoglobulin superfamily. The intracellular portion of CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are implicated in inhibition of cellular activity.
# Clinical significance
CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), an Antibody-drug conjugate for the treatment of patients with acute myeloid leukemia. The drug is a recombinant, humanized anti-CD33 monoclonal antibody (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic calicheamicin (N-acetyl-γ-calicheamicin) via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid).
On September 1, 2017, the FDA approved Pfizer's Mylotarg.
Gemtuzumab ozogamicin was initially approved by the U.S. Food and Drug Administration in 2000. However, during post marketing clinical trials researchers noticed a greater number of deaths in the group of patients who received gemtuzumab ozogamicin compared with those receiving chemotherapy alone. Based on these results, Pfizer voluntarily withdrew gemtuzumab ozogamicin from the market in mid-2010, but was reintroduced to the market in 2017.
CD33 is also the target in Vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate being developed by Seattle Genetics, utilizing this company's ADC technology. | CD33
CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage.[1] It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.[2]
It binds sialic acids, therefore is a member of the SIGLEC family of lectins.
# Structure
The extracellular portion of this receptor contains two immunoglobulin domains (one IgV and one IgC2 domain), placing CD33 within the immunoglobulin superfamily. The intracellular portion of CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are implicated in inhibition of cellular activity.[3]
# Clinical significance
CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories), [4] an Antibody-drug conjugate for the treatment of patients with acute myeloid leukemia. The drug is a recombinant, humanized anti-CD33 monoclonal antibody (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic calicheamicin (N-acetyl-γ-calicheamicin) via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid).[5]
On September 1, 2017, the FDA approved Pfizer's Mylotarg. [6]
Gemtuzumab ozogamicin was initially approved by the U.S. Food and Drug Administration in 2000. However, during post marketing clinical trials researchers noticed a greater number of deaths in the group of patients who received gemtuzumab ozogamicin compared with those receiving chemotherapy alone. Based on these results, Pfizer voluntarily withdrew gemtuzumab ozogamicin from the market in mid-2010, but was reintroduced to the market in 2017. [7] [8] [9]
CD33 is also the target in Vadastuximab talirine (SGN-CD33A), a novel antibody-drug conjugate being developed by Seattle Genetics, utilizing this company's ADC technology.[10] | https://www.wikidoc.org/index.php/CD33 | |
3ffd37c64fdce2d97af145acbe598e7f859effb9 | wikidoc | CD34 | CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first described on hematopoietic stem cells independently by Civin et al. and Tindle et al. as a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of hematopoietic stem cells to bone marrow extracellular matrix or directly to stromal cells. Clinically, it is associated with the selection and enrichment of hematopoietic stem cells for bone marrow transplants. Due to these historical and clinical associations, CD34 expression is almost ubiquitously related to hematopoietic cells however it is actually found on many other cell types as well.
# Function
The CD34 protein is a member of a family of single-pass transmembrane sialomucin proteins that show expression on early hematopoietic and vascular-associated tissue. However, little is known about its exact function.
CD34 is also an important adhesion molecule and is required for T cells to enter lymph nodes. It is expressed on lymph node endothelia, whereas the L-selectin to which it binds is on the T cell. Conversely, under other circumstances CD34 has been shown to act as molecular "Teflon" and block mast cell, eosinophil and dendritic cell precursor adhesion, and to facilitate opening of vascular lumina. Finally, recent data suggest CD34 may also play a more selective role in chemokine-dependent migration of eosinophils and dendritic cell precursors. Regardless of its mode of action, under all circumstances CD34, and its relatives podocalyxin and endoglycan, facilitates cell migration.
# Tissue distribution
Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells, or in mesenchymal stem cells, endothelial progenitor cells, endothelial cells of blood vessels but not lymphatics (except pleural lymphatics), mast cells, a sub-population of dendritic cells (which are factor XIIIa-negative) in the interstitium and around the adnexa of dermis of skin, as well as cells in soft tissue tumors like DFSP, GIST, SFT, HPC, and to some degree in MPNSTs, etc. The presence of CD34 on non-hematopoietic cells in various tissues has been linked to progenitor and adult stem cell phenotypes.
It is important to mention that Long-Term Hematopoietic Stem Cells (LT-HSCs) in mice and humans are the hematopoietic cells with the greatest self-renewal capacity. Human HSCs express the CD34 marker.
CD34 is expressed in roughly 20% of murine hematopoietic stem cells, and can be stimulated and reversed.
# Clinical applications
CD34+ cells may be isolated from blood samples using immunomagnetic or immunofluorescent methods.
Antibodies are used to quantify and purify hematopoietic progenitor stem cells for research and for clinical bone marrow transplantation. However, counting CD34+ mononuclear cells may overestimate myeloid blasts in bone marrow smears due to hematogones (B lymphocyte precursors) and CD34+ megakaryocytes.
Cells observed as CD34+ and CD38- are of an undifferentiated, primitive form; i.e., they are multipotential hemopoietic stem cells. Thus, because of their CD34+ expression, such undifferentiated cells can be sorted out.
In tumors, CD34 is found in alveolar soft part sarcoma, preB-ALL (positive in 75%), AML (40%), AML-M7 (most), dermatofibrosarcoma protuberans, gastrointestinal stromal tumors, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, mengingeal hemangiopericytomas, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.
A negative CD34 may exclude Ewing's sarcoma/PNET, myofibrosarcoma of the breast, and inflammatory myofibroblastic tumors of the stomach.
Injection of CD34+ hematopoietic stem cells has been clinically applied to treat various diseases including spinal cord injury, liver cirrhosis and peripheral vascular disease.
# Interactions
CD34 has been shown to interact with CRKL. It also interacts with L-selectin, important in inflammation. | CD34
CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.[1][2][3]
CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first described on hematopoietic stem cells independently by Civin et al. and Tindle et al.[4][5][6][7] as a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of hematopoietic stem cells to bone marrow extracellular matrix or directly to stromal cells. Clinically, it is associated with the selection and enrichment of hematopoietic stem cells for bone marrow transplants. Due to these historical and clinical associations, CD34 expression is almost ubiquitously related to hematopoietic cells however it is actually found on many other cell types as well.[8]
# Function
The CD34 protein is a member of a family of single-pass transmembrane sialomucin proteins that show expression on early hematopoietic and vascular-associated tissue.[9] However, little is known about its exact function.[10]
CD34 is also an important adhesion molecule and is required for T cells to enter lymph nodes. It is expressed on lymph node endothelia, whereas the L-selectin to which it binds is on the T cell.[11][12] Conversely, under other circumstances CD34 has been shown to act as molecular "Teflon" and block mast cell, eosinophil and dendritic cell precursor adhesion, and to facilitate opening of vascular lumina.[13][14] Finally, recent data suggest CD34 may also play a more selective role in chemokine-dependent migration of eosinophils and dendritic cell precursors.[15][16] Regardless of its mode of action, under all circumstances CD34, and its relatives podocalyxin and endoglycan, facilitates cell migration.[9][15]
# Tissue distribution
Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells, or in mesenchymal stem cells, endothelial progenitor cells, endothelial cells of blood vessels but not lymphatics (except pleural lymphatics), mast cells, a sub-population of dendritic cells (which are factor XIIIa-negative) in the interstitium and around the adnexa of dermis of skin, as well as cells in soft tissue tumors like DFSP, GIST, SFT, HPC, and to some degree in MPNSTs, etc. The presence of CD34 on non-hematopoietic cells in various tissues has been linked to progenitor and adult stem cell phenotypes.[8]
It is important to mention that Long-Term Hematopoietic Stem Cells (LT-HSCs) in mice and humans are the hematopoietic cells with the greatest self-renewal capacity.[citation needed] Human HSCs express the CD34 marker.[citation needed]
CD34 is expressed in roughly 20% of murine hematopoietic stem cells,[17] and can be stimulated and reversed.[18]
# Clinical applications
CD34+ cells may be isolated from blood samples using immunomagnetic or immunofluorescent methods.
Antibodies are used to quantify and purify hematopoietic progenitor stem cells for research and for clinical bone marrow transplantation. However, counting CD34+ mononuclear cells may overestimate myeloid blasts in bone marrow smears due to hematogones (B lymphocyte precursors) and CD34+ megakaryocytes.
Cells observed as CD34+ and CD38- are of an undifferentiated, primitive form; i.e., they are multipotential hemopoietic stem cells. Thus, because of their CD34+ expression, such undifferentiated cells can be sorted out.
In tumors, CD34 is found in alveolar soft part sarcoma, preB-ALL (positive in 75%), AML (40%), AML-M7 (most), dermatofibrosarcoma protuberans, gastrointestinal stromal tumors, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, mengingeal hemangiopericytomas, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.
A negative CD34 may exclude Ewing's sarcoma/PNET, myofibrosarcoma of the breast, and inflammatory myofibroblastic tumors of the stomach.
Injection of CD34+ hematopoietic stem cells has been clinically applied to treat various diseases including spinal cord injury,[19] liver cirrhosis[20] and peripheral vascular disease.[21]
# Interactions
CD34 has been shown to interact with CRKL.[22] It also interacts with L-selectin, important in inflammation. | https://www.wikidoc.org/index.php/CD34 | |
6b13269ee1be050d06aae1bf398d1e6d3e69e02d | wikidoc | CD36 | CD36
CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
Work in genetically modified rodents suggest a role for CD36 in fatty acid metabolism, heart disease, taste, and dietary fat processing in the intestine. It may be involved in glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy and Alzheimer's disease.
# Structure
## Primary
In humans, rats and mice, CD36 consists of 472 amino acids with a predicted molecular weight of approximately 53,000 Da. However, CD36 is extensively glycosylated and has an apparent molecular weight of 88,000 Da as determined by SDS polyacrylamide gel electrophoresis.
## Tertiary
Using Kyte-Doolittle analysis, the amino acid sequence of CD36 predicts a hydrophobic region near each end of the protein large enough to span cellular membranes. Based on this notion and the observation that CD36 is found on the surface of cells, CD36 is thought to have a 'hairpin-like' structure with α-helices at the C- and N- termini projecting through the membrane and a larger extracellular loop (Fig. 1). This topology is supported by transfection experiments in cultured cells using deletion mutants of CD36.
Based on the crystal structure of the homologous SCARB2, a model of the extracellullar domain of CD36 has been produced. Like SCARB2, CD36 is proposed to contain an antiparallel β-barrel core with many short α-helices adorning it. The structure is predicted to contain a hydrophobic transport tunnel.
Disulfide linkages between 4 of the 6 cysteine residues in the extracellular loop are required for efficient intracellular processing and transport of CD36 to the plasma membrane. It is not clear what role these linkages play on the function of the mature CD36 protein on the cell surface.
## Posttranslational modification
Besides glycosylation, additional posttranslational modifications have been reported for CD36. CD36 is modified with 4 palmitoyl chains, 2 on each of the two intracellular domains. The function of these lipid modifications is currently unknown but they likely promote the association of CD36 with the membrane and possibly lipid rafts which appear to be important for some CD36 functions. CD36 could be also phosphorylated at Y62, T92, T323, ubiquitinated at K56, K469, K472 and acetylated at K52, K56, K166, K231, K394, K398, K403.
## Protein-protein interactions
In the absence of ligand, membrane bound CD36 exists primarily in a monomeric state. However exposure to the thrombospondin ligand causes CD36 to dimerize. This dimerization has been proposed to play an important role in CD36 signal transduction.
# Genetics
In humans, The gene is located on the long arm of chromosome 7 at band 11.2 (7q11.2) and is encoded by 15 exons that extend over more than 32 kilobases. Both the 5' and the 3' untranslated regions contain introns: the 5' with two and the 3' one. Exons 1, 2 and first 89 nucleotides of exon 3 and as well as exon 15 are non-coding. Exon 3 contains encodes the N-terminal cytoplasmic and transmembrane domains. The C-terminal cytoplasmic and transmembrane regions is encoded by exon 14. The extracellular domain is encoded by the central 11 exons. Alternative splicing of the untranslated regions gives rise to at least two mRNA species.
The transcription initiation site of the CD36 gene has been mapped to 289 nucleotides upstream from the translational start codon and a TATA box and several putative cis regulatory regions lie further 5'. A binding site for PEBP2/CBF factors has been identified between -158 and -90 and disruption of this site reduces expression. The gene is the transcriptional control of the nuclear receptor PPAR/RXR heterodimer (Peroxisome proliferator-activated receptor – Retinoid X receptor) and gene expression can be up regulated using synthetic and natural ligands for PPAR and RXR, including the thiazolidinedione class of anti-diabetic drugs and the vitamin A metabolite 9-cis-retinoic acid respectively.
# Tissue distribution
CD36 is found on platelets, erythrocytes, monocytes, differentiated adipocytes, skeletal muscle, mammary epithelial cells, spleen cells and some skin microdermal endothelial cells.
# Function
The protein itself belongs to the class B scavenger receptor family which includes receptors for selective cholesteryl ester uptake, scavenger receptor class B type I (SR-BI) and lysosomal integral membrane protein II (LIMP-II).
CD36 interacts with a number of ligands, including collagen types I and IV, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, platelet-agglutinating protein p37, oxidized low density lipoprotein and long-chain fatty acids.
On macrophages CD36 forms part of a non-opsonic receptor (the scavenger receptor CD36/alphaV beta3 complex) and is involved in phagocytosis.
CD36 has also been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis.
On binding a ligand the protein and ligand are internalized. This internalization is independent of macropinocytosis and occurs by an actin dependent mechanism requiring the activation Src-family kinases, JNK and Rho-family GTPases. Unlike macropinocytosis this process is not affected by inhibitors of phosphatidylinositol 3-kinase or Na+/H+ exchange.
CD36 ligands have also been shown to promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.
Recently, CD36 was linked to store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2
CD36 function in long-chain fatty acid uptake and signaling can be irreversibly inhibited by sulfo-N-succinimidyl oleate (SSO), which binds lysine 164 within a hydrophobic pocked shared by several CD36 ligands, e.g. fatty acid and oxLDL.
# Clinical significance
## Malaria
Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite and CD36 has been shown to be a major sequestration receptor on microvascular endothelial cells. Parasitised erythrocytes adhere to endothelium at the trophozoite/schizonts stage simultaneous with the appearance of the var gene product (erythrocyte membrane protein 1) on the erythrocyte surface. The appearance of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on the erythrocyte surface is a temperature dependent phenomenon which is due to increased protein trafficking to the erythrocyte surface at the raised temperature. PfEMP1 can bind other endothelial receptors - thrombospondin (TSP) and intercellular adhesion molecule 1 (ICAM-1) – in addition to CD36 - and genes other than PfEMP1 also bind to CD36: cytoadherence linked protein (clag) and sequestrin. The PfEMP1 binding site on CD36 is known to be located on exon 5.
CD36 on the surface of the platelets has been shown to be involved in adherence but direct adherence to the endothelium by the infected erythrocytes also occurs. Autoaggregation of infected erythrocytes by platelets has been shown to correlate with severe malaria and cerebral malaria in particular and antiplatelet antibodies may offer some protection.
Several lines of evidence suggest that mutations in CD36 are protective against malaria: mutations in the promoters and within introns and in exon 5 reduce the risk of severe malaria. Gene diversity studies suggest there has been positive selection on this gene presumably due to malarial selection pressure. Dissenting reports are also known
suggesting that CD36 is not the sole determinant of severe malaria. In addition a role for CD36 has been found in the clearance of gametocytes (stages I and II).
CD36 has been shown to have a role in the innate immune response to malaria in mouse models. Compared with wild type mice CD36 (-/-) mice the cytokine induction response and parasite clearance were impaired. Earlier peak parasitemias, higher parasite densities and higher mortality were noted. It is thought that CD36 is involved in the Plasmodium falciparum glycophosphatidylinositol (PfGPI) induced MAPK activation and proinflammatory cytokine secretion. When macrophages were exposed to PfGPI the proteins ERK1/2, JNK, p38, and c-Jun became phosphorylated. All these proteins are involved as secondary messengers in the immune response. These responses were blunted in the CD36 (-/-) mice. Also in the CD36 (-/-) macrophages secreted significantly less TNF-alpha on exposure to PfGPI. Work is ongoing to determine how these exactly how these responses provide protection against malaria.
## CD36 deficiency and alloimmune thrombocytopenia
CD36 is also known as glycoprotein IV (gpIV) or glycoprotein IIIb (gpIIIb) in platelets and gives rise to the Naka antigen. The Naka null phenotype is found in 0.3% of Caucasians and appears to be asymptomatic. The null phenotype is more common in African (2.5%), Japanese, and other Asian populations (5-11%).
Mutations in the human CD36 gene were first identified in a patient who, despite multiple platelet transfusions, continued to exhibit low platelet levels. This condition is known as refractoriness to platelet transfusion. Subsequent studies have shown that CD36 found on the surface of platelets. This antigen is recognized by the monoclonal antibodies (MAbs) OKM5 and OKM8. It is bound by the Plasmodium falciparum protein sequestrin.
Depending on the nature of the mutation in codon 90 CD36 may be absent either on both platelets and monocytes (type 1) or platelets alone (type 2). Type 2 has been divided into two subtypes - a and b. Deficiency restricted to the platelets alone is known as type 2a; if CD36 is also absent from the erythoblasts the phenotype is classified as type 2b. The molecular basis is known for some cases: T1264G in both Kenyans and Gambians; C478T (50%), 539 deletion of AC and 1159 insertion of an A, 1438-1449 deletion and a combined 839-841 deletion GAG and insertion of AAAAC in Japanese.
In a study of 827 apparently healthy Japanese volunteers, type I and II deficiencies were found in 8 (1.0%) and 48 (5.8%) respectively. In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found. In a second group only 1 of 301 white test subjects was found to be CD36 deficient. 16 of the 206 sub-Saharan black Africans and 1 of 148 black Caribbeans were found to be CD36 -ve. Three of 13 CD36 -ve persons examined had anti CD36 antibodies. In a group of 250 black American blood donors 6 (2.4%) were found to be Naka antigen negative.
CD36 deficiency may be a cause of post transfusion purpura.
## Blood pressure
Below normal levels of CD36 expression in the kidneys has been implicated as a genetic risk factor for hypertension (high blood pressure).
## Fatty acid uptake
An association with myocardial fatty acid uptake in humans has been noted. The data suggest a link between hypertrophic cardiomyopathy and CD36 but this needs to be confirmed.
## Tuberculosis
RNAi screening in a Drosophila model has revealed that a member of the CD36 family is required for phagocytosis of Mycobacterium tuberculosis into macrophage phagosomes.
## Obesity
CD36's association with the ability to taste fats has made it a target for various studies regarding obesity and alteration of lipid tasting. CD36 mRNA expression was found to be reduced in taste bud cells (TBC) of obese sand rats (P. obesus) compared to lean controls, implicating an association between CD36 and obesity. Although actual levels of CD36 protein were not different between the obese and control rat cells, Abdoul-Azize et al. hypothesize that the physical distribution of CD36 could differ in obese rat cells. Changes in calcium mediation have been associated with CD36 and obesity as well. Taste bud cells (more specifically, cells from the circumvallate papillae) containing CD36 that were isolated from obese mice exhibited a significantly smaller increase in calcium after fatty acid stimulation when compared to control mice: CD36 associated calcium regulation is impaired when mice are made to be obese (but not in normal weight mice), and this could be a mechanism contributing to behavior changes in the obese mice, such as decreased lipid taste sensitivity and decreased attraction to fats.
There has been some investigation into human CD36 as well. A study examined oral detection of fat in obese subjects with genetic bases for high, medium, and low expression of the CD36 receptor. Those subjects with high CD36 expression were eight times more sensitive to certain fats (oleic acid and triolein) than the subjects with low CD36 expression. Those subjects with an intermediate amount of CD36 expression were sensitive to fat at a level between the high and low groups. This study demonstrates that there is a significant relationship between oral fat sensitivity and the amount of CD36 receptor expression, but further investigation into CD36 could be useful for learning more about lipid tasting in the context of obesity, as CD36 may be a target for therapies in the future.
## Establishment of cellular senescence
Upregulation of CD36 could contribute to membrane remodeling during senescence. In response to various senescence‐inducing stimuli, CD36 stimulate NF-κB‐dependent inflammatory cytokine and chemokine production, a phenomenon known as the senescence‐associated secretory phenotype (SASP). This secretory molecule production leads to the onset of a comprehensive senescent cell fate.
# Cancer
CD36 plays a role in the regulation of angiogenesis, which may be a therapeutic strategy for controlling the spread of cancer. Some data from in vitro and animal studies suggested that fatty acid uptake through CD36 may promote cancer cell migration and proliferation in hepatocellular carcinoma, glioblastoma, and potentially other cancers; there was limited data from observational studies in people that low CD36 may correlate with a slightly better outcome in glioblastoma.
# Interactions
CD36 has been shown to interact with FYN.
# Related proteins
Other human scavenger receptors related to CD36 are SCARB1 and SCARB2 proteins. | CD36
CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen,[1] thrombospondin,[2] erythrocytes parasitized with Plasmodium falciparum,[3] oxidized low density lipoprotein,[4][5] native lipoproteins,[6] oxidized phospholipids,[7] and long-chain fatty acids.[8]
Work in genetically modified rodents suggest a role for CD36 in fatty acid metabolism,[9][10] heart disease,[11] taste,[12][13][14] and dietary fat processing in the intestine.[15] It may be involved in glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy and Alzheimer's disease.[16]
# Structure
## Primary
In humans, rats and mice, CD36 consists of 472 amino acids with a predicted molecular weight of approximately 53,000 Da. However, CD36 is extensively glycosylated and has an apparent molecular weight of 88,000 Da as determined by SDS polyacrylamide gel electrophoresis.[17]
## Tertiary
Using Kyte-Doolittle analysis,[18] the amino acid sequence of CD36 predicts a hydrophobic region near each end of the protein large enough to span cellular membranes. Based on this notion and the observation that CD36 is found on the surface of cells, CD36 is thought to have a 'hairpin-like' structure with α-helices at the C- and N- termini projecting through the membrane and a larger extracellular loop (Fig. 1). This topology is supported by transfection experiments in cultured cells using deletion mutants of CD36.[19][20]
Based on the crystal structure of the homologous SCARB2, a model of the extracellullar domain of CD36 has been produced.[21] Like SCARB2, CD36 is proposed to contain an antiparallel β-barrel core with many short α-helices adorning it. The structure is predicted to contain a hydrophobic transport tunnel.
Disulfide linkages between 4 of the 6 cysteine residues in the extracellular loop are required for efficient intracellular processing and transport of CD36 to the plasma membrane.[22] It is not clear what role these linkages play on the function of the mature CD36 protein on the cell surface.
## Posttranslational modification
Besides glycosylation, additional posttranslational modifications have been reported for CD36. CD36 is modified with 4 palmitoyl chains, 2 on each of the two intracellular domains.[20] The function of these lipid modifications is currently unknown but they likely promote the association of CD36 with the membrane and possibly lipid rafts which appear to be important for some CD36 functions.[23][24] CD36 could be also phosphorylated at Y62, T92, T323,[25] ubiquitinated at K56, K469, K472 and acetylated at K52, K56, K166, K231, K394, K398, K403.[26][27][28]
## Protein-protein interactions
In the absence of ligand, membrane bound CD36 exists primarily in a monomeric state. However exposure to the thrombospondin ligand causes CD36 to dimerize. This dimerization has been proposed to play an important role in CD36 signal transduction.[29]
# Genetics
In humans, The gene is located on the long arm of chromosome 7 at band 11.2 (7q11.2[30]) and is encoded by 15 exons that extend over more than 32 kilobases. Both the 5' and the 3' untranslated regions contain introns: the 5' with two and the 3' one. Exons 1, 2 and first 89 nucleotides of exon 3 and as well as exon 15 are non-coding. Exon 3 contains encodes the N-terminal cytoplasmic and transmembrane domains. The C-terminal cytoplasmic and transmembrane regions is encoded by exon 14. The extracellular domain is encoded by the central 11 exons. Alternative splicing of the untranslated regions gives rise to at least two mRNA species.
The transcription initiation site of the CD36 gene has been mapped to 289 nucleotides upstream from the translational start codon and a TATA box and several putative cis regulatory regions lie further 5'. A binding site for PEBP2/CBF factors has been identified between -158 and -90 and disruption of this site reduces expression. The gene is the transcriptional control of the nuclear receptor PPAR/RXR heterodimer (Peroxisome proliferator-activated receptor – Retinoid X receptor) and gene expression can be up regulated using synthetic and natural ligands for PPAR and RXR, including the thiazolidinedione class of anti-diabetic drugs and the vitamin A metabolite 9-cis-retinoic acid respectively.
# Tissue distribution
CD36 is found on platelets, erythrocytes, monocytes, differentiated adipocytes, skeletal muscle, mammary epithelial cells, spleen cells and some skin microdermal endothelial cells.
# Function
The protein itself belongs to the class B scavenger receptor family which includes receptors for selective cholesteryl ester uptake, scavenger receptor class B type I (SR-BI) and lysosomal integral membrane protein II (LIMP-II).
CD36 interacts with a number of ligands, including collagen types I and IV, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, platelet-agglutinating protein p37, oxidized low density lipoprotein and long-chain fatty acids.[citation needed]
On macrophages CD36 forms part of a non-opsonic receptor (the scavenger receptor CD36/alphaV beta3 complex) and is involved[clarification needed] in phagocytosis.[citation needed]
CD36 has also been implicated in hemostasis, thrombosis, malaria, inflammation, lipid metabolism and atherogenesis.[citation needed]
On binding a ligand the protein and ligand are internalized. This internalization is independent of macropinocytosis and occurs by an actin dependent mechanism requiring the activation Src-family kinases, JNK and Rho-family GTPases.[31] Unlike macropinocytosis this process is not affected by inhibitors of phosphatidylinositol 3-kinase or Na+/H+ exchange.
CD36 ligands have also been shown to promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.[32]
Recently, CD36 was linked to store-operated calcium flux, phospholipase A2 activation, and production of prostaglandin E2[33]
CD36 function in long-chain fatty acid uptake and signaling can be irreversibly inhibited by sulfo-N-succinimidyl oleate (SSO), which binds lysine 164 within a hydrophobic pocked shared by several CD36 ligands, e.g. fatty acid and oxLDL.[27]
# Clinical significance
## Malaria
Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite and CD36 has been shown to be a major sequestration receptor on microvascular endothelial cells. Parasitised erythrocytes adhere to endothelium at the trophozoite/schizonts stage simultaneous with the appearance of the var gene product (erythrocyte membrane protein 1) on the erythrocyte surface. The appearance of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on the erythrocyte surface is a temperature dependent phenomenon which is due to increased protein trafficking to the erythrocyte surface at the raised temperature. PfEMP1 can bind other endothelial receptors - thrombospondin (TSP) and intercellular adhesion molecule 1 (ICAM-1) – in addition to CD36 - and genes other than PfEMP1 also bind to CD36: cytoadherence linked protein (clag) and sequestrin. The PfEMP1 binding site on CD36 is known to be located on exon 5.
CD36 on the surface of the platelets has been shown to be involved in adherence but direct adherence to the endothelium by the infected erythrocytes also occurs. Autoaggregation of infected erythrocytes by platelets has been shown to correlate with severe malaria and cerebral malaria in particular and antiplatelet antibodies may offer some protection.
Several lines of evidence suggest that mutations in CD36 are protective against malaria: mutations in the promoters and within introns and in exon 5 reduce the risk of severe malaria. Gene diversity studies suggest there has been positive selection on this gene presumably due to malarial selection pressure. Dissenting reports are also known
suggesting that CD36 is not the sole determinant of severe malaria. In addition a role for CD36 has been found in the clearance of gametocytes (stages I and II).
CD36 has been shown to have a role in the innate immune response to malaria in mouse models.[34] Compared with wild type mice CD36 (-/-) mice the cytokine induction response and parasite clearance were impaired. Earlier peak parasitemias, higher parasite densities and higher mortality were noted. It is thought that CD36 is involved in the Plasmodium falciparum glycophosphatidylinositol (PfGPI) induced MAPK activation and proinflammatory cytokine secretion. When macrophages were exposed to PfGPI the proteins ERK1/2, JNK, p38, and c-Jun became phosphorylated. All these proteins are involved as secondary messengers in the immune response. These responses were blunted in the CD36 (-/-) mice. Also in the CD36 (-/-) macrophages secreted significantly less TNF-alpha on exposure to PfGPI. Work is ongoing to determine how these exactly how these responses provide protection against malaria.
## CD36 deficiency and alloimmune thrombocytopenia
CD36 is also known as glycoprotein IV (gpIV) or glycoprotein IIIb (gpIIIb) in platelets and gives rise to the Naka antigen. The Naka null phenotype is found in 0.3% of Caucasians and appears to be asymptomatic. The null phenotype is more common in African (2.5%), Japanese, and other Asian populations (5-11%).
Mutations in the human CD36 gene were first identified in a patient who, despite multiple platelet transfusions, continued to exhibit low platelet levels.[35][36] This condition is known as refractoriness to platelet transfusion. Subsequent studies have shown that CD36 found on the surface of platelets. This antigen is recognized by the monoclonal antibodies (MAbs) OKM5 and OKM8. It is bound by the Plasmodium falciparum protein sequestrin.[37]
Depending on the nature of the mutation in codon 90 CD36 may be absent either on both platelets and monocytes (type 1) or platelets alone (type 2). Type 2 has been divided into two subtypes - a and b. Deficiency restricted to the platelets alone is known as type 2a; if CD36 is also absent from the erythoblasts the phenotype is classified as type 2b.[38] The molecular basis is known for some cases: T1264G in both Kenyans and Gambians; C478T (50%), 539 deletion of AC and 1159 insertion of an A, 1438-1449 deletion and a combined 839-841 deletion GAG and insertion of AAAAC in Japanese.
In a study of 827 apparently healthy Japanese volunteers, type I and II deficiencies were found in 8 (1.0%) and 48 (5.8%) respectively.[39] In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found.[40] In a second group only 1 of 301 white test subjects was found to be CD36 deficient. 16 of the 206 sub-Saharan black Africans and 1 of 148 black Caribbeans were found to be CD36 -ve. Three of 13 CD36 -ve persons examined had anti CD36 antibodies. In a group of 250 black American blood donors 6 (2.4%) were found to be Naka antigen negative.[41]
CD36 deficiency may be a cause of post transfusion purpura.[42]
## Blood pressure
Below normal levels of CD36 expression in the kidneys has been implicated as a genetic risk factor for hypertension (high blood pressure).[43]
## Fatty acid uptake
An association with myocardial fatty acid uptake in humans has been noted.[44] The data suggest a link between hypertrophic cardiomyopathy and CD36 but this needs to be confirmed.
## Tuberculosis
RNAi screening in a Drosophila model has revealed that a member of the CD36 family is required for phagocytosis of Mycobacterium tuberculosis into macrophage phagosomes.[45]
## Obesity
CD36's association with the ability to taste fats has made it a target for various studies regarding obesity and alteration of lipid tasting. CD36 mRNA expression was found to be reduced in taste bud cells (TBC) of obese sand rats (P. obesus) compared to lean controls, implicating an association between CD36 and obesity.[46] Although actual levels of CD36 protein were not different between the obese and control rat cells, Abdoul-Azize et al. hypothesize that the physical distribution of CD36 could differ in obese rat cells.[46] Changes in calcium mediation have been associated with CD36 and obesity as well. Taste bud cells (more specifically, cells from the circumvallate papillae) containing CD36 that were isolated from obese mice exhibited a significantly smaller increase in calcium after fatty acid stimulation when compared to control mice:[47] CD36 associated calcium regulation is impaired when mice are made to be obese (but not in normal weight mice), and this could be a mechanism contributing to behavior changes in the obese mice, such as decreased lipid taste sensitivity and decreased attraction to fats.[47]
There has been some investigation into human CD36 as well. A study examined oral detection of fat in obese subjects with genetic bases for high, medium, and low expression of the CD36 receptor. Those subjects with high CD36 expression were eight times more sensitive to certain fats (oleic acid and triolein) than the subjects with low CD36 expression.[13] Those subjects with an intermediate amount of CD36 expression were sensitive to fat at a level between the high and low groups.[13] This study demonstrates that there is a significant relationship between oral fat sensitivity and the amount of CD36 receptor expression, but further investigation into CD36 could be useful for learning more about lipid tasting in the context of obesity, as CD36 may be a target for therapies in the future.
## Establishment of cellular senescence
Upregulation of CD36 could contribute to membrane remodeling during senescence.[48] In response to various senescence‐inducing stimuli, CD36 stimulate NF-κB‐dependent inflammatory cytokine and chemokine production, a phenomenon known as the senescence‐associated secretory phenotype (SASP).[49] This secretory molecule production leads to the onset of a comprehensive senescent cell fate.
# Cancer
CD36 plays a role in the regulation of angiogenesis, which may be a therapeutic strategy for controlling the spread of cancer.[50] Some data from in vitro and animal studies suggested that fatty acid uptake through CD36 may promote cancer cell migration and proliferation in hepatocellular carcinoma, glioblastoma, and potentially other cancers; there was limited data from observational studies in people that low CD36 may correlate with a slightly better outcome in glioblastoma.[51]
# Interactions
CD36 has been shown to interact with FYN.[52][53]
# Related proteins
Other human scavenger receptors related to CD36 are SCARB1 and SCARB2 proteins. | https://www.wikidoc.org/index.php/CD36 | |
97877e6702380958fe9afe9b711e43317e0f0ccc | wikidoc | CD38 | CD38
CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.
In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4.
# Function
CD38 is a multifunctional ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose in addition to synthesis of NAADP from NADP+. These reaction products are essential for the regulation of intracellular Ca2+.
# Clinical significance
The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.
The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.
Daratumumab which targets CD38 has been used in treating multiple myeloma.
Increased expression of CD 38 is an unfavourable diagnostic marker in chronic lymphocytic leukemia and is associated with increased disease progression.
# Application
CD38 has been used as a prognostic marker in leukemia. CD38 is also used as a target for daratumumab (Darzalex), a medicine that has been approved for the treatment of multiple myeloma.
The use of Daratumumab can interfere with pre-Blood transfusion tests, as CD38 is weakly expressed on the surface of erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false-positive results. This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.
# Animal studies
A gradual increase in CD38 has been implicated in the decline of NAD+ with age. Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline. | CD38
CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein[1] found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.[2]
In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4.[3][4]
# Function
CD38 is a multifunctional ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose in addition to synthesis of NAADP from NADP+.[5] These reaction products are essential for the regulation of intracellular Ca2+.[6]
# Clinical significance
The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[6][7]
The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.[7]
Daratumumab which targets CD38 has been used in treating multiple myeloma.[8][9]
Increased expression of CD 38 is an unfavourable diagnostic marker in chronic lymphocytic leukemia and is associated with increased disease progression.[10]
# Application
CD38 has been used as a prognostic marker in leukemia.[11] CD38 is also used as a target for daratumumab (Darzalex), a medicine that has been approved for the treatment of multiple myeloma.
The use of Daratumumab can interfere with pre-Blood transfusion tests, as CD38 is weakly expressed on the surface of erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false-positive results.[12] This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.
# Animal studies
A gradual increase in CD38 has been implicated in the decline of NAD+ with age.[13][14] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.[15] | https://www.wikidoc.org/index.php/CD38 | |
2a8442b5a545394b6286a647adec33a6532ece5d | wikidoc | CD44 | CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on Chromosome 11. CD44 has been referred to as HCAM (homing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
# Tissue distribution and isoforms
CD44 is expressed in a large number of mammalian cell types. The standard isoform, designated CD44s, comprising exons 1–5 and 16–20 is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v. Some epithelial cells also express a larger isoform (CD44E), which includes exons v8–10.
# Function
CD44 participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis.
CD44 is a receptor for hyaluronic acid and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). CD44 function is controlled by its posttranslational modifications. One critical modification involves discrete sialofucosylations rendering the selectin-binding glycoform of CD44 called HCELL (for Hematopoietic Cell E-selectin/L-selectin Ligand). (see below)
Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct isoforms; however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. Splice variants of CD44 on colon cancer cells display sialofucosylated HCELL glycoforms that serve as P-, L-, and E-selectin ligands and fibrin, but not fibrinogen, receptors under hemodynamic flow conditions pertinent to the process of cancer metastasis.
CD44 gene transcription is at least in part activated by beta-catenin and Wnt signalling (also linked to tumour development).
## HCELL
The HCELL glycoform was originally discovered on human hematopoietic stem cells and leukemic blasts, and was subsequently identified on cancer cells. HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and mesenchymal stem cells to bone marrow. Ex vivo glycan engineering of the surface of live cells has been used to enforce HCELL expression on any cell that expresses CD44. CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen.
# Clinical significance
The protein is a determinant for the Indian blood group system.
- CD44, along with CD25, is used to track early T cell development in the thymus.
- CD44 expression is an indicative marker for effector-memory T-cells. Memory cell proliferation (activation) can also be assayed in vitro with CFSE chemical tagging.
In addition, variations in CD44 are reported as cell surface markers for some breast and prostate cancer stem cells. In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.
Endometrial cells in women with endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.
CD44 variant isoforms are also relevant to the progression of head and neck squamous cell carcinoma.
Monoclonal antibodies against CD44 variants include bivatuzumab for v6.
# CD44 in cancer
CD44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, cell migration, angiogenesis, presentation of cytokines, chemokines, and growth factors to the corresponding receptors, and docking of proteases at the cell membrane, as well as in signaling for cell survival. All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of cancer cells. Experiments in animals have shown that targeting of CD44 by antibodies, antisense oligonucleotides, and CD44-soluble proteins markedly reduces the malignant activities of various neoplasms, stressing the therapeutic potential of anti-CD44 agents. High levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia. Furthermore, because alternative splicing and posttranslational modifications generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach. However, in many cancers (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome. On the contrary, in some neoplasms CD44 upregulation is associated with a favorable outcome. Additionally, in many cases different research groups analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers.
# Interactions
CD44 has been shown to interact with:
- ARHGEF1,
- Ezrin, via PIP2,
- Epidermal Growth Factor Receptor (Hyaluronan-dependent),
- Fibrin and immobilized fibrinogen,
- Fibronectin,
- FYN,
- Hyaluronan,
- Lck,
- Osteopontin
- Selectins, and
- Src. | CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on Chromosome 11.[1] CD44 has been referred to as HCAM (homing cell adhesion molecule), Pgp-1 (phagocytic glycoprotein-1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
# Tissue distribution and isoforms
CD44 is expressed in a large number of mammalian cell types. The standard isoform, designated CD44s, comprising exons 1–5 and 16–20 is expressed in most cell types. CD44 splice variants containing variable exons are designated CD44v. Some epithelial cells also express a larger isoform (CD44E), which includes exons v8–10.[2]
# Function
CD44 participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis.
CD44 is a receptor for hyaluronic acid and can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). CD44 function is controlled by its posttranslational modifications. One critical modification involves discrete sialofucosylations rendering the selectin-binding glycoform of CD44 called HCELL (for Hematopoietic Cell E-selectin/L-selectin Ligand).[3] (see below)
Transcripts for this gene undergo complex alternative splicing that results in many functionally distinct isoforms; however, the full length nature of some of these variants has not been determined. Alternative splicing is the basis for the structural and functional diversity of this protein, and may be related to tumor metastasis. Splice variants of CD44 on colon cancer cells display sialofucosylated HCELL glycoforms that serve as P-, L-, and E-selectin ligands and fibrin, but not fibrinogen, receptors under hemodynamic flow conditions pertinent to the process of cancer metastasis.[4][5]
CD44 gene transcription is at least in part activated by beta-catenin and Wnt signalling (also linked to tumour development).
## HCELL
The HCELL glycoform was originally discovered on human hematopoietic stem cells and leukemic blasts,[3][6][7][8] and was subsequently identified on cancer cells.[5][9][10][11][12] HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and mesenchymal stem cells to bone marrow.[7] Ex vivo glycan engineering of the surface of live cells has been used to enforce HCELL expression on any cell that expresses CD44.[13] CD44 glycosylation also directly controls its binding capacity to fibrin and immobilized fibrinogen.[4][14]
# Clinical significance
The protein is a determinant for the Indian blood group system.
- CD44, along with CD25, is used to track early T cell development in the thymus.
- CD44 expression is an indicative marker for effector-memory T-cells. Memory cell proliferation (activation) can also be assayed in vitro with CFSE chemical tagging.
In addition, variations in CD44 are reported as cell surface markers for some breast and prostate cancer stem cells. In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics[15] and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.[16]
Endometrial cells in women with endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.[17]
CD44 variant isoforms are also relevant to the progression of head and neck squamous cell carcinoma.[18][19]
Monoclonal antibodies against CD44 variants include bivatuzumab for v6.
# CD44 in cancer
CD44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, cell migration, angiogenesis, presentation of cytokines, chemokines, and growth factors to the corresponding receptors, and docking of proteases at the cell membrane, as well as in signaling for cell survival. All these biological properties are essential to the physiological activities of normal cells, but they are also associated with the pathologic activities of cancer cells. Experiments in animals have shown that targeting of CD44 by antibodies, antisense oligonucleotides, and CD44-soluble proteins markedly reduces the malignant activities of various neoplasms, stressing the therapeutic potential of anti-CD44 agents. High levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia.[20] Furthermore, because alternative splicing and posttranslational modifications generate many different CD44 sequences, including, perhaps, tumor-specific sequences, the production of anti-CD44 tumor-specific agents may be a realistic therapeutic approach.[21] However, in many cancers (renal cancer and non-Hodgkin's lymphomas are exceptions), a high level of CD44 expression is not always associated with an unfavorable outcome. On the contrary, in some neoplasms CD44 upregulation is associated with a favorable outcome. Additionally, in many cases different research groups analyzing the same neoplastic disease reached contradictory conclusions regarding the correlation between CD44 expression and disease prognosis, possibly due to differences in methodology. These problems must be resolved before applying anti-CD44 therapy to human cancers.[22]
# Interactions
CD44 has been shown to interact with:
- ARHGEF1,[23]
- Ezrin, via PIP2,[24]
- Epidermal Growth Factor Receptor (Hyaluronan-dependent),[25]
- Fibrin and immobilized fibrinogen,[4][14]
- Fibronectin,[26]
- FYN,[27]
- Hyaluronan,[28]
- Lck,[27][29]
- Osteopontin[30]
- Selectins,[10][11][12] and
- Src.[31] | https://www.wikidoc.org/index.php/CD44 | |
4e823ac23dde801dff98fc3fa798e6622a2ab12e | wikidoc | CD46 | CD46
CD46 complement regulatory protein also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein is a protein which in humans is encoded by the CD46 gene. CD46 is an inhibitory complement receptor.
# Gene
This gene is found in a cluster on chromosome 1q32 with other genes encoding structural components of the complement system. At least fourteen different transcript variants encoding fourteen different isoforms have been found for this gene.
# Function
The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system.
The encoded protein has cofactor activity for inactivation (through cleavage) of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement.
The protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization.
# Clinical significance
The encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6 (HHV-6), and type IV pili of pathogenic Neisseria.
The extracellular region of CD46 contains four short consensus repeats (SCR) of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops. As has been demonstrated for CD46 with other ligands, the CD46 protein structure is believed to linearize upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated to be required for HHV-6 receptor binding and cellular entry. The heterotetramer gH/gL/gQ1/gQ2 complex of HHV-6 has been identified as a CD46 ligand.
Established medulloblastoma (a malignant brain tumor common in childhood) specimens express CD46, and that medulloblastoma specimens removed from patients had a high level of CD46 expression. Therefore, a vaccine made of the Edmonston strain of measles virus could treat the medulloblastoma. Such a vaccine has already been tested in a number of trials involving other tumor types which have a high expression of CD46, including one type of adult brain tumor.
# Interactions
CD46 has been shown to interact with CD9, CD151 and CD29. | CD46
CD46 complement regulatory protein also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein is a protein which in humans is encoded by the CD46 gene.[1] CD46 is an inhibitory complement receptor.[2]
# Gene
This gene is found in a cluster on chromosome 1q32 with other genes encoding structural components of the complement system. At least fourteen different transcript variants encoding fourteen different isoforms have been found for this gene.[3]
# Function
The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system.
The encoded protein has cofactor activity for inactivation (through cleavage) of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement.[4]
The protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization.[5]
# Clinical significance
The encoded protein can act as a receptor for the Edmonston strain of measles virus,[6] human herpesvirus-6 (HHV-6), and type IV pili of pathogenic Neisseria.[7]
The extracellular region of CD46 contains four short consensus repeats (SCR) of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops.[8] As has been demonstrated for CD46 with other ligands, the CD46 protein structure is believed to linearize upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated to be required for HHV-6 receptor binding and cellular entry. The heterotetramer gH/gL/gQ1/gQ2 complex of HHV-6 has been identified as a CD46 ligand.[9]
Established medulloblastoma (a malignant brain tumor common in childhood) specimens express CD46, and that medulloblastoma specimens removed from patients had a high level of CD46 expression. Therefore, a vaccine made of the Edmonston strain of measles virus could treat the medulloblastoma. Such a vaccine has already been tested in a number of trials involving other tumor types which have a high expression of CD46, including one type of adult brain tumor.[10]
# Interactions
CD46 has been shown to interact with CD9,[11] CD151[11] and CD29.[11] | https://www.wikidoc.org/index.php/CD46 | |
d76787f9f9e285cb9835a3c10fa9346225950319 | wikidoc | CD47 | CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a key role in immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells. Expression in equine cutaneous tumors has been reported as well.
# Structure
CD47 is a 50 kDa membrane receptor that has extracellular N-terminal IgV domain, five transmembrane domains, and a short C-terminal intracellular tail. There are four alternatively spliced isoforms of CD47 that differ only in the length of their cytoplasmic tail.
Form 2 is the most widely expressed form that is found in all circulating and immune cells. The second most abundant isoform is form 4, which is predominantly expressed in the brain and in the peripheral nervous system. Only keratinocytes expressed significant amounts of form 1. Little is known about the functional significance of this alternative splicing. However, these isoforms are highly conserved between mouse and man, suggesting an important role for the cytoplasmic domains in CD47 function.
# Interactions
## Thrombospondin (TSP)
CD47 is a high affinity receptor for thrombospondin-1 (TSP-1), a secreted glycoprotein that plays a role in vascular development and angiogenesis, and in this later capacity the TSP1-CD47 interaction inhibits nitric oxide signaling at multiple levels in vascular cells. Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.
## Signal-regulatory protein (SIRP)
CD47 interacts with signal-regulatory protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.
## Integrins
CD47 interacts with several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that affect a range of cell functions including adhesion, spreading and migration.
# Function
## Tumor cells
Due to the ubiquitous expression of CD47, signaling differs according to cell type. It is likely that intracellular and membrane-associated partners are crucial in determining the cellular response of CD47 signaling.
### Cell proliferation
The role of CD47 in promoting cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation.
Activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma cells but not normal astrocytes. Additionally, CD47 blocking antibodies inhibit proliferation of unstimulated astrocytoma cells but not normal astrocytes. Though the exact mechanism is unclear, it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells.
Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. Expression of several stem cell markers, including c-Myc, is elevated in CD47-null endothelial cells and a human T cell line lacking CD47. Activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors.
### Cell death
CD47 ligation leads to cell death in many normal and tumor cell lines via apoptosis or autophagy.
The activation of CD47 induces rapid apoptosis of T cells. Jurkat cells and peripheral blood mononuclear cells (PBMC) incubated with the monoclonal antibody Ad22 results in apoptosis within 3 hours. However, apoptosis was not observed following culture with other anti-CD47 antibodies. The apoptosis inducing function of CD47 appears to be dependent on activation of specific epitopes on the extracellular domain.
Similarly, CD47 ligation rapidly induces apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells. Treatment with a disulfide-linked antibody dimer induces apoptosis of CD47-positive primary B-CLL and leukemic cells (MOLT-4 and JOK-1). In addition, administration of the antibody prolonged survival of SCID mice implanted with JOK-1 cells. Apoptosis induction appears to be regulated by the hypoxia inducible factor 1α (HIF-1α) pathway.
The RAS-transformed cell lines MDFB6 and B6ras show near complete loss of TSP-1 expression. Activation of CD47 with TSP-1 results in loss of viability in these RAS-expressing cells. Affected cells do not exhibit hallmarks of apoptosis but rather autophagy as seen by staining with acridine orange and immunoreactivity for LC3.
### Migration
Cell migration appears to be universally stimulated by CD47 ligation and activation. The role of CD47 in cell migration was first demonstrated for neutrophils, where CD47 blocking antibodies inhibited transmigration of neutrophils and monocytes through the endothelium. These effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane.
Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanoma, prostate cancer and ovarian cancer-derived cells. In a mouse model of multiple myeloma, tumor metastasis to bone was decreased in CD47-deficient mice compared with wild type controls. In mice xenografted with human non-Hodgkin lymphoma (NHL) cells, blocking CD47 function with shRNA or antibodies led to a dramatic reduction in metastasis to major organs.
## Stromal cells
### Angiogenesis
Loss of CD47 promotes proliferation and increases asymmetric division of primary murine endothelial cells. Additionally, activation of CD47 with TSP-1 in wild-type primary mouse cerebral endothelial cells induces cytotoxicity, which is significantly decreased in cerebral endothelial cells derived from CD47 knockout mice.
CD47 signaling may suppress angiogenesis as TSP-1 activation significantly inhibited endothelial cell migration and tube formation in vitro. In vivo, injections of TSP-1 in mice after hindlimb ischemia induces a significant decrease of blood flow recovery. The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells. CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis.
### Inflammatory response
Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 knockout mice show reduced recruitment of blood T cells as well as neutrophils and monocytes in areas of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Red blood cells that lack CD47 are rapidly cleared from the bloodstream by macrophages, a process that is mediated by interaction with SIRPα. Mouse hematopoietic stem cells (HSCs) and progenitors transiently upregulate CD47 during their migratory phase, which reduces macrophage engulfment in vivo.
Tumor cells can also evade macrophage phagocytosis through the expression of CD47. CD47 is highly expressed in bladder tumor initiating cells (T-ICs) compared with the rest of the tumor. Blockade of CD47 with a monoclonal antibody results in macrophage engulfment of bladder cancer cells in vitro. CD47 is also upregulated in mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line allows these cells to evade phagocytosis.
# Clinical significance
CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s. Since then, CD47 has been found to be expressed on multiple human tumor types including acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, and other solid tumors. CD47 is also highly expressed on pediatric and adult brain tumors.
High levels of CD47 allows cancer cells to avoid phagocytosis despite having a higher level of calreticulin - the dominant pro-phagocytic signal. This is due to engagement of the SIRP-α of macrophage by CD47. Engagement of SIRP-α leads to inhibition of phagocytosis. Thus blocking CD47 with antibody turns off “don’t eat me” signal and favors phagocytosis.
## As a potential drug target
Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response. Noteworthy, anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but also fosters the activation of cancer-specific lymphocytes: cancer cells now display mutant proteins to which the immune system can react. Humanized anti-CD47 antibody is being evaluated for the treatment of various cancers, eg diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). | CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily[1] and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα).[2] CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.[3]
CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a key role in immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells.[2][4] Expression in equine cutaneous tumors has been reported as well.[5]
# Structure
CD47 is a 50 kDa membrane receptor that has extracellular N-terminal IgV domain, five transmembrane domains, and a short C-terminal intracellular tail. There are four alternatively spliced isoforms of CD47 that differ only in the length of their cytoplasmic tail.[6]
Form 2 is the most widely expressed form that is found in all circulating and immune cells. The second most abundant isoform is form 4, which is predominantly expressed in the brain and in the peripheral nervous system. Only keratinocytes expressed significant amounts of form 1. Little is known about the functional significance of this alternative splicing. However, these isoforms are highly conserved between mouse and man, suggesting an important role for the cytoplasmic domains in CD47 function.[2][6][7]
# Interactions
## Thrombospondin (TSP)
CD47 is a high affinity receptor for thrombospondin-1 (TSP-1), a secreted glycoprotein that plays a role in vascular development and angiogenesis, and in this later capacity the TSP1-CD47 interaction inhibits nitric oxide signaling at multiple levels in vascular cells.[8] Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.[2]
## Signal-regulatory protein (SIRP)
CD47 interacts with signal-regulatory protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.[2][9][10]
## Integrins
CD47 interacts with several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that affect a range of cell functions including adhesion, spreading and migration.[2][10]
# Function
## Tumor cells
Due to the ubiquitous expression of CD47, signaling differs according to cell type. It is likely that intracellular and membrane-associated partners are crucial in determining the cellular response of CD47 signaling.
### Cell proliferation
The role of CD47 in promoting cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation.
Activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma cells but not normal astrocytes. Additionally, CD47 blocking antibodies inhibit proliferation of unstimulated astrocytoma cells but not normal astrocytes. Though the exact mechanism is unclear, it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells.[11]
Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. Expression of several stem cell markers, including c-Myc, is elevated in CD47-null endothelial cells and a human T cell line lacking CD47. Activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors.[12]
### Cell death
CD47 ligation leads to cell death in many normal and tumor cell lines via apoptosis or autophagy.
The activation of CD47 induces rapid apoptosis of T cells. Jurkat cells and peripheral blood mononuclear cells (PBMC) incubated with the monoclonal antibody Ad22 results in apoptosis within 3 hours. However, apoptosis was not observed following culture with other anti-CD47 antibodies. The apoptosis inducing function of CD47 appears to be dependent on activation of specific epitopes on the extracellular domain.[13]
Similarly, CD47 ligation rapidly induces apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells. Treatment with a disulfide-linked antibody dimer induces apoptosis of CD47-positive primary B-CLL and leukemic cells (MOLT-4 and JOK-1). In addition, administration of the antibody prolonged survival of SCID mice implanted with JOK-1 cells. Apoptosis induction appears to be regulated by the hypoxia inducible factor 1α (HIF-1α) pathway.[14]
The RAS-transformed cell lines MDFB6 and B6ras show near complete loss of TSP-1 expression. Activation of CD47 with TSP-1 results in loss of viability in these RAS-expressing cells. Affected cells do not exhibit hallmarks of apoptosis but rather autophagy as seen by staining with acridine orange and immunoreactivity for LC3.[15]
### Migration
Cell migration appears to be universally stimulated by CD47 ligation and activation. The role of CD47 in cell migration was first demonstrated for neutrophils, where CD47 blocking antibodies inhibited transmigration of neutrophils and monocytes through the endothelium. These effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane.[2][10]
Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanoma, prostate cancer and ovarian cancer-derived cells.[16] In a mouse model of multiple myeloma, tumor metastasis to bone was decreased in CD47-deficient mice compared with wild type controls.[17] In mice xenografted with human non-Hodgkin lymphoma (NHL) cells, blocking CD47 function with shRNA or antibodies led to a dramatic reduction in metastasis to major organs.[18]
## Stromal cells
### Angiogenesis
Loss of CD47 promotes proliferation and increases asymmetric division of primary murine endothelial cells.[12] Additionally, activation of CD47 with TSP-1 in wild-type primary mouse cerebral endothelial cells induces cytotoxicity, which is significantly decreased in cerebral endothelial cells derived from CD47 knockout mice.[19]
CD47 signaling may suppress angiogenesis as TSP-1 activation significantly inhibited endothelial cell migration and tube formation in vitro.[19] In vivo, injections of TSP-1 in mice after hindlimb ischemia induces a significant decrease of blood flow recovery.[20] The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells.[8] CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis.[20]
### Inflammatory response
Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 knockout mice show reduced recruitment of blood T cells as well as neutrophils and monocytes in areas of inflammation.[21] CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Red blood cells that lack CD47 are rapidly cleared from the bloodstream by macrophages, a process that is mediated by interaction with SIRPα.[22] Mouse hematopoietic stem cells (HSCs) and progenitors transiently upregulate CD47 during their migratory phase, which reduces macrophage engulfment in vivo.[23]
Tumor cells can also evade macrophage phagocytosis through the expression of CD47.[4] CD47 is highly expressed in bladder tumor initiating cells (T-ICs) compared with the rest of the tumor. Blockade of CD47 with a monoclonal antibody results in macrophage engulfment of bladder cancer cells in vitro.[24] CD47 is also upregulated in mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line allows these cells to evade phagocytosis.[23]
# Clinical significance
CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s. Since then, CD47 has been found to be expressed on multiple human tumor types including acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, and other solid tumors.[4] CD47 is also highly expressed on pediatric and adult brain tumors.[25]
High levels of CD47 allows cancer cells to avoid phagocytosis despite having a higher level of calreticulin - the dominant pro-phagocytic signal.[26] This is due to engagement of the SIRP-α of macrophage by CD47. Engagement of SIRP-α leads to inhibition of phagocytosis. Thus blocking CD47 with antibody turns off “don’t eat me” signal and favors phagocytosis.
## As a potential drug target
Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response. Noteworthy, anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but also fosters the activation of cancer-specific lymphocytes: cancer cells now display mutant proteins to which the immune system can react.[27][28] Humanized anti-CD47 antibody is being evaluated for the treatment of various cancers, eg diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).[29] | https://www.wikidoc.org/index.php/CD47 | |
5e9f5e7fe9478212f9b88c1554fa917fc15ef2a6 | wikidoc | CD48 | CD48
CD48 antigen (Cluster of Differentiation 48) also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.
CD48 is a member of the CD2 subfamily of the immunoglobulin superfamily (IgSF) which includes SLAM (signaling lymphocyte activation molecules) proteins, such as CD84, CD150, CD229 and CD244. CD48 is found on the surface of lymphocytes and other immune cells, dendritic cells and endothelial cells, and participates in activation and differentiation pathways in these cells.
CD48 was the first B-cell-specific cellular differentiation antigen identified in transformed B lymphoblasts.
# Structure
The gene for CD48 is located in chromosome 1q23 and contains 4 exons, each exon encoding one of the 4 domains of CD48: signal peptide, variable (V) domain, constant 2 (C2) domain and the glycophosphatidylinositol anchor (GPI anchor). The cDNA sequence of 1137 nucleotides encodes a 243 amino acid polypeptide of about 45 kDa. It consists of a 26 amino acid signal peptide, 194 amino acids of mature CD48 (V and C2 domains) and the C-terminal 23 amino acid segment comprising the GPI anchor. The GPI linkage of CD48 to the cell surface is through serine residue 220. CD48 does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which can be cleaved to yield a soluble form of the receptor. The CD48 protein is heavily glycosylated, with five possible asparagine-linked glycosylation sites at positions 40, 44, 104, 162 and 189, respectively. Approximately 35-40% of the total molecular weight is attributed to the carbohydrate side chains.
# Interactions
CD48 was found to have a very low affinity for CD2 with dissociation constant (K_{D}) K_{D} = 8 μM which is about 5 - 10 times stronger than for CD2.
# Function
## Cell distribution
CD48 is expressed on all peripheral blood lymphocytes (PBL) including T cells, B cells, NK cells and thymocytes. It is also found on the surface of activated T cells, mast cells, monocytes and granulocytes. Like all other GPI anchor protein (GPI-AP), CD48 is deficient in erythrocytes (red blood cells).
## T cell activation
CD48 and CD2 molecular coupling together with other interaction pairs of CD28 and CD80, TCR and peptide-MHC and LFA-1 and ICAM-1 contribute to the formation of an immunological synapse between a T cell and an antigen presenting cell. CD48 interaction with CD2 has been shown to promote lipid raft formation, T cell activation and the formation of caveolae for macrophages through cell signal transductionthe via GPI moieties.
# Clinical Significance
CD48 is being investigated amongst other markers in research on inflammation markers and therapies for HIV/AIDS. | CD48
CD48 antigen (Cluster of Differentiation 48) also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.[1]
CD48 is a member of the CD2 subfamily of the immunoglobulin superfamily (IgSF) which includes SLAM (signaling lymphocyte activation molecules) proteins, such as CD84, CD150, CD229 and CD244. CD48 is found on the surface of lymphocytes and other immune cells, dendritic cells and endothelial cells, and participates in activation and differentiation pathways in these cells.[1]
CD48 was the first B-cell-specific cellular differentiation antigen identified in transformed B lymphoblasts.[2][3]
# Structure
The gene for CD48 is located in chromosome 1q23 and contains 4 exons, each exon encoding one of the 4 domains of CD48: signal peptide, variable (V) domain, constant 2 (C2) domain and the glycophosphatidylinositol anchor (GPI anchor). The cDNA sequence of 1137 nucleotides encodes a 243 amino acid polypeptide of about 45 kDa.[4][5] It consists of a 26 amino acid signal peptide, 194 amino acids of mature CD48 (V and C2 domains) and the C-terminal 23 amino acid segment comprising the GPI anchor.[6][7] The GPI linkage of CD48 to the cell surface is through serine residue 220.[6][7] CD48 does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which can be cleaved to yield a soluble form of the receptor.[1] The CD48 protein is heavily glycosylated, with five possible asparagine-linked glycosylation sites at positions 40, 44, 104, 162 and 189, respectively.[2][3][4][8][9] Approximately 35-40% of the total molecular weight is attributed to the carbohydrate side chains.[8][9][10]
# Interactions
CD48 was found to have a very low affinity for CD2 with dissociation constant (<math>K_{D}</math>) < 0.5 mM.[11] It was found that the preferred ligand of CD48 is 2B4 (CD244), which is also a member of the CD2 subfamily SLAM of IgSF expressed on natural killer cells (NK cells) and other leukocytes. The affinity of CD244 for CD48 is at <math>K_{D}</math> = 8 μM which is about 5 - 10 times stronger than for CD2.[12][13][14]
# Function
## Cell distribution
CD48 is expressed on all peripheral blood lymphocytes (PBL) including T cells, B cells, NK cells and thymocytes.[3][4][10][15] It is also found on the surface of activated T cells, mast cells, monocytes and granulocytes.[8] Like all other GPI anchor protein (GPI-AP), CD48 is deficient in erythrocytes (red blood cells).
## T cell activation
CD48 and CD2 molecular coupling together with other interaction pairs of CD28 and CD80, TCR and peptide-MHC and LFA-1 and ICAM-1 contribute to the formation of an immunological synapse between a T cell and an antigen presenting cell.[16] CD48 interaction with CD2 has been shown to promote lipid raft formation, T cell activation and the formation of caveolae for macrophages through cell signal transductionthe via GPI moieties.[17][18]
# Clinical Significance
CD48 is being investigated amongst other markers in research on inflammation markers and therapies for HIV/AIDS. | https://www.wikidoc.org/index.php/CD48 | |
54d189a14cb4f55082a8654551a3e484aee52b1b | wikidoc | CD52 | CD52
CAMPATH-1 antigen, also known as cluster of differentiation 52 (CD52), is a glycoprotein that in humans is encoded by the CD52 gene.
CD52 is present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived. It also is found on monocytes and dendritic cells. Further, it is found within the male genital tract and is present on the surface of mature sperm cells.
CD52 is a peptide of 12 amino acids, anchored to glycosylphosphatidylinositol (GPI). Since it is highly negatively charged and present on sperm cells and lymphocytes, it has been conjectured that its function is anti-adhesion, allowing cells to freely move around.
CD52 binds the ITIM (immunoreceptor tyrosine-based inhibitory motif)-bearing sialic acid-binding lectin SIGLEC10.
# Clinical significance
It is associated with certain types of lymphoma.
It is the protein targeted by alemtuzumab, a monoclonal antibody used for the treatment of chronic lymphocytic leukemia. A phase III trial into treatment of relapsing-remitting multiple sclerosis showed a reduction in relapse rate, but no statistically significant reduction in accumulated disability, when used as a first-line therapy. However, a sister study looking at patients in whom relapses had occurred despite treatment with interferon beta or glatiramer demonstrated reduction in both relapse rate and accumulated disability. 20% patients randomised to interferon beta 1a had "sustained accumulation of disability" compared with 13% in the alemtuzumab group. . | CD52
CAMPATH-1 antigen, also known as cluster of differentiation 52 (CD52), is a glycoprotein that in humans is encoded by the CD52 gene.
CD52 is present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived. It also is found on monocytes[1] and dendritic cells.[2] Further, it is found within the male genital tract and is present on the surface of mature sperm cells.
CD52 is a peptide of 12 amino acids, anchored to glycosylphosphatidylinositol (GPI). Since it is highly negatively charged and present on sperm cells and lymphocytes, it has been conjectured that its function is anti-adhesion, allowing cells to freely move around.[3]
CD52 binds the ITIM (immunoreceptor tyrosine-based inhibitory motif)-bearing sialic acid-binding lectin SIGLEC10.
# Clinical significance
It is associated with certain types of lymphoma.[4]
It is the protein targeted by alemtuzumab, a monoclonal antibody used for the treatment of chronic lymphocytic leukemia. A phase III trial into treatment of relapsing-remitting multiple sclerosis showed a reduction in relapse rate, but no statistically significant reduction in accumulated disability, when used as a first-line therapy.[5] However, a sister study looking at patients in whom relapses had occurred despite treatment with interferon beta or glatiramer demonstrated reduction in both relapse rate and accumulated disability. 20% patients randomised to interferon beta 1a had "sustained accumulation of disability" compared with 13% in the alemtuzumab group. .[6] | https://www.wikidoc.org/index.php/CD52 | |
9ee5440ae11be834b873dff0177c3948b6853f1b | wikidoc | CD58 | CD58
CD58, or lymphocyte function-associated antigen 3 (LFA-3), is a cell adhesion molecule expressed on Antigen Presenting Cells (APC), particularly macrophages.
It binds to CD2 (LFA-2) on T cells and is important in strengthening the adhesion between the T cells and Professional Antigen Presenting Cells. This adhesion occurs as part of the transitory initial encounters between T cells and Antigen Presenting Cells before T cell activation, when T cells are roaming the lymph nodes looking at the surface of APCs for peptide:MHC complexes the T-cell receptors are reactive to.
Polymorphisms in the CD58 gene are associated with increased risk for multiple sclerosis.. Genomic region containing the single-nucleotide polymorphism rs1335532, associated with high risk of multiple sclerosis, has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. The protective (C) rs1335532 allele creates functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway | CD58
CD58, or lymphocyte function-associated antigen 3 (LFA-3), is a cell adhesion molecule expressed on Antigen Presenting Cells (APC), particularly macrophages.[1][2]
It binds to CD2 (LFA-2) [3][4] on T cells and is important in strengthening the adhesion between the T cells and Professional Antigen Presenting Cells. This adhesion occurs as part of the transitory initial encounters between T cells and Antigen Presenting Cells before T cell activation, when T cells are roaming the lymph nodes looking at the surface of APCs for peptide:MHC complexes the T-cell receptors are reactive to.
Polymorphisms in the CD58 gene are associated with increased risk for multiple sclerosis.[5]. Genomic region containing the single-nucleotide polymorphism rs1335532, associated with high risk of multiple sclerosis, has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. The protective (C) rs1335532 allele creates functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway [6] | https://www.wikidoc.org/index.php/CD58 | |
3f59eb7b8021850f0e94c4a1c40b0f698776bf53 | wikidoc | CD59 | CD59
CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the CD59 gene. It belongs to the LY6/uPAR/alpha-neurotoxin protein family.
CD59 attaches to host cells via a glycophosphatidylinositol (GPI) anchor. When complement activation leads to deposition of C5b678 on host cells, CD59 can prevent C9 from polymerizing and forming the complement membrane attack complex. It may also signal the cell to perform active measures such as endocytosis of the CD59-CD9 complex.
Mutations affecting GPI that reduce expression of CD59 and decay-accelerating factor on red blood cells result in paroxysmal nocturnal hemoglobinuria.
Viruses such as HIV, human cytomegalovirus and vaccinia incorporate host cell CD59 into their own viral envelope to prevent lysis by complement. | CD59
CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the CD59 gene.[1] It belongs to the LY6/uPAR/alpha-neurotoxin protein family.[2]
CD59 attaches to host cells via a glycophosphatidylinositol (GPI) anchor. When complement activation leads to deposition of C5b678 on host cells, CD59 can prevent C9 from polymerizing and forming the complement membrane attack complex.[3] It may also signal the cell to perform active measures such as endocytosis of the CD59-CD9 complex.[2]
Mutations affecting GPI that reduce expression of CD59 and decay-accelerating factor on red blood cells result in paroxysmal nocturnal hemoglobinuria.[4]
Viruses such as HIV, human cytomegalovirus and vaccinia incorporate host cell CD59 into their own viral envelope to prevent lysis by complement.[5] | https://www.wikidoc.org/index.php/CD59 | |
5670057548543b8ea609f9054cc79a681b22f85e | wikidoc | CD61 | CD61
Integrin beta-3 (β3) or CD61 is a protein that in humans is encoded by the ITGB3 gene. CD61 is a cluster of differentiation found on thrombocytes.
# Structure and function
The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface-mediated signaling.
# Role in endometriosis
Defectively expressed β3 integrin subunit has been correlated with presence of endometriosis, and has been suggested as a putative marker of this condition.
# Interactions
CD61 has been shown to interact with PTK2, ITGB3BP, TLN1 and CIB1. | CD61
Integrin beta-3 (β3) or CD61 is a protein that in humans is encoded by the ITGB3 gene.[1] CD61 is a cluster of differentiation found on thrombocytes.[2]
# Structure and function
The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface-mediated signaling.[3]
# Role in endometriosis
Defectively expressed β3 integrin subunit has been correlated with presence of endometriosis, and has been suggested as a putative marker of this condition.[4]
# Interactions
CD61 has been shown to interact with PTK2,[5][6] ITGB3BP,[7][8] TLN1[9][10] and CIB1.[11] | https://www.wikidoc.org/index.php/CD61 | |
c24ebb82c74ed3dca52f774dec34906cbfffc626 | wikidoc | CD63 | CD63
CD63 antigen is a protein that in humans is encoded by the CD63 gene. CD63 is mainly associated with membranes of intracellular vesicles, although cell surface expression may be induced.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth, and motility.
This encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak Syndrome . Also this gene has been associated with tumor progression. The use of alternate polyadenylation sites has been found for this gene. Alternative splicing results in multiple transcript variants encoding different proteins.
# Allergy diagnosis
CD63 is a good marker for flow cytometric quantification of in vitro activated basophils for diagnosis of IgE-mediated allergy. The test is commonly designated as basophil activation test (BAT).
# Research
Initially, deletion and point mutants were used to investigate the role of the C-terminus, which contains a putative lysosomal-targeting/internalisation motif (GYEVM). C-terminal mutants showed increased surface expression and decreased intracellular localisation relative to CD63Wt. Antibody induced internalisation was reduced in C-terminal deletion mutants and abolished in G→A and Y→A mutants, showing the crucial role of these residues in internalisation.
CD63 is extensively and variably glycosylated and the EC2 region contain three potential N-linked glycosylation sites (N130, N150, and N172). Mutants N130A and N150A were similar to hCD63Wt with respect to intracellular localisation and internalisation. However, the hCD63N172A mutant showed a mainly cell surface localisation and low internalisation. Expression of a mutant lacking all three glycosylation sites was very unstable. It was speculated that the reduced internalisation of CD63N172A might be due to changes in its interaction with cell surface molecules. Immunoprecipitation experiments showed some evidence of a protein (100kDa) associating with CD63N172A, but this was not consistent. However, an association between CD63Wt and β2 integrin (CD18) was shown by co-internalisation of these proteins. Interactions with CD63 may therefore affect the trafficking and function of β2 integrins.
A recent investigation showed that expression of CD63 positively correlates with the invasiveness of ovarian cancer.
In cell biology, CD63 is often used as a marker for multivesicular bodies, which are enriched with CD63.
# Interactions
CD63 has been shown to interact with CD117 and CD82. | CD63
CD63 antigen is a protein that in humans is encoded by the CD63 gene.[1] CD63 is mainly associated with membranes of intracellular vesicles, although cell surface expression may be induced.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth, and motility.
This encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak Syndrome . Also this gene has been associated with tumor progression. The use of alternate polyadenylation sites has been found for this gene. Alternative splicing results in multiple transcript variants encoding different proteins.[1]
# Allergy diagnosis
CD63 is a good marker for flow cytometric quantification of in vitro activated basophils for diagnosis of IgE-mediated allergy. The test is commonly designated as basophil activation test (BAT).
# Research
Initially, deletion and point mutants were used to investigate the role of the C-terminus, which contains a putative lysosomal-targeting/internalisation motif (GYEVM). C-terminal mutants showed increased surface expression and decreased intracellular localisation relative to CD63Wt. Antibody induced internalisation was reduced in C-terminal deletion mutants and abolished in G→A and Y→A mutants, showing the crucial role of these residues in internalisation.
CD63 is extensively and variably glycosylated and the EC2 region contain three potential N-linked glycosylation sites (N130, N150, and N172). Mutants N130A and N150A were similar to hCD63Wt with respect to intracellular localisation and internalisation. However, the hCD63N172A mutant showed a mainly cell surface localisation and low internalisation. Expression of a mutant lacking all three glycosylation sites was very unstable. It was speculated that the reduced internalisation of CD63N172A might be due to changes in its interaction with cell surface molecules. Immunoprecipitation experiments showed some evidence of a protein (100kDa) associating with CD63N172A, but this was not consistent. However, an association between CD63Wt and β2 integrin (CD18) was shown by co-internalisation of these proteins. Interactions with CD63 may therefore affect the trafficking and function of β2 integrins.
A recent investigation showed that expression of CD63 positively correlates with the invasiveness of ovarian cancer.[2]
In cell biology, CD63 is often used as a marker for multivesicular bodies, which are enriched with CD63.[3]
# Interactions
CD63 has been shown to interact with CD117[4] and CD82.[5] | https://www.wikidoc.org/index.php/CD63 | |
daa41368cc084f29a496c6c30882b74f4d6bf114 | wikidoc | CD68 | CD68
CD68 (Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia).
# Structure and function
Human CD68 is a transmembrane glycoprotein, heavily glycosylated in its extracellular domain, with a molecular weight of 110 kD. Its primary sequence consists of 354 amino acids with predicted molecular weight of 37.4 kD if it were not glycosylated. The human CD68 protein is encoded by the "CD68" gene which maps to Chromosome 17. Other names or aliases for this gene in humans and other animals include: CD68 Molecule, CD68 Antigen, GP110, Macrosialin, Scavenger Receptor Class D, Member 1, SCARD1, and LAMP4. The mouse equivalent is known as "macrosialin".
CD68 is functionally and evolutionarily related to other gene/protein family members, as follows:
- the hematopoietic mucin-like family of molecules that includes leukosialin/CD43 and stem cell antigen CD34;
- the lysosomal/endosomal-associated membrane glycoprotein (LAMP) family, CD68 localizes primarily to lysosomes and endosomes but with a smaller fraction circulating to the cell surface;
- the scavenger receptor family which typically function to clear cellular debris, promote phagocytosis, and mediate the recruitment and activation of macrophages.
Functionally, the CD68 protein binds to tissue- and organ-specific lectins or selectins, allowing macrophages to home in on particular targets. It is thought that rapid recirculation of CD68 from endosomes and lysosomes to the plasma membrane allows macrophages to crawl over selectin-bearing substrates or other cells.
# Use in pathology and research
Immunohistochemistry can be used to identify the presence of CD68, which is found in the cytoplasmic granules of a range of different blood cells and myocytes. It is particularly useful as a marker for the various cells of the macrophage lineage, including monocytes, histiocytes, giant cells, Kupffer cells, and osteoclasts. This allows it to be used to distinguish diseases of otherwise similar appearance, such as the monocyte/macrophage and lymphoid forms of leukaemia (the latter being CD68 negative). Its presence in macrophages also makes it useful in diagnosing conditions related to proliferation or abnormality of these cells, such as malignant histiocytosis, histiocytic lymphoma, and Gaucher's disease.
Anti-CD68 monoclonal antibodies that react with tissues of rodent and other species include ED1, FA-11, KP1 (a.k.a. C68/684), 6A326, 6F3, 12E2, 10B1909, and SPM130. Monoclonals that react with humans include, Ki-M7, PG-M1, 514H12, ABM53F5, 3F7C6, 3F7D3, Y1/82A, EPR20545, CDLA68-1, LAMP4-824.
## ED1
ED1 is the most widely used monoclonal antibody clone directed against the rat CD68 protein and is used to identify macrophages, Kupffer cells, osteoclasts, monocytes, and activated microglia in rat tissues. In this species, it is expressed in most macrophage populations and thus ED1 is commonly used as a pan-macrophage marker. However, in some cell types it is detectable only when up-regulated, such as activated but not quiescent microglia, and can thus be used as a marker of inflammatory conditions and immune reactions in those instances. Commercial suppliers report that ED1 is used for detection of the CD68 protein by immunohistochemical staining, flow cytometry, and western blot methods and that in addition to rat it cross-reacts with bovine species.
The ED1 anti-CD68 antibody is not to be confused with the fibronectin extra domain ED1. | CD68
CD68 (Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia).[1]
# Structure and function
Human CD68 is a transmembrane glycoprotein, heavily glycosylated in its extracellular domain, with a molecular weight of 110 kD. Its primary sequence consists of 354 amino acids with predicted molecular weight of 37.4 kD if it were not glycosylated.[2] The human CD68 protein is encoded by the "CD68" gene which maps to Chromosome 17.[3] Other names or aliases for this gene in humans and other animals include: CD68 Molecule, CD68 Antigen, GP110, Macrosialin, Scavenger Receptor Class D, Member 1, SCARD1, and LAMP4.[3][4] The mouse equivalent is known as "macrosialin".
CD68 is functionally and evolutionarily related to other gene/protein family members, as follows:[2][4][5]
- the hematopoietic mucin-like family of molecules that includes leukosialin/CD43 and stem cell antigen CD34;
- the lysosomal/endosomal-associated membrane glycoprotein (LAMP) family, CD68 localizes primarily to lysosomes and endosomes but with a smaller fraction circulating to the cell surface;
- the scavenger receptor family which typically function to clear cellular debris, promote phagocytosis, and mediate the recruitment and activation of macrophages.
Functionally, the CD68 protein binds to tissue- and organ-specific lectins or selectins, allowing macrophages to home in on particular targets. It is thought that rapid recirculation of CD68 from endosomes and lysosomes to the plasma membrane allows macrophages to crawl over selectin-bearing substrates or other cells.
# Use in pathology and research
Immunohistochemistry can be used to identify the presence of CD68, which is found in the cytoplasmic granules of a range of different blood cells and myocytes. It is particularly useful as a marker for the various cells of the macrophage lineage, including monocytes, histiocytes, giant cells, Kupffer cells, and osteoclasts. This allows it to be used to distinguish diseases of otherwise similar appearance, such as the monocyte/macrophage and lymphoid forms of leukaemia (the latter being CD68 negative). Its presence in macrophages also makes it useful in diagnosing conditions related to proliferation or abnormality of these cells, such as malignant histiocytosis, histiocytic lymphoma, and Gaucher's disease.[6][7]
Anti-CD68 monoclonal antibodies that react with tissues of rodent and other species include ED1, FA-11, KP1 (a.k.a. C68/684), 6A326, 6F3, 12E2, 10B1909, and SPM130. Monoclonals that react with humans include, Ki-M7, PG-M1, 514H12, ABM53F5, 3F7C6, 3F7D3, Y1/82A, EPR20545, CDLA68-1, LAMP4-824.[8]
## ED1
ED1 is the most widely used monoclonal antibody clone directed against the rat CD68 protein and is used to identify macrophages, Kupffer cells, osteoclasts, monocytes, and activated microglia in rat tissues.[9][10][11] In this species, it is expressed in most macrophage populations and thus ED1 is commonly used as a pan-macrophage marker.[12] However, in some cell types it is detectable only when up-regulated, such as activated but not quiescent microglia, and can thus be used as a marker of inflammatory conditions and immune reactions in those instances. Commercial suppliers report that ED1 is used for detection of the CD68 protein by immunohistochemical staining, flow cytometry, and western blot methods and that in addition to rat it cross-reacts with bovine species.
The ED1 anti-CD68 antibody is not to be confused with the fibronectin extra domain ED1.[13] | https://www.wikidoc.org/index.php/CD68 | |
fe3064a5d8a2a28786d69484d20440fff9c01a9e | wikidoc | CD69 | CD69
CD69 (Cluster of Differentiation 69) is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentation as well as lymphocyte retention in lymphoid organs.
# Function
The activation of T lymphocytes and Natural Killer (NK) Cells, both in vivo and in vitro, induces expression of CD69. This molecule, which appears to be the earliest inducible cell surface glycoprotein acquired during lymphoid activation, is involved in lymphocyte proliferation and functions as a signal-transmitting receptor in lymphocytes, including natural killer (NK) cells, and platelets (Cambiaggi et al., 1992) .
# Structure and ligands
The gene encoding CD69 is located in the NK gene complex on chromosome 6 and chromosome 12 in mice and humans respectively. Activation signaling pathways in lymphocytes, NK cells, dendritic cells and other cell types upregulate transcription factors, such as NF-κB, ERG-1 (erythroblast transformation-specific related gene-1), and AP-1 (activator protein), in order to promote the transcription of the CD69 gene. The CD69 protein is subject to post-translational modifications. Namely, it is differentially glycosylated to produce either a 28 kDa peptide or a 32 kDa peptide. Two of these peptides randomly combine to form a homodimer linked by a disulfide bond. These subunits have a C-type lectin domain (CTLD) that binds ligands, a transmembrane domain, and a cytoplasmic tail that relays signals to the cell interior.
CD69 lacks the characteristic Ca2+ binding residues in CTLDs, indicating that it might bind to proteins rather than carbohydrates, the usual ligand of CTLDs. It has been shown that CD69 binds to Gal-1, a carbohydrate binding protein located on some dendritic cells and macrophages, in addition to Myl9/12. Other ligands have yet to be identified. However, it is known that binding of the ligands initiates the Jak/Stat signaling pathway as well as the mTOR/HIF1-α pathway. CD69 is also known to interact with and mediate S1P and LAT1 receptors, which influence lymphocyte egress in lymphoid organs among other responses. More work must be done to fully characterize CD69-ligand interactions as well as CD69’s method of transducing intracellular signals.
# T cell differentiation
CD69 expression has been associated with both regulatory T cell (Treg), memory T cell and Bcl6 loCD69 hiLZ GC B plasmablast precursors. Treg precursors exit the thymus expressing CD69 and complete differentiation into Treg cells in peripheral tissues when they encounter antigens and other cytokines, like IL-2. Through the JAK/STAT signaling pathway, CD69 activation also induces the production of TGF-β as well as IL-2, which contribute to the differentiation of Treg cells as mentioned above. Furthermore, CD69 is also known to be upregulated by NF-κB signaling at the onset of an immune response. A prolonged immune response is then maintained by the non-canonical NF-κB pathway, which in turn is associated with Treg differentiation.
In addition to Treg differentiation, CD69 is a common marker of precursor and mature resident memory T cells (TRMs) that are localized in peripheral tissues. TGF-β is also responsible for the development of TRMs, thus promoting TRM differentiation in a manner similar to Treg differentiation.
# Lymphocyte migration
Most lymphocytes express sphingosine-1-phosphate receptors (S1P1-5), which are G protein-coupled receptors located in the cell membrane that bind to the ligand sphingosine-1-phosphate (S1P). S1P is a sphingolipid metabolite that is abundant in the bloodstream and, upon binding to S1P1, promotes lymphocyte egress from lymphoid organs so they can travel to affected tissues. However, when a T cell is activated in a lymphoid organ through cytokine and TCR signaling, CD69 is expressed and forms a complex with S1P1 (not S1P3 or S1P5). This association is dependent on the interaction between the CD69 transmembrane domain and helix-4 of S1P1. Following formation of this complex, S1P1 is internalized and is destroyed within the cell, inhibiting its ability to bind S1P and initiate downstream signaling. This in turn results in temporary lymphocyte retention in the lymph organs. It is thought that retention of lymphocytes in the lymph nodes may increase the chance of successful lymphocyte activation, especially if the initial activation signal was weak. Similarly, CD69 expressed in thymocytes following positive selection may ensure that T cells fully mature in the thymus prior to entering circulation.
Some research has shown that S1P1 and CD69 co-regulate so that when CD69 is in greater abundance, it results in the removal of S1P1 from the membrane as mentioned above. However, if S1P1 is more abundant than CD69, as would be the case in mature T cells, CD69 membrane localization is reduced. In this manner, regulation of CD69 and S1P1 expression and localization jointly impact lymphocyte egress and migration. | CD69
CD69 (Cluster of Differentiation 69) is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system.[1] It is also implicated in T cell differentation as well as lymphocyte retention in lymphoid organs.
# Function
The activation of T lymphocytes and Natural Killer (NK) Cells, both in vivo and in vitro, induces expression of CD69. This molecule, which appears to be the earliest inducible cell surface glycoprotein acquired during lymphoid activation, is involved in lymphocyte proliferation and functions as a signal-transmitting receptor in lymphocytes, including natural killer (NK) cells, and platelets (Cambiaggi et al., 1992) [supplied by OMIM].[2]
# Structure and ligands
The gene encoding CD69 is located in the NK gene complex on chromosome 6 and chromosome 12 in mice and humans respectively.[3] Activation signaling pathways in lymphocytes, NK cells, dendritic cells and other cell types upregulate transcription factors, such as NF-κB, ERG-1 (erythroblast transformation-specific related gene-1), and AP-1 (activator protein), in order to promote the transcription of the CD69 gene.[4][3] The CD69 protein is subject to post-translational modifications. Namely, it is differentially glycosylated to produce either a 28 kDa peptide or a 32 kDa peptide. Two of these peptides randomly combine to form a homodimer linked by a disulfide bond.[3] These subunits have a C-type lectin domain (CTLD) that binds ligands, a transmembrane domain, and a cytoplasmic tail that relays signals to the cell interior.[3]
CD69 lacks the characteristic Ca2+ binding residues in CTLDs, indicating that it might bind to proteins rather than carbohydrates, the usual ligand of CTLDs.[5][3] It has been shown that CD69 binds to Gal-1, a carbohydrate binding protein located on some dendritic cells and macrophages, in addition to Myl9/12.[4] Other ligands have yet to be identified. However, it is known that binding of the ligands initiates the Jak/Stat signaling pathway as well as the mTOR/HIF1-α pathway.[5][4][3] CD69 is also known to interact with and mediate S1P and LAT1 receptors, which influence lymphocyte egress in lymphoid organs among other responses.[6][4] More work must be done to fully characterize CD69-ligand interactions as well as CD69’s method of transducing intracellular signals.
# T cell differentiation
CD69 expression has been associated with both regulatory T cell (Treg), memory T cell and Bcl6 loCD69 hiLZ GC B plasmablast precursors.[7] Treg precursors exit the thymus expressing CD69 and complete differentiation into Treg cells in peripheral tissues when they encounter antigens and other cytokines, like IL-2.[8] Through the JAK/STAT signaling pathway, CD69 activation also induces the production of TGF-β as well as IL-2, which contribute to the differentiation of Treg cells as mentioned above.[4] Furthermore, CD69 is also known to be upregulated by NF-κB signaling at the onset of an immune response. A prolonged immune response is then maintained by the non-canonical NF-κB pathway, which in turn is associated with Treg differentiation.[3]
In addition to Treg differentiation, CD69 is a common marker of precursor and mature resident memory T cells (TRMs) that are localized in peripheral tissues.[9][5] TGF-β is also responsible for the development of TRMs, thus promoting TRM differentiation in a manner similar to Treg differentiation.[10]
# Lymphocyte migration
Most lymphocytes express sphingosine-1-phosphate receptors (S1P1-5), which are G protein-coupled receptors located in the cell membrane that bind to the ligand sphingosine-1-phosphate (S1P). S1P is a sphingolipid metabolite that is abundant in the bloodstream and, upon binding to S1P1, promotes lymphocyte egress from lymphoid organs so they can travel to affected tissues.[11][4] However, when a T cell is activated in a lymphoid organ through cytokine and TCR signaling, CD69 is expressed and forms a complex with S1P1 (not S1P3 or S1P5). This association is dependent on the interaction between the CD69 transmembrane domain and helix-4 of S1P1. Following formation of this complex, S1P1 is internalized and is destroyed within the cell, inhibiting its ability to bind S1P and initiate downstream signaling. This in turn results in temporary lymphocyte retention in the lymph organs.[4] It is thought that retention of lymphocytes in the lymph nodes may increase the chance of successful lymphocyte activation, especially if the initial activation signal was weak. Similarly, CD69 expressed in thymocytes following positive selection may ensure that T cells fully mature in the thymus prior to entering circulation.[6]
Some research has shown that S1P1 and CD69 co-regulate so that when CD69 is in greater abundance, it results in the removal of S1P1 from the membrane as mentioned above.[6] However, if S1P1 is more abundant than CD69, as would be the case in mature T cells, CD69 membrane localization is reduced. In this manner, regulation of CD69 and S1P1 expression and localization jointly impact lymphocyte egress and migration.[6] | https://www.wikidoc.org/index.php/CD69 | |
5a2fcb93773c964cf2ebfd71a73485accfba9bdb | wikidoc | CD70 | CD70
CD70 (Cluster of Differentiation 70) is a ligand for CD27.
# Clinical significance
The CD70 protein is expressed on highly activated lymphocytes (like in T- and B-cell lymphomas). It is therefore suggested that anti-CD70 antibodies might be a possible treatment for CD70 positive lymphomas as normal lymphocytes have low CD70 expression.
# Drug development
ARGX-110 is a CD70-specific antibody that is currently under investigation for the treatment of hematological malignancies. It is being developed by the Belgian company arGEN-X. In December 2013 a first part of a phase 1b trial was completed. In January 2014 a safety and efficacy phase of the study started.
Vorsetuzumab mafodotin is a CD70-targeted antibody-drug conjugate that started clinical trials for renal cell carcinoma. | CD70
CD70 (Cluster of Differentiation 70) is a ligand for CD27.
# Clinical significance
The CD70 protein is expressed on highly activated lymphocytes (like in T- and B-cell lymphomas). It is therefore suggested that anti-CD70 antibodies might be a possible treatment for CD70 positive lymphomas as normal lymphocytes have low CD70 expression.[1]
# Drug development
ARGX-110 is a CD70-specific antibody that is currently under investigation for the treatment of hematological malignancies. It is being developed by the Belgian company arGEN-X. In December 2013 a first part of a phase 1b trial was completed. In January 2014 a safety and efficacy phase of the study started.[2]
Vorsetuzumab mafodotin is a CD70-targeted antibody-drug conjugate that started clinical trials for renal cell carcinoma.[3] | https://www.wikidoc.org/index.php/CD70 | |
a7e41c68c41e01f7267c9c19ed20e6220b6a578a | wikidoc | CD74 | CD74
HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the CD74 gene. The invariant chain (Abbreviated Ii) is a polypeptide involved in the formation and transport of MHC class II protein. The cell surface form of the invariant chain is known as CD74.
# Function
The nascent MHC class II protein in the rough ER binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide binding groove and prevent formation of a closed conformation.
The invariant chain also facilitates MHC class II's export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant for MHC class I molecules accidentally bind to the groove of MHC class II molecules. The Ii is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP remaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded. CLIP blocks peptide binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. In some cases, CLIP dissociates without any further molecular interactions, but in other cases the binding to the MHC is more stable.
The stable MHC class-II with antigen complex is then presented on the cell surface. Without CLIP, MHC class II aggregates, disassemble, and/or denature in the endosomes, and proper antigen presentation is impaired
# Clinical significance
## Cancer
Found on a number of cancer cell types. Possible cancer therapy target. See Milatuzumab#CD74
## Axial Spondyloarthritis
Autoantibodies against CD74 have been identified as a promising biomarkers in the early diagnosis of the autoimmune disease called axial spondyloarthritis (non-radiographic axial Spondyloarthritis and radiographic axial Spondyloarthritis / Ankylosing spondylitis).
# Interactions
CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor to mediate its proinflammatory functions. | CD74
HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the CD74 gene.[1][2] The invariant chain (Abbreviated Ii) is a polypeptide involved in the formation and transport of MHC class II protein.[3] The cell surface form of the invariant chain is known as CD74.
# Function
The nascent MHC class II protein in the rough ER binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide binding groove and prevent formation of a closed conformation.
The invariant chain also facilitates MHC class II's export from the ER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant for MHC class I molecules accidentally bind to the groove of MHC class II molecules.[4] The Ii is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP remaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded.[4] CLIP blocks peptide binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. In some cases, CLIP dissociates without any further molecular interactions, but in other cases the binding to the MHC is more stable.[5]
The stable MHC class-II with antigen complex is then presented on the cell surface. Without CLIP, MHC class II aggregates, disassemble, and/or denature in the endosomes, and proper antigen presentation is impaired[6]
# Clinical significance
## Cancer
Found on a number of cancer cell types. Possible cancer therapy target. See Milatuzumab#CD74
## Axial Spondyloarthritis
Autoantibodies against CD74 have been identified as a promising biomarkers in the early diagnosis of the autoimmune disease called axial spondyloarthritis (non-radiographic axial Spondyloarthritis and radiographic axial Spondyloarthritis / Ankylosing spondylitis). [7]
# Interactions
CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor to mediate its proinflammatory functions[8].[9][10][11][12][13] | https://www.wikidoc.org/index.php/CD74 | |
b9c6933649c61e223e54da68695c160ce34d649b | wikidoc | CD81 | CD81
CD81 molecule, also known as CD81 (Cluster of Differentiation 81), is a protein which in humans is encoded by the CD81 gene. It is also known as 26 kDa cell surface protein, TAPA-1 (Target of the Antiproliferative Antibody 1), and Tetraspanin-28 (Tspan-28).
# Gene
The gene is located on the Watson (plus) strand of the short arm of chromosome 11 (11p15.5). It is 20,103 bases in length and encodes a protein of 236 amino acids (predicted molecular weight 25.809 kDa).
The protein does not appear to be post translationally modified and has four transmembrane domains. Both the N-terminus and C-terminus lie on the intracellular side of the membrane.
The gene is expressed in hemopoietic, endothelial, and epithelial cells. It is absent from erythrocytes, platelets, and neutrophils.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies.
The tetraspanin family includes CD9, CD37, CD53, CD63, CD81 (this protein), CD82 and CD151.
CD81 interacts directly with immunoglobulin superfamily member 8 (IGSF8, CD316) and CD36. It forms a signal transduction complex with CD19, CD21 and Leu-13 (CD225) on the surface of the B cell. On T cells CD81 associates with CD4 and CD8 and provides a costimulatory signal with CD3.
# Clinical significance
This protein plays a critical role in Hepatitis C attachment and/or cell entry by interacting with virus' E1/E2 glycoproteins heterodimer. The large extracellular loop(LEL) of CD81 binds the hepatitis E2 glycoprotein dimer. HCV-E2 and CD81 binding Kd is 1.8 nM. HCV-E2 engaged CD81 is only 30% internalized after 12hr, suggesting CD81 may be primarily an attachment receptor for HCV.
It also appears to play a role in liver invasion by Plasmodium species. CD81 is required for Plasmodium vivax sporozoite entry into human hepatocytes and for Plasmodium yoelii sporozoite entry into murine hepatocytes.
HIV gag proteins use tetraspanin enriched microdomains (containing minimally CD81, CD82, CD63) as a platform for virion assembly and release. Purified HIV produced by MOLT\HIV cells contains CD81. Anti-CD81 antibodies downregulate HIV production 3 fold, however the CD81 protein free virus is more infectious. Engagement of CD81 lowers the signaling threshold required to trigger T-Cell\CD3 mediated proviral DNA in CD4+ T cells.
CD81 appears to play a role in the pathogenesis of influenza.
# Interactions
CD81 has been shown to interact with TSPAN4, CD19, CD9, PTGFRN, CD117 and CD29.
## Ligands
Benzyl salicylate and terfenadine have been shown to bind to CD81. | CD81
CD81 molecule, also known as CD81 (Cluster of Differentiation 81), is a protein which in humans is encoded by the CD81 gene.[1][2] It is also known as 26 kDa cell surface protein, TAPA-1 (Target of the Antiproliferative Antibody 1), and Tetraspanin-28 (Tspan-28).
# Gene
The gene is located on the Watson (plus) strand of the short arm of chromosome 11 (11p15.5). It is 20,103 bases in length and encodes a protein of 236 amino acids (predicted molecular weight 25.809 kDa).[2]
The protein does not appear to be post translationally modified and has four transmembrane domains. Both the N-terminus and C-terminus lie on the intracellular side of the membrane.
The gene is expressed in hemopoietic, endothelial, and epithelial cells. It is absent from erythrocytes, platelets, and neutrophils.
# Function
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. Also it may be involved in signal transduction. This gene is localized in the tumor-suppressor gene region and thus it is a candidate gene for malignancies.[1]
The tetraspanin family includes CD9, CD37, CD53, CD63, CD81 (this protein), CD82 and CD151.
CD81 interacts directly with immunoglobulin superfamily member 8 (IGSF8,[3] CD316) and CD36. It forms a signal transduction complex with CD19, CD21 and Leu-13 (CD225) on the surface of the B cell.[4] On T cells CD81 associates with CD4 and CD8 and provides a costimulatory signal with CD3.[4]
# Clinical significance
This protein plays a critical role in Hepatitis C attachment and/or cell entry by interacting with virus' E1/E2 glycoproteins heterodimer.[5] The large extracellular loop(LEL) of CD81 binds the hepatitis E2 glycoprotein dimer. HCV-E2 and CD81 binding Kd is 1.8 nM. HCV-E2 engaged CD81 is only 30% internalized after 12hr, suggesting CD81 may be primarily an attachment receptor for HCV.[6]
It also appears to play a role in liver invasion by Plasmodium species.[7] CD81 is required for Plasmodium vivax sporozoite entry into human hepatocytes and for Plasmodium yoelii sporozoite entry into murine hepatocytes.[8]
HIV gag proteins use tetraspanin enriched microdomains (containing minimally CD81, CD82, CD63) as a platform for virion assembly and release. Purified HIV produced by MOLT\HIV cells contains CD81. Anti-CD81 antibodies downregulate HIV production 3 fold, however the CD81 protein free virus is more infectious.[9] Engagement of CD81 lowers the signaling threshold required to trigger T-Cell\CD3 mediated proviral DNA in CD4+ T cells.[10]
CD81 appears to play a role in the pathogenesis of influenza.[11]
# Interactions
CD81 has been shown to interact with TSPAN4,[12] CD19,[13][14][15] CD9,[15][16] PTGFRN,[17][18] CD117[19] and CD29.[20][21]
## Ligands
Benzyl salicylate[22] and terfenadine[23] have been shown to bind to CD81. | https://www.wikidoc.org/index.php/CD81 | |
b21d124af7ff40f94151bc5d9855517e6f70550f | wikidoc | CD90 | CD90
Thy-1 or CD90 (Cluster of Differentiation 90) is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.
# Discovery and nomenclature
The antigen Thy-1 was the first T cell marker to be identified. Thy-1 was discovered by Reif and Allen in 1964 during a search for heterologous antisera against mouse leukemia cells, and was demonstrated by them to be present on murine thymocytes, on T lymphocytes, and on neuronal cells. It was originally named theta (θ) antigen, then Thy-1 (THYmocyte differentiation antigen 1) due to its prior identification in thymocytes (precursors of T cells in the thymus). The human homolog was isolated in 1980 as a 25kDa protein (p25) of T-lymphoblastoid cell line MOLT-3 binding with anti-monkey-thymocyte antisera. The discovery of Thy-1 in mice and humans led to the subsequent discovery of many other T cell markers, which is very significant to the field of immunology since T cells (along with B cells) are the major cellular components of the adaptive immune response.
# The conserved gene and its alleles
Thy-1 has been conserved throughout vertebrate evolution and even in some invertebrates, with homologs described in many species like squid, frogs, chickens, mice, rats, dogs, and humans.
The Thy-1 gene is located at human chromosome 11q22.3 (mouse chromosome 9qA5.1). In AceView, it covers 6.82 kb, from 119294854 to 119288036 (NCBI 37, August 2010), on the reverse strand. This locus is very close to CD3 & CD56/NCAM genes. Some believe that there may be a functional significance of both this gene and CD3 delta subunit (T3D) mapping to chromosome 11q in man and chromosome 9 in mouse, though there is no homology (in fact this speculation lead to its localization in chromosome 11q - the human chromosome region syntenic to mouse chromosome 9 which harbored T3D). In mice, there are two alleles: Thy1.1 (Thy 1a, CD90.1) and Thy1.2 (Thy 1b, CD90.2). They differ by only one amino acid at position 108; an arginine in Thy-1.1 and a glutamine in Thy-1.2. Thy 1.2 is expressed by most strains of mice, whereas Thy1.1 is expressed by some like AKR/J and PL mouse strains.
# The Protein
The 25-kDa core protein (excluding the heavy glycosylation) of rodent Thy-1 is 111 or 112 amino acids in length, and is N-glycosylated at three sites (In contrast to only two glycosylation sites for human Thy-1). The 162aa (murine, 161 for human) Thy1 precursor has 19 amino acid (aa 1-19) signal sequence and 31 amino acid (aa 132-162) C-terminal transmembrane domain that is present in pro form but removed when transferring the 112 amino acid (aa 20-131) mature peptide to GPI anchor which would attach through the aa 131.
Some of the common monoclonal antibodies used to detect this protein are clones OX7, 5E10, K117 and L127.
There have been some reports of Thy1 monoclonal antibodies cross reacting with some cytoskeletal elements: anti Thy-1.2 with actin in marsupial, murine, and human cells and anti Thy-1.1 with vimentin, and were suggested to be due to sequence homology by studies done more than 20 years back.
Thy-1, like many other GPI anchored proteins can be shed by special types of Phospholipase C e.g. PI-PLC (phosphatidyl-Inositol Phospholipase C, or PLC β). it can also be involved in cell to cell transfer of GPI anchored proteins like CD55 and CD59.
# Glycosylation
Thy-1 is one of the most heavily glycosylated membrane proteins with a carbohydrate content up to 30% of its molecular mass. Thy1 in most species has 3 N-glycosylation sites (Asn 23, 74 and 98) but no O-glycosylation. The composition of Thy-1 carbohydrate moieties varies considerably between different tissues or even among cells of the same lineage at different stages of differentiation: e.g., galactosamine only in brain Thy-1, sialic acid in thymic Thy-1 in far excess than brain Thy-1, that too increasing in parallel with T cell maturation. In this regard it has yet another historic association: Thy1 happens to be the first glycoprotein in which cell type specificity of variant glycosylation on an invariant protein was demonstrated. Analysis of Differencial glycosylation of Thy-1 from brain and thymus showed that all the complex N-linked structures differed between the two forms, superimposed upon a site specific common core. In case of Thy1 this core pattern was constituted by Asn23 carrying mostly oligomannose structures, Asn74 carrying the most extended complex structures, and Asn98 carrying smaller complex structure. The structure of the sugar residues in the GPI anchor and their associated esterified structures (e.g. additional fatty acids and alcohols) also can be cell type and species specific.
# Expression
Thy1 expression varies between species. Amongst the cells reported to generally express Thy-1 are thymocytes (precursor of T cells in the thymus) & CD34(+) prothymocytes; neurons, mesenchymal stem cells, hematopoietic stem cells, NK cells, murine T-cells, endothelium (mainly in high endothelial venules or HEVs where diapedesis takes place), renal glomerular mesangial cells, circulating metastatic melanoma cells, follicular dendritic cells (FDC), a fraction of fibroblasts and myofibroblasts.
## Detailed expression of Thy-1
- In mice, Thy-1 is also found on thymocytes, peripheral T cells, myoblasts, epidermal cells, and keratinocytes. It is one of the "pan T cell markers"(of mice) like CD2, CD5 and CD28.
- In humans, Thy-1 is also expressed by endothelial cells, smooth muscle cells, a subset of CD34+ bone marrow cells, and umbilical cord blood-, cardiac fibroblasts, and fetal liver-derived hemopoietic cells.
- Thy-1 is present on a fraction of brain cells and a fraction of fibroblasts of most vertebrate species studied.
- Nervous tissue: Thy-1 expression in the nervous system is predominantly neuronal, but some glial cells also express Thy-1 especially at later stages of their differentiation. One study compared Thy-1 expression in four human neuronal cell lines, two neuroglial cell lines, and fresh tumor cells of neuronal origin and found three of the four neuronal cell lines, all of the neuroglial cell lines, and 80% of the tumors to be strongly positive for Thy-1. Brain part specific ELISA reports are available which show highest concentrations of Thy1 protein in the striatum and hippocampus, followed by the neocortex, cerebellum, spinal cord, and the retina and optic nerve. Thy1 promoter has often been assumed to be "brain specific". "Neuron specific" mouse thy1 promoter has been used to drive "brain specific" forced expression of proteins e.g. mutated Amyloid precursor protein(APP) as transgenic animal models of Alzheimer's disease. Thy-1 expression in the brain is developmentally regulated. Thy-1 levels in the neonatal rat brain, as well as the developing human brain, are low compared to adult brain. During the first few weeks of postnatal development, Thy-1 levels increase exponentially as the brain matures.
- Lymphoid tissue Thy-1 expression is highly variable between species. In humans, Thy-1 expression is restricted to only a small population of cortical thymocytes and not expressed in mature human T cells. It is probably the most abundant glycoprotein of murine thymocytes, with about One million copies per cell covering up to 10–20% of the cell surface. Mouse cortical thymocytes express higher levels of Thy-1 than medullary thymocytes which in turn express more than lymph node cells (~200,000 copies/cell). A similar inverse developmental temporal expression profile is seen in rats T cells, although rat Thy-1 is lost at an earlier stage of T cell maturation. Thy-1 is only expressed on thymocytes in rats (contrast to thymocytes and splenocytes in mice). The third intron of the mouse Thy-1 gene has a 36 base pair region that recruits nuclear transcription factors, such as Ets-1-like NF, expressed in thymocytes and splenocytes. The homologous region of the rat gene lacks the Ets-1-like NF binding site, but instead binds another NF expressed in rat thymocytes but not splenocytes.
## Induction of Thy-1 expression
- Agents shown to induce Thy1 expression include: Thymopoietin, thymosin, prostaglandins, nerve growth factor, IL-1, TNF, PMA, Ca2+ ionophore, and diacylglycerol (DAG).
# Localization
As a GPI-anchored protein, Thy-1 is present in the outer leaflet of lipid rafts in the cell membrane. In case of neurons it is known to be expressed strongly in the mature axon. The axon hillock can act as a barrier for its lateral spread even though it has no transmembrane segment. Thy-1 has been suggested to interact with G inhibitory proteins, the Src family kinase (SFK) member c-fyn, and tubulin within lipid rafts. In rats and mice, Thy-1 protein is present on the soma (cell body) and dendrites of neurons but is not expressed on axons until axonal growth is complete, and is again temporarily suppressed during axonal injury. HIV-1 Matrix co-localizes with Thy-1 in lipid rafts, the site of virus particle budding from cells, and Thy-1 is incorporated into virus particles as a result of this process.
# Function
The function of Thy-1 has not yet been fully elucidated. It has speculated roles in cell-cell and cell-matrix interactions, with implication in neurite outgrowth, nerve regeneration, apoptosis, metastasis, inflammation, and fibrosis.
## Role in cognition
The Thy-1 knockout (KO) mice are viable and appear grossly normal. They display normal social interactions and normal learning in a maze, but fail to learn from social cues (e.g. learning from other mice which foods are safe to eat as compared to wild-type mice). This failure can be rescued by the transgenic expression of Thy-1 or pharmacologic treatment with a GABA (A) receptor antagonists. This suggests that Thy-1 KO mice have excessive GABAergic inhibition in the dentate gyrus and regional inhibition of long-term potentiation.
## Axon growth regulation
Crosslinking anti-Thy-1 Ab can promote neurite outgrowth which is dependent on G{alpha}i and L- and N-type calcium channel activation. The ligand for promotion of neurite outgrowth on astrocytes is not yet identified, but the inhibitory ligand has been suggested to be integrins. Thy1 is one of the known ligands of beta 3 integrins. Interaction of thy1 expressed on maturing axons with beta 3 integrins expressed on mature astrocytes may be the cause of halting of axon growth.
## T-cell activation
Crosslinking Thy-1 molecules in the membrane raft, in the context of strong costimulatory signaling through CD28 in mouse T cells can act to some extent as a substitute activating signal for T-cell receptor signaling. Conversely it can substitute CD28 costimulation for activation through the TCR.
## Apoptosis/Necrosis
Cross linking antibody induced aggregation of Thy1 cause death of thymocytes and mesangial cells mainly by apoptosis despite Bcl2 upregulation. The death of mesangial cells seems to be apoptosis by TUNEL staining or annexin V staining, but electron microscopy suggest it is necrosis.
### Antibody target for animal model of Glomerulonephritis
Single tail vein intravenous injection of antibody (OX7 mouse monoclonal IgG) against Thy1.1 in rats is used as a standard animal model to produce experimental mesangioproliferative glomerulonephritis which is popularly known in the field of nephrology as antiThy1 GN.
## Tumor suppression
It has also been proven to be a tumor suppressor for some tumors. It probably is aided by its action in upregulating thrombospondin, SPARC (osteonectin), and fibronectin. However it has also been speculated to aid in extravasation in circulating melanoma cells. In case of prostate cancer it has been shown to be expressed in cancer associated stroma but not in normal stroma and has been suggested to be of potential help for cancer specific drug targeting .
## Role in cell adhesion, extravasation, migration
Acting through several integrins and probably a few yet unknown other receptors Thy-1 mediates adhesion of leukocytes and monocytes to endothelial cells and fibroblasts, melanoma cells to endothelium, and thymocytes to thymic epithelium. Thy1 expression comes on when endothelial cells are activated. It has been shown to interact with the leukocyte integrin Mac1 (CD11b/CD18) and may play a role in leukocyte homing and recruitment.
## Modulating fibrosis
Role of Thy-1 in fibrosis and fibroblast differention may have some tissue variation. In lung fibrosis Thy-1 level is suppressed in stimulated fibroblasts. Thy1 knock out mice have increased fibrosis in the lung. Fibrosis induced by radiation mimicking chemotherapeutic agent Bleomycin is also increased in these mice.
# Other roles
Thy-1 knock out mice also show impaired cutaneous immune responses and abnormal retinal development: thinning of the inner nuclear, inner plexiform, ganglion cell, and outer segment layers of the retina.
# Use in stem cell biology
Thy-1 can be considered as a surrogate marker for various kind of stem cells (e.g. hematopoietic stem cells or HSCs). It is one of the popular combinatorial surface markers for FACS for stem cells in combination with other markers like CD34. In humans, Thy-1 is expressed on neurons and HSCs among others. It is considered a major marker of HSC pluripotency in concordance with CD34. In human HSCs, Thy1 cells are all CD34 positive. Thy 1 is also a marker of other kind of stem cells, for example: mesenchymal stem cells, hepatic stem cells ("oval cells"), keratinocyte stem cells, putative endometrial progenitor/(?)stem cells. | CD90
Thy-1 or CD90 (Cluster of Differentiation 90) is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.
# Discovery and nomenclature
The antigen Thy-1 was the first T cell marker to be identified. Thy-1 was discovered by Reif and Allen in 1964[1] during a search for heterologous antisera against mouse leukemia cells, and was demonstrated by them to be present on murine thymocytes, on T lymphocytes, and on neuronal cells. It was originally named theta (θ) antigen, then Thy-1 (THYmocyte differentiation antigen 1) due to its prior identification in thymocytes (precursors of T cells in the thymus). The human homolog was isolated in 1980 as a 25kDa protein (p25) of T-lymphoblastoid cell line MOLT-3 binding with anti-monkey-thymocyte antisera.[2] The discovery of Thy-1 in mice and humans led to the subsequent discovery of many other T cell markers, which is very significant to the field of immunology since T cells (along with B cells) are the major cellular components of the adaptive immune response.[2]
# The conserved gene and its alleles
Thy-1 has been conserved throughout vertebrate evolution and even in some invertebrates, with homologs described in many species like squid, frogs, chickens, mice, rats, dogs, and humans.
The Thy-1 gene is located at human chromosome 11q22.3 (mouse chromosome 9qA5.1). In AceView, it covers 6.82 kb, from 119294854 to 119288036 (NCBI 37, August 2010), on the reverse strand. This locus is very close to CD3 & CD56/NCAM genes. Some believe that there may be a functional significance of both this gene and CD3 delta subunit (T3D) mapping to chromosome 11q in man and chromosome 9 in mouse, though there is no homology (in fact this speculation lead to its localization in chromosome 11q - the human chromosome region syntenic to mouse chromosome 9 which harbored T3D). In mice, there are two alleles: Thy1.1 (Thy 1a, CD90.1) and Thy1.2 (Thy 1b, CD90.2). They differ by only one amino acid at position 108; an arginine in Thy-1.1 and a glutamine in Thy-1.2. Thy 1.2 is expressed by most strains of mice, whereas Thy1.1 is expressed by some like AKR/J and PL mouse strains.
# The Protein
The 25-kDa core protein (excluding the heavy glycosylation) of rodent Thy-1 is 111 or 112 amino acids in length, and is N-glycosylated at three sites (In contrast to only two glycosylation sites for human Thy-1). The 162aa (murine, 161 for human) Thy1 precursor has 19 amino acid (aa 1-19) signal sequence and 31 amino acid (aa 132-162) C-terminal transmembrane domain that is present in pro form but removed when transferring the 112 amino acid (aa 20-131) mature peptide to GPI anchor which would attach through the aa 131.
Some of the common monoclonal antibodies used to detect this protein are clones OX7, 5E10, K117 and L127.
There have been some reports of Thy1 monoclonal antibodies cross reacting with some cytoskeletal elements: anti Thy-1.2 with actin in marsupial, murine, and human cells and anti Thy-1.1 with vimentin, and were suggested to be due to sequence homology by studies done more than 20 years back.[3]
Thy-1, like many other GPI anchored proteins can be shed by special types of Phospholipase C e.g. PI-PLC (phosphatidyl-Inositol Phospholipase C, or PLC β). it can also be involved in cell to cell transfer of GPI anchored proteins like CD55 and CD59.
# Glycosylation
Thy-1 is one of the most heavily glycosylated membrane proteins with a carbohydrate content up to 30% of its molecular mass.[4] Thy1 in most species has 3 N-glycosylation sites (Asn 23, 74 and 98) but no O-glycosylation. The composition of Thy-1 carbohydrate moieties varies considerably between different tissues or even among cells of the same lineage at different stages of differentiation: e.g., galactosamine only in brain Thy-1, sialic acid in thymic Thy-1 in far excess than brain Thy-1, that too increasing in parallel with T cell maturation. In this regard it has yet another historic association: Thy1 happens to be the first glycoprotein in which cell type specificity of variant glycosylation on an invariant protein was demonstrated. Analysis of Differencial glycosylation of Thy-1 from brain and thymus showed that all the complex N-linked structures differed between the two forms, superimposed upon a site specific common core. In case of Thy1 this core pattern was constituted by Asn23 carrying mostly oligomannose structures, Asn74 carrying the most extended complex structures, and Asn98 carrying smaller complex structure. The structure of the sugar residues in the GPI anchor and their associated esterified structures (e.g. additional fatty acids and alcohols) also can be cell type and species specific.
# Expression
Thy1 expression varies between species. Amongst the cells reported to generally express Thy-1 are thymocytes (precursor of T cells in the thymus) & CD34(+) prothymocytes; neurons, mesenchymal stem cells, hematopoietic stem cells, NK cells, murine T-cells, endothelium (mainly in high endothelial venules or HEVs where diapedesis takes place), renal glomerular mesangial cells, circulating metastatic melanoma cells, follicular dendritic cells (FDC), a fraction of fibroblasts and myofibroblasts.
## Detailed expression of Thy-1
- In mice, Thy-1 is also found on thymocytes, peripheral T cells, myoblasts, epidermal cells, and keratinocytes. It is one of the "pan T cell markers"(of mice) like CD2, CD5 and CD28.
- In humans, Thy-1 is also expressed by endothelial cells, smooth muscle cells, a subset of CD34+ bone marrow cells, and umbilical cord blood-, cardiac fibroblasts, and fetal liver-derived hemopoietic cells.
- Thy-1 is present on a fraction of brain cells and a fraction of fibroblasts of most vertebrate species studied.
- Nervous tissue: Thy-1 expression in the nervous system is predominantly neuronal, but some glial cells also express Thy-1 especially at later stages of their differentiation. One study compared Thy-1 expression in four human neuronal cell lines, two neuroglial cell lines, and fresh tumor cells of neuronal origin and found three of the four neuronal cell lines, all of the neuroglial cell lines, and 80% of the tumors to be strongly positive for Thy-1.[5] Brain part specific ELISA reports are available which show highest concentrations of Thy1 protein in the striatum and hippocampus, followed by the neocortex, cerebellum, spinal cord, and the retina and optic nerve. Thy1 promoter has often been assumed to be "brain specific". "Neuron specific" mouse thy1 promoter has been used to drive "brain specific" forced expression of proteins e.g. mutated Amyloid precursor protein(APP) as transgenic animal models of Alzheimer's disease.[6] Thy-1 expression in the brain is developmentally regulated. Thy-1 levels in the neonatal rat brain, as well as the developing human brain, are low compared to adult brain. During the first few weeks of postnatal development, Thy-1 levels increase exponentially as the brain matures.
- Lymphoid tissue Thy-1 expression is highly variable between species. In humans, Thy-1 expression is restricted to only a small population of cortical thymocytes[7] and not expressed in mature human T cells.[8] It is probably the most abundant glycoprotein of murine thymocytes, with about One million copies per cell covering up to 10–20% of the cell surface.[9] Mouse cortical thymocytes express higher levels of Thy-1 than medullary thymocytes which in turn express more than lymph node cells (~200,000 copies/cell). A similar inverse developmental temporal expression profile is seen in rats T cells, although rat Thy-1 is lost at an earlier stage of T cell maturation.[10] Thy-1 is only expressed on thymocytes in rats (contrast to thymocytes and splenocytes in mice). The third intron of the mouse Thy-1 gene has a 36 base pair region that recruits nuclear transcription factors, such as Ets-1-like NF, expressed in thymocytes and splenocytes. The homologous region of the rat gene lacks the Ets-1-like NF binding site, but instead binds another NF expressed in rat thymocytes but not splenocytes.
## Induction of Thy-1 expression
- Agents shown to induce Thy1 expression include: Thymopoietin, thymosin, prostaglandins, nerve growth factor, IL-1, TNF, PMA, Ca2+ ionophore, and diacylglycerol (DAG).[11]
# Localization
As a GPI-anchored protein, Thy-1 is present in the outer leaflet of lipid rafts in the cell membrane. In case of neurons it is known to be expressed strongly in the mature axon. The axon hillock can act as a barrier for its lateral spread even though it has no transmembrane segment. Thy-1 has been suggested to interact with G inhibitory proteins, the Src family kinase (SFK) member c-fyn, and tubulin within lipid rafts. In rats and mice, Thy-1 protein is present on the soma (cell body) and dendrites of neurons but is not expressed on axons until axonal growth is complete, and is again temporarily suppressed during axonal injury. HIV-1 Matrix co-localizes with Thy-1 in lipid rafts, the site of virus particle budding from cells, and Thy-1 is incorporated into virus particles as a result of this process.
# Function
The function of Thy-1 has not yet been fully elucidated. It has speculated roles in cell-cell and cell-matrix interactions, with implication in neurite outgrowth, nerve regeneration, apoptosis, metastasis, inflammation, and fibrosis.
## Role in cognition
The Thy-1 knockout (KO) mice are viable and appear grossly normal. They display normal social interactions and normal learning in a maze, but fail to learn from social cues (e.g. learning from other mice which foods are safe to eat as compared to wild-type mice). This failure can be rescued by the transgenic expression of Thy-1 or pharmacologic treatment with a GABA (A) receptor antagonists. This suggests that Thy-1 KO mice have excessive GABAergic inhibition in the dentate gyrus and regional inhibition of long-term potentiation.
## Axon growth regulation
Crosslinking anti-Thy-1 Ab can promote neurite outgrowth which is dependent on G{alpha}i and L- and N-type calcium channel activation. The ligand for promotion of neurite outgrowth on astrocytes is not yet identified, but the inhibitory ligand has been suggested to be integrins. Thy1 is one of the known ligands of beta 3 integrins. Interaction of thy1 expressed on maturing axons with beta 3 integrins expressed on mature astrocytes may be the cause of halting of axon growth.
## T-cell activation
Crosslinking Thy-1 molecules in the membrane raft, in the context of strong costimulatory signaling through CD28 in mouse T cells can act to some extent as a substitute activating signal for T-cell receptor signaling. Conversely it can substitute CD28 costimulation for activation through the TCR.[11]
## Apoptosis/Necrosis
Cross linking antibody induced aggregation of Thy1 cause death of thymocytes and mesangial cells mainly by apoptosis despite Bcl2 upregulation. The death of mesangial cells seems to be apoptosis by TUNEL staining or annexin V staining, but electron microscopy suggest it is necrosis.
### Antibody target for animal model of Glomerulonephritis
Single tail vein intravenous injection of antibody (OX7 mouse monoclonal IgG) against Thy1.1 in rats is used as a standard animal model to produce experimental mesangioproliferative glomerulonephritis[12] which is popularly known in the field of nephrology as antiThy1 GN.
## Tumor suppression
It has also been proven to be a tumor suppressor for some tumors.[13] It probably is aided by its action in upregulating thrombospondin, SPARC (osteonectin), and fibronectin. However it has also been speculated to aid in extravasation in circulating melanoma cells. In case of prostate cancer it has been shown to be expressed in cancer associated stroma but not in normal stroma and has been suggested to be of potential help for cancer specific drug targeting [2].
## Role in cell adhesion, extravasation, migration
Acting through several integrins and probably a few yet unknown other receptors Thy-1 mediates adhesion of leukocytes and monocytes to endothelial cells and fibroblasts, melanoma cells to endothelium, and thymocytes to thymic epithelium.[14] Thy1 expression comes on when endothelial cells are activated. It has been shown to interact with the leukocyte integrin Mac1 (CD11b/CD18) and may play a role in leukocyte homing and recruitment.[15]
## Modulating fibrosis
Role of Thy-1 in fibrosis and fibroblast differention may have some tissue variation. In lung fibrosis Thy-1 level is suppressed in stimulated fibroblasts. Thy1 knock out mice have increased fibrosis in the lung. Fibrosis induced by radiation mimicking chemotherapeutic agent Bleomycin is also increased in these mice.
# Other roles
Thy-1 knock out mice also show impaired cutaneous immune responses and abnormal retinal development: thinning of the inner nuclear, inner plexiform, ganglion cell, and outer segment layers of the retina.
# Use in stem cell biology
Thy-1 can be considered as a surrogate marker for various kind of stem cells (e.g. hematopoietic stem cells or HSCs). It is one of the popular combinatorial surface markers for FACS for stem cells in combination with other markers like CD34. In humans, Thy-1 is expressed on neurons and HSCs among others. It is considered a major marker of HSC pluripotency in concordance with CD34. In human HSCs, Thy1 cells are all CD34 positive.[16][17][18][19] Thy 1 is also a marker of other kind of stem cells, for example: mesenchymal stem cells, hepatic stem cells ("oval cells"),[20] keratinocyte stem cells,[21] putative endometrial progenitor/(?)stem cells.[22] | https://www.wikidoc.org/index.php/CD90 | |
6cfcb2a361e5dc5836edc353666bf991c61efb70 | wikidoc | CD93 | CD93
CD93 (Cluster of Differentiation 93) is a protein that in humans is encoded by the CD93 gene. CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.
# Family
CD93 belongs to the Group XIV C-Type lectin family, a group containing three other members, endosialin (CD248), CLEC14A and thrombomodulin, a well characterized anticoagulant. All of them contain a C-type lectin domain, a series of epidermal growth factor like domains, a highly glycosylated mucin-like domain, a unique transmembrane domain and a short cytoplasmic tail. Due to their strong homology and their close proximity on chromosome 20, CD93 has been suggested to have arisen from the thrombomodulin gene through a duplication event.
# Expression
CD93 was originally identified in mice as an early B cell marker through the use of AA4.1 monoclonal antibody. Then this molecule was shown to be expressed on an early population of hematopoietic stem cells, which give rise to the entire spectrum of mature cells in the blood. Now CD93 is known to be expressed by a wide variety of cells such as platelets, monocytes, microglia and endothelial cells. In the immune system CD93 is also expressed on neutrophils, activated macrophages, B cell precursors until the T2 stage in the spleen, a subset of dendritic cells and of natural killer cells. Molecular characterization of CD93 revealed that this protein is identical with C1qRp, a human protein identified as a putative C1q receptor. C1q belongs to the complement activation proteins and plays a major role in the activation of the classical pathway of the complement, which leads to the formation of the membrane attack complex. C1q is also involved in other immunological processes such as enhancement of bacterial phagocytosis, clearance of apoptotic cells or neutralisation of virus. Strikingly, it has been shown that anti-C1qRp significantly reduced C1q enhanced phagocytosis. A more recent study confirmed that C1qRp is identical to CD93 protein, but failed to demonstrate a direct interaction between CD93 and C1q under physiological conditions. Recently it has been shown that CD93 is re-expressed during the late B cell differentiation and CD93 can be used in this context as a plasma cell maturation marker. CD93 has been found to be differentially expressed in grade IV glioma vasculature when compared to low grade glioma or normal brain and its high expression correlated with the poor survival of the patients.
# Function
CD93 was initially thought to be a receptor for C1q, but now is thought to instead be involved in intercellular adhesion and in the clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein contains two highly conserved domains which may be involved in CD93 function. Indeed, the highly charged juxtamembrane domain has been found to interact with moesin, a protein known to play a role in linking transmembrane proteins to the cytoskeleton and in the remodelling of the cytoskeleton. This process appears crucial for both adhesion, migration and phagocytosis, three functions in which CD93 may be involved.
In the context of late B cell differentiation, CD93 has been shown to be important for the maintenance of high antibody titres after immunization and in the survival of long-lived plasma cells in the bone marrow. Indeed, CD93 deficient mice failed to maintain high antibody level upon immunization and present a lower amount of antigen specific plasma cells in the bone marrow.
In the context of the endothelial cells, CD93 is involved in endothelial cell-cell adhesion, cell spreading, cell migration, cell polarization as well as tubular morphogenesis. Recently it has been found that CD93 is able to control endothelial cell dynamics through its interaction with an extracellular matrix gycoprotein MMRN2. Absence of CD93 or its interacting partner MMRN2 in the endothelial cells lead to disruption of extracellular matrix protein fibronectin fibrillogenesis and decreased integrin B1 activation.
CD93 plays a significant role in the glioma development. CD93 knockout mice with glioma show smaller tumor size and improved survival. The tumors also show disrupted fibronectin fibrillogenesis and decreased integrin B1 activation. | CD93
CD93 (Cluster of Differentiation 93) is a protein that in humans is encoded by the CD93 gene.[1][2][3] CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.[3]
# Family
CD93 belongs to the Group XIV C-Type lectin family, a group containing three other members, endosialin (CD248), CLEC14A[4] and thrombomodulin, a well characterized anticoagulant. All of them contain a C-type lectin domain, a series of epidermal growth factor like domains, a highly glycosylated mucin-like domain, a unique transmembrane domain and a short cytoplasmic tail. Due to their strong homology and their close proximity on chromosome 20, CD93 has been suggested to have arisen from the thrombomodulin gene through a duplication event.
# Expression
CD93 was originally identified in mice as an early B cell marker through the use of AA4.1 monoclonal antibody.[5][6] Then this molecule was shown to be expressed on an early population of hematopoietic stem cells, which give rise to the entire spectrum of mature cells in the blood. Now CD93 is known to be expressed by a wide variety of cells such as platelets, monocytes, microglia and endothelial cells. In the immune system CD93 is also expressed on neutrophils, activated macrophages, B cell precursors until the T2 stage in the spleen, a subset of dendritic cells and of natural killer cells. Molecular characterization of CD93 revealed that this protein is identical with C1qRp, a human protein identified as a putative C1q receptor.[7] C1q belongs to the complement activation proteins and plays a major role in the activation of the classical pathway of the complement, which leads to the formation of the membrane attack complex. C1q is also involved in other immunological processes such as enhancement of bacterial phagocytosis, clearance of apoptotic cells or neutralisation of virus. Strikingly, it has been shown that anti-C1qRp significantly reduced C1q enhanced phagocytosis. A more recent study confirmed that C1qRp is identical to CD93 protein, but failed to demonstrate a direct interaction between CD93 and C1q under physiological conditions. Recently it has been shown that CD93 is re-expressed during the late B cell differentiation and CD93 can be used in this context as a plasma cell maturation marker. CD93 has been found to be differentially expressed in grade IV glioma vasculature when compared to low grade glioma or normal brain and its high expression correlated with the poor survival of the patients.[8][9]
# Function
CD93 was initially thought to be a receptor for C1q, but now is thought to instead be involved in intercellular adhesion and in the clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein contains two highly conserved domains which may be involved in CD93 function. Indeed, the highly charged juxtamembrane domain has been found to interact with moesin, a protein known to play a role in linking transmembrane proteins to the cytoskeleton and in the remodelling of the cytoskeleton. This process appears crucial for both adhesion, migration and phagocytosis, three functions in which CD93 may be involved.
In the context of late B cell differentiation, CD93 has been shown to be important for the maintenance of high antibody titres after immunization and in the survival of long-lived plasma cells in the bone marrow. Indeed, CD93 deficient mice failed to maintain high antibody level upon immunization and present a lower amount of antigen specific plasma cells in the bone marrow.
In the context of the endothelial cells, CD93 is involved in endothelial cell-cell adhesion, cell spreading, cell migration, cell polarization as well as tubular morphogenesis.[9] Recently it has been found that CD93 is able to control endothelial cell dynamics through its interaction with an extracellular matrix gycoprotein MMRN2.[10] Absence of CD93 or its interacting partner MMRN2 in the endothelial cells lead to disruption of extracellular matrix protein fibronectin fibrillogenesis and decreased integrin B1 activation.[10]
CD93 plays a significant role in the glioma development. CD93 knockout mice with glioma show smaller tumor size and improved survival.[9] The tumors also show disrupted fibronectin fibrillogenesis and decreased integrin B1 activation.[10] | https://www.wikidoc.org/index.php/CD93 | |
b62d24421363ed7ae5d03e833e1f9ca4d04b3b94 | wikidoc | CD97 | CD97
Cluster of differentiation 97 is a protein also known as BL-Ac encoded by the ADGRE5 gene. CD97 is a member of the adhesion GPCR family.
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts.
In the case of CD97 the N-terminal domains consist of alternatively spliced epidermal growth factor (EGF)-like domains. Alternative splicing has been observed for this gene and three variants have been found. The N-terminal fragment of CD97 contains 3-5 EGF-like domains in human and 3-4 EGF-like domains in mice.
# Ligands
Decay accelerating factor (DAF/CD55), a regulatory protein of the complement cascade, interacts with the first and second EGF-like domains of CD97; chondroitin sulfate B with the fourth EGF-like domain; α5β1 and αvβ3 integrins with an RGD downstream the EGF-like domains; and CD90 (Thy-1) with the GAIN domain. N-glycosylation of CD97 within the EGF domains is crucial for CD55 binding.
# Signaling
Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt. Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling. Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive Gi/o protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce in breast cancer cells.
# Function
In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation. Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis. Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes. Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism. Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.
Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis. CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis. In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier. Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.
Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling. Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation. CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle. In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.
# Clinical significance
CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases. CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells. In addition, enhanced CD97 expression has been found at the invasion front of tumors, suggesting a possible role in tumor migration/invasion, and correlated with a poorer clinical prognosis. CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma; the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.
Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8. Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression. CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling. It has been shown that CD97 regulates localization and degradation of β-catenin. GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes. Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone. Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress. | CD97
Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene.[1][2][3][4] CD97 is a member of the adhesion GPCR family.[5][6]
Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[7]
CD97 is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts.[8][9][10][11][12][13]
In the case of CD97 the N-terminal domains consist of alternatively spliced epidermal growth factor (EGF)-like domains. Alternative splicing has been observed for this gene and three variants have been found.[3] The N-terminal fragment of CD97 contains 3-5 EGF-like domains in human and 3-4 EGF-like domains in mice.[14]
# Ligands
Decay accelerating factor (DAF/CD55), a regulatory protein of the complement cascade, interacts with the first and second EGF-like domains of CD97;[15] chondroitin sulfate B with the fourth EGF-like domain;[16] α5β1 and αvβ3 integrins with an RGD downstream the EGF-like domains;[17] and CD90 (Thy-1) with the GAIN domain.[18] N-glycosylation of CD97 within the EGF domains is crucial for CD55 binding.[19]
# Signaling
Transgenic expression of a CD97 in mice enhanced levels of nonphosphorylated membrane-bound β-catenin and phosphorylated Akt.[20] Furthermore, ectopic CD97 expression facilitated RhoA activation through binding of Gα12/13 as well as induced Ki67 expression and phosphorylated ERK and Akt through enhancing lysophosphatidic acid receptor 1 (LPAR1) signaling.[21][22] Lysophosphatidylethanolamine (LPE; a plasma membrane component) and lysophosphatidic acid (LPA) use heterodimeric LPAR1–CD97 to drive Gi/o protein–phospholipase C–inositol 1,4,5-trisphosphate signaling and induce [Ca2+] in breast cancer cells.[23]
# Function
In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation.[24] Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Mice lacking CD97 or its ligand CD55 have twice as many granulocytes as wild-type mice possibly due to enhanced granulopoiesis.[25] Antibodies against CD97 have been demonstrated to diminish various inflammatory disorders by depleting granulocytes.[26] Notably, CD97 antibody-mediated granulocytopenia only happens under the condition of pro-inflammation via an Fc receptor-associated mechanism.[27] Finally, the interaction between CD97 and its ligand CD55 regulates T-cell activation and increases proliferation and cytokine production.[28][29]
Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. The expression of CD97 on macrophage and the abundant presence of its ligand CD55 on fibroblast-like synovial cells suggest that the CD97-CD55 interaction is involved in the recruitment and/or retention of macrophages into the synovial tissue in rheumatoid arthritis.[30] CD97 antibodies and lack of CD97 or CD55 in mice reduced synovial inflammation and joint damage in collagen- and K/BxN serum transfer-induced arthritis.[31][32] In brain tissue, CD97 is undetectable in normal white matter, and expression of CD55 is fairly restricted to the endothelium. In pre-active lesion, increased expression of CD55 in endothelial cells and robust CD97 expression on infiltrating leukocytes suggest a possible role of both molecules in immune cell migration through the blood-brain barrier.[33] Additionally, soluble N-terminal fragment (NTF)s of CD97 are detectable in the serum of patients with rheumatoid arthritis and multiple sclerosis.[30]
Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 in colonic enterocytes strengthens E-cadherin-based adherens junctions to maintain lateral cell-cell contacts and regulates the localization and degradation of β-catenin through glycogen synthase kinase-3β (GSK-3β) and Akt signaling.[20] Ectopic CD97 expression upregulates the expression of N-cadherin and β-catenin in HT1080 fibrosarcoma cells leading to enhanced cell-cell aggregation.[34] CD97 is expressed at the sarcoplasmic reticulum and the peripheral sarcolemma in skeletal muscle. However, lack of CD97 only affects the structure of the sarcoplasmic reticulum, but not the function of skeletal muscle.[13] In addition, CD97 promotes angiogenesis of the endothelium through to α5β1 and αvβ3 integrins, which contributes to cell attachment.[17]
# Clinical significance
CD97 expression in cancer was first reported for dedifferentiated thyroid carcinoma and their lymph node metastases.[35] CD97 is expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells.[35][36][37][38][39][40][41] In addition, enhanced CD97 expression has been found at the invasion front of tumors,[42] suggesting a possible role in tumor migration/invasion,[39][42] and correlated with a poorer clinical prognosis.[40][37][38][43][44] CD97 has isoform-specific functions in some tumors. For instance, the small EGF(1,2,5) isoform promoted tumor invasion and metastasis in gastric carcinoma;[45] the small EGF(1,2,5) isoform induced but the full length EGF(1-5) isoform suppressed gastric carcinoma invasion.[46]
Forced CD97 expression induced cell migration, activated proteolytic matrix metalloproteinases (MMPs), and enhanced secretion of the chemokines interleukin (IL)-8.[47] Tumor suppressor microRNA-126, often downregulated in cancer, was found to target CD97 thereby modulating cancer progression.[48] CD97 can heterodimerize with the LPAR1, a canonical GPCR that is implied in tumor progression, to modulate synergistic functions and LPA-mediated Rho signaling.[22][21] It has been shown that CD97 regulates localization and degradation of β-catenin.[20] GSK-3β, inhibited in some cancer, regulates the stability of β-catenin in cytoplasm and subsequently, cytosolic β-catenin moves into the nucleus to facilitate expression of pro-oncogenic genes.[49][50] Because of its role in tumor invasion and angiogenesis, CD97 is a potential therapeutic target. Several treatments reduce CD97 expression in tumor cells such as cytokine tumor growth factor (TGF)β as well as the compounds sodium butyrate, retinoic acid, and troglitazone.[37][38][51] Taken together, experimental evidence indicates that CD97 plays multiple roles in tumor progress. | https://www.wikidoc.org/index.php/CD97 | |
a0f681d136181034e60b2d6012422582d0249a98 | wikidoc | CD98 | CD98
CD98 is a glycoprotein that is a heterodimer composed of SLC3A2 and SLC7A5 that forms the large neutral amino acid transporter (LAT1). LAT1 is a heterodimeric membrane transport protein that preferentially transports branched-chain (valine, leucine, isoleucine) and aromatic (tryptophan, tyrosine) amino acids. LAT is highly expressed in brain capillaries (which form the blood–brain barrier) relative to other tissues.
A functional LAT1 transporter is composed of two proteins encoded by two distinct genes:
- 4F2hc/CD98 heavy subunit protein encoded by the SLC3A2 gene
- CD98 light subunit protein encoded by the SLC7A5 gene | CD98
CD98 is a glycoprotein[1][2] that is a heterodimer composed of SLC3A2 and SLC7A5 that forms the large neutral amino acid transporter (LAT1). LAT1 is a heterodimeric membrane transport protein that preferentially transports branched-chain (valine, leucine, isoleucine) and aromatic (tryptophan, tyrosine) amino acids.[3] LAT is highly expressed in brain capillaries (which form the blood–brain barrier) relative to other tissues.[3]
A functional LAT1 transporter is composed of two proteins encoded by two distinct genes:
- 4F2hc/CD98 heavy subunit protein encoded by the SLC3A2 gene [4]
- CD98 light subunit protein encoded by the SLC7A5 gene[5] | https://www.wikidoc.org/index.php/CD98 | |
042b92c2583c114d2ca155cf2989d3c0af35bd99 | wikidoc | CD99 | CD99
CD99 antigen (Cluster of differentiation 99), also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the CD99 gene in humans. The protein has a mass of 32 kD. Unusually for a gene present on the X chromosome, the CD99 gene does not undergo X inactivation, and it was the first such pseudoautosomal gene to be discovered in humans.
# Expression
It is expressed on all leukocytes but highest on thymocytes and is believed to augment T-cell adhesion and apoptosis of double positive t cells. It has been found in endothelial cells and in the periodontium, including gingival fibroblasts and gingival epithelial cells. It also participates in migration and activation. There is also experimental evidence that it binds to cyclophilin A.
It is found on the cell surface of Ewing's sarcoma tumors and is positive in granulosa cell tumors. It is more expressed in malignant gliomas than in the brain, and such overexpression results in higher levels of invasiveness and lower rates of survival. Antibodies to CD99 are used in diagnostic immunohistochemistry to distinguish Ewing's sarcoma from other tumours of similar histological appearance, as well as for the identification of thymic tumours, and of spindle cell tumours, such as synovial sarcoma, haemangiopericytoma, and meningioma. EWS/FLI is thought to regulate CD99, but knockdown of EWS/FLI results in only a modest reduction in CD99. When CD99 expression is knocked down in human cells with Ewing's sarcoma and those cells are grafted onto mice, tumor and bone metastasis development is reduced.
Reducing CD99 expression results in higher β-III tubulin expression and more neurite outgrowth.
Upregulating CD99 expression in the cell line L428, a Hodgkin's lymphoma line, resulted in those cells redifferentiating towards B cells. Consequently, the loss of B-cell differentiation in Hodgkin's lymphoma may be due to CD99 downregulation.
Men appear to express higher levels of CD99 than women.
# Prognostic Value
In patients with diffuse large B-cell lymphoma (DLBCL) with the germinal center B-cell (GCB, classified according to the Muris algorithm) subtype, positive expression of CD99 resulted in better 2-year event free survival (EFS) and 2-year overall survival (OS) compared to negative expression of CD99. In patients with DLBCL with non-GCB, however, negative expression of CD99 resulted in better 2-year EFS and 2-year OS.
In patients with non-small cell lung cancer (NSCLC), higher CD99 expression in the stroma results in better prognosis.
# Interactions
There is evidence that through suppressing β1 integrin affinity, CD99 inhibits cell-extracellular matrix adhesion. | CD99
CD99 antigen (Cluster of differentiation 99), also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the CD99 gene in humans.[1][2][3] The protein has a mass of 32 kD. Unusually for a gene present on the X chromosome, the CD99 gene does not undergo X inactivation, and it was the first such pseudoautosomal gene to be discovered in humans.[4]
# Expression
It is expressed on all leukocytes but highest on thymocytes[5][6][7] and is believed to augment T-cell adhesion [8][9] and apoptosis of double positive t cells.[10] It has been found in endothelial cells and in the periodontium, including gingival fibroblasts and gingival epithelial cells.[3] It also participates in migration and activation.[11] There is also experimental evidence that it binds to cyclophilin A.[12]
It is found on the cell surface of Ewing's sarcoma tumors [13] and is positive in granulosa cell tumors.[14] It is more expressed in malignant gliomas than in the brain, and such overexpression results in higher levels of invasiveness and lower rates of survival.[15] Antibodies to CD99 are used in diagnostic immunohistochemistry to distinguish Ewing's sarcoma from other tumours of similar histological appearance, as well as for the identification of thymic tumours, and of spindle cell tumours, such as synovial sarcoma, haemangiopericytoma, and meningioma.[4] EWS/FLI is thought to regulate CD99, but knockdown of EWS/FLI results in only a modest reduction in CD99. When CD99 expression is knocked down in human cells with Ewing's sarcoma and those cells are grafted onto mice, tumor and bone metastasis development is reduced.[13]
Reducing CD99 expression results in higher β-III tubulin expression and more neurite outgrowth.[13]
Upregulating CD99 expression in the cell line L428, a Hodgkin's lymphoma line, resulted in those cells redifferentiating towards B cells. Consequently, the loss of B-cell differentiation in Hodgkin's lymphoma may be due to CD99 downregulation.[16]
Men appear to express higher levels of CD99 than women.[17]
# Prognostic Value
In patients with diffuse large B-cell lymphoma (DLBCL) with the germinal center B-cell (GCB, classified according to the Muris algorithm) subtype, positive expression of CD99 resulted in better 2-year event free survival (EFS) and 2-year overall survival (OS) compared to negative expression of CD99. In patients with DLBCL with non-GCB, however, negative expression of CD99 resulted in better 2-year EFS and 2-year OS.[18]
In patients with non-small cell lung cancer (NSCLC), higher CD99 expression in the stroma results in better prognosis.[19]
# Interactions
There is evidence that through suppressing β1 integrin affinity, CD99 inhibits cell-extracellular matrix adhesion.[20] | https://www.wikidoc.org/index.php/CD99 | |
71001aa175d4f6487c2f051d6eaa896a724035b0 | wikidoc | Cdk1 | Cdk1
Cell division cycle 2, G1 to S and G2 to M, also known as Cdk1 (CDC2), is a human gene. The protein encoded by this gene is called p34cdk1 and is a cyclin-dependent kinase in the Ser/Thr protein kinase family. This protein is a catalytic subunit of the highly conserved protein kinase complex known as maturation promoting factor (MPF), which is essential for G1/S and G2/M phase transitions of eukaryotic cell cycle. Mitotic cyclins stably associate with this protein and function as regulatory subunits. The kinase activity of this protein is controlled by cyclin accumulation and destruction through the cell cycle. The phosphorylation and dephosphorylation of this protein also play important regulatory roles in cell cycle control.
Cdk1 is one of the components of the maturation promoting factor (MPF) which controls the cell division cycle in yeast. Cdk1 is a cyclin-dependent kinase (CDK) which, when bound to cyclin B, allows a dividing cell to enter into mitosis from G2 (in the absence of inhibitory proteins such as Wee1). Cdk1 also permits the transition from G1 through S in conjunction with cyclin A and cyclin E.
In humans, the functions of cdc2 are divided between its homologues. Some important ones are Cdk1, Cdk2, Cdk4, and Cdk6 (See cyclin-dependent kinase), which associate with different cyclins and regulate stage transitions during the cell cycle.
Other "Cell division cycle" genes (cdc's) are also involved in complex regulatory pathways during the cell cycle. Cdc's were originally discovered in Saccharomyces cerevisiae, and are followed by a number which signifies the order in which they were discovered (e.g. cdc2, cdc20, cdc25, etc). | Cdk1
Cell division cycle 2, G1 to S and G2 to M, also known as Cdk1 (CDC2), is a human gene. The protein encoded by this gene is called p34cdk1 and is a cyclin-dependent kinase in the Ser/Thr protein kinase family. This protein is a catalytic subunit of the highly conserved protein kinase complex known as maturation promoting factor (MPF), which is essential for G1/S and G2/M phase transitions of eukaryotic cell cycle. Mitotic cyclins stably associate with this protein and function as regulatory subunits. The kinase activity of this protein is controlled by cyclin accumulation and destruction through the cell cycle. The phosphorylation and dephosphorylation of this protein also play important regulatory roles in cell cycle control.[1]
Cdk1 is one of the components of the maturation promoting factor (MPF) which controls the cell division cycle in yeast. Cdk1 is a cyclin-dependent kinase (CDK) which, when bound to cyclin B, allows a dividing cell to enter into mitosis from G2 (in the absence of inhibitory proteins such as Wee1). Cdk1 also permits the transition from G1 through S in conjunction with cyclin A and cyclin E.[2]
In humans, the functions of cdc2 are divided between its homologues. Some important ones are Cdk1, Cdk2, Cdk4, and Cdk6 (See cyclin-dependent kinase), which associate with different cyclins and regulate stage transitions during the cell cycle.
Other "Cell division cycle" genes (cdc's) are also involved in complex regulatory pathways during the cell cycle. Cdc's were originally discovered in Saccharomyces cerevisiae, and are followed by a number which signifies the order in which they were discovered (e.g. cdc2, cdc20, cdc25, etc). | https://www.wikidoc.org/index.php/CDC2_gene | |
e450b4fd744ea68e0df2b55916f77a2586acdb8e | wikidoc | CDC6 | CDC6
Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in the cell nucleus during cell cycle phase G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during the cell cycle is regulated through its phosphorylation by cyclin-dependent kinases. Transcription of this protein was reported to be regulated in response to mitogenic signals through a transcriptional control mechanism involving E2F proteins.
# Interactions
CDC6 has been shown to interact with ORC1L, ORC2L, Cyclin A2, PPP2R3B, MCM3, PPP2R3A, MCM7 and PSKH1. | CDC6
Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.[1][2]
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in the cell nucleus during cell cycle phase G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during the cell cycle is regulated through its phosphorylation by cyclin-dependent kinases. Transcription of this protein was reported to be regulated in response to mitogenic signals through a transcriptional control mechanism involving E2F proteins.[3]
# Interactions
CDC6 has been shown to interact with ORC1L,[2][4] ORC2L,[4][5] Cyclin A2,[2][6] PPP2R3B,[7] MCM3,[5][8] PPP2R3A,[9] MCM7[4][8] and PSKH1.[6] | https://www.wikidoc.org/index.php/CDC6 | |
9dae332be3d247df23f118be31355038ad0b828d | wikidoc | CDH2 | CDH2
N-cadherin, also known as Cadherin-2 (CDH2) or neural cadherin (NCAD) is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). N-cadherin is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, N-cadherin is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. While mutations in CDH2 have not thus far been associated with human disease, alterations in expression and integrity of N-cadherin protein has been observed in various forms of disease, including human dilated cardiomyopathy.
# Structure
N-cadherin is a protein with molecular weight of 99.7 kDa, and 906 amino acids in length. N-cadherin, a classical cadherin from the cadherin superfamily, is composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. N-cadherin, as well as other cadherins, interact with N-cadherin on an adjacent cell in an anti-parallel conformation, thus creating a linear, adhesive "zipper" between cells.
# Function
N-cadherin, originally named for its role in neural tissue, plays a role in neurons and later was found to also play a role in cardiac muscle and in cancer metastasis. N-cadherin is a transmembrane, homophilic glycoprotein belonging to the calcium-dependent cell adhesion molecule family. These proteins have extracellular domains that mediate homophilic interactions between adjacent cells, and C-terminal, cytoplasmic tails that mediate binding to catenins, which in turn interact with
the actin cytoskeleton.
## Role in development
N-cadherin plays a role in development as a calcium dependent cell–cell adhesion glycoprotein that functions during gastrulation and is required for establishment of left-right asymmetry.
N-cadherin is widely expressed in the embryo post-implantation, showing high levels in the mesoderm with sustained expression through adulthood. N-cadherin mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated myocytes and abnormal heart tube development occur. N-cadherin plays a role in the development of the vertebrate heart at the transition of epithelial cells to trabecular and compact myocardial cell layer formation. An additional study showed that myocytes expressing a dominant negative N-cadherin mutant showed significant abnormalities in myocyte distribution and migration towards the endocardium, resulting in defects in trabecular formation within the myocardium.
## Role in cardiac muscle
In cardiac muscle, N-cadherin is found at intercalated disc structures which provide end-on cell–cell connections that facilitate mechanical and electrical coupling between adjacent cardiomyocytes. Within intercalated discs are three types of junctions: adherens junctions, desmosomes and gap junctions; N-cadherin is an essential component in adherens junctions, which enables cell–cell adhesion and force transmission across the sarcolemma. N-cadherin complexed to catenins has been described as a master regulator of intercalated disc function. N-cadherin appears at cell–cell junctions prior to gap junction formation, and is critical for normal myofibrillogenesis. Expression of a mutant form of N-cadherin harboring a large deletion in the extracellular domain inhibited the function of endogenous N-cadherin in adult ventricular cardiomyocytes, and neighboring cardiomyocytes lost cell–cell contact and gap junction plaques as well.
Mouse models employing transgenesis have highlighted the function of N-cadherin in cardiac muscle. Mice with altered expression of N-cadherin and/or E-cadherin showed a dilated cardiomyopathy phenotype, likely due to malfunction of intercalated discs. In agreement with this, mice with ablation of N-cadherin in adult hearts via a cardiac-specific tamoxifen-inducible Cre N-cadherin transgene showed disrupted assembly of intercalated discs, dilated cardiomyopathy, impaired cardiac function, decreased sarcomere length, increased Z-line thickness, decreases in connexin 43, and a loss in muscular tension. Mice died within two months of transgene expression, mainly due to spontaneous ventricular tachycardia. Further analysis of N-cadherin knockout mice revealed that the arrhythmias were likely due to ion channel remodeling and aberrant Kv1.5 channel function. These animals showed a prolonged action potential duration, reduced density of inward rectifier potassium channel and decreased expression of Kv1.5, KCNE2 and cortactin combined with disrupted actin cytoskeleton at the sarcolemma.
## Role in neurons
In neural cells, at certain central nervous system synapses, presynaptic to postsynaptic adhesion is mediated at least in part by N-cadherin. N-cadherins interact with catenins to play an important role in learning and memory (For full article see Cadherin-catenin complex in learning and memory).
## Role in cancer metastasis
N-Cadherin is commonly found in cancer cells and provides a mechanism for transendothelial migration. When a cancer cell adheres to the endothelial cells of a blood vessel it up-regulates the src kinase pathway, which phosphorylates beta-catenins attached to both N-cadherin (this protein) and E-cadherins. This causes the intercellular connection between two adjacent endothelial cells to fail and allows the cancer cell to slip through.
# Clinical significance
Mutations in CDH2 have not been conclusively linked to any human disorders. One study investigating genetic underpinnings of obsessive-compulsive disorder and Tourette disorder found that while CDH2 variants are likely not disease-causing as single entities, they may confer risk when examined as part of a panel of related cell–cell adhesion genes. Further studies in larger cohorts will be required to unequivocally determine this.
In human dilated cardiomyopathy, it was shown that N-cadherin expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of N-cadherin protein in heart disease may be a component of remodeling.
# Interactions
CDH2 has been shown to interact with:
- Beta-catenin,
- CDH11,
- type IIb RPTPs including PTPmu (CTNND1),
- CTNNA1,
- LRRC7,
- PTPRM)
- PTPrho (PTPRT), and
- Plakoglobin.
- XIRP1
- SCARB2 | CDH2
N-cadherin, also known as Cadherin-2 (CDH2) or neural cadherin (NCAD) is a protein that in humans is encoded by the CDH2 gene.[1][2] CDH2 has also been designated as CD325 (cluster of differentiation 325). N-cadherin is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, N-cadherin is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. While mutations in CDH2 have not thus far been associated with human disease, alterations in expression and integrity of N-cadherin protein has been observed in various forms of disease, including human dilated cardiomyopathy.
# Structure
N-cadherin is a protein with molecular weight of 99.7 kDa, and 906 amino acids in length.[3] N-cadherin, a classical cadherin from the cadherin superfamily, is composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. N-cadherin, as well as other cadherins, interact with N-cadherin on an adjacent cell in an anti-parallel conformation, thus creating a linear, adhesive "zipper" between cells.[4]
# Function
N-cadherin, originally named for its role in neural tissue, plays a role in neurons and later was found to also play a role in cardiac muscle and in cancer metastasis. N-cadherin is a transmembrane, homophilic glycoprotein belonging to the calcium-dependent cell adhesion molecule family. These proteins have extracellular domains that mediate homophilic interactions between adjacent cells, and C-terminal, cytoplasmic tails that mediate binding to catenins, which in turn interact with
the actin cytoskeleton.[5][6][7]
## Role in development
N-cadherin plays a role in development as a calcium dependent cell–cell adhesion glycoprotein that functions during gastrulation and is required for establishment of left-right asymmetry.[8]
N-cadherin is widely expressed in the embryo post-implantation, showing high levels in the mesoderm with sustained expression through adulthood.[9] N-cadherin mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated myocytes and abnormal heart tube development occur.[10] N-cadherin plays a role in the development of the vertebrate heart at the transition of epithelial cells to trabecular and compact myocardial cell layer formation.[11] An additional study showed that myocytes expressing a dominant negative N-cadherin mutant showed significant abnormalities in myocyte distribution and migration towards the endocardium, resulting in defects in trabecular formation within the myocardium.[12][13]
## Role in cardiac muscle
In cardiac muscle, N-cadherin is found at intercalated disc structures which provide end-on cell–cell connections that facilitate mechanical and electrical coupling between adjacent cardiomyocytes. Within intercalated discs are three types of junctions: adherens junctions, desmosomes and gap junctions;[14] N-cadherin is an essential component in adherens junctions, which enables cell–cell adhesion and force transmission across the sarcolemma.[15] N-cadherin complexed to catenins has been described as a master regulator of intercalated disc function.[16] N-cadherin appears at cell–cell junctions prior to gap junction formation,[17][18] and is critical for normal myofibrillogenesis.[19] Expression of a mutant form of N-cadherin harboring a large deletion in the extracellular domain inhibited the function of endogenous N-cadherin in adult ventricular cardiomyocytes, and neighboring cardiomyocytes lost cell–cell contact and gap junction plaques as well.[20]
Mouse models employing transgenesis have highlighted the function of N-cadherin in cardiac muscle. Mice with altered expression of N-cadherin and/or E-cadherin showed a dilated cardiomyopathy phenotype, likely due to malfunction of intercalated discs.[21] In agreement with this, mice with ablation of N-cadherin in adult hearts via a cardiac-specific tamoxifen-inducible Cre N-cadherin transgene showed disrupted assembly of intercalated discs, dilated cardiomyopathy, impaired cardiac function, decreased sarcomere length, increased Z-line thickness, decreases in connexin 43, and a loss in muscular tension. Mice died within two months of transgene expression, mainly due to spontaneous ventricular tachycardia.[22] Further analysis of N-cadherin knockout mice revealed that the arrhythmias were likely due to ion channel remodeling and aberrant Kv1.5 channel function. These animals showed a prolonged action potential duration, reduced density of inward rectifier potassium channel and decreased expression of Kv1.5, KCNE2 and cortactin combined with disrupted actin cytoskeleton at the sarcolemma.[23]
## Role in neurons
In neural cells, at certain central nervous system synapses, presynaptic to postsynaptic adhesion is mediated at least in part by N-cadherin.[24] N-cadherins interact with catenins to play an important role in learning and memory (For full article see Cadherin-catenin complex in learning and memory).
## Role in cancer metastasis
N-Cadherin is commonly found in cancer cells and provides a mechanism for transendothelial migration. When a cancer cell adheres to the endothelial cells of a blood vessel it up-regulates the src kinase pathway, which phosphorylates beta-catenins attached to both N-cadherin (this protein) and E-cadherins. This causes the intercellular connection between two adjacent endothelial cells to fail and allows the cancer cell to slip through.[25]
# Clinical significance
Mutations in CDH2 have not been conclusively linked to any human disorders. One study investigating genetic underpinnings of obsessive-compulsive disorder and Tourette disorder found that while CDH2 variants are likely not disease-causing as single entities, they may confer risk when examined as part of a panel of related cell–cell adhesion genes.[26] Further studies in larger cohorts will be required to unequivocally determine this.
In human dilated cardiomyopathy, it was shown that N-cadherin expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of N-cadherin protein in heart disease may be a component of remodeling.[27]
# Interactions
CDH2 has been shown to interact with:
- Beta-catenin,[28][29]
- CDH11,[28]
- type IIb RPTPs including PTPmu (CTNND1),[28][29]
- CTNNA1,[28][29]
- LRRC7,[30]
- PTPRM)[31][32]
- PTPrho (PTPRT),[33] and
- Plakoglobin.[28][34]
- XIRP1[35]
- SCARB2[36] | https://www.wikidoc.org/index.php/CDH2 | |
7f6c4faad875bf3538cae279a757ea1b7af04986 | wikidoc | CDK9 | CDK9
CDK9 or cyclin-dependent kinase 9 is a cyclin-dependent kinase associated with P-TEFb.
The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS.
CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle. | CDK9
CDK9 or cyclin-dependent kinase 9 is a cyclin-dependent kinase associated with P-TEFb.
The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS. [1]
CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle. [2] | https://www.wikidoc.org/index.php/CDK9 | |
c62772dbd01a6446c1735f0214afd88ee03d4ff3 | wikidoc | CDON | CDON
Cell adhesion molecule-related/down-regulated by oncogenes is a protein that in humans is encoded by the CDON gene.
CDON and BOC are cell surface receptors of the immunoglobulin (Ig)/fibronectin type III (FNIII) repeat family involved in myogenic differentiation. CDON and BOC are coexpressed during development, form complexes with each other in a cis fashion, and are related to each other in their ectodomains, but each has a unique long cytoplasmic tail.
# Structure and function
Cell adhesion molecule-related/down-regulated by oncogenes (CDON) is a conserved transmembrane glycoprotein belonging to a subgroup of the immunoglobulin superfamily of cell adhesion molecules. It is highly expressed in both the somites and dorsal lips of the neural tube of embryonic day 8.5 mice. It is expressed in proliferating and differentiating myoblast cell lines, there is evidence showing its role in mediating the effects of cell–cell interactions between muscle precursors that are critical in myogenesis. It is also expressed in neural crest precursor cells, it regulates the localization of N-cadherin providing a mechanism for directed neural crest migration. CDON protein was shown to bind to all three mammalian isoforms of hedgehog proteins: Sonic Hh, Indian Hh, and Desert Hh.
# Clinical significance
CDON mutations are thought to diminish sonic hedgehog (SHH)-pathway activity which is important in stimulating cell proliferation, differentiation, and tissue patterning at multiple points in animal development. CDON was shown to play a role in differentiation of midbrain dopaminergic neurons through the interference with of Shh signaling pathway. Mutations in CDON gene has been associated with Holoprosencephaly which is structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. CDON mutations synergistically interact with prenatal alcohol exposure to increase susceptibility to Holoprosencephaly.
# Gene knockdown studies
CDON knockdown using morpholinos in zebra fish altered the eye development, CDON was shown important in restraining the size of the optic stalk and ventral retina in chick embryos. Additionally, double CDON knock out mice display optic nerve hypoplasia (ONH), a prominent feature of septo-optic dysplasia (SOD), the same phenotype shown by treating mice prenatally with ethanol. CDON−/− animals also show cardiac dysfunction with increased fibrosis, those cardiac effects are mediated through hyperactivation of WNT/β-catenin signaling.
# Interactions
CDON has been shown to interact with CDH1 and BOC. | CDON
Cell adhesion molecule-related/down-regulated by oncogenes is a protein that in humans is encoded by the CDON gene.[1][2]
CDON and BOC are cell surface receptors of the immunoglobulin (Ig)/fibronectin type III (FNIII) repeat family involved in myogenic differentiation. CDON and BOC are coexpressed during development, form complexes with each other in a cis fashion, and are related to each other in their ectodomains, but each has a unique long cytoplasmic tail.[2]
# Structure and function
Cell adhesion molecule-related/down-regulated by oncogenes (CDON) is a conserved transmembrane glycoprotein belonging to a subgroup of the immunoglobulin superfamily of cell adhesion molecules.[3] It is highly expressed in both the somites and dorsal lips of the neural tube of embryonic day 8.5 mice. It is expressed in proliferating and differentiating myoblast cell lines, there is evidence showing its role in mediating the effects of cell–cell interactions between muscle precursors that are critical in myogenesis.[4] It is also expressed in neural crest precursor cells, it regulates the localization of N-cadherin providing a mechanism for directed neural crest migration.[5] CDON protein was shown to bind to all three mammalian isoforms of hedgehog proteins: Sonic Hh, Indian Hh, and Desert Hh.[6]
# Clinical significance
CDON mutations are thought to diminish sonic hedgehog (SHH)-pathway activity which is important in stimulating cell proliferation, differentiation, and tissue patterning at multiple points in animal development. CDON was shown to play a role in differentiation of midbrain dopaminergic neurons through the interference with of Shh signaling pathway.[7] Mutations in CDON gene has been associated with Holoprosencephaly which is structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres.[8] CDON mutations synergistically interact with prenatal alcohol exposure to increase susceptibility to Holoprosencephaly.[9]
# Gene knockdown studies
CDON knockdown using morpholinos in zebra fish altered the eye development, CDON was shown important in restraining the size of the optic stalk and ventral retina in chick embryos.[9] Additionally, double CDON knock out mice display optic nerve hypoplasia (ONH), a prominent feature of septo-optic dysplasia (SOD), the same phenotype shown by treating mice prenatally with ethanol.[10] CDON−/− animals also show cardiac dysfunction with increased fibrosis, those cardiac effects are mediated through hyperactivation of WNT/β-catenin signaling.[11]
# Interactions
CDON has been shown to interact with CDH1[12] and BOC.[13] | https://www.wikidoc.org/index.php/CDON | |
a288db55b3c48df0b329d29265af7187bb9d1516 | wikidoc | CDS2 | CDS2
Phosphatidate cytidylyltransferase 2 is an enzyme that in humans is encoded by the CDS2 gene.
Breakdown products of phosphoinositides are ubiquitous second messengers that function downstream of many G protein-coupled receptors and tyrosine kinases regulating cell growth, calcium metabolism, and protein kinase C activity. This gene encodes an enzyme which regulates the amount of phosphatidylinositol available for signaling by catalyzing the conversion of phosphatidic acid to CDP-diacylglycerol. This enzyme is an integral membrane protein localized to two subcellular domains, the matrix side of the inner mitochondrial membrane where it is thought to be involved in the synthesis of phosphatidylglycerol and cardiolipin. and the cytoplasmic side of the endoplasmic reticulum where it functions in phosphatidylinositol biosynthesis. Two genes encoding this enzyme have been identified in humans, one mapping to human chromosome 4q21 (CDS1) and a second (this gene) to 20p13.
# Model organisms
Model organisms have been used in the study of CDS2 function. A conditional knockout mouse line, called Cds2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals. | CDS2
Phosphatidate cytidylyltransferase 2 is an enzyme that in humans is encoded by the CDS2 gene.[1][2][3]
Breakdown products of phosphoinositides are ubiquitous second messengers that function downstream of many G protein-coupled receptors and tyrosine kinases regulating cell growth, calcium metabolism, and protein kinase C activity. This gene encodes an enzyme which regulates the amount of phosphatidylinositol available for signaling by catalyzing the conversion of phosphatidic acid to CDP-diacylglycerol. This enzyme is an integral membrane protein localized to two subcellular domains, the matrix side of the inner mitochondrial membrane where it is thought to be involved in the synthesis of phosphatidylglycerol and cardiolipin.[4][5] and the cytoplasmic side of the endoplasmic reticulum where it functions in phosphatidylinositol biosynthesis. Two genes encoding this enzyme have been identified in humans, one mapping to human chromosome 4q21 (CDS1) and a second (this gene) to 20p13.[6]
# Model organisms
Model organisms have been used in the study of CDS2 function. A conditional knockout mouse line, called Cds2tm1a(KOMP)Wtsi[11][12] 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.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty six tests were carried out and two phenotypes were reported. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no significant abnormalities were observed in these animals. [9] | https://www.wikidoc.org/index.php/CDS2 | |
851fa0ded1791ef9394c8ac18d1ffb9c3589b24f | wikidoc | CDX1 | CDX1
Homeobox protein CDX-1 is a protein in humans that is encoded by the CDX1 gene. CDX1 is expressed in the developing endoderm and its expression persists in the intestine throughout adulthood. CDX1 protein expression varies along the intestine, with high expression in intestinal crypts and diminishing expression along intestinal villi.
# Function
This gene is a member of the caudal-related homeobox transcription factor family. The encoded DNA-binding protein regulates intestine-specific gene expression and enterocyte differentiation. It has been shown to induce expression of the intestinal alkaline phosphatase gene, and inhibit beta-catenin/T-cell factor transcriptional activity.
CDX1 has also been shown to play an important role in embryonic epicardial development. It has been demonstrated that CDX proteins suppress cardiac differentiation in both zebrafish and mouse embryonic stem cells, but the overall mechanism for how this happens is poorly understood. However, CDX1 has been shown to be transiently expressed in the embryonic heart 11.5 days post coitum (dpc). This transient expression is thought to induce epicardial epithelial-to-mesynchemal transition and thus proper cardiovascular formation. It has been shown that low-dose CDX1 induction caused enhanced migration and differentiation of epicardium-derived cells into vascular smooth muscle, where as continued high dose induction of CDX1 or CDX1 deficiency diminished the ability of these cells to migrate and differentiate into smooth muscle by the actions of TGF-β1. Furthermore, CDX1 induction also altered transcript expression of genes related to cell adhesions for EMT and angiogenesis. Therefore, along with its known roles in intestinal patterning and differentiation, CDX1 is also shown to be important in epicardial development. | CDX1
Homeobox protein CDX-1 is a protein in humans that is encoded by the CDX1 gene.[1][2] CDX1 is expressed in the developing endoderm and its expression persists in the intestine throughout adulthood.[3] CDX1 protein expression varies along the intestine, with high expression in intestinal crypts and diminishing expression along intestinal villi.[4]
# Function
This gene is a member of the caudal-related homeobox transcription factor family. The encoded DNA-binding protein regulates intestine-specific gene expression and enterocyte differentiation. It has been shown to induce expression of the intestinal alkaline phosphatase gene, and inhibit beta-catenin/T-cell factor transcriptional activity.[2]
CDX1 has also been shown to play an important role in embryonic epicardial development. It has been demonstrated that CDX proteins suppress cardiac differentiation in both zebrafish and mouse embryonic stem cells, but the overall mechanism for how this happens is poorly understood.[5] However, CDX1 has been shown to be transiently expressed in the embryonic heart 11.5 days post coitum (dpc). This transient expression is thought to induce epicardial epithelial-to-mesynchemal transition and thus proper cardiovascular formation. It has been shown that low-dose CDX1 induction caused enhanced migration and differentiation of epicardium-derived cells into vascular smooth muscle, where as continued high dose induction of CDX1 or CDX1 deficiency diminished the ability of these cells to migrate and differentiate into smooth muscle by the actions of TGF-β1. Furthermore, CDX1 induction also altered transcript expression of genes related to cell adhesions for EMT and angiogenesis.[6] Therefore, along with its known roles in intestinal patterning and differentiation, CDX1 is also shown to be important in epicardial development. | https://www.wikidoc.org/index.php/CDX1 | |
ac917fe1db5c3ea5c1e047c87a70dd6dd5b994d7 | wikidoc | CDX2 | CDX2
Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. This gene is a member of the caudal-related homeobox transcription factor family that is expressed in the nuclei of intestinal epithelial cells.
# Function
Cdx2 is the gene that directs early embryogenesis in mice. It is required to form the placenta.
Ectopic expression of CDX2 was reported in more than 85% of the human patients with acute myeloid leukemia (AML). Ectopic expression of Cdx2 in murine bone marrow induced AML in mice and upregulate Hox genes in bone marrow progenitors. CDX2 is also implicated in the pathogenesis of Barrett's esophagus where it has been shown that components from gastroesophageal reflux such as bile acids are able to induce the expression of an intestinal differentiation program through up-regulation of NF-κB and CDX2.
# Biomarker for intestinal cancer
CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.
# Possible use in stem cell research
This gene (or, more specifically, the equivalent gene in humans) has come up in the proposal by the President's Council on Bioethics, as a solution to the stem cell controversy. According to one of the plans put forth, by deactivating the gene, it would not be possible for a properly organized embryo to form, thus providing stem cells without requiring the destruction of an embryo. Other genes that have been proposed for this purpose include Hnf4, which is required for gastrulation.
# Interactions
CDX2 has been shown to interact with EP300, and PAX6. | CDX2
Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. This gene is a member of the caudal-related homeobox transcription factor family that is expressed in the nuclei of intestinal epithelial cells.[1]
# Function
Cdx2 is the gene that directs early embryogenesis in mice. It is required to form the placenta.[2]
Ectopic expression of CDX2 was reported in more than 85% of the human patients with acute myeloid leukemia (AML). Ectopic expression of Cdx2 in murine bone marrow induced AML in mice and upregulate Hox genes in bone marrow progenitors.[3][3][4] CDX2 is also implicated in the pathogenesis of Barrett's esophagus where it has been shown that components from gastroesophageal reflux such as bile acids are able to induce the expression of an intestinal differentiation program through up-regulation of NF-κB and CDX2.[5]
# Biomarker for intestinal cancer
CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.[6]
# Possible use in stem cell research
This gene (or, more specifically, the equivalent gene in humans) has come up in the proposal by the President's Council on Bioethics, as a solution to the stem cell controversy.[7] According to one of the plans put forth, by deactivating the gene, it would not be possible for a properly organized embryo to form, thus providing stem cells without requiring the destruction of an embryo.[8] Other genes that have been proposed for this purpose include Hnf4, which is required for gastrulation.[7][9]
# Interactions
CDX2 has been shown to interact with EP300,[10] and PAX6.[10] | https://www.wikidoc.org/index.php/CDX2 | |
0ed6ef774320219a8af726e077279fd328db866b | wikidoc | CHD1 | CHD1
Chromodomain-helicase-DNA-binding protein 1 is an enzyme that in humans is encoded by the CHD1 gene.
The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template.
# Interactions
CHD1 has been shown to interact with Nuclear receptor co-repressor 1. | CHD1
Chromodomain-helicase-DNA-binding protein 1 is an enzyme that in humans is encoded by the CHD1 gene.[1][2][3]
The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template.[3]
# Interactions
CHD1 has been shown to interact with Nuclear receptor co-repressor 1.[4] | https://www.wikidoc.org/index.php/CHD1 | |
ec420ccd80d96af54272dc76e66923be0e16c021 | wikidoc | CHD2 | CHD2
Chromodomain-helicase-DNA-binding protein 2 is an enzyme that in humans is encoded by the CHD2 gene.
# Function
The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. CHD2 catalyzes the assembly of chromatin into periodic arrays; and the N-terminal region of CHD2, which contains tandem chromodomains, serves an auto-inhibitory role in both the DNA-binding and ATPase activities of CHD2. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Clinical significance
De Novo Mutations and deletions in this gene have been associated with cases of epileptic encephalopathies.
CHD2 epilepsy is increasingly being identified as a subpopulation of Lennox-Gastaut Syndrome.
Recently, de novo mutations or deletions in CHD2 has been linked to intellectual disability and to autism. Researchers found 27 genes which abolish function of the corresponding protein — in at least two people with autism, and 6 genes are mutated in three or more people with autism. These six genes — CHD8, DYRK1A, ANK2, GRIN2B, DSCAM and CHD2 — are the strongest autism candidates identified so far.
# Family support
Syndromes associated with mutations or deletions in CHD2 can be devastating. Families of individuals with CHD2 mutations or deletions can join a research and support group. | CHD2
Chromodomain-helicase-DNA-binding protein 2 is an enzyme that in humans is encoded by the CHD2 gene.[1][2]
# Function
The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. CHD2 catalyzes the assembly of chromatin into periodic arrays; and the N-terminal region of CHD2, which contains tandem chromodomains, serves an auto-inhibitory role in both the DNA-binding and ATPase activities of CHD2.[3] Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]
# Clinical significance
De Novo Mutations and deletions in this gene have been associated with cases of epileptic encephalopathies.[4][5][6][7][8]
CHD2 epilepsy is increasingly being identified as a subpopulation of Lennox-Gastaut Syndrome.[9][10]
Recently, de novo mutations or deletions in CHD2 has been linked to intellectual disability[11] and to autism.[12][13][14] Researchers found 27 genes which abolish function of the corresponding protein — in at least two people with autism, and 6 genes are mutated in three or more people with autism. These six genes — CHD8, DYRK1A, ANK2, GRIN2B, DSCAM and CHD2 — are the strongest autism candidates identified so far.
# Family support
Syndromes associated with mutations or deletions in CHD2 can be devastating. Families of individuals with CHD2 mutations or deletions can join a research and support group.[15] | https://www.wikidoc.org/index.php/CHD2 | |
81af9af5ac59b4d2343d793f0e51c38b42e3074a | wikidoc | CHD3 | CHD3
Chromodomain-helicase-DNA-binding protein 3 is an enzyme that in humans is encoded by the CHD3 gene.
# Function
This gene encodes a member of the CHD family of proteins which are characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription. Autoantibodies against this protein are found in a subset of patients with dermatomyositis. Three alternatively spliced transcripts encoding different isoforms have been described.
Mutations in CHD3 cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.
# Interactions
CHD3 has been shown to interact with:
- HDAC1,
- Histone deacetylase 2 and
- SERBP1. | CHD3
Chromodomain-helicase-DNA-binding protein 3 is an enzyme that in humans is encoded by the CHD3 gene.[1][2][3]
# Function
This gene encodes a member of the CHD family of proteins which are characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription. Autoantibodies against this protein are found in a subset of patients with dermatomyositis. Three alternatively spliced transcripts encoding different isoforms have been described.[3]
Mutations in CHD3 cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.[4]
# Interactions
CHD3 has been shown to interact with:
- HDAC1,[5][6]
- Histone deacetylase 2[5][7][8] and
- SERBP1.[9][10] | https://www.wikidoc.org/index.php/CHD3 | |
cfbb9f5a8e0c6f7f54f6a5acf21139fa111afe1b | wikidoc | CHD4 | CHD4
Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene.
# Function
The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein.
# Interactions
CHD4 has been shown to interact with HDAC1, Histone deacetylase 2, MTA2, SATB1 and Ataxia telangiectasia and Rad3 related. | CHD4
Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene.[1][2][3]
# Function
The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein.[3]
# Interactions
CHD4 has been shown to interact with HDAC1,[4][5][6] Histone deacetylase 2,[6][7][8] MTA2,[4] SATB1[9] and Ataxia telangiectasia and Rad3 related.[8] | https://www.wikidoc.org/index.php/CHD4 | |
452206f14f5f54975422f59390754c66d23f281f | wikidoc | CHD7 | CHD7
Chromodomain-helicase-DNA-binding protein 7 also known as ATP-dependent helicase CHD7 is an enzyme that in humans is encoded by the CHD7 gene.
CHD7 is an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax-group protein Kismet. Mutations in CHD7 are associated with CHARGE syndrome.
# Model organisms
Model organisms have been used in the study of CHD7 function. A conditional knockout mouse line, called Chd7tm2a(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 four tests were carried out on mutant mice and five significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Male heterozygotes displayed abnormal pelvic elevation in a modified SHIRPA test and have a high incidence of Bergmeister's papilla in both eyes. When the brains of heterozygous animals were studied, an absence of corpus callosum was observed. | CHD7
Chromodomain-helicase-DNA-binding protein 7 also known as ATP-dependent helicase CHD7 is an enzyme that in humans is encoded by the CHD7 gene.[1][2]
CHD7 is an ATP-dependent chromatin remodeler homologous to the Drosophila trithorax-group protein Kismet.[3] Mutations in CHD7 are associated with CHARGE syndrome.[4]
# Model organisms
Model organisms have been used in the study of CHD7 function. A conditional knockout mouse line, called Chd7tm2a(EUCOMM)Wtsi[12][13] 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.[14][15][16]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty four tests were carried out on mutant mice and five significant abnormalities were observed.[10] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Male heterozygotes displayed abnormal pelvic elevation in a modified SHIRPA test and have a high incidence of Bergmeister's papilla in both eyes. When the brains of heterozygous animals were studied, an absence of corpus callosum was observed.[10] | https://www.wikidoc.org/index.php/CHD7 | |
890befbac0ba4b90c57c980dab646b4b6b998d1c | wikidoc | CHD8 | CHD8
Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.
# Function
The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8, which is a chromatin regulator enzyme that is essential during fetal development. CHD8 is an ATP dependent enzyme.
The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to ADP. CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes. CHD8 negatively regulates Wnt signaling. Wnt signaling is important in the vertebrate early development and morphogenesis. It is believed that CHD8 also recruits the linker histone H1 and causes the repression of β-catenin and p53 target genes. The importance of CHD8 can be observed in studies where CHD8-knockout mice died after 5.5 embryonic days because of widespread p53 induced apoptosis.
# Clinical significance
Mutations in this gene have been linked to a subset of autism cases.
Mutations in CHD8 could lead to upregulation of β-catenin-regulated genes, in some part of the brain this upregulation can cause brain overgrowth also known as macrocephaly, which occurs in 15-35% of autistic children.
Some studies have determined the role of CHD8 in autism spectrum disorder (ASD). CHD8 expression significantly increases during human mid-fetal development. The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology. The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes. The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8. | CHD8
Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.[1][2]
# Function
The gene CHD8 encodes the protein chromodomain helicase DNA binding protein 8,[3] which is a chromatin regulator enzyme that is essential during fetal development.[4] CHD8 is an ATP dependent enzyme.[5]
The protein contains an Snf2 helicase domain that is responsible for the hydrolysis of ATP to ADP.[5] CHD8 encodes for a DNA helicase that function as a transcription repressor by remodeling chromatin structure by altering the position of nucleosomes.[4] CHD8 negatively regulates Wnt signaling.[6] Wnt signaling is important in the vertebrate early development and morphogenesis. It is believed that CHD8 also recruits the linker histone H1 and causes the repression of β-catenin and p53 target genes.[3] The importance of CHD8 can be observed in studies where CHD8-knockout mice died after 5.5 embryonic days because of widespread p53 induced apoptosis.[3]
# Clinical significance
Mutations in this gene have been linked to a subset of autism[7] cases.
Mutations in CHD8 could lead to upregulation of β-catenin-regulated genes, in some part of the brain this upregulation can cause brain overgrowth also known as macrocephaly, which occurs in 15-35% of autistic children.[4]
Some studies have determined the role of CHD8 in autism spectrum disorder (ASD).[4] CHD8 expression significantly increases during human mid-fetal development.[3] The chromatin remodeling activity and its interaction with transcriptional regulators have shown to play an important role in ASD aetiology.[8] The developing mammalian brain has a conserved CHD8 target regions that are associated with ASD risk genes.[4] The knockdown of CHD8 in human neural stem cells results in dysregulation of ASD risk genes that are targeted by CHD8.[9] | https://www.wikidoc.org/index.php/CHD8 | |
5bcd16b77f845a3866eb29ade81e192f123a5425 | wikidoc | CHKA | CHKA
Choline kinase alpha is an enzyme that in humans is encoded by the CHKA gene.
The major pathway for the biosynthesis of phosphatidylcholine occurs via the CDP-choline pathway. The protein encoded by this gene is the initial enzyme in the sequence and may play a regulatory role. The encoded protein also catalyzes the phosphorylation of ethanolamine. Two transcript variants encoding different isoforms have been found for this gene.
In melanocytic cells CHKA gene expression may be regulated by MITF. | CHKA
Choline kinase alpha is an enzyme that in humans is encoded by the CHKA gene.[1][2][3]
The major pathway for the biosynthesis of phosphatidylcholine occurs via the CDP-choline pathway. The protein encoded by this gene is the initial enzyme in the sequence and may play a regulatory role. The encoded protein also catalyzes the phosphorylation of ethanolamine. Two transcript variants encoding different isoforms have been found for this gene.[3]
In melanocytic cells CHKA gene expression may be regulated by MITF.[4] | https://www.wikidoc.org/index.php/CHKA | |
9350efabc56937fd51d1cfa51611a22727fd452e | wikidoc | CHL1 | CHL1
Neural cell adhesion molecule L1-like protein also known as close homolog of L1 (CHL1) is a protein that in humans is encoded by the CHL1 gene.
CHL1 is a cell adhesion molecule closely related to the L1. In melanocytic cells CHL1 gene expression may be regulated by MITF, and can act as a helicase protein during the interphase stage of mitosis.
The protein, however, has dynamic localisation, meaning that it has not only multiple roles in the cell, but also various locations. | CHL1
Neural cell adhesion molecule L1-like protein also known as close homolog of L1 (CHL1) is a protein that in humans is encoded by the CHL1 gene.[2]
CHL1 is a cell adhesion molecule closely related to the L1. In melanocytic cells CHL1 gene expression may be regulated by MITF,[3] and can act as a helicase protein during the interphase stage of mitosis.
The protein, however, has dynamic localisation, meaning that it has not only multiple roles in the cell, but also various locations. | https://www.wikidoc.org/index.php/CHL1 | |
7ff8b9fd2c35c001026fb4c4b540885a05250f2a | wikidoc | CHOP | CHOP
CHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP stands for Cytoxan, Hydroxydaunorubicin (Adriamycin), Oncovin (Vincristine), Prednisone/Prednisolone.
# Uses and indications
CHOP consists of:
- Cyclophosphamide
- Hydroxydaunorubicin (alternative name) - doxorubicin
- Oncovin® (brand name) - vincristine
- Prednisone or Prednisolone.
This regimen can also be combined with the monoclonal antibody rituximab if the lymphoma is of B cell origin (R-CHOP or CHOP-R). Typically, courses are administered at an interval of three weeks. A staging CT scan is generally performed after three cycles to assess whether the disease is responding to treatment.
In patients with a history of cardiovascular disease, the doxorubicin (which is cardiotoxic) is often deemed to be too great a risk and is omitted from the regimen. The combination is then referred to as COP or CVP.
# Side-effects and complications
The combination is generally well tolerated. Chemotherapy-induced nausea and vomiting may require antiemetics (such as ondansetron), and hemorrhagic cystitis is prevented with administration of mesna. Alopecia (hair loss) is common.
Neutropenia generally develops in the second week. During this period, many clinicians recommend prophylactic use of ciprofloxacin. If a fever develops in the neutropenic period, urgent medical assessment is required for neutropenic sepsis, as infections in patients with low neutrophil counts may progress rapidly.
Allopurinol is typically co-administered prophylactically to prevent tumor lysis syndrome, the result of rapid death of tumor cells.
# History
A pivotal study published in 1993 compared CHOP to several other chemotherapy regimens (e.g. m-BACOD, ProMACE-CytaBOM, MACOP-B). CHOP emerged as the regimen with the least toxicity but similar efficacy. | CHOP
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
CHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP stands for Cytoxan, Hydroxydaunorubicin (Adriamycin), Oncovin (Vincristine), Prednisone/Prednisolone.
# Uses and indications
CHOP consists of:
- Cyclophosphamide
- Hydroxydaunorubicin (alternative name) - doxorubicin
- Oncovin® (brand name) - vincristine
- Prednisone or Prednisolone.
This regimen can also be combined with the monoclonal antibody rituximab if the lymphoma is of B cell origin (R-CHOP or CHOP-R). Typically, courses are administered at an interval of three weeks. A staging CT scan is generally performed after three cycles to assess whether the disease is responding to treatment.
In patients with a history of cardiovascular disease, the doxorubicin (which is cardiotoxic) is often deemed to be too great a risk and is omitted from the regimen. The combination is then referred to as COP or CVP.
# Side-effects and complications
The combination is generally well tolerated. Chemotherapy-induced nausea and vomiting may require antiemetics (such as ondansetron), and hemorrhagic cystitis is prevented with administration of mesna. Alopecia (hair loss) is common.
Neutropenia generally develops in the second week. During this period, many clinicians recommend prophylactic use of ciprofloxacin[2]. If a fever develops in the neutropenic period, urgent medical assessment is required for neutropenic sepsis, as infections in patients with low neutrophil counts may progress rapidly.
Allopurinol is typically co-administered prophylactically to prevent tumor lysis syndrome, the result of rapid death of tumor cells.
# History
A pivotal study published in 1993 compared CHOP to several other chemotherapy regimens (e.g. m-BACOD, ProMACE-CytaBOM, MACOP-B).[3] CHOP emerged as the regimen with the least toxicity but similar efficacy. | https://www.wikidoc.org/index.php/CHOP | |
e11e375f0746971fa7e1c9de419f8617bb2507fb | wikidoc | CHUK | CHUK
Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.
# Function
## NF-κB response
IKK-α is a member of the serine/threonine protein kinase family and forms a complex in the cell with IKK-β and NEMO. NF-κB transcription factors are normally held in an inactive state by the inhibitory proteins IκBs. IKK-α and IKK-β phosphorylate the IκB proteins, marking them for degradation via ubiquitination and allowing NF-κB transcription factors to go into the nucleus.
Once activated, NF-κB transcription factors regulate genes that are implicated in many important cellular processes, including immune response, inflammation, cell death, and cell proliferation.
## Epidermal differentiation
IKK-α has been shown to function in epidermal differentiation independently of the NF-κB pathway. In the mouse, IKK-α is required for cell cycle exit and differentiation of the embryonic keratinocytes. IKK-α null mice have a truncated snout and limbs, shiny skin, and die shortly after birth due to dehydration. Their epidermis retains a proliferative precursor cell population and lacks the outer two most differentiated cell layers. This function of IKK-α has been shown to be independent of the protein's kinase activity and of the NF-κB pathway. Instead it is thought that IKK-α regulates skin differentiation by acting as a cofactor in the TGF-β / Smad2/3 signaling pathway.
The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium. Zebrafish embryos born from mothers that are mutant in IKK-α do not produce a differentiated outer epithelial monolayer. Instead, the outermost cells in these embryos are hyperproliferative and fail to turn on critical epidermal genes. Different domains of the protein are required for this function of IKK-α in zebrafish than in mice, but in neither case does the NF-κB pathway seem to be implicated.
## Keratinocyte migration
IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.
Activation of three major hydrogen peroxide-dependent pathways, EGF, FOXO1, and IKK-α occur during injury-induced epidermal keratinocyte migration, adhesion, cytoprotection and wound healing. IKKα regulates human keratinocyte migration by surveillance of the redox environment after wounding. IKK-α is sulfenylated at a conserved cysteine residue in the kinase domain, which correlated with derepression of EGF promoter activity and increased EGF expression, indicating that IKK-α stimulatea migration through dynamic interactions with the EGF promoter depending on the redox state within cells.
## Other cellular targets
IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.
# Clinical significance
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.
Mutations in IKK-α in humans have been linked to lethal fetal malformations. The phenotype of these mutant fetuses is similar to the mouse IKK-α null phenotype, and is characterized by shiny, thickened skin and truncated limbs.
Decreased IKK-α activity has been reported in a large percentage of human squamous cell carcinomas, and restoring IKK-α in mouse models of skin cancer has been shown to have an anti-tumorigenic effect.
# Interactions
IKK-α has been shown to interact with:
- AKT1,
- AKT2,
- CTNNB1,
- FANCA,
- IKBKG
- IKK2,
- IRAK1,
- MAP3K14,
- MAP3K7,
- MAP3K8,
- NFKBIA,
- NCOA3,
- PPM1B,
- PRKDC, and
- TRAF2. | CHUK
Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene.[1] IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor.[2] However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.[3][4]
# Function
## NF-κB response
IKK-α is a member of the serine/threonine protein kinase family and forms a complex in the cell with IKK-β and NEMO. NF-κB transcription factors are normally held in an inactive state by the inhibitory proteins IκBs. IKK-α and IKK-β phosphorylate the IκB proteins, marking them for degradation via ubiquitination and allowing NF-κB transcription factors to go into the nucleus.[5]
Once activated, NF-κB transcription factors regulate genes that are implicated in many important cellular processes, including immune response, inflammation, cell death, and cell proliferation.
## Epidermal differentiation
IKK-α has been shown to function in epidermal differentiation independently of the NF-κB pathway. In the mouse, IKK-α is required for cell cycle exit and differentiation of the embryonic keratinocytes. IKK-α null mice have a truncated snout and limbs, shiny skin, and die shortly after birth due to dehydration.[6] Their epidermis retains a proliferative precursor cell population and lacks the outer two most differentiated cell layers. This function of IKK-α has been shown to be independent of the protein's kinase activity and of the NF-κB pathway. Instead it is thought that IKK-α regulates skin differentiation by acting as a cofactor in the TGF-β / Smad2/3 signaling pathway.[3]
The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium.[7] Zebrafish embryos born from mothers that are mutant in IKK-α do not produce a differentiated outer epithelial monolayer. Instead, the outermost cells in these embryos are hyperproliferative and fail to turn on critical epidermal genes. Different domains of the protein are required for this function of IKK-α in zebrafish than in mice, but in neither case does the NF-κB pathway seem to be implicated.
## Keratinocyte migration
IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.[8]
Activation of three major hydrogen peroxide-dependent pathways, EGF, FOXO1, and IKK-α occur during injury-induced epidermal keratinocyte migration, adhesion, cytoprotection and wound healing.[9] IKKα regulates human keratinocyte migration by surveillance of the redox environment after wounding. IKK-α is sulfenylated at a conserved cysteine residue in the kinase domain, which correlated with derepression of EGF promoter activity and increased EGF expression, indicating that IKK-α stimulatea migration through dynamic interactions with the EGF promoter depending on the redox state within cells.[10]
## Other cellular targets
IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.[11][12]
# Clinical significance
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[13]
Mutations in IKK-α in humans have been linked to lethal fetal malformations.[14] The phenotype of these mutant fetuses is similar to the mouse IKK-α null phenotype, and is characterized by shiny, thickened skin and truncated limbs.
Decreased IKK-α activity has been reported in a large percentage of human squamous cell carcinomas, and restoring IKK-α in mouse models of skin cancer has been shown to have an anti-tumorigenic effect.[15]
# Interactions
IKK-α has been shown to interact with:
- AKT1,[16][17]
- AKT2,[18]
- CTNNB1,[19]
- FANCA,[20][21]
- IKBKG[22][23][24][25]
- IKK2,[21][23][24][26][27][28][29]
- IRAK1,[30][31]
- MAP3K14,[32][33][34][35]
- MAP3K7,[35][36]
- MAP3K8,[37]
- NFKBIA,[28][35][38][39]
- NCOA3,[40]
- PPM1B,[41]
- PRKDC,[42] and
- TRAF2.[32][43][44] | https://www.wikidoc.org/index.php/CHUK | |
8ad119f82ac6605d7c1a84c37dfe1d7218a2a574 | wikidoc | CIB1 | CIB1
Calcium and integrin-binding protein 1 is a protein that in humans is encoded by the CIB1 gene.
The protein encoded by this gene is a member of the calcium-binding protein family. The specific function of this protein has not yet been determined; however this protein is known to interact with DNA-dependent protein kinase and may play a role in kinase-phosphatase regulation of DNA end-joining. This protein also interacts with integrin alpha(IIb)beta(3), which may implicate this protein as a regulatory molecule for alpha(IIb)beta(3).
# Interactions
CIB1 has been shown to interact with RAC3, PSEN2, DNA-PKcs, UBR5 and CD61. | CIB1
Calcium and integrin-binding protein 1 is a protein that in humans is encoded by the CIB1 gene.[1][2][3]
The protein encoded by this gene is a member of the calcium-binding protein family. The specific function of this protein has not yet been determined; however this protein is known to interact with DNA-dependent protein kinase and may play a role in kinase-phosphatase regulation of DNA end-joining. This protein also interacts with integrin alpha(IIb)beta(3), which may implicate this protein as a regulatory molecule for alpha(IIb)beta(3).[3]
# Interactions
CIB1 has been shown to interact with RAC3,[4] PSEN2,[5] DNA-PKcs,[6] UBR5[7] and CD61.[1] | https://www.wikidoc.org/index.php/CIB1 | |
d8c3085318d6b56b94d7ac480b7b40735ec35bc2 | wikidoc | CISH | CISH
Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene. CISH orthologs have been identified in most mammals with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.
# Function
The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling.
The expression of this gene can be induced by IL-2, IL-3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor.
CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation. The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.
# Model organisms
Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cishtm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.
# Interactions
CISH has been shown to interact with IL2RB and Growth hormone receptor. and PLCG1. | CISH
Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene.[1][2][3] CISH orthologs [4] have been identified in most mammals with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.[5]
# Function
The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling.
The expression of this gene can be induced by IL-2, IL-3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor.[3]
CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.[6] The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.
# Model organisms
Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cishtm1a(KOMP)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[9]
# Interactions
CISH has been shown to interact with IL2RB[17] and Growth hormone receptor.[18] and PLCG1.[6] | https://www.wikidoc.org/index.php/CISH | |
96cbd1bdddf40b94bc0269f8445982bedcd89881 | wikidoc | CIZ1 | CIZ1
Cip1-interacting zinc finger protein is a protein that in humans is encoded by the CIZ1 gene.
# Function
The protein encoded by this gene is a zinc finger DNA binding transcription factor that interacts with CIP1 (p21 / CDKN1A), part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1.
# Clinical significance
An altered circulating form of the Ciz1 protein is synthesized by lung cancer cells, even when they are at a very early stage. Hence detection of this protein variant in blood could be used as a biomarker for early detection of lung cancer.
# Interactions
CIZ1 has been shown to interact with P21. | CIZ1
Cip1-interacting zinc finger protein is a protein that in humans is encoded by the CIZ1 gene.[1][2]
# Function
The protein encoded by this gene is a zinc finger DNA binding transcription factor that interacts with CIP1 (p21 / CDKN1A), part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1.[2]
# Clinical significance
An altered circulating form of the Ciz1 protein is synthesized by lung cancer cells, even when they are at a very early stage. Hence detection of this protein variant in blood could be used as a biomarker for early detection of lung cancer.[3]
# Interactions
CIZ1 has been shown to interact with P21.[1] | https://www.wikidoc.org/index.php/CIZ1 | |
701546411c54148c701f523d4032230728f34f8f | wikidoc | CLN3 | CLN3
Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16. Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter. In humans, it belongs to the atypical SLCs due to its structurally and phylogenetically similarity to other SLC transporters.
# Function
Battenin is involved in lysosomal function. Many alternatively spliced transcript variants have been found for this gene.
Battenin is a transmembrane protein predicted to be composed of 11 transmembrane helices, yet no crystal structure is available.
# Clinical significance
Mutations in this gene, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease, also known as Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) or Juvenile Batten disease. | CLN3
Battenin is a protein that in humans is encoded by the CLN3 gene located on chromosome 16.[1][2] Battenin is not clustered into any Pfam clan, but it is included in the TCDB suggesting that it is a transporter.[3] In humans, it belongs to the atypical SLCs[3][4] due to its structurally and phylogenetically similarity to other SLC transporters.
# Function
Battenin is involved in lysosomal function. Many alternatively spliced transcript variants have been found for this gene.[2]
Battenin is a transmembrane protein predicted to be composed of 11 transmembrane helices,[4] yet no crystal structure is available.
# Clinical significance
Mutations in this gene, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease, also known as Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) or Juvenile Batten disease. | https://www.wikidoc.org/index.php/CLN3 | |
5e625fee9ed1f55016f955b3d12b4d5831d9cd8e | wikidoc | CLN8 | CLN8
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.
# Molecular biology
This gene encodes a transmembrane protein that localizes to the endoplasmic reticulum (ER) and recycles between the ER and the Golgi apparatus via COPII- and COPI-coated vesicles. CLN8 protein functions as a cargo receptor for lysosomal soluble proteins in the ER.
# Clinical
Mutations in this gene are associated with progressive epilepsy with mental retardation (EPMR), a subtype of neuronal ceroid lipofuscinosis (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. | CLN8
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.[1][2]
# Molecular biology
This gene encodes a transmembrane protein that localizes to the endoplasmic reticulum (ER) and recycles between the ER and the Golgi apparatus via COPII- and COPI-coated vesicles.[3] CLN8 protein functions as a cargo receptor for lysosomal soluble proteins in the ER.[3]
# Clinical
Mutations in this gene are associated with progressive epilepsy with mental retardation (EPMR), a subtype of neuronal ceroid lipofuscinosis (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. | https://www.wikidoc.org/index.php/CLN8 | |
afde2a37d0e1dfe01b1f6254dd700e1363a01ccf | wikidoc | CLPB | CLPB
Caseinolytic peptidase B protein homolog(CLPB), also known as mitochondrial AAA ATPase chaperonin, is an enzyme that in humans is encoded by the CLPB gene, which encodes an ATP-dependent protease and chaperone. CLPB is localized in mitochondria and widely expressed in human tissues. High expression in adult brain and low expression in granulocyte is found. It is a chaperone involved in disaggregating proteins and also has a role in de novo protein synthesis under mild stress conditions. Mutations in "CLPB" gene could cause autosomal recessive metabolic disorder with intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.
# Structure
## Gene
The CLPB gene has 19 exons and is located at the chromosome band 11q13.4.
## Protein
CLPB has five isoforms due to alternative splicing. Isoform 1 is considered to have the 'canonical' sequence. The protein is 78.7 kDa in size and composed of 707 amino acids. It contains an N-terminal mitochondrial targeting sequence (1-36 amino acids). After processing, the mature mitochondrial protein has a theoretical pI of 8.53. CLPB has a specific C-terminal D2 domain and proteins with this domain form the sub-family of Caseinolytic peptidase (Clp) proteins, also called HSP100. The domain composition of human CLPB is different from that of microbial or plant orthologs. Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi.
# Function
CLPB belongs to the large AAA+ superfamily. The unifying characteristic of this family is the hydrolysis of ATP through the AAA+ domain to produce energy required to catalyze protein unfolding, disassembly and disaggregation. CLPB cooperates with HSP70 and its in vivo ATPase activity has been confirmed. This protein contributes to the thermotolerance of cells and appears to be required for mitochondrial function by acting as a protein chaperone. The interaction with protein like HAX1 suggests that human CLPB may be involved in apoptosis. In humans, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi, which might have evolved to ensure more elaborate substrate recognition or to support a putative chaperone function. With only one ATPase domain, CLPB is postulated competent in the use of ATP hydrolysis energy for threading unfolded polypeptide through the central channel of the hexamer ring.
# Clinical significance
Neonatal encephalopathy is a kind of severe neurological impairment in the newborn with no specific clinical sign at the early stage of life, and its diagnosis remains a challenge. This neonatal encephalopathy includes a heterogeneous group of 3- methylgutaconic aciduria syndromes and loss of CLPB function is reported to be one of the causes. Knocking down "CLPB" gene in the zebrafish induced reduction of growth and increment of motor activity, which is similar to the signs observed in patients. Its loss may lead to a broad phenotypic spectrum encompassing intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, and bilateral cataracts, with 3-methylglutaconic aciduria. Further investigation into CLPB may shed a new light on the diagnosis of this disease.
# Interactions
This protein is known to interact with:
- HAX1
- HSP70 | CLPB
Caseinolytic peptidase B protein homolog(CLPB), also known as mitochondrial AAA ATPase chaperonin, is an enzyme that in humans is encoded by the CLPB gene,[1][2][3] which encodes an ATP-dependent protease and chaperone. CLPB is localized in mitochondria and widely expressed in human tissues. High expression in adult brain and low expression in granulocyte is found.[4][5] It is a chaperone involved in disaggregating proteins and also has a role in de novo protein synthesis under mild stress conditions. Mutations in "CLPB" gene could cause autosomal recessive metabolic disorder with intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.[4][6]
# Structure
## Gene
The CLPB gene has 19 exons and is located at the chromosome band 11q13.4.[3]
## Protein
CLPB has five isoforms due to alternative splicing. Isoform 1 is considered to have the 'canonical' sequence. The protein is 78.7 kDa in size and composed of 707 amino acids. It contains an N-terminal mitochondrial targeting sequence (1-36 amino acids). After processing, the mature mitochondrial protein has a theoretical pI of 8.53.[7] CLPB has a specific C-terminal D2 domain and proteins with this domain form the sub-family of Caseinolytic peptidase (Clp) proteins, also called HSP100.[8] The domain composition of human CLPB is different from that of microbial or plant orthologs. Notably, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi.[9][10]
# Function
CLPB belongs to the large AAA+ superfamily. The unifying characteristic of this family is the hydrolysis of ATP through the AAA+ domain to produce energy required to catalyze protein unfolding, disassembly and disaggregation.[11][12] CLPB cooperates with HSP70 and its in vivo ATPase activity has been confirmed. This protein contributes to the thermotolerance of cells and appears to be required for mitochondrial function by acting as a protein chaperone.[11][13] The interaction with protein like HAX1 suggests that human CLPB may be involved in apoptosis.[4] In humans, the presence of ankyrin repeats replaced the first of two ATPase domains found in bacteria and fungi, which might have evolved to ensure more elaborate substrate recognition or to support a putative chaperone function.[9][10] With only one ATPase domain, CLPB is postulated competent in the use of ATP hydrolysis energy for threading unfolded polypeptide through the central channel of the hexamer ring.[14][15][16]
# Clinical significance
Neonatal encephalopathy is a kind of severe neurological impairment in the newborn with no specific clinical sign at the early stage of life, and its diagnosis remains a challenge. This neonatal encephalopathy includes a heterogeneous group of 3- methylgutaconic aciduria syndromes and loss of CLPB function is reported to be one of the causes. Knocking down "CLPB" gene in the zebrafish induced reduction of growth and increment of motor activity, which is similar to the signs observed in patients.[11] Its loss may lead to a broad phenotypic spectrum encompassing intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, and bilateral cataracts, with 3-methylglutaconic aciduria.[4][6][17] Further investigation into CLPB may shed a new light on the diagnosis of this disease.
# Interactions
This protein is known to interact with:
- HAX1[4]
- HSP70[14] | https://www.wikidoc.org/index.php/CLPB | |
2356c3e2e0a982246fda6a4ca65da69a533f85dd | wikidoc | CMAH | CMAH
Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein is an enzyme that in humans is encoded by the CMAH gene.
# Function
Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand–receptor, cell–cell, and cell–pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans.
The absence of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly similar. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues.
The deletion that deactivated this gene occurred approximately 3.2 mya, after the divergence of humans from the African great apes, and quickly swept to fixation in the human population. The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 Mya, with a complex subsequent history. Causes of the selection against the CMAH gene could include a severe infectious disease that specifically binds to Neu5Gc, a change in binding preference of a sialic acid binding protein favoring the loss of Neu5Gc or accumulation of Neu5Ac, or protection from viruses originating in individuals with Neu5Gc due to anti-Neu5Gc antibodies in CMAH-negative individuals
# Effects of loss of functioning human CMAH
The functional loss of this gene after the divergence of humans from the great apes leads to several possible implications for its role in human development, the most notable of which being less constrained brain growth. In most mammals, CMAH expression is down-regulated in the brain.
In fact, when higher expression of CMAH is forced in mouse brains, it proves lethal. Human brains are different from most primate brains in that they continue to grow for some time postnatally, unlike primate brains that stop growing soon after birth. It is therefore possible that even the small amounts of Neu5Gc present in most mammalian brains could be inhibiting their brain growth; losing the CMAH gene may have released the human brain from this constraint.
The loss of CMAH has also played a role in human viral history. On one side, it has made humans more susceptible to some viruses by decreasing sialic acid diversity. Viruses that bind to Neu5Ac before entering the cell will see their binding enhanced via the cluster glycoside effect, which wouldn't be seen as strongly if other sialic acids like Neu5Gc were also present. A potential example of this is the most serious form of malaria in humans, P. falciparum, which initially targets Neu5Ac on red blood cells for binding. Oppositely though, losing CMAH should protect humans against any virus that targets Neu5Gc, such as those that cause certain diarrheal diseases in livestock, E. coli K99, transmissible gastroenteritis coronavirus, and simian virus 40 (SV40). Another form of malaria, P. reichenowii, may have been the original selecting agent against Neu5Gc. Thus only organisms negative for Neu5Gc would survive, with the outcome being humans who are completely resistant. Further support from this idea comes from the fact that P. falciparum malaria appears to have evolved in the last tens of thousands of years.
Even though humans do not have a functioning CMAH gene, Neu5Gc has been found present in normal human tissue, with larger amounts found in both fetal and cancerous tissues. In fact, studies suggest that it could be an excellent cancer cell marker. Since Neu5Gc can only be made by functioning cytidine monophosphate-N-acetylneuraminic acid hydroxylase, another explanation of how it comes to be found in human tissue is needed. Current research indicates it is incorporated into human tissues through food sources, most notably from red meats (beef, pork, lamb) and to a lesser extent, dairy. This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter. Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways. The immune system does not work the same way, however; all humans have varying, though still significant, amounts of a diverse spectrum of anti-Neu5Gc antibodies, with the commonest being from the IgG class; these, in combination with constant incorporation of Neu5Gc into tissue, can be a source of chronic inflammation, especially in blood vessels and the linings of hollow organs. These sites are also common places for atherosclerosis and epithelial carcinomas, both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation. Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependent macular degeneration so Neu5Gc may be linked to the development of these disorders as well.
As for accounting for the larger amounts of Neu5Gc found in tumors, recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation. In addition, growth factors may activate enhanced macropinocytosis, which can also augment Neu5Gc incorporation in tissues. Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels there.
The presence of Neu5Gc in various biotherapeutics derived from mammals or animal products may also be an issue, and indeed, short- and long-term effects of these are still being studied. Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune-complex formation, boosting of Neu5Gc antibody levels, enhancing immune reactivity against the underlying biotherapeutic polypeptide and directly loading more Neu5Gc into tissues.
Genomic analyses indicate that the gene CMAH is present only in deuterostomes, some unicellular algae and some bacteria. In addition to humans, the CMAH gene has been lost also in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, most reptiles, and all birds. Among mammals, the gene is missing or inactivated in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus . These animals lacking a functional CMAH gene are not expected to exhibit endogenous Neu5Gc. | CMAH
Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein is an enzyme that in humans is encoded by the CMAH gene.[1][2][3]
# Function
Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand–receptor, cell–cell, and cell–pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans.[3]
The absence of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly similar. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues.[3]
The deletion that deactivated this gene occurred approximately 3.2 mya, after the divergence of humans from the African great apes, and quickly swept to fixation in the human population. The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 Mya, with a complex subsequent history.[4] Causes of the selection against the CMAH gene could include a severe infectious disease that specifically binds to Neu5Gc, a change in binding preference of a sialic acid binding protein favoring the loss of Neu5Gc or accumulation of Neu5Ac, or protection from viruses originating in individuals with Neu5Gc due to anti-Neu5Gc antibodies in CMAH-negative individuals [5]
# Effects of loss of functioning human CMAH
The functional loss of this gene after the divergence of humans from the great apes leads to several possible implications for its role in human development, the most notable of which being less constrained brain growth. In most mammals, CMAH expression is down-regulated in the brain[6].
In fact, when higher expression of CMAH is forced in mouse brains, it proves lethal.[1] Human brains are different from most primate brains in that they continue to grow for some time postnatally, unlike primate brains that stop growing soon after birth. It is therefore possible that even the small amounts of Neu5Gc present in most mammalian brains could be inhibiting their brain growth; losing the CMAH gene may have released the human brain from this constraint.[6]
The loss of CMAH has also played a role in human viral history. On one side, it has made humans more susceptible to some viruses by decreasing sialic acid diversity.[7] Viruses that bind to Neu5Ac before entering the cell will see their binding enhanced via the cluster glycoside effect,[8] which wouldn't be seen as strongly if other sialic acids like Neu5Gc were also present. A potential example of this is the most serious form of malaria in humans, P. falciparum,[5] which initially targets Neu5Ac on red blood cells for binding.[7] Oppositely though, losing CMAH should protect humans against any virus that targets Neu5Gc, such as those that cause certain diarrheal diseases in livestock,[7] E. coli K99, transmissible gastroenteritis coronavirus, and simian virus 40 (SV40).[5] Another form of malaria, P. reichenowii, may have been the original selecting agent against Neu5Gc. Thus only organisms negative for Neu5Gc would survive, with the outcome being humans who are completely resistant. Further support from this idea comes from the fact that P. falciparum malaria appears to have evolved in the last tens of thousands of years.[5]
Even though humans do not have a functioning CMAH gene, Neu5Gc has been found present in normal human tissue, with larger amounts found in both fetal[7] and cancerous [2][7] tissues. In fact, studies suggest that it could be an excellent cancer cell marker.[2] Since Neu5Gc can only be made by functioning cytidine monophosphate-N-acetylneuraminic acid hydroxylase, another explanation of how it comes to be found in human tissue is needed. Current research indicates it is incorporated into human tissues through food sources, most notably from red meats (beef, pork, lamb) and to a lesser extent, dairy. This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.[9] Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways.[9] The immune system does not work the same way, however; all humans have varying, though still significant, amounts of a diverse spectrum of anti-Neu5Gc antibodies, with the commonest being from the IgG class; these, in combination with constant incorporation of Neu5Gc into tissue, can be a source of chronic inflammation, especially in blood vessels and the linings of hollow organs. These sites are also common places for atherosclerosis and epithelial carcinomas, both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation.[5] Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependent macular degeneration so Neu5Gc may be linked to the development of these disorders as well.[9]
As for accounting for the larger amounts of Neu5Gc found in tumors, recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation.[5][9] In addition, growth factors may activate enhanced macropinocytosis, which can also augment Neu5Gc incorporation in tissues.[9] Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels there.[5]
The presence of Neu5Gc in various biotherapeutics derived from mammals or animal products may also be an issue, and indeed, short- and long-term effects of these are still being studied. Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune-complex formation, boosting of Neu5Gc antibody levels, enhancing immune reactivity against the underlying biotherapeutic polypeptide and directly loading more Neu5Gc into tissues.[5]
Genomic analyses indicate that the gene CMAH is present only in deuterostomes, some unicellular algae and some bacteria. In addition to humans, the CMAH gene has been lost also in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, most reptiles, and all birds. Among mammals, the gene is missing or inactivated in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus [10]. These animals lacking a functional CMAH gene are not expected to exhibit endogenous Neu5Gc. | https://www.wikidoc.org/index.php/CMAH | |
9d191727d35dd508f1cb38389067ff3c6162aaa5 | wikidoc | GJB1 | GJB1
Lua error in Module:Redirect at line 65: could not parse redirect on page "CMTX".
Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32) is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system.
Mutations of the GJB1 gene affecting the signalling of and trafficking through gap junctions, resulting in an inherited peripheral neuropathy called X-linked Charcot-Marie-Tooth Disease. Complications include the demyelination of oligodendrocytes and Schwann cells, causing delayed transmission rates of nerve communication in the peripheral nervous system, due to irregularities in the normal function of the cells. This condition leads to a number of symptoms, most commonly muscle weakness and sensory problems in the outer extremities of the limbs. As a result, muscle atrophy and soft tissue injuries due to delayed nerve transmission can occur. In males, due to the hemizygousity of the X-chromosome, the symptoms and issues surrounding X-linked Charcot-Marie-Tooth disease are more prevalent.
# Function
Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. For a general discussion of connexin proteins, see GJB2.
In melanocytic cells GJB1 gene expression may be regulated by MITF.
# Gene
The gene that encodes the human GJB1 protein is found on the x chromosome, on the long arm at position q13.1, in interval 8, from base pair 71,215,212 to base pair 71,225,215.
## Mutations
Approximately four hundred type X Charcot-Marie-Tooth causing mutations have been identified within the GJB1 gene, and it is the only known gene to be associated with this disease,. The majority of these mutations only change a single amino acid within the protein chain, which result in a different protein being produced. Mutations within the GJB1 gene consist of novel, missense, double-missense, amino acid deletion, nonsense, frameshift, and in-frame deletions/insertions. These mutations most commonly result in proteins that work incorrectly, less effectively, degrade faster, are not present in adequate numbers or may not function at all.
# Structure
The GJB1 gene is approximately 10kb in length, with one coding exon and three non-coding exons. GJB1 is a gap junction, beta 1 protein also identified as connexin 32, with 238 amino acids. This protein contains four transmembrane domains, which when assembled form gap junctions. Each of these gap junctions consist of two hemichannels (connexions), which in turn consist of six connexin molecules (gap junction trans-membrane proteins)., This enables communication between Schwann cell nuclei and axons through a radial diffusion pathway.
# Function
GJB1 functions as a radial diffusion pathway, allowing the communication and diffusion of nutrients, ions and small molecules between cells. The GJB1 protein is found in a number of organs, including the liver, kidney, pancreas and nervous system. In normal circumstances this protein is located in the cell membrane of Schwann cells and oligodendrocytes, specialised cells of the nervous system., These cells typically encapsulate nerves that are involved in the assembly and preservation of myelin, to ensure reliable and rapid transmission of nerve signals., Typically the GJB1 protein forms channels through the myelin to the internal Schwann cell or oligodendrocyte, allowing effective transportation and communication.,
# Type X Charcot-Marie-Tooth disease
Approximately four hundred mutations of the GJB1 gene have been identified in people with X-linked Charcot-Marie-Tooth disease (CMTX). CMTX is predominantly classified with symptoms related to muscle weakness and sensory problems, especially in the outer extremities of the limbs. CMTX is the second most common type of CMT (about 10% of all patients) and is transmitted as an x-linked dominant trait. It is categorised by the lack of male-to-male transmission of the mutated GJB1 gene and the differences in severity between heterozygous women and hemizygous men, with the later being more severely affected.
Most of the mutations of the GJB1 gene switch or change a single amino acid in the gap junction (connexin-32) protein, although some may result in a protein of irregular size. Some of these mutations also cause hearing loss in patients with CMTX. Currently it is unknown how the mutations of the GJB1 gene lead to these specific features of Charcot-Marie-Tooth disease, however it is theorised that the cause is due to the demyelination of nerve cells. As a result, transmission rates of nerve communication in the peripheral nervous system are delayed, which in turn would cause irregularities in the normal function of Schwann cells.
Whilst CMTX is more commonly known to affect the peripheral nervous system some cases have been reported in which there is evidence of demyelination of the central nervous system. These abnormalities whilst not presenting any symptoms were identified through nerve impulse and imaging studies, and are believed to also be caused through mutations on the GJB1 gene.
## Diagnosis/testing
Historically CMTX could only be diagnosed through symptoms or measurement of the speed of nerve impulses. With the creation of genetic testing, 90% of CMTX cases are now diagnosed using the mutations of the GJB1 (Cx32) gene. The genetic screening of families has also become common after the diagnosis of CMTX in a patient, to further identify other family members that may be suffering from the disease. This screening is also used systematically by researchers to identify new mutations within the gene.
## Management
Currently CMTX is an incurable condition, instead patients are evaluated and treated for symptoms caused by the disease. Treatment is limited to rehabilitative therapy, use of assistive devices such as orthoses and in some cases surgical treatment of skeletal deformities and soft-tissue abnormalities. Surgical treatment most commonly includes osteotomies, soft-tissue surgery (including tendon transfers) and/or joint fusions.
## Genetic counseling
Due to the nature of inheritance of CMTX, affected males will pass the GJB1 gene mutation to all female children and none of their male children, whilst females who are carriers will have a 50% chance of passing on the mutation to each of their offspring. With the development of genetic testing, it is possible to perform both prenatal and pre-implantation testing elected by the patient, when their type of mutation has been identified. Results from genetic testing can then be used to prevent the transmission of this disease to their offspring. | GJB1
Lua error in Module:Redirect at line 65: could not parse redirect on page "CMTX".
Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32) is a transmembrane protein that in humans is encoded by the GJB1 gene.[1] Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system.[2]
Mutations of the GJB1 gene affecting the signalling of and trafficking through gap junctions, resulting in an inherited peripheral neuropathy called X-linked Charcot-Marie-Tooth Disease. Complications include the demyelination of oligodendrocytes and Schwann cells, causing delayed transmission rates of nerve communication in the peripheral nervous system, due to irregularities in the normal function of the cells. This condition leads to a number of symptoms, most commonly muscle weakness and sensory problems in the outer extremities of the limbs. As a result, muscle atrophy and soft tissue injuries due to delayed nerve transmission can occur. In males, due to the hemizygousity of the X-chromosome, the symptoms and issues surrounding X-linked Charcot-Marie-Tooth disease are more prevalent.[3]
# Function
Connexins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells.[4] For a general discussion of connexin proteins, see GJB2.[5]
In melanocytic cells GJB1 gene expression may be regulated by MITF.[6]
# Gene
The gene that encodes the human GJB1 protein is found on the x chromosome, on the long arm at position q13.1, in interval 8, from base pair 71,215,212 to base pair 71,225,215.[1][4]
## Mutations
Approximately four hundred type X Charcot-Marie-Tooth causing mutations have been identified within the GJB1 gene, and it is the only known gene to be associated with this disease,.[7][8] The majority of these mutations only change a single amino acid within the protein chain, which result in a different protein being produced. Mutations within the GJB1 gene consist of novel, missense, double-missense, amino acid deletion, nonsense, frameshift, and in-frame deletions/insertions.[2][3][4][9] These mutations most commonly result in proteins that work incorrectly, less effectively, degrade faster, are not present in adequate numbers or may not function at all.
# Structure
The GJB1 gene is approximately 10kb in length, with one coding exon and three non-coding exons. GJB1 is a gap junction, beta 1 protein also identified as connexin 32, with 238 amino acids.[3] This protein contains four transmembrane domains, which when assembled form gap junctions. Each of these gap junctions consist of two hemichannels (connexions), which in turn consist of six connexin molecules (gap junction trans-membrane proteins).,[3][4] This enables communication between Schwann cell nuclei and axons through a radial diffusion pathway.[3]
# Function
GJB1 functions as a radial diffusion pathway, allowing the communication and diffusion of nutrients, ions and small molecules between cells.[3] The GJB1 protein is found in a number of organs, including the liver, kidney, pancreas and nervous system.[2][4] In normal circumstances this protein is located in the cell membrane of Schwann cells and oligodendrocytes, specialised cells of the nervous system.,[4][10] These cells typically encapsulate nerves that are involved in the assembly and preservation of myelin, to ensure reliable and rapid transmission of nerve signals.,[4][10] Typically the GJB1 protein forms channels through the myelin to the internal Schwann cell or oligodendrocyte, allowing effective transportation and communication.,[4][10]
# Type X Charcot-Marie-Tooth disease
Approximately four hundred mutations of the GJB1 gene have been identified in people with X-linked Charcot-Marie-Tooth disease (CMTX).[10] CMTX is predominantly classified with symptoms related to muscle weakness and sensory problems, especially in the outer extremities of the limbs.[4] CMTX is the second most common type of CMT (about 10% of all patients) and is transmitted as an x-linked dominant trait.[3] It is categorised by the lack of male-to-male transmission of the mutated GJB1 gene and the differences in severity between heterozygous women and hemizygous men, with the later being more severely affected.[7]
Most of the mutations of the GJB1 gene switch or change a single amino acid in the gap junction (connexin-32) protein, although some may result in a protein of irregular size.[3][7][9][10] Some of these mutations also cause hearing loss in patients with CMTX.[10] Currently it is unknown how the mutations of the GJB1 gene lead to these specific features of Charcot-Marie-Tooth disease, however it is theorised that the cause is due to the demyelination of nerve cells.[10] As a result, transmission rates of nerve communication in the peripheral nervous system are delayed, which in turn would cause irregularities in the normal function of Schwann cells.[10]
Whilst CMTX is more commonly known to affect the peripheral nervous system some cases have been reported in which there is evidence of demyelination of the central nervous system.[2][10] These abnormalities whilst not presenting any symptoms were identified through nerve impulse and imaging studies, and are believed to also be caused through mutations on the GJB1 gene.[10]
## Diagnosis/testing
Historically CMTX could only be diagnosed through symptoms or measurement of the speed of nerve impulses. With the creation of genetic testing, 90% of CMTX cases are now diagnosed using the mutations of the GJB1 (Cx32) gene.[7] The genetic screening of families has also become common after the diagnosis of CMTX in a patient, to further identify other family members that may be suffering from the disease. This screening is also used systematically by researchers to identify new mutations within the gene.[2][8][9]
## Management
Currently CMTX is an incurable condition, instead patients are evaluated and treated for symptoms caused by the disease. Treatment is limited to rehabilitative therapy, use of assistive devices such as orthoses and in some cases surgical treatment of skeletal deformities and soft-tissue abnormalities.[7] Surgical treatment most commonly includes osteotomies, soft-tissue surgery (including tendon transfers) and/or joint fusions.[7]
## Genetic counseling
Due to the nature of inheritance of CMTX, affected males will pass the GJB1 gene mutation to all female children and none of their male children, whilst females who are carriers will have a 50% chance of passing on the mutation to each of their offspring.[7] With the development of genetic testing, it is possible to perform both prenatal and pre-implantation testing elected by the patient, when their type of mutation has been identified.[7] Results from genetic testing can then be used to prevent the transmission of this disease to their offspring. | https://www.wikidoc.org/index.php/CMTX | |
d7fb79518257b6da0296d51b7ee27b1762e1cd09 | wikidoc | COA3 | COA3
Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.
# Structure
The COA3 gene is located on the q arm of chromosome 17 at position 21.2 and it spans 1,107 base pairs. The COA3 gene produces a 7.8 kDa protein composed of 71 amino acids. COA3 is a component of the enzyme MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, and the structure contains a C-terminal coiled-coil domain as well as a central single pass transmembrane domain.
# Function
The COA3 gene encodes for a Core protein of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. The MITRAC complex is essential in the assembly of cytochrome c oxidase (complex IV) of the mitochondrial respiratory chain, which is responsible for the catalysis of oxidation of cytochrome c by molecular oxygen. The MITRAC complex regulates both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. In addition, COA3 is required for efficient translation of MT-CO1 and assembly of the mitochondrial respiratory chain complex IV.
# Clinical significance
Variants of COA3 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 missense mutation of c.215A>G in the COA3 gene has been found to result in a severe decrease in protein levels with symptoms of exercise intolerance and peripheral neuropathy.
# Interactions
Like COX14, COA3 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 MT-CO1, COX1, SMIM20, SURF1, TIMM21, and others. | COA3
Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.[1][2][3]
# Structure
The COA3 gene is located on the q arm of chromosome 17 at position 21.2 and it spans 1,107 base pairs.[3] The COA3 gene produces a 7.8 kDa protein composed of 71 amino acids.[4][5] COA3 is a component of the enzyme MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, and the structure contains a C-terminal coiled-coil domain as well as a central single pass transmembrane domain.[6]
# Function
The COA3 gene encodes for a Core protein of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex. The MITRAC complex is essential in the assembly of cytochrome c oxidase (complex IV) of the mitochondrial respiratory chain, which is responsible for the catalysis of oxidation of cytochrome c by molecular oxygen.[7] The MITRAC complex regulates both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. In addition, COA3 is required for efficient translation of MT-CO1 and assembly of the mitochondrial respiratory chain complex IV.[1][2]
# Clinical significance
Variants of COA3 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] 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 missense mutation of c.215A>G in the COA3 gene has been found to result in a severe decrease in protein levels with symptoms of exercise intolerance and peripheral neuropathy.[7]
# Interactions
Like COX14, COA3 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 MT-CO1, COX1, SMIM20, SURF1, TIMM21, and others.[10][1] | https://www.wikidoc.org/index.php/COA3 | |
84dc42df0d4b22930443714b4fab3d9ac33b85df | wikidoc | COA5 | COA5
Cytochrome c oxidase assembly factor 5 is a protein that in humans is encoded by the COA5 gene. This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency.
# Structure
The COA5 gene is located on the q arm of chromosome 2 at position 11.2 and it spans 9,195 base pairs. The COA5 gene produces an 8 kDa protein composed of 73 amino acids. The structure of the protein contains the twin CX9C motif of yeast Pet191, which is conserved in the 74-amino acid deduced human protein. An example of the twin CX9C would be a repeated motif of 2 cysteines.
# Function
The COA3 gene encodes for a protein involved in an early step of the complex IV assembly process. The conserved cysteines in the twin CX9C motif, which is a part of the COA3 protein, has been shown to be essential in cell viability as well as the proper function and assembly of the cytochrome c oxidase complex.
# Clinical Significance
Variants of COA5 have been mainly associated with a mitochondrial complex IV deficiency, a deficiency of the enzyme complex Complex IV, which is responsible for the catalysis of oxidation of cytochrome c using molecular oxygen. The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other phenotypes include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Mutations in COA5 has also known to be associated with Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 (CEMCOX3). CEMCOX3 is an infantile disorder associated with a severely fatal course during the first weeks of life. It is characterized by hypertrophic cardiomyopathy and is caused by mitochondrial complex IV deficiency. Postmortem microscopic investigations have shown accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation. A homozygous mutation of 157G>C has resulted in decreased complex IV in fibroblasts and heart muscle.
# Interactions
COA5 has been known to have unique protein–protein interactions with APP, KRT31, and CHCHD4. | COA5
Cytochrome c oxidase assembly factor 5 is a protein that in humans is encoded by the COA5 gene. This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency.[1]
# Structure
The COA5 gene is located on the q arm of chromosome 2 at position 11.2 and it spans 9,195 base pairs.[1] The COA5 gene produces an 8 kDa protein composed of 73 amino acids.[2][3] The structure of the protein contains the twin CX9C motif of yeast Pet191, which is conserved in the 74-amino acid deduced human protein. An example of the twin CX9C would be a repeated motif of 2 cysteines.[4]
# Function
The COA3 gene encodes for a protein involved in an early step of the complex IV assembly process.[5][6] The conserved cysteines in the twin CX9C motif, which is a part of the COA3 protein, has been shown to be essential in cell viability as well as the proper function and assembly of the cytochrome c oxidase complex.[4]
# Clinical Significance
Variants of COA5 have been mainly associated with a mitochondrial complex IV deficiency, a deficiency of the enzyme complex Complex IV, which is responsible for the catalysis of oxidation of cytochrome c using molecular oxygen. The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other phenotypes include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation.[7][1] Mutations in COA5 has also known to be associated with Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 (CEMCOX3). CEMCOX3 is an infantile disorder associated with a severely fatal course during the first weeks of life. It is characterized by hypertrophic cardiomyopathy and is caused by mitochondrial complex IV deficiency. Postmortem microscopic investigations have shown accumulation of lipid droplets in cardiomyocytes and mitochondrial proliferation.[5][6] A homozygous mutation of 157G>C has resulted in decreased complex IV in fibroblasts and heart muscle.[8]
# Interactions
COA5 has been known to have unique protein–protein interactions with APP, KRT31, and CHCHD4.[9] | https://www.wikidoc.org/index.php/COA5 | |
7ed8650e3705e51be5b7bc18cfdc5df5550b4b92 | wikidoc | COA6 | COA6
Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene. Mitochondrial respiratory chain Complex IV, or cytochrome c oxidase, is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family. This protein is located in the intermembrane space, associating with SCO2 and COX2. It stabilizes newly formed COX2 and is part of the mitochondrial copper relay system. Mutations in this gene result in fatal infantile cardioencephalomyopathy.
# Structure
The COA6 gene is located on the q arm of chromosome 1 in position 42.2 and spans 10,612 base pairs. The gene produces a 14.1 kDa protein composed of 125 amino acids. The COA6 protein is found a complex with TMEM177, COX20, MT-CO2/COX2, COX18, SCO1 and SCO2. This protein localizes to the intermembrane space, associating with the inner membrane and transmembrane proteins such as SCO2 and COX2.
# Function
The COA6 encodes a protein which is an assembly factor for Complex IV. This protein is specifically required for COX2 biogenesis and stability; the absence of this protein will cause fast turnover of newly synthesized COX2. As a constituent of mitochondrial copper relay system, this protein possibly relays copper ions from SCO2 to COX2.
# Clinical Significance
Two mutations have been identified in this protein: W66R and W59C. The latter mutation results in the protein being mistargeted to the mitochondrial matrix, resulting in the loss of interaction with SCO2 and COX2. Inheritance of this mutation is autosomal recessive and results in a phenotype of fatal infantile cardioencephalomyopathy due to Complex IV deficiency. Symptoms include hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, and metabolic hypotonia.
# Interactions
This protein interacts transiently with the copper-containing catalytic domain of newly synthesized COX2 via its C-terminal tail exposed to the intermembrane space. It also interacts selectively with the copper metallochaperone SCO2 in a COX2-dependent manner and with COX20 in a COX2- and COX18-dependent manner. Additionally, this protein interacts with COA1, SCO1, COX16, TTC19, DTX2, NADSYN1, GABARAP, AIFM1, COX4I1, CD81, COX14, SFXN1, and PLGRKT. | COA6
Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene.[1] Mitochondrial respiratory chain Complex IV, or cytochrome c oxidase, is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis.[2][3] The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family.[1][4] This protein is located in the intermembrane space, associating with SCO2 and COX2. It stabilizes newly formed COX2 and is part of the mitochondrial copper relay system.[5] Mutations in this gene result in fatal infantile cardioencephalomyopathy.[4]
# Structure
The COA6 gene is located on the q arm of chromosome 1 in position 42.2 and spans 10,612 base pairs.[1] The gene produces a 14.1 kDa protein composed of 125 amino acids.[6][7] The COA6 protein is found a complex with TMEM177, COX20, MT-CO2/COX2, COX18, SCO1 and SCO2.[2][3] This protein localizes to the intermembrane space, associating with the inner membrane and transmembrane proteins such as SCO2 and COX2.[5]
# Function
The COA6 encodes a protein which is an assembly factor for Complex IV.[1] This protein is specifically required for COX2 biogenesis and stability; the absence of this protein will cause fast turnover of newly synthesized COX2. As a constituent of mitochondrial copper relay system, this protein possibly relays copper ions from SCO2 to COX2.[5]
# Clinical Significance
Two mutations have been identified in this protein: W66R and W59C. The latter mutation results in the protein being mistargeted to the mitochondrial matrix, resulting in the loss of interaction with SCO2 and COX2.[2][3] Inheritance of this mutation is autosomal recessive and results in a phenotype of fatal infantile cardioencephalomyopathy due to Complex IV deficiency.[4] Symptoms include hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, and metabolic hypotonia.[2][3]
# Interactions
This protein interacts transiently with the copper-containing catalytic domain of newly synthesized COX2 via its C-terminal tail exposed to the intermembrane space. It also interacts selectively with the copper metallochaperone SCO2 in a COX2-dependent manner and with COX20 in a COX2- and COX18-dependent manner.[5] Additionally, this protein interacts with COA1, SCO1, COX16, TTC19, DTX2, NADSYN1, GABARAP, AIFM1, COX4I1, CD81, COX14, SFXN1, and PLGRKT.[2][3][8] | https://www.wikidoc.org/index.php/COA6 | |
203ff59d3b692492c8cfc3e2824b2f77898712a3 | wikidoc | COA7 | COA7
Cytochrome c oxidase assembly factor 7 (putative) (COA7), also known as Beta-lactamase hap-like protein, Respiratory chain assembly factor 1 (RESA1), Sel1 repeat-containing protein 1 (SELRC1), or C1orf163 is a protein that in humans is encoded by the COA7 gene. The protein encoded by COA7 is an assembly factor important for the mitochondrial respiratory chain. Mutations in COA7 have been associated with cytochrome c oxidase deficiency resulting in spinocerebellar ataxia with axonal neuropathy type 3 and mitochondrial myopathy.
# Structure
COA7 is located on the p arm of chromosome 1 in position 32.3 and has 3 exons. The COA7 gene produces a 25.7 kDa protein composed of 231 amino acids. COA7, the protein encoded by this gene, is a member of the hcp beta-lactamase family. This protein has a series of 5 Sel1-like tetratricopeptide repeat domains. It is also believed to be a soluble mitochondrial protein that contains large amounts of cysteine. Additionally, COA7 contains an N-acetylalanine amino acid modification at position 2.
# Function
COA7 is a protein assembly factor that is important for normal mitochondrial respiratory chain activity. It is believed to be involved in the assembly of cytochrome c oxidase (complex IV), but may also have effects on complex I and even complex III as well. It has been suggested that COA7 is a mitochondrial soluble intermembrane space protein, however, others have indicated that this soluble protein may actually be localized to the mitochondrial matrix.
# Clinical significance
Mutations in COA7 have been associated with spinocerebellar ataxia with axonal neuropathy type 3 and mitochondrial myopathy resulting from cytochrome c oxidase (complex IV) deficiency. Complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. In cases of pathogenic COA7 mutations, patient clinical manifestations can include sensory disturbance, decreased deep tendon reflexes, dysarthria, peripheral neuropathy, axonal sensorimotor neuropathy, ataxia, cerebellar and spinal cord atrophy, leukoencephalopathy, elevated serum creatine kinase levels, ragged-red fibers, and cognitive impairment. COA7 loss-of-function has been shown to lead to the disruption of oxidative phosphorylation, with cytochrome c oxidase activity being the most affected complex. Pathogenic variations have been known to include D6G, S149I, G144fs, and Y137C amino acid changes in addition to a c.115C>T exon 2 deletion.
# Interactions
COA7 has been shown to have 27 binary protein-protein interactions including 16 co-complex interactions. COA7 appears to interact with EFHC1, SNRPB, SUOX, AES, ENKD1, and GPSM3. | COA7
Cytochrome c oxidase assembly factor 7 (putative) (COA7), also known as Beta-lactamase hap-like protein, Respiratory chain assembly factor 1 (RESA1), Sel1 repeat-containing protein 1 (SELRC1), or C1orf163 is a protein that in humans is encoded by the COA7 gene.[1][2][3] The protein encoded by COA7 is an assembly factor important for the mitochondrial respiratory chain.[4] Mutations in COA7 have been associated with cytochrome c oxidase deficiency resulting in spinocerebellar ataxia with axonal neuropathy type 3 and mitochondrial myopathy.[5][6]
# Structure
COA7 is located on the p arm of chromosome 1 in position 32.3 and has 3 exons.[1] The COA7 gene produces a 25.7 kDa protein composed of 231 amino acids.[7][8] COA7, the protein encoded by this gene, is a member of the hcp beta-lactamase family. This protein has a series of 5 Sel1-like tetratricopeptide repeat domains.[6] It is also believed to be a soluble mitochondrial protein that contains large amounts of cysteine.[4] Additionally, COA7 contains an N-acetylalanine amino acid modification at position 2.[2][3]
# Function
COA7 is a protein assembly factor that is important for normal mitochondrial respiratory chain activity. It is believed to be involved in the assembly of cytochrome c oxidase (complex IV), but may also have effects on complex I and even complex III as well. It has been suggested that COA7 is a mitochondrial soluble intermembrane space protein, however, others have indicated that this soluble protein may actually be localized to the mitochondrial matrix.[4][6]
# Clinical significance
Mutations in COA7 have been associated with spinocerebellar ataxia with axonal neuropathy type 3 and mitochondrial myopathy resulting from cytochrome c oxidase (complex IV) deficiency. Complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs.[9][3] In cases of pathogenic COA7 mutations, patient clinical manifestations can include sensory disturbance, decreased deep tendon reflexes, dysarthria, peripheral neuropathy, axonal sensorimotor neuropathy, ataxia, cerebellar and spinal cord atrophy, leukoencephalopathy, elevated serum creatine kinase levels, ragged-red fibers, and cognitive impairment. COA7 loss-of-function has been shown to lead to the disruption of oxidative phosphorylation, with cytochrome c oxidase activity being the most affected complex. Pathogenic variations have been known to include D6G, S149I, G144fs, and Y137C amino acid changes in addition to a c.115C>T exon 2 deletion.[5][6]
# Interactions
COA7 has been shown to have 27 binary protein-protein interactions including 16 co-complex interactions. COA7 appears to interact with EFHC1, SNRPB, SUOX, AES, ENKD1, and GPSM3.[10] | https://www.wikidoc.org/index.php/COA7 | |
73c7ae3957c59b158d29b7875ef3da1a13cef82a | wikidoc | COG2 | COG2
Conserved oligomeric Golgi complex subunit 2 is a protein that in humans is encoded by the COG2 gene.
Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modification. Several complexes have been identified, including the Golgi transport complex (GTC), the LDLC complex, which is involved in glycosylation reactions, and the SEC34 complex, which is involved in vesicular transport. These 3 complexes are identical and have been termed the conserved oligomeric Golgi (COG) complex, which includes COG2 (Ungar et al., 2002).
# Model organisms
Model organisms have been used in the study of COG2 function. A conditional knockout mouse line, called Cog2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five were carried out on mutant mice and one significant abnormality was observed: no homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.
# Interactions
COG2 has been shown to interact with COG4 and COG3. | COG2
Conserved oligomeric Golgi complex subunit 2 is a protein that in humans is encoded by the COG2 gene.[1][2]
Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modification. Several complexes have been identified, including the Golgi transport complex (GTC), the LDLC complex, which is involved in glycosylation reactions, and the SEC34 complex, which is involved in vesicular transport. These 3 complexes are identical and have been termed the conserved oligomeric Golgi (COG) complex, which includes COG2 (Ungar et al., 2002).[2]
# Model organisms
Model organisms have been used in the study of COG2 function. A conditional knockout mouse line, called Cog2tm1a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty five were carried out on mutant mice and one significant abnormality was observed: no homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[5][5]
# Interactions
COG2 has been shown to interact with COG4[13] and COG3.[14] | https://www.wikidoc.org/index.php/COG2 | |
0678ca43d22e68a0df7e50ca0478b432d585d9b8 | wikidoc | COG4 | COG4
Conserved oligomeric Golgi complex subunit 4 is a protein that in humans is encoded by the COG4 gene.
Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modification. Several complexes have been identified, including the Golgi transport complex (GTC), the LDLC complex, which is involved in glycosylation reactions, and the SEC34 complex, which is involved in vesicular transport. These 3 complexes are identical and have been termed the conserved oligomeric Golgi (COG) complex, which includes COG4 (Ungar et al., 2002).
# Interactions
COG4 has been shown to interact with COG7, COG2, COG1 and COG5. | COG4
Conserved oligomeric Golgi complex subunit 4 is a protein that in humans is encoded by the COG4 gene.[1][2]
Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modification. Several complexes have been identified, including the Golgi transport complex (GTC), the LDLC complex, which is involved in glycosylation reactions, and the SEC34 complex, which is involved in vesicular transport. These 3 complexes are identical and have been termed the conserved oligomeric Golgi (COG) complex, which includes COG4 (Ungar et al., 2002).[supplied by OMIM][2]
# Interactions
COG4 has been shown to interact with COG7,[3] COG2,[3] COG1[3] and COG5.[3] | https://www.wikidoc.org/index.php/COG4 | |
b9ad37741ee8ec4d6f046f741060d38f601ece3f | wikidoc | COQ6 | COQ6
Coenzyme Q6 monooxygenase is a protein that in humans is encoded by the COQ6 gene.
# Function
The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis.
# Clinical significance
Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. | COQ6
Coenzyme Q6 monooxygenase is a protein that in humans is encoded by the COQ6 gene.[1]
# Function
The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis.[1]
# Clinical significance
Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[2] | https://www.wikidoc.org/index.php/COQ6 | |
af7f964399ae4572ee0b743b23425401254c5dd1 | wikidoc | COQ7 | COQ7
The clk-1 (clock-1) gene encodes an enzyme (demethoxyubiquinone monooxygenase) that is necessary for ubiquinone biosynthesis in the worm Caenorhabditis elegans and other eukaryotes. The mouse version of the gene is called mclk-1 and the human, fruit fly and yeast homolog COQ7 (coenzyme Q biosynthesis protein 7).
CLK-1 is not to be confused with the unrelated human protein CLK1 which plays a role in RNA splicing.
# Structure
The protein has two repeats of approximately 90 amino acids, that contain two conserved motifs predicted to be important for coordination of iron. The structure and function of the gene are highly conserved among different species.
The C. elegans protein contains 187 amino acid residues (20 kilodaltons), the human homolog 217 amino acid residues (24 kilodaltons, gene consisting of six exons spanning 11 kb and located on chromosome 16).
# Mitochondrial function
Ubiquinone is a small redox active lipid that is found in most cellular membranes where it acts as a cofactor in numerous cellular redox processes, including mitochondrial electron transport. As a cofactor, ubiquinone is often involved in processes that produce reactive oxygen species (ROS). In addition, ubiquinone is one of the main endogenous antioxidants of the cell. The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.
It has been shown that mutations in the gene are associated with increased lifespan. Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging.
# Nuclear function
CLK-1 and COQ7 predominantly localise to mitochondria to participate in the ubiquinone biosynthetic pathway which is found there. However, a small pool of CLK-1 and COQ7 translocates to the nucleus in response to the production of ROS by normally functioning mitochondria in both worms and human cells, respectively. Translocation of CLK-1 and COQ7 represents a mitochondrial to nuclear retrograde signalling pathway that acts to suppress mitochondrial stress responses. The mitochondrial and nuclear pools of CLK-1 are thought to contribute independently to worm lifespan regulation. The nuclear form of CLK-1 and COQ7 is thought to regulate gene expression through an unidentified mechanism. | COQ7
The clk-1 (clock-1) gene encodes an enzyme (demethoxyubiquinone monooxygenase) that is necessary for ubiquinone biosynthesis in the worm Caenorhabditis elegans and other eukaryotes. The mouse version of the gene is called mclk-1 and the human, fruit fly and yeast homolog COQ7 (coenzyme Q biosynthesis protein 7).[1][2]
CLK-1 is not to be confused with the unrelated human protein CLK1 which plays a role in RNA splicing.
# Structure
The protein has two repeats of approximately 90 amino acids, that contain two conserved motifs predicted to be important for coordination of iron. The structure and function of the gene are highly conserved among different species.[3]
The C. elegans protein contains 187 amino acid residues (20 kilodaltons), the human homolog 217 amino acid residues (24 kilodaltons, gene consisting of six exons spanning 11 kb and located on chromosome 16).[4]
# Mitochondrial function
Ubiquinone is a small redox active lipid that is found in most cellular membranes where it acts as a cofactor in numerous cellular redox processes, including mitochondrial electron transport. As a cofactor, ubiquinone is often involved in processes that produce reactive oxygen species (ROS). In addition, ubiquinone is one of the main endogenous antioxidants of the cell. The CLK-1 enzyme is responsible for the hydroxylation of 5-demethoxyubiquinone to 5-hydroxyubiquinone.
It has been shown that mutations in the gene are associated with increased lifespan.[1][3] Defects of the gene slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging.[5]
# Nuclear function
CLK-1 and COQ7 predominantly localise to mitochondria to participate in the ubiquinone biosynthetic pathway which is found there. However, a small pool of CLK-1 and COQ7 translocates to the nucleus in response to the production of ROS by normally functioning mitochondria in both worms and human cells, respectively.[6] Translocation of CLK-1 and COQ7 represents a mitochondrial to nuclear retrograde signalling pathway that acts to suppress mitochondrial stress responses. The mitochondrial and nuclear pools of CLK-1 are thought to contribute independently to worm lifespan regulation. The nuclear form of CLK-1 and COQ7 is thought to regulate gene expression through an unidentified mechanism. | https://www.wikidoc.org/index.php/COQ7 | |
dbdb8ddaf1b40fc5b85b3963847c7623caec6f45 | wikidoc | COQ9 | COQ9
Ubiquinone biosynthesis protein COQ9, mitochondrial, also known as coenzyme Q9 homolog (COQ9), is a protein that in humans is encoded by the COQ9 gene.
# Function
This locus represents a mitochondrial ubiquinone biosynthesis gene. The encoded protein is likely necessary for biosynthesis of coenzyme Q10, as mutations at this locus have been associated with autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency.
# Clinical significance
It may be associated with Coenzyme Q10 deficiency.
# Model organisms
Model organisms have been used in the study of COQ9 function. A conditional knockout mouse line, called Coq9tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: females displayed hyperactivity in an open field test. | COQ9
Ubiquinone biosynthesis protein COQ9, mitochondrial, also known as coenzyme Q9 homolog (COQ9), is a protein that in humans is encoded by the COQ9 gene.[1]
# Function
This locus represents a mitochondrial ubiquinone biosynthesis gene. The encoded protein is likely necessary for biosynthesis of coenzyme Q10, as mutations at this locus have been associated with autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency.[1]
# Clinical significance
It may be associated with Coenzyme Q10 deficiency.[2]
# Model organisms
Model organisms have been used in the study of COQ9 function. A conditional knockout mouse line, called Coq9tm1a(KOMP)Wtsi[9][10] 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.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: females displayed hyperactivity in an open field test.[7] | https://www.wikidoc.org/index.php/COQ9 | |
9ee8a1925c51e5851f248ff2c298aa7ba82b04db | wikidoc | CPA3 | CPA3
Carboxypeptidase A3 (mast cell carboxypeptidase A), also known as CPA3, is an enzyme which in humans is encoded by the CPA3 gene. The "CPA3" gene expression has only been detected in mast cells and mast-cell-like lines, and CPA3 is located in secretory granules. CPA3 is one of 8-9 members of the A/B subfamily that includes the well-studied pancreatic enzymes carboxypeptidase A1 (CPA1), carboxypeptidase A2 (CPA2), and carboxypeptidase B. This subfamily includes 6 carboxypeptidase A-like enzymes, numbered 1-6. The enzyme now called CPA3 was originally named mast cell carboxypeptidase A, and another protein was initially called CPA3. A gene nomenclature committee renamed mast cell carboxypeptidase A as CPA3, and the original CPA3 reported by Huang et al. became CPA4 to reflect the order of their discovery.
# Structure
## Gene
The "CPA3" gene is a 32kb-gene located at chromosome 3q24, consisting of 11 exons.
## Protein
CPA3 shares significant homology with the CPA subfamily of metalloprecarboxypeptidases and all the residues essential for the coordination of the Zn2+ active site, substrate peptide anchoring, and CP activity are preserved in the putative CPA3 protein. It resembles pancreatic CPA1 in cleaving C-terminal aromatic and aliphatic amino acid residues.CPA3 contains an N-terminal sequence of 16 amino acids and a pro-peptide between the NH2-terminal signial peptide sequence and COOH-terminal CP moiety.
# Function
CPA3 has a pH optimum in the neutral to basic range. CPA3 functions together with endopeptidases secreted from mast cells such as chymases and tryptases to degrade proteins and peptides,including the apolipoprotein B component of LDL particles and angiotensin Ⅰ. Upon mast cell activation and degranulation, CPA3, the chymases, and tryptases are released in complexes with heparin proteoglycan.The parasitic nematode Ascaris produces CPA3 inhibitors, which increase its survival during infection. This finding implies that CPA3 might be involved in host defense against certain parasites. CPA3 is also reported to have an important role in the protection towards snake venom toxins and vasoconstricting peptide endothelin 1(ET1).
# Clinical significance
CPA3 provides protection from ET-1-induced damage, suggesting CPA3 could have a role in regulating sepsis. The involvement of CPA3 in autoimmune disease models makes it a potential diagnostic parameter of related diseases. The significantly increased concentration of CPA3 in drug-induced anaphylaxis also implies that CPA3 could serve as a diagnostic parameter and detection of it could improve the forensic identification. A new mast cell subtype reported to appear in mucosa is implicated in allergic inflammation and these mast cells have high levels of CPA3. The highly upregulated transcript of CPA3 is readily detected in luminal brushings and biopsies, making it a useful biomarker of allergic inflammation.
# Interactions
CPA3 has been known to interact with:
- Heparin
- PCI
- SR48692
- Tissue carboxypeptidase inhibitor
- Neurotensin | CPA3
Carboxypeptidase A3 (mast cell carboxypeptidase A), also known as CPA3, is an enzyme which in humans is encoded by the CPA3 gene.[1][2] The "CPA3" gene expression has only been detected in mast cells and mast-cell-like lines, and CPA3 is located in secretory granules. CPA3 is one of 8-9 members of the A/B subfamily that includes the well-studied pancreatic enzymes carboxypeptidase A1 (CPA1), carboxypeptidase A2 (CPA2), and carboxypeptidase B. This subfamily includes 6 carboxypeptidase A-like enzymes, numbered 1-6. The enzyme now called CPA3 was originally named mast cell carboxypeptidase A, and another protein was initially called CPA3.[3] A gene nomenclature committee renamed mast cell carboxypeptidase A as CPA3, and the original CPA3 reported by Huang et al. became CPA4 to reflect the order of their discovery.
# Structure
## Gene
The "CPA3" gene is a 32kb-gene located at chromosome 3q24, consisting of 11 exons.
## Protein
CPA3 shares significant homology with the CPA subfamily of metalloprecarboxypeptidases and all the residues essential for the coordination of the Zn2+ active site, substrate peptide anchoring, and CP activity are preserved in the putative CPA3 protein. It resembles pancreatic CPA1 in cleaving C-terminal aromatic and aliphatic amino acid residues.CPA3 contains an N-terminal sequence of 16 amino acids and a pro-peptide between the NH2-terminal signial peptide sequence and COOH-terminal CP moiety.[4][3]
# Function
CPA3 has a pH optimum in the neutral to basic range. CPA3 functions together with endopeptidases secreted from mast cells such as chymases and tryptases to degrade proteins and peptides,including the apolipoprotein B component of LDL particles and angiotensin Ⅰ.[5][6] Upon mast cell activation and degranulation, CPA3, the chymases, and tryptases are released in complexes with heparin proteoglycan.The parasitic nematode Ascaris produces CPA3 inhibitors, which increase its survival during infection. This finding implies that CPA3 might be involved in host defense against certain parasites.[7] CPA3 is also reported to have an important role in the protection towards snake venom toxins and vasoconstricting peptide endothelin 1(ET1).[8][9]
# Clinical significance
CPA3 provides protection from ET-1-induced damage, suggesting CPA3 could have a role in regulating sepsis. The involvement of CPA3 in autoimmune disease models makes it a potential diagnostic parameter of related diseases.[10] The significantly increased concentration of CPA3 in drug-induced anaphylaxis also implies that CPA3 could serve as a diagnostic parameter and detection of it could improve the forensic identification.[11] A new mast cell subtype reported to appear in mucosa is implicated in allergic inflammation and these mast cells have high levels of CPA3. The highly upregulated transcript of CPA3 is readily detected in luminal brushings and biopsies, making it a useful biomarker of allergic inflammation.[12][13]
# Interactions
CPA3 has been known to interact with:
- Heparin[14]
- PCI[15]
- SR48692[16]
- Tissue carboxypeptidase inhibitor[17]
- Neurotensin[18] | https://www.wikidoc.org/index.php/CPA3 | |
03f44373ea01265daf8db0278b17a5a2099c455c | wikidoc | CPN1 | CPN1
Carboxypeptidase N catalytic chain is an enzyme that in humans is encoded by the CPN1 gene.
Carboxypeptidase N is a plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins. The enzyme is important in the regulation of peptides like kinins and anaphylatoxins, and has also been known as kininase-1 and anaphylatoxin inactivator. This enzyme is a tetramer composed of two identical regulatory subunits and two identical catalytic subunits; this gene encodes the catalytic subunit. Mutations in this gene can be associated with angioedema or chronic urticaria resulting from carboxypeptidase N deficiency.
In melanocytic cells CPN1 gene expression may be regulated by MITF. | CPN1
Carboxypeptidase N catalytic chain is an enzyme that in humans is encoded by the CPN1 gene.[1][2][3]
Carboxypeptidase N is a plasma metallo-protease that cleaves basic amino acids from the C terminal of peptides and proteins. The enzyme is important in the regulation of peptides like kinins and anaphylatoxins, and has also been known as kininase-1 and anaphylatoxin inactivator. This enzyme is a tetramer composed of two identical regulatory subunits and two identical catalytic subunits; this gene encodes the catalytic subunit. Mutations in this gene can be associated with angioedema or chronic urticaria resulting from carboxypeptidase N deficiency.[3]
In melanocytic cells CPN1 gene expression may be regulated by MITF.[4] | https://www.wikidoc.org/index.php/CPN1 | |
427466330522acb04d3b37000d138cd5f3e6d3d7 | wikidoc | CPVL | CPVL
Probable serine carboxypeptidase CPVL is an enzyme that in humans is encoded by the CPVL gene. The "CPVL" gene is expressed mainly in monocytes and macrophages, and it is located in the endoplasmatic reticulum and in the endosomal/lysosomal compartment. The distribution of CPVL suggests that the enzyme may be involved in antigen processing and the secretory pathway. Besides those macrophages-rich tissues, the heart and kidney also express high levels of CPVL mRNA.The enzyme is similar to the carboxypeptidases CATHA and SCPEP1, but no direct confirmation of the enzymatic activity was obtained so far. The exact function of this protein, however, has not been determined.
# Structure
## Gene
"CPVL" gene is located at chromosome 7p15.1, consisting of 14 exons.At least two alternatively spliced transcripts which encode the same protein have been observed.
## Protein
The designation of CPVL is a true serine carboxypeptidase. Although the primary sequence displays the expected serine carboxypeptidase active site, the enzymatic activity remains to be demonstrated. The primary sequence of CPVL contains a putative signal sequence, four potential N-linked glycosylation sites and four myristoylation sites, but no transmembrane domain, suggesting that it may be luminal in an organelle and/or involved in the secretory pathway.
# Function
Although the primary sequence of CPVL bears every hallmarks of a serine carboxypeptidase, the enzymatic function of CPVL has not been confirmed. On the basis of its localization, CPVL is postulated to play a role in the biosynthesis of secretory molecules or in the processing and transport of peptides for loading onto MHC Ⅰ molecules, or in MHC Ⅱ-dependent APC functions. The high-level expression of CPVL mRNA in heart and kidney implies that CPVL may also have extraimmune functions, such as regulation of cardiovascular homeostasis.
# Clinical significance
The deletion of this gene has been reported associated with Wilms tumor. GWAS show that genetic variations of the CPVL gene are associated with susceptibility to diabetic nephropathy in European Americans, Japanese and Chinese. CPVL is also reported to be one of the four down-regulated proteins which is related to severity of inflammation, and it may be a potential biomarker for identification of infection and prediction of outcome. | CPVL
Probable serine carboxypeptidase CPVL is an enzyme that in humans is encoded by the CPVL gene.[1][2] The "CPVL" gene is expressed mainly in monocytes and macrophages,[1] and it is located in the endoplasmatic reticulum and in the endosomal/lysosomal compartment. The distribution of CPVL suggests that the enzyme may be involved in antigen processing and the secretory pathway.[3] Besides those macrophages-rich tissues, the heart and kidney also express high levels of CPVL mRNA.The enzyme is similar to the carboxypeptidases CATHA and SCPEP1, but no direct confirmation of the enzymatic activity was obtained so far.[4] The exact function of this protein, however, has not been determined.
# Structure
## Gene
"CPVL" gene is located at chromosome 7p15.1, consisting of 14 exons.At least two alternatively spliced transcripts which encode the same protein have been observed.[2]
## Protein
The designation of CPVL is a true serine carboxypeptidase. Although the primary sequence displays the expected serine carboxypeptidase active site, the enzymatic activity remains to be demonstrated. The primary sequence of CPVL contains a putative signal sequence, four potential N-linked glycosylation sites and four myristoylation sites, but no transmembrane domain, suggesting that it may be luminal in an organelle and/or involved in the secretory pathway.[3]
# Function
Although the primary sequence of CPVL bears every hallmarks of a serine carboxypeptidase, the enzymatic function of CPVL has not been confirmed. On the basis of its localization, CPVL is postulated to play a role in the biosynthesis of secretory molecules or in the processing and transport of peptides for loading onto MHC Ⅰ molecules, or in MHC Ⅱ-dependent APC functions.[3] The high-level expression of CPVL mRNA in heart and kidney implies that CPVL may also have extraimmune functions, such as regulation of cardiovascular homeostasis.[1]
# Clinical significance
The deletion of this gene has been reported associated with Wilms tumor.[5] GWAS show that genetic variations of the CPVL gene are associated with susceptibility to diabetic nephropathy in European Americans, Japanese and Chinese.[6][7][8] CPVL is also reported to be one of the four down-regulated proteins which is related to severity of inflammation, and it may be a potential biomarker for identification of infection and prediction of outcome.[9] | https://www.wikidoc.org/index.php/CPVL | |
9dd0b3c20bf8f577afcbb3007121ebc90afcf247 | wikidoc | CRKL | CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.
# Function
v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase and plays a role in fibroblast transformation by BCR-ABL. In addition, CRKL has oncogenic potential.
CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.
# Interactions
CRKL has been shown to interact with:
- Abl gene,
- BCAR1,
- BCR gene,
- CBLB,
- CD117,
- CD34,
- Cbl gene,
- Dock2,
- EPOR,
- GAB1,
- GAB2,
- INPP5D,
- MAP4K1,
- MAP4K5,
- NEDD9,
- PIK3R2,
- Paxillin
- RAPGEF1,
- RICS,
- STAT5A,
- Syk, and
- WAS. | CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.[1][2]
# Function
v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase and plays a role in fibroblast transformation by BCR-ABL. In addition, CRKL has oncogenic potential.[3]
CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.[4][5]
# Interactions
CRKL has been shown to interact with:
- Abl gene,[6][7][8]
- BCAR1,[9][10]
- BCR gene,[7][11][12][13]
- CBLB,[14]
- CD117,[15][16]
- CD34,[17]
- Cbl gene,[6][16][18][19][20][21][22][23][24][25]
- Dock2,[26]
- EPOR,[18][27]
- GAB1,[28]
- GAB2,[29]
- INPP5D,[27]
- MAP4K1,[30][31][32]
- MAP4K5,[33]
- NEDD9,[6][10][24][34]
- PIK3R2,[16]
- Paxillin[35][36]
- RAPGEF1,[6][18][28][37][38][39][40]
- RICS,[41]
- STAT5A,[42]
- Syk,[43] and
- WAS.[43] | https://www.wikidoc.org/index.php/CRKL | |
41860c07354b1311e41b3cd4e87de8cf1b2d61a7 | wikidoc | CRYM | CRYM
Mu-crystallin homolog also known as NADP-regulated thyroid-hormone-binding protein (THBP) is a protein that in humans is encoded by the CRYM gene. Multiple alternatively spliced transcript variants have been found for this gene.
# Function
Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles.
Its enzyme function has been determined as a ketimine reductase, reducing cyclic ketimines to their reduced forms. Either NADH or NADPH can be used as cofactor. The most active substrate at pH 5.0 is aminoethylcysteine ketimine (AECK), however at neutral pH (pH 7.2) the most active substrate is 1-piperideine-2-carboxylate which is an important part of the pipecolic acid pathway. The active form of thyroxine, T3, has been found to be a potent inhibitor at nanomolar concentrations.
Besides its role in lens biology, CRYM seems also to be involved in thyroid hormone signalling in other tissues. It could be demonstrated that CRYM mutations may cause deafness through thyroid hormone binding effects on the fibrocytes of the cochlea. Disruption of the CRYM gene leads to decreased T3 concentrations in both tissues and serum without alteration of peripheral T3 action in vivo.
The existence of intracellular thyroid hormone binding proteins has been postulated from mathematical modelling of pituitary-thyroid homeostasis. Binding properties have been assumed to be similar to those of extracellular binding proteins, however it is not clear, if THBP is the only intracellular thyroid hormone binding protein. | CRYM
Mu-crystallin homolog also known as NADP-regulated thyroid-hormone-binding protein (THBP) is a protein that in humans is encoded by the CRYM gene. Multiple alternatively spliced transcript variants have been found for this gene.[1][2]
# Function
Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles.[2]
Its enzyme function has been determined as a ketimine reductase, reducing cyclic ketimines to their reduced forms. Either NADH or NADPH can be used as cofactor. The most active substrate at pH 5.0 is aminoethylcysteine ketimine (AECK), however at neutral pH (pH 7.2) the most active substrate is 1-piperideine-2-carboxylate which is an important part of the pipecolic acid pathway. The active form of thyroxine, T3, has been found to be a potent inhibitor at nanomolar concentrations.[3]
Besides its role in lens biology, CRYM seems also to be involved in thyroid hormone signalling in other tissues. It could be demonstrated that CRYM mutations may cause deafness through thyroid hormone binding effects on the fibrocytes of the cochlea.[4] Disruption of the CRYM gene leads to decreased T3 concentrations in both tissues and serum without alteration of peripheral T3 action in vivo.[5][6]
The existence of intracellular thyroid hormone binding proteins has been postulated from mathematical modelling of pituitary-thyroid homeostasis.[7] Binding properties have been assumed to be similar to those of extracellular binding proteins,[8] however it is not clear, if THBP is the only intracellular thyroid hormone binding protein. | https://www.wikidoc.org/index.php/CRYM | |
c0f2775d05443aab6f3fc201b93d22838716bb04 | wikidoc | CST1 | CST1
Cystatin-SN is a protein that in humans is encoded by the CST1 gene.
"The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a cysteine proteinase inhibitor found in saliva, tears, urine, and seminal fluid."
# Gene
## Transcriptions
The "four cystatin genes contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes." | CST1
Associate Editor(s)-in-Chief: Henry A. Hoff
Cystatin-SN is a protein that in humans is encoded by the CST1 gene.[1]
"The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a cysteine proteinase inhibitor found in saliva, tears, urine, and seminal fluid."[2]
# Gene
## Transcriptions
The "four cystatin genes [GeneID: 1469 CST1, GeneID: 1470 CST2, GeneID: 1471 CST3, and GeneID: 1472 CST4] contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."[3] | https://www.wikidoc.org/index.php/CST1 | |
359fe28a06c52aec45498e7a97e28719ca1ed8c9 | wikidoc | CST2 | CST2
Cystatin-SA is a protein that in humans is encoded by the CST2 gene.
"The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a secreted thiol protease inhibitor found at high levels in saliva, tears and seminal plasma."
# Gene
## Transcriptions
The "four cystatin genes contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes." | CST2
Associate Editor(s)-in-Chief: Henry A. Hoff
Cystatin-SA is a protein that in humans is encoded by the CST2 gene.[1]
"The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a secreted thiol protease inhibitor found at high levels in saliva, tears and seminal plasma."[2]
# Gene
## Transcriptions
The "four cystatin genes [GeneID: 1469 CST1, GeneID: 1470 CST2, GeneID: 1471 CST3, and GeneID: 1472 CST4] contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."[3] | https://www.wikidoc.org/index.php/CST2 | |
c183879a41f43f8b3f970f9424ce1728d6c038e8 | wikidoc | CST4 | CST4
Cystatin-S is a protein that in humans is encoded by the CST4 gene.
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a type 2 salivary cysteine peptidase inhibitor. The protein is an S-type cystatin, based on its high level of expression in saliva, tears and seminal plasma. The specific role in these fluids is unclear but antibacterial and antiviral activity is present, consistent with a protective function.
# Gene
## Transcriptions
The "four cystatin genes contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes." | CST4
Associate Editor(s)-in-Chief: Henry A. Hoff
Cystatin-S is a protein that in humans is encoded by the CST4 gene.[1][2]
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes a type 2 salivary cysteine peptidase inhibitor. The protein is an S-type cystatin, based on its high level of expression in saliva, tears and seminal plasma. The specific role in these fluids is unclear but antibacterial and antiviral activity is present, consistent with a protective function.[2]
# Gene
## Transcriptions
The "four cystatin genes [GeneID: 1469 CST1, GeneID: 1470 CST2, GeneID: 1471 CST3, and GeneID: 1472 CST4] contain the ATA-box sequence (ATAAA) in their 5'-flanking regions; however, the CAT-box sequence (CAT), a binding site of the transcription factor, CTF, is found only in the 5'-flanking region of the S-type cystatin genes."[3] | https://www.wikidoc.org/index.php/CST4 | |
f51b28a31cb2f19dfbadf1822bd5a6bf02a203d8 | wikidoc | CTCF | CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.
# Discovery
CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken c-myc gene. This protein was found to be binding to three regularly spaced repeats of the core sequence CCCTC and thus was named CCCTC binding factor.
# Function
The primary role of CTCF is thought to be in regulating the 3D structure of chromatin. CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina. It also defines the boundaries between active and heterochromatic DNA.
Since the 3D structure of DNA influences the regulation of genes, CTCF's activity influences the expression of genes. CTCF is thought to be a primary part of the activity of insulators, sequences that block the interaction between enhancers and promoters. CTCF binding has also been both shown to promote and repress gene expression. It is unknown whether CTCF affects gene expression solely through its looping activity, or if it has some other, unknown, activity.
# Observed activity
The binding of CTCF has been shown to have many effects, which are enumerated below. In each case, it is unknown if CTCF directly evokes the outcome or if it does so indirectly (in particular through its looping role).
## Transcriptional regulation
The protein CTCF plays a heavy role in repressing the insulin-like growth factor 2 gene, by binding to the H-19 imprinting control region (ICR) along with differentially-methylated region-1 (DMR1) and MAR3.
## Insulation
Binding of targeting sequence elements by CTCF can block the interaction between enhancers and promoters, therefore limiting the activity of enhancers to certain functional domains. Besides acting as enhancer blocking, CTCF can also act as a chromatin barrier by preventing the spread of heterochromatin structures.
## Regulation of chromatin architecture
CTCF physically binds to itself to form homodimers,
which causes the bound DNA to form loops. CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina. Using chromatin immuno-precipitation (ChIP) followed by ChIP-seq, it was found that CTCF localizes with cohesin genome-wide and affects gene regulatory mechanisms and the higher-order chromatin structure.
## Regulation of RNA splicing
CTCF binding has been shown to influence mRNA splicing.
# DNA binding
CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation). This sequence is defined by 11 zinc finger motifs in its structure. CTCF's binding is disrupted by CpG methylation of the DNA it binds to.
CTCF binds to an average of about 55,000 DNA sites in 19 diverse cell types (12 normal and 7 immortal) and in total 77,811 distinct binding sites across all 19 cell types.
CTCF’s ability to bind to multiple sequences through the usage of various combinations of its zinc fingers earned it the status of a “multivalent protein”. More than 30,000 CTCF binding sites have been characterized. The human genome contains anywhere between 15,000-40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation. In addition CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified. On the other hand, high-resolution nucleosome mapping studies have demonstrated that the differences of CTCF binding between cell types may be attributed to the differences in nucleosome locations.
# Protein-protein interactions
CTCF binds to itself to form homodimers. This activity is one possibility of the mechanism of its looping activity.
CTCF has also been shown to interact with Y box binding protein 1. CTCF also co-localizes with cohesin, which stabilizes the repressive loops organized by the CTCF. | CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene.[1][2] CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination[3] and regulation of chromatin architecture.[4]
# Discovery
CCCTC-Binding factor or CTCF was initially discovered as a negative regulator of the chicken c-myc gene. This protein was found to be binding to three regularly spaced repeats of the core sequence CCCTC and thus was named CCCTC binding factor.[5]
# Function
The primary role of CTCF is thought to be in regulating the 3D structure of chromatin.[4] CTCF binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures like the nuclear lamina.[6] It also defines the boundaries between active and heterochromatic DNA.
Since the 3D structure of DNA influences the regulation of genes, CTCF's activity influences the expression of genes. CTCF is thought to be a primary part of the activity of insulators, sequences that block the interaction between enhancers and promoters. CTCF binding has also been both shown to promote and repress gene expression. It is unknown whether CTCF affects gene expression solely through its looping activity, or if it has some other, unknown, activity.[4]
# Observed activity
The binding of CTCF has been shown to have many effects, which are enumerated below. In each case, it is unknown if CTCF directly evokes the outcome or if it does so indirectly (in particular through its looping role).
## Transcriptional regulation
The protein CTCF plays a heavy role in repressing the insulin-like growth factor 2 gene, by binding to the H-19 imprinting control region (ICR) along with differentially-methylated region-1 (DMR1) and MAR3.[7][8]
## Insulation
Binding of targeting sequence elements by CTCF can block the interaction between enhancers and promoters, therefore limiting the activity of enhancers to certain functional domains. Besides acting as enhancer blocking, CTCF can also act as a chromatin barrier[9] by preventing the spread of heterochromatin structures.
## Regulation of chromatin architecture
CTCF physically binds to itself to form homodimers,[10]
which causes the bound DNA to form loops.[11] CTCF also occurs frequently at the boundaries of sections of DNA bound to the nuclear lamina.[6] Using chromatin immuno-precipitation (ChIP) followed by ChIP-seq, it was found that CTCF localizes with cohesin genome-wide and affects gene regulatory mechanisms and the higher-order chromatin structure.[12]
## Regulation of RNA splicing
CTCF binding has been shown to influence mRNA splicing.[13]
# DNA binding
CTCF binds to the consensus sequence CCGCGNGGNGGCAG (in IUPAC notation).[14] This sequence is defined by 11 zinc finger motifs in its structure. CTCF's binding is disrupted by CpG methylation of the DNA it binds to.[15]
CTCF binds to an average of about 55,000 DNA sites in 19 diverse cell types (12 normal and 7 immortal) and in total 77,811 distinct binding sites across all 19 cell types.[16]
CTCF’s ability to bind to multiple sequences through the usage of various combinations of its zinc fingers earned it the status of a “multivalent protein”.[1] More than 30,000 CTCF binding sites have been characterized.[17] The human genome contains anywhere between 15,000-40,000 CTCF binding sites depending on cell type, suggesting a widespread role for CTCF in gene regulation.[9][14][18] In addition CTCF binding sites act as nucleosome positioning anchors so that, when used to align various genomic signals, multiple flanking nucleosomes can be readily identified.[9][19] On the other hand, high-resolution nucleosome mapping studies have demonstrated that the differences of CTCF binding between cell types may be attributed to the differences in nucleosome locations.[20]
# Protein-protein interactions
CTCF binds to itself to form homodimers.[10] This activity is one possibility of the mechanism of its looping activity.
CTCF has also been shown to interact with Y box binding protein 1.[21] CTCF also co-localizes with cohesin, which stabilizes the repressive loops organized by the CTCF.[22] | https://www.wikidoc.org/index.php/CTCF | |
be869a20415a040c6bd44090f9b37a2c946ccedf | wikidoc | CTGF | CTGF
CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.
# Structure and binding partners
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a cysteine knot motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including integrin receptors, cell surface heparan sulfate proteoglycans (HSPGs), LRPs, and TrkA. In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan, the TSR domain interacts with VEGF, and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins.
# Role in development
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe chondrodysplasia. Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane. CTGF is also important for pancreatic beta cell development, and is critical for normal ovarian follicle development and ovulation.
# Clinical significance
CTGF is associated with wound healing and virtually all fibrotic pathology. It is thought that CTGF can cooperate with TGF-β to induce sustained fibrosis and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions. Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung, and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis.
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, diabetic nephropathy and retinopathy, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, and pancreatic cancer. | CTGF
CTGF, also known as CCN2 or connective tissue growth factor,[1][2] is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein).[3][4][5] CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.[1][2][6]
# Structure and binding partners
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, the von Willebrand type C repeats (vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a cysteine knot motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including integrin receptors,[7][8][9] cell surface heparan sulfate proteoglycans (HSPGs),[10] LRPs,[11] and TrkA.[12] In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan,[13] the TSR domain interacts with VEGF,[14] and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins.[1][2]
# Role in development
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe chondrodysplasia.[15] Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane.[16] CTGF is also important for pancreatic beta cell development,[17] and is critical for normal ovarian follicle development and ovulation.[18]
# Clinical significance
CTGF is associated with wound healing and virtually all fibrotic pathology.[5][19] It is thought that CTGF can cooperate with TGF-β to induce sustained fibrosis[20] and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions.[19] Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung,[21] and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis.[22]
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, diabetic nephropathy[23] and retinopathy, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, and pancreatic cancer.[1] | https://www.wikidoc.org/index.php/CTGF | |
11152abadedc0c1bcee98e2d271e4043b21a4ad2 | wikidoc | CUL1 | CUL1
Cullin 1, also known as CUL1, is a human protein and gene from cullin family.
This protein plays an important role in protein degradation and protein ubiquitination.
This is an essential component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, it serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme.
This protein is a part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2. It also interacts with RNF7. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction negatively regulates the association with SKP1 in the SCF complex. Interacts with COPS2.
It is expressed in lung fibroblasts.
The protein is neddylated, which enhances the ubiquitination activity of SCF. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
# Further reading
- Kipreos ET, Lander LE, Wing JP, et al. (1996). "cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family". Cell. 85 (6): 829–39. doi:10.1016/S0092-8674(00)81267-2. PMID 8681378..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Lisztwan J, Marti A, Sutterlüty H, et al. (1998). "Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway". EMBO J. 17 (2): 368–83. doi:10.1093/emboj/17.2.368. PMC 1170388. PMID 9430629.
- Michel JJ, Xiong Y (1998). "Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A.". Cell Growth Differ. 9 (6): 435–49. PMID 9663463.
- Ng RW, Arooz T, Yam CH, et al. (1998). "Characterization of the cullin and F-box protein partner Skp1". FEBS Lett. 438 (3): 183–9. doi:10.1016/S0014-5793(98)01299-X. PMID 9827542.
- Winston JT, Strack P, Beer-Romero P, et al. (1999). "The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro". Genes Dev. 13 (3): 270–83. doi:10.1101/gad.13.3.270. PMC 316433. PMID 9990852.
- Tan P, Fuchs SY, Chen A, et al. (1999). "Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha". Mol. Cell. 3 (4): 527–33. doi:10.1016/S1097-2765(00)80481-5. PMID 10230406.
- Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Mol. Cell. 3 (4): 535–41. doi:10.1016/S1097-2765(00)80482-7. PMID 10230407.
- Marti A, Wirbelauer C, Scheffner M, Krek W (1999). "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nat. Cell Biol. 1 (1): 14–9. doi:10.1038/8984. PMID 10559858.
- Hori T, Osaka F, Chiba T, et al. (2000). "Covalent modification of all members of human cullin family proteins by NEDD8". Oncogene. 18 (48): 6829–34. doi:10.1038/sj.onc.1203093. PMID 10597293.
- Read MA, Brownell JE, Gladysheva TB, et al. (2000). "Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha". Mol. Cell. Biol. 20 (7): 2326–33. doi:10.1128/MCB.20.7.2326-2333.2000. PMC 85397. PMID 10713156.
- Morimoto M, Nishida T, Honda R, Yasuda H (2000). "Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1)". Biochem. Biophys. Res. Commun. 270 (3): 1093–6. doi:10.1006/bbrc.2000.2576. PMID 10772955.
- Swaroop M, Wang Y, Miller P, et al. (2000). "Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation". Oncogene. 19 (24): 2855–66. doi:10.1038/sj.onc.1203635. PMID 10851089.
- Furukawa M, Zhang Y, McCarville J, et al. (2000). "The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1". Mol. Cell. Biol. 20 (21): 8185–97. doi:10.1128/MCB.20.21.8185-8197.2000. PMC 86428. PMID 11027288.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Lyapina S, Cope G, Shevchenko A, et al. (2001). "Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome". Science. 292 (5520): 1382–5. doi:10.1126/science.1059780. PMID 11337588.
- Fukuchi M, Imamura T, Chiba T, et al. (2001). "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins". Mol. Biol. Cell. 12 (5): 1431–43. doi:10.1091/mbc.12.5.1431. PMC 34595. PMID 11359933.
- Senadheera D, Haataja L, Groffen J, Heisterkamp N (2001). "The small GTPase Rac interacts with ubiquitination complex proteins Cullin-1 and CDC23". Int. J. Mol. Med. 8 (2): 127–33. doi:10.3892/ijmm.8.2.127. PMID 11445862.
- Kiernan RE, Emiliani S, Nakayama K, et al. (2001). "Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome". Mol. Cell. Biol. 21 (23): 7956–70. doi:10.1128/MCB.21.23.7956-7970.2001. PMC 99964. PMID 11689688. | CUL1
Cullin 1, also known as CUL1, is a human protein and gene from cullin family.
This protein plays an important role in protein degradation and protein ubiquitination.
This is an essential component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, it serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme.
This protein is a part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2. It also interacts with RNF7. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction negatively regulates the association with SKP1 in the SCF complex. Interacts with COPS2.
It is expressed in lung fibroblasts.
The protein is neddylated, which enhances the ubiquitination activity of SCF. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
# Further reading
- Kipreos ET, Lander LE, Wing JP, et al. (1996). "cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family". Cell. 85 (6): 829–39. doi:10.1016/S0092-8674(00)81267-2. PMID 8681378..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Lisztwan J, Marti A, Sutterlüty H, et al. (1998). "Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway". EMBO J. 17 (2): 368–83. doi:10.1093/emboj/17.2.368. PMC 1170388. PMID 9430629.
- Michel JJ, Xiong Y (1998). "Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A.". Cell Growth Differ. 9 (6): 435–49. PMID 9663463.
- Ng RW, Arooz T, Yam CH, et al. (1998). "Characterization of the cullin and F-box protein partner Skp1". FEBS Lett. 438 (3): 183–9. doi:10.1016/S0014-5793(98)01299-X. PMID 9827542.
- Winston JT, Strack P, Beer-Romero P, et al. (1999). "The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro". Genes Dev. 13 (3): 270–83. doi:10.1101/gad.13.3.270. PMC 316433. PMID 9990852.
- Tan P, Fuchs SY, Chen A, et al. (1999). "Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha". Mol. Cell. 3 (4): 527–33. doi:10.1016/S1097-2765(00)80481-5. PMID 10230406.
- Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Mol. Cell. 3 (4): 535–41. doi:10.1016/S1097-2765(00)80482-7. PMID 10230407.
- Marti A, Wirbelauer C, Scheffner M, Krek W (1999). "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nat. Cell Biol. 1 (1): 14–9. doi:10.1038/8984. PMID 10559858.
- Hori T, Osaka F, Chiba T, et al. (2000). "Covalent modification of all members of human cullin family proteins by NEDD8". Oncogene. 18 (48): 6829–34. doi:10.1038/sj.onc.1203093. PMID 10597293.
- Read MA, Brownell JE, Gladysheva TB, et al. (2000). "Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha". Mol. Cell. Biol. 20 (7): 2326–33. doi:10.1128/MCB.20.7.2326-2333.2000. PMC 85397. PMID 10713156.
- Morimoto M, Nishida T, Honda R, Yasuda H (2000). "Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1)". Biochem. Biophys. Res. Commun. 270 (3): 1093–6. doi:10.1006/bbrc.2000.2576. PMID 10772955.
- Swaroop M, Wang Y, Miller P, et al. (2000). "Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation". Oncogene. 19 (24): 2855–66. doi:10.1038/sj.onc.1203635. PMID 10851089.
- Furukawa M, Zhang Y, McCarville J, et al. (2000). "The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1". Mol. Cell. Biol. 20 (21): 8185–97. doi:10.1128/MCB.20.21.8185-8197.2000. PMC 86428. PMID 11027288.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Lyapina S, Cope G, Shevchenko A, et al. (2001). "Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome". Science. 292 (5520): 1382–5. doi:10.1126/science.1059780. PMID 11337588.
- Fukuchi M, Imamura T, Chiba T, et al. (2001). "Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins". Mol. Biol. Cell. 12 (5): 1431–43. doi:10.1091/mbc.12.5.1431. PMC 34595. PMID 11359933.
- Senadheera D, Haataja L, Groffen J, Heisterkamp N (2001). "The small GTPase Rac interacts with ubiquitination complex proteins Cullin-1 and CDC23". Int. J. Mol. Med. 8 (2): 127–33. doi:10.3892/ijmm.8.2.127. PMID 11445862.
- Kiernan RE, Emiliani S, Nakayama K, et al. (2001). "Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome". Mol. Cell. Biol. 21 (23): 7956–70. doi:10.1128/MCB.21.23.7956-7970.2001. PMC 99964. PMID 11689688.
# External links
- Human CUL1 genome location and CUL1 gene details page in the UCSC Genome Browser. | https://www.wikidoc.org/index.php/CUL1 | |
89b336e7275ba99cf5a2ff7ee3fc45f6ae44af0e | wikidoc | CUL3 | CUL3
Cullin 3 is a protein that in humans is encoded by the CUL3 gene.
Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9). Cullin proteins are an evolutionarily conserved family of proteins throughout bacteria, plants and mammals.
# Protein function
Cullin 3 is a component of Cullin-RING E3 ubiquitin ligases complexes (CRLs) which are involved in protein ubiquitylation and represent a part of ubiquitin–proteasome system (UPS). Added ubiquitin moieties to the lysine residue by CRLs then target the protein for the proteasomal degradation. Cullin-RING E3 ubiquitin ligases are involved in many cellular processes responsible for cell cycle regulation, stress response, protein trafficking, signal transduction, DNA replication, transcription, protein quality control, circadian clock and development.
Deletion of CUL3 gene in mice causes embryonic lethality.
## Cullin 3-RING E3 ubiquitin ligases
Cullin 3-RING complex consists of Cullin 3 protein, RING-box protein 1 (RBX1), which recruits the ubiquitin-conjugating enzyme (E2), and a Bric-a-brac/Tramtrack/Broad (BTB) protein, a substrate recognition subunit. Cullin 3 protein is a core scaffold protein coordinating other components of the CRL complex. Cullin 3-RING complexes can also dimerise via their BTB domains which lead to creation of two substrate receptors and two catalytic RING domains.
Activation of the complex is regulated by the attachment of the ubiquitin-like protein NEDD8 to a conserved Lys residue in the cullin-homology domain, the process called neddylation. Deneddylation is conducted by an eight-subunit CSN complex which mediates the cleavage of the isopeptidic bond between NEDD8 and cullin protein. Another protein that interacts with cullin is CAND1 which binds to deneddylated form of cullin protein and disrupts the interaction between cullin and other subunits of the complex leading to inhibition of the E3 ubiquitin ligase activity. Therefore, dynamic neddylation and deneddylation of cullin is important for regulation of CRL complex activity.
# Clinical significance
## Familial hyperkalemic hypertension
Mutations in CUL3 gene are associated with Familial hyperkalemic hypertension disease. CRL complex containing Cullin 3 controls the activity of Na+ Cl- cotransporter (NCC) in the kidney by regulating the proteasomal degradation of With-no-lysine kinases WNK1 and WNK4. It was shown that mutations in CUL3 gene lead to WNKs accumulation. The abundance of these kinases leads to increased phosphorylation of NCC and its activation. As a consequence, Na+ reabsorption is increasing resulting in high blood pressure.
## Cancer
Deregulation of Cullin 3 expression level was observed in human cancers. It was shown that Cullin 3 is overexpressed in invasive cancers, and the protein expression level positively correlates with tumour stage. In breast cancer, the overexpression of Cullin 3 protein results in a decrease of Nrf2 protein level. This protein is a transcription factor regulating the expression of some detoxification and antioxidant enzymes. Another substrate of CRL complex is a candidate tumour suppressor protein RhoBTB2.
# Interactions
CUL3 has been shown to interact with:
- CAND1,
- Cyclin E1,
- DCUN1D1,
- KEAP1, and
- KLHL12. | CUL3
Cullin 3 is a protein that in humans is encoded by the CUL3 gene.[1][2][3]
Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9).[4] Cullin proteins are an evolutionarily conserved family of proteins throughout bacteria, plants and mammals.[5]
# Protein function
Cullin 3 is a component of Cullin-RING E3 ubiquitin ligases complexes (CRLs) which are involved in protein ubiquitylation and represent a part of ubiquitin–proteasome system (UPS). Added ubiquitin moieties to the lysine residue by CRLs then target the protein for the proteasomal degradation.[6] Cullin-RING E3 ubiquitin ligases are involved in many cellular processes responsible for cell cycle regulation, stress response, protein trafficking, signal transduction, DNA replication, transcription, protein quality control, circadian clock and development.[7][8]
Deletion of CUL3 gene in mice causes embryonic lethality.[9]
## Cullin 3-RING E3 ubiquitin ligases
Cullin 3-RING complex consists of Cullin 3 protein, RING-box protein 1 (RBX1), which recruits the ubiquitin-conjugating enzyme (E2), and a Bric-a-brac/Tramtrack/Broad (BTB) protein, a substrate recognition subunit. Cullin 3 protein is a core scaffold protein coordinating other components of the CRL complex.[10] Cullin 3-RING complexes can also dimerise via their BTB domains which lead to creation of two substrate receptors and two catalytic RING domains.[11]
Activation of the complex is regulated by the attachment of the ubiquitin-like protein NEDD8 to a conserved Lys residue in the cullin-homology domain, the process called neddylation.[12] Deneddylation is conducted by an eight-subunit CSN complex which mediates the cleavage of the isopeptidic bond between NEDD8 and cullin protein.[13] Another protein that interacts with cullin is CAND1 which binds to deneddylated form of cullin protein and disrupts the interaction between cullin and other subunits of the complex leading to inhibition of the E3 ubiquitin ligase activity.[14] Therefore, dynamic neddylation and deneddylation of cullin is important for regulation of CRL complex activity.[15]
# Clinical significance
## Familial hyperkalemic hypertension
Mutations in CUL3 gene are associated with Familial hyperkalemic hypertension disease. CRL complex containing Cullin 3 controls the activity of Na+ Cl- cotransporter (NCC) in the kidney by regulating the proteasomal degradation of With-no-lysine [K] kinases WNK1 and WNK4. It was shown that mutations in CUL3 gene lead to WNKs accumulation.[16] The abundance of these kinases leads to increased phosphorylation of NCC and its activation. As a consequence, Na+ reabsorption is increasing resulting in high blood pressure.[17]
## Cancer
Deregulation of Cullin 3 expression level was observed in human cancers. It was shown that Cullin 3 is overexpressed in invasive cancers, and the protein expression level positively correlates with tumour stage. In breast cancer, the overexpression of Cullin 3 protein results in a decrease of Nrf2 protein level. This protein is a transcription factor regulating the expression of some detoxification and antioxidant enzymes. Another substrate of CRL complex is a candidate tumour suppressor protein RhoBTB2.[18]
# Interactions
CUL3 has been shown to interact with:
- CAND1,[19]
- Cyclin E1,[20]
- DCUN1D1,[21]
- KEAP1,[22][23] and
- KLHL12.[24] | https://www.wikidoc.org/index.php/CUL3 | |
b6aab2b88ff9488194db332a575ce00a914e08f0 | wikidoc | CUL5 | CUL5
Cullin-5 is a protein that in humans is encoded by the CUL5 gene.
# Discovery
The mammalian gene product was originally discovered by expression cloning, due to the protein's ability to mobilize intracellular calcium in response to the peptide hormone arginine vasopressin. It was first titled VACM-1, for vasopressin-activated, calcium-mobilizing receptor. Since then, VACM-1 has been shown to be homologous to the Cullin family of proteins, and was subsequently dubbed cul5.
# Tissue distribution
Studies have shown that the cul5 protein is expressed at its highest levels in heart and skeletal tissue, and is specifically expressed in vascular endothelium and renal collecting tubules.
# Function
Cul5 inhibits cellular proliferation, potentially through its involvement in the SOCS/ BC-box/ eloBC/ cul5/ RING E3 ligase complex, which functions as part of the ubiquitin system for protein degradation.
One study have shown that Cul5 plays a role in Reelin signaling cascade, participating in the DAB1 degradation and thus ensuring the negative feedback mechanism of Reelin signaling during corticogenesis.
# Interactions
CUL5 has been shown to interact with RBX1. | CUL5
Cullin-5 is a protein that in humans is encoded by the CUL5 gene.[1][2][3]
# Discovery
The mammalian gene product was originally discovered by expression cloning, due to the protein's ability to mobilize intracellular calcium in response to the peptide hormone arginine vasopressin. It was first titled VACM-1, for vasopressin-activated, calcium-mobilizing receptor.[4] Since then, VACM-1 has been shown to be homologous to the Cullin family of proteins, and was subsequently dubbed cul5.
# Tissue distribution
Studies have shown that the cul5 protein is expressed at its highest levels in heart and skeletal tissue, and is specifically expressed in vascular endothelium and renal collecting tubules.[5]
# Function
Cul5 inhibits cellular proliferation, potentially through its involvement in the SOCS/ BC-box/ eloBC/ cul5/ RING E3 ligase complex, which functions as part of the ubiquitin system for protein degradation.[6]
One study have shown that Cul5 plays a role in Reelin signaling cascade, participating in the DAB1 degradation and thus ensuring the negative feedback mechanism of Reelin signaling during corticogenesis.[7]
# Interactions
CUL5 has been shown to interact with RBX1.[8][9] | https://www.wikidoc.org/index.php/CUL5 | |
3891ffa6f1cb738d95506ec42e991b53ba4a0b38 | wikidoc | CYBB | CYBB
Cytochrome b-245 heavy chain also known as cytochrome b(558) subunit beta or NADPH oxidase 2 or Nox2 is a protein that in humans is encoded by the CYBB gene. The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS).
# Function
Nox2, or Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.
Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558. After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane. Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH.
There has been recent evidence that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta.
It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment.
Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.
In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with Sepsis-associated encephalopathy (SAE).
Lastly, due to recent experiments, it seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases.
# Clinical significance
CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.
Since Nox2 was shown to play a huge part in determining the size of a myocardial infarction, this transforms the protein into a possible future target through drug medication due to its negative effect on myocardial reperfusion.
Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation.
Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area.
# Interactions
Nox2 has been shown to interact directly with podocyte TRPC6 channels. | CYBB
Cytochrome b-245 heavy chain also known as cytochrome b(558) subunit beta or NADPH oxidase 2 or Nox2 is a protein that in humans is encoded by the CYBB gene.[1] The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS).
# Function
Nox2, or Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.[1]
Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558.[2] After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane.[3] Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH.[4]
There has been recent evidence that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta.[5]
It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment.[6]
Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.[6]
In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with Sepsis-associated encephalopathy (SAE).[7]
Lastly, due to recent experiments, it seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases.[8]
# Clinical significance
CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. [4] In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.[1]
Since Nox2 was shown to play a huge part in determining the size of a myocardial infarction, this transforms the protein into a possible future target through drug medication due to its negative effect on myocardial reperfusion.[6]
Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation.[9]
Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area.[10]
# Interactions
Nox2 has been shown to interact directly with podocyte TRPC6 channels.[11] | https://www.wikidoc.org/index.php/CYBB | |
1e6325a11a63cd3034edda5598666d60af0c69f1 | wikidoc | CYC1 | CYC1
Cytochrome c1, heme protein, mitochondrial (CYC1), also known as UQCR4, MC3DN6, Complex III subunit 4, Cytochrome b-c1 complex subunit 4, or Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit is a protein that in humans is encoded by the CYC1 gene. CYC1 is a respiratory subunit of Ubiquinol Cytochrome c Reductase (complex III), which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear, type 6.
# Structure
CYC1 is located on the q arm of chromosome 8 in position 24.3 and has 8 exons. The CYC1 gene produces a 13.5 kDa protein composed of 130 amino acids. CYC1 belongs to the cytochrome c family. CYC1 is a phosphoprotein and subunit of Ubiquinol Cytochrome c Reductase that binds heme groups. It has helix, transit peptide, and transmembrane domains and contains 9 alpha helixes, 5 beta strands, and 3 turns. The transmembrane protein passes through the inner mitochondrial membrane once and the majority of the protein is found on the intermembrane side. CYC1 contains covalent heme bindings sites at positions 121 and 124 and heme axial ligand iron-metal binding sites at positions 125 and 244.
# Function
CYC1 encodes a protein that is located in the inner mitochondrial membrane and is part of Ubiquinol Cytochrome c Reductase (complex III). The encoded protein, CYC1, is a respiratory subunit of the cytochrome bc1 complex, which plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c.
# Species
CYC1 is a human gene that is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, zebrafish, fruit fly, mosquito, C. elegans, S. cerevisiae, K. lactis, E. gossypii, S. pombe, N. crassa, A. thaliana, rice, and frog. There are orthologs of CYC1 in 137 known organisms.
# Clinical Significance
Variants of CYC1 have been associated with mitochondrial complex III deficiency, nuclear, type 6. Mitochondrial complex III deficiency, nuclear, type 6 is an autosomal recessive disorder of the mitochondrial respiratory chain resulting from a defect in Ubiquinol Cytochrome c Reductase (complex III) that leads to reduced complex III activity. Clinical features tend to emerge in early childhood and include episodic acute lactic acidosis, ketoacidosis, insulin-responsive hyperglycemia, liver dysfunction, encephalopathy, and associated infection, although psychomotor development may remain normal. Pathogenic mutations have included c.288G>T, p.Trp96Cys and c.643C>T p.Leu215Phe.
# Interactions
CYC1 has 78 protein-protein interactions with 72 of them being co-complex interactions. CYC1 is one of 11 subunits of Ubiquinol Cytochrome c Reductase (b1-c complex) that includes the respiratory subunits cytochrome b, cytochrome c1 (CYC1), UQCRFS1, the core proteins UQCRC1 and UQCRC2, and the low-molecular weight proteins UQCRH, UQCRB, UQCRQ, UQCR10, UQCR11, as well as an additional cleavage product of UQCRFS1. Additionally, CCP1, CDKA-1, and CDKB1-1 have also been found to interact with CYC1. | CYC1
Cytochrome c1, heme protein, mitochondrial (CYC1), also known as UQCR4, MC3DN6, Complex III subunit 4, Cytochrome b-c1 complex subunit 4, or Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit is a protein that in humans is encoded by the CYC1 gene. CYC1 is a respiratory subunit of Ubiquinol Cytochrome c Reductase (complex III), which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear, type 6.[1][2][3]
# Structure
CYC1 is located on the q arm of chromosome 8 in position 24.3 and has 8 exons.[1] The CYC1 gene produces a 13.5 kDa protein composed of 130 amino acids.[4][5] CYC1 belongs to the cytochrome c family. CYC1 is a phosphoprotein and subunit of Ubiquinol Cytochrome c Reductase that binds heme groups. It has helix, transit peptide, and transmembrane domains and contains 9 alpha helixes, 5 beta strands, and 3 turns. The transmembrane protein passes through the inner mitochondrial membrane once and the majority of the protein is found on the intermembrane side. CYC1 contains covalent heme bindings sites at positions 121 and 124 and heme axial ligand iron-metal binding sites at positions 125 and 244.[2][3]
# Function
CYC1 encodes a protein that is located in the inner mitochondrial membrane and is part of Ubiquinol Cytochrome c Reductase (complex III). The encoded protein, CYC1, is a respiratory subunit of the cytochrome bc1 complex, which plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c.[1][2][3]
# Species
CYC1 is a human gene that is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, zebrafish, fruit fly, mosquito, C. elegans, S. cerevisiae, K. lactis, E. gossypii, S. pombe, N. crassa, A. thaliana, rice, and frog.[6] There are orthologs of CYC1 in 137 known organisms.[7]
# Clinical Significance
Variants of CYC1 have been associated with mitochondrial complex III deficiency, nuclear, type 6. Mitochondrial complex III deficiency, nuclear, type 6 is an autosomal recessive disorder of the mitochondrial respiratory chain resulting from a defect in Ubiquinol Cytochrome c Reductase (complex III) that leads to reduced complex III activity. Clinical features tend to emerge in early childhood and include episodic acute lactic acidosis, ketoacidosis, insulin-responsive hyperglycemia, liver dysfunction, encephalopathy, and associated infection, although psychomotor development may remain normal. Pathogenic mutations have included c.288G>T, p.Trp96Cys and c.643C>T p.Leu215Phe.[2][3][8]
# Interactions
CYC1 has 78 protein-protein interactions with 72 of them being co-complex interactions.[9] CYC1 is one of 11 subunits of Ubiquinol Cytochrome c Reductase (b1-c complex) that includes the respiratory subunits cytochrome b, cytochrome c1 (CYC1), UQCRFS1, the core proteins UQCRC1 and UQCRC2, and the low-molecular weight proteins UQCRH, UQCRB, UQCRQ, UQCR10, UQCR11, as well as an additional cleavage product of UQCRFS1.[2][3] Additionally, CCP1, CDKA-1, and CDKB1-1 have also been found to interact with CYC1.[9] | https://www.wikidoc.org/index.php/CYC1 | |
6596d4b004fdbb42cab89a6f21d945b806bd484b | wikidoc | EDTA | EDTA
# Overview
EDTA is a widely-used abbreviation for the chemical compound ethylenediaminetetraacetic acid (and many other names, see table). EDTA refers to the chelating agent with the formula (HO2CCH2)2NCH2CH2N(CH2CO2H)2. This amino acid is widely used to sequester di- and trivalent metal ions. EDTA binds to metals via four carboxylate and two amine groups. EDTA forms especially strong complexes with Mn(II), Cu(II), Fe(III), and Co(III).
# Synthesis
EDTA is mostly synthesised from 1,2-diaminoethane (ethylenediamine), formaldehyde (methanal), water and sodium cyanide. This yields the tetra sodium salt, which can be converted into the acidic forms by acidification.
Pioneering work on the development of EDTA was undertaken by Gerold Schwarzenbach in the 1940's.
# Nomenclature
## Popular vs. chemical nomenclature
To describe EDTA and its various protonated forms, chemists use a more cumbersome but more precise acronym that distinguishes between EDTA4−, the conjugate base that is the ligand, and H4EDTA, the precursor to that ligand.
## Synonyms
EDTA is also known as H4EDTA, diaminoethanetetraacetic acid, edetic acid, edetate, ethylenedinitrilotetraacetic acid, celon A, gluma cleanser, versene acid, nervanaid B avid, nullapon B acid, ethylene diamine tetracetic acid, tetrine acid, trilon BS, vinkeil 100, warkeelate acid, N,N'-1,2-ethanediylbis(N-(carboxymethyl)glycine)edetic acid, YD-30.
# Coordination chemistry principles
In coordination chemistry, H4EDTA is a member of the aminocarboxylate family of ligands that includes imidodiacetic acid ("H2IDA") and nitrilotriacetic acid ("H3NTA"). More specialized relatives include N,N'-ethylenediaminediacetic acid ("H2EDDA") and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid ("H4CyDTA"). These ligands are all formally derived from the amino acid glycine.
H4EDTA forms highly stable coordination compounds that are soluble in water. In these complexes, the ligand is usually either hexa- or pentadentate, EDTA4− or HEDTA3−, respectively. Such complexes are chiral, and − has been resolved into enantiomers.
# Uses
In 1999, the annual consumption of EDTA was equivalent to about 35,000 tons in Europe and 50,000 tons in the US. The most important uses are:
- Industrial cleaning: complexation of Ca2+ and Mg2+ ions, binding of heavy metals.
- Detergents: complexation of Ca2+ and Mg2+ (reduction of water hardness).
- Photography: use of Fe(III)EDTA as oxidizing agent.
- Pulp and paper industry: complexation of heavy metals during chlorine-free bleaching, stabilization of hydrogen peroxide.
- Textile industry: complexation of heavy metals, bleach stabilizer.
- Agrochemicals: Fe, Zn and Cu fertilizer, especially in calcareous soils.
- Hydroponics: iron-EDTA is used to solubilize iron in nutrient solutions.
More specialised uses of EDTA are:
- Food: added as preservative to prevent catalytic oxidation by metal ions or stabilizer and for iron fortification.
- Approved by the FDA as a preservative in packaged foods, vitamins, and baby food.
- Personal care: added to cosmetics to improve product stability.
- Oil production: added into the borehole to inhibit mineral precipitation.
- Dairy and beverage industry: cleaning milk stains from bottles.
- Flue gas cleaning: removal of NOx.
- Soft drinks containing ascorbic acid and sodium benzoate, to mitigate formation of benzene (a carcinogen).
- Recycling: recovery of lead from used lead acid batteries.
Medicine:
- EDTA is used in chelation therapy for acute hypercalcemia, mercury poisoning and lead poisoning.
- EDTA has been considered an alternative medicine for the treatment of atherosclerotic disease. Most recently, the Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled, 2x2 factorial trial, investigated the effect of EDTA-based infusions among stable post-myocardial infarction patients more than 50 years of age and with fairly normal kidney function. TACT revealed a modest decrease in major adverse cardiovascular events among enrolled patients randomized to EDTA-based infusions. When the pre-specified subgroup of patients with diabetes was analyzed, the decrease in adverse cardiovascular outcomes was even more robust. To read more about chelation therapy for cardiovascular disease click here.
- Combined with chromium, EDTA is used to evaluate kidney function. It is administered intravenously and its filtration into the urine is monitored. This method is considered the gold standard for evaluating glomerular filtration rate, Cr-EDTA's sole way out of the body is via glomerular filtration as it is not secreted or metabolised in any other way.
- Used as anticoagulant for blood samples
- In veterinary ophthalmology EDTA may be used as an anticollagenase to prevent the worsening of corneal ulcers in animals.
- Some laboratory studies also suggest that EDTA chelation may prevent collection of platelets ( which can otherwise lead to formation of blood clots and prevent blood flow) on the walls of blood vessels . These ideas are theoretical, however a major clinical study of the effects of EDTA on coronary arteries is currently (2008) proceeding
- Dentistry as a root canal irrigant to remove inorganic debris (smear layer) and prepare root canals for obturation.
In laboratory science, EDTA is also used for:
- Scavenging metal ions: in biochemistry and molecular biology, ion depletion is commonly used to inactivate metal-dependent enzymes which could damage DNA or proteins
- Complexometric titrations.
- Buffer solutions.
- Determination of water hardness.
- EDTA may be used as a masking agent to remove a metal ion which would interfere with the analysis of a second metal ion present
- An anticoagulant in medical and laboratory equipment.
- A preservative (usually to enhance the action of another preservative such as benzalkonium chloride or thiomersal) in ocular preparations and eyedrops. See "les conservateurs en opthalmologie" Doctors Patrice Vo Tan & Yves lachkar, Librarie Médicale Théa.
- A titrant used to determine nickel concentration in an electroless nickel plating bath.
- In metallography to remove staining due to etchants. Metal oxides are removed by gently swabbing with EDTA and rinsing in water.
- In cell cultures EDTA is used as a chelating agent which binds to calcium and prevents joining of cadherins between cells, preventing cell clumping. (often used in cell culture control).
# Toxicity
EDTA has been found to be both cytotoxic and weakly genotoxic in laboratory animals. Oral exposures have been noted to cause reproductive and developmental effects. The same study by Lanigan also found that both dermal exposure to EDTA in most cosmetic formulations and inhalation exposure to EDTA in aerosolized cosmetic formulations would produce systemic effects below those seen to be toxic in oral dosing studies.
# Environmental behavior
Widespread use of EDTA and its slow removal under many environmental conditions has led to its status as the most abundant anthropogenic compound in many European surface waters. River concentrations in Europe are reported as 10-100 μg/L, and lake concentrations are in the 1-10 μg/L range. EDTA concentrations in U.S. groundwater receiving wastewater effluent discharge have been reported at 1-72 μg/L, and EDTA was found to be an effective tracer for effluent, with higher concentrations of EDTA corresponding to a greater percentage of reclaimed water in drinking water production wells.
EDTA is not degraded or removed during conventional wastewater treatment. However, an adjustment of pH and sludge residence time can result in almost complete mineralization of EDTA. A variety of microorganisms have been isolated from water, soils, sediments and sludges that are able to completely mineralize EDTA as a sole source of carbon, nitrogen and energy.
Recalcitrant chelating agents such as EDTA are an environmental concern predominantly because of their persistence and strong metal chelating properties. The presence of chelating agents in high concentrations in wastewaters and surface waters has the potential to remobilize heavy metals from river sediments and treated sludges, although low and environmentally relevant concentrations seem to have only a very minor influence on metal solubility. Low concentrations of chelating agents may either stimulate or decrease plankton or algae growth, while high concentrations always inhibit activity. Chelating agents are nontoxic to many forms of life on acute exposure; the effects of longer-term low-level exposure are unknown. EDTA at elevated concentrations is toxic to bacteria due to chelation of metals in the outer membrane. EDTA ingestion at high concentrations by mammals changes excretion of metals and can affect cell membrane permeability.
# Methods of detection and analysis
The most sensitive method of detecting and measuring EDTA in biological samples is selected-reaction-monitoring capillary-electrophoresis mass-spectrometry (abbreviation SRM-CE/MS) which has a detection limit of 7.3 ng/mL in human plasma and a quantitation limit of 15 ng/mL. This method works with sample volumes as small as ~7-8 nL.
EDTA has also been measured in non-alcoholic beverages using high performance liquid chromatography (HPLC) which has a detection limit of 0.6 μg/mL and a quantitation limit of 2.0 μg/mL.
# Forensics
- EDTA played a role in the O.J. Simpson trial when one of the blood samples collected from Simpson's estate was found to contain traces of the compound. This was used by the defense to indicate that the sample had been planted from one of the vials collected during the investigation. Prosecution claimed EDTA might have appeared in the sample as a result of eating McDonald's foods (either through bloodstream or, more likely, via contamination of blood flowing over the hand used in grabbing the food). | EDTA
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
EDTA is a widely-used abbreviation for the chemical compound ethylenediaminetetraacetic acid (and many other names, see table). EDTA refers to the chelating agent with the formula (HO2CCH2)2NCH2CH2N(CH2CO2H)2. This amino acid is widely used to sequester di- and trivalent metal ions. EDTA binds to metals via four carboxylate and two amine groups. EDTA forms especially strong complexes with Mn(II), Cu(II), Fe(III), and Co(III).[1]
# Synthesis
EDTA is mostly synthesised from 1,2-diaminoethane (ethylenediamine), formaldehyde (methanal), water and sodium cyanide.[2] This yields the tetra sodium salt, which can be converted into the acidic forms by acidification.
Pioneering work on the development of EDTA was undertaken by Gerold Schwarzenbach in the 1940's.[3]
# Nomenclature
## Popular vs. chemical nomenclature
To describe EDTA and its various protonated forms, chemists use a more cumbersome but more precise acronym that distinguishes between EDTA4−, the conjugate base that is the ligand, and H4EDTA, the precursor to that ligand.
## Synonyms
EDTA is also known as H4EDTA, diaminoethanetetraacetic acid, edetic acid, edetate, ethylenedinitrilotetraacetic acid, celon A, gluma cleanser, versene acid, nervanaid B avid, nullapon B acid, ethylene diamine tetracetic acid, tetrine acid, trilon BS, vinkeil 100, warkeelate acid, N,N'-1,2-ethanediylbis(N-(carboxymethyl)glycine)edetic acid, YD-30.
# Coordination chemistry principles
In coordination chemistry, H4EDTA is a member of the aminocarboxylate family of ligands that includes imidodiacetic acid ("H2IDA") and nitrilotriacetic acid ("H3NTA"). More specialized relatives include N,N'-ethylenediaminediacetic acid ("H2EDDA") and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid ("H4CyDTA"). These ligands are all formally derived from the amino acid glycine.
H4EDTA forms highly stable coordination compounds that are soluble in water. In these complexes, the ligand is usually either hexa- or pentadentate, EDTA4− or HEDTA3−, respectively. Such complexes are chiral, and [Co(EDTA)]− has been resolved into enantiomers.[4]
# Uses
In 1999, the annual consumption of EDTA was equivalent to about 35,000 tons in Europe and 50,000 tons in the US.[citation needed] The most important uses are:
- Industrial cleaning: complexation of Ca2+ and Mg2+ ions, binding of heavy metals.
- Detergents: complexation of Ca2+ and Mg2+ (reduction of water hardness).
- Photography: use of Fe(III)EDTA as oxidizing agent.
- Pulp and paper industry: complexation of heavy metals during chlorine-free bleaching, stabilization of hydrogen peroxide.
- Textile industry: complexation of heavy metals, bleach stabilizer.
- Agrochemicals: Fe, Zn and Cu fertilizer, especially in calcareous soils.
- Hydroponics: iron-EDTA is used to solubilize iron in nutrient solutions.
More specialised uses of EDTA are:
- Food: added as preservative to prevent catalytic oxidation by metal ions or stabilizer and for iron fortification.[citation needed]
- Approved by the FDA as a preservative in packaged foods, vitamins, and baby food.
- Personal care: added to cosmetics to improve product stability.[5]
- Oil production: added into the borehole to inhibit mineral precipitation.[citation needed]
- Dairy and beverage industry: cleaning milk stains from bottles.[citation needed]
- Flue gas cleaning: removal of NOx.
- Soft drinks containing ascorbic acid and sodium benzoate, to mitigate formation of benzene (a carcinogen).[citation needed]
- Recycling: recovery of lead from used lead acid batteries.
Medicine:
- EDTA is used in chelation therapy for acute hypercalcemia, mercury poisoning and lead poisoning[6].
- EDTA has been considered an alternative medicine for the treatment of atherosclerotic disease. Most recently, the Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled, 2x2 factorial trial, investigated the effect of EDTA-based infusions among stable post-myocardial infarction patients more than 50 years of age and with fairly normal kidney function. TACT revealed a modest decrease in major adverse cardiovascular events among enrolled patients randomized to EDTA-based infusions. When the pre-specified subgroup of patients with diabetes was analyzed, the decrease in adverse cardiovascular outcomes was even more robust.[7] To read more about chelation therapy for cardiovascular disease click here.
- Combined with chromium, EDTA is used to evaluate kidney function. It is administered intravenously and its filtration into the urine is monitored. This method is considered the gold standard for evaluating glomerular filtration rate, Cr-EDTA's sole way out of the body is via glomerular filtration as it is not secreted or metabolised in any other way.
- Used as anticoagulant for blood samples
- In veterinary ophthalmology EDTA may be used as an anticollagenase to prevent the worsening of corneal ulcers in animals.
- Some laboratory studies also suggest that EDTA chelation may prevent collection of platelets ([or plaque] which can otherwise lead to formation of blood clots and prevent blood flow) on the walls of blood vessels [such as arteries]. These ideas are theoretical, however a major clinical study of the effects of EDTA on coronary arteries is currently (2008) proceeding [8] [3]
- Dentistry as a root canal irrigant to remove inorganic debris (smear layer) and prepare root canals for obturation.
In laboratory science, EDTA is also used for:
- Scavenging metal ions: in biochemistry and molecular biology, ion depletion is commonly used to inactivate metal-dependent enzymes which could damage DNA or proteins
- Complexometric titrations.
- Buffer solutions.
- Determination of water hardness.
- EDTA may be used as a masking agent to remove a metal ion which would interfere with the analysis of a second metal ion present
- An anticoagulant in medical and laboratory equipment.
- A preservative (usually to enhance the action of another preservative such as benzalkonium chloride or thiomersal) in ocular preparations and eyedrops. See "les conservateurs en opthalmologie" Doctors Patrice Vo Tan & Yves lachkar, Librarie Médicale Théa.
- A titrant used to determine nickel concentration in an electroless nickel plating bath.
- In metallography to remove staining due to etchants. Metal oxides are removed by gently swabbing with EDTA and rinsing in water.
- In cell cultures EDTA is used as a chelating agent which binds to calcium and prevents joining of cadherins between cells, preventing cell clumping. (often used in cell culture control).
# Toxicity
EDTA has been found to be both cytotoxic and weakly genotoxic in laboratory animals. Oral exposures have been noted to cause reproductive and developmental effects.[5] The same study by Lanigan[5] also found that both dermal exposure to EDTA in most cosmetic formulations and inhalation exposure to EDTA in aerosolized cosmetic formulations would produce systemic effects below those seen to be toxic in oral dosing studies.
# Environmental behavior
Widespread use of EDTA and its slow removal under many environmental conditions has led to its status as the most abundant anthropogenic compound in many European surface waters. River concentrations in Europe are reported as 10-100 μg/L, and lake concentrations are in the 1-10 μg/L range. EDTA concentrations in U.S. groundwater receiving wastewater effluent discharge have been reported at 1-72 μg/L, and EDTA was found to be an effective tracer for effluent, with higher concentrations of EDTA corresponding to a greater percentage of reclaimed water in drinking water production wells.
EDTA is not degraded or removed during conventional wastewater treatment. However, an adjustment of pH and sludge residence time can result in almost complete mineralization of EDTA. A variety of microorganisms have been isolated from water, soils, sediments and sludges that are able to completely mineralize EDTA as a sole source of carbon, nitrogen and energy.
Recalcitrant chelating agents such as EDTA are an environmental concern predominantly because of their persistence and strong metal chelating properties. The presence of chelating agents in high concentrations in wastewaters and surface waters has the potential to remobilize heavy metals from river sediments and treated sludges, although low and environmentally relevant concentrations seem to have only a very minor influence on metal solubility. Low concentrations of chelating agents may either stimulate or decrease plankton or algae growth, while high concentrations always inhibit activity. Chelating agents are nontoxic to many forms of life on acute exposure; the effects of longer-term low-level exposure are unknown. EDTA at elevated concentrations is toxic to bacteria due to chelation of metals in the outer membrane. EDTA ingestion at high concentrations by mammals changes excretion of metals and can affect cell membrane permeability.
# Methods of detection and analysis
The most sensitive method of detecting and measuring EDTA in biological samples is selected-reaction-monitoring capillary-electrophoresis mass-spectrometry (abbreviation SRM-CE/MS) which has a detection limit of 7.3 ng/mL in human plasma and a quantitation limit of 15 ng/mL.[9] This method works with sample volumes as small as ~7-8 nL.[9]
EDTA has also been measured in non-alcoholic beverages using high performance liquid chromatography (HPLC) which has a detection limit of 0.6 μg/mL and a quantitation limit of 2.0 μg/mL.[10][11]
# Forensics
- EDTA played a role in the O.J. Simpson trial when one of the blood samples collected from Simpson's estate was found to contain traces of the compound. This was used by the defense to indicate that the sample had been planted from one of the vials collected during the investigation. Prosecution claimed EDTA might have appeared in the sample as a result of eating McDonald's foods (either through bloodstream or, more likely, via contamination of blood flowing over the hand used in grabbing the food). | https://www.wikidoc.org/index.php/Calcium_Disodium_Versenate | |
cae968c3107978be8158e667993808c256790db7 | wikidoc | Iron | Iron
# Overview
Iron is a chemical element with symbol Fe (from Template:Lang-la) and atomic number 26. It is a metal in the first transition series. It is by mass the most common element on Earth, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust. Its abundance in rocky planets like Earth is due to its abundant production by fusion in high-mass stars, where the production of nickel-56 (which decays to the most common isotope of iron) is the last nuclear fusion reaction that is exothermic. Consequently, radioactive nickel is the last element to be produced before the violent collapse of a supernova scatters precursor radionuclide of iron into space.
Like other group 8 elements, iron exists in a wide range of oxidation states, −2 to +6, although +2 and +3 are the most common. Elemental iron occurs in meteoroids and other low oxygen environments, but is reactive to oxygen and water. Fresh iron surfaces appear lustrous silvery-gray, but oxidize in normal air to give hydrated iron oxides, commonly known as rust. Unlike many other metals which form passivating oxide layers, iron oxides occupy more volume than the metal and thus flake off, exposing fresh surfaces for corrosion.
Iron metal has been used since ancient times, although copper alloys, which have lower melting temperatures, were used even earlier in human history. Pure iron is relatively soft, but is unobtainable by smelting. The material is significantly hardened and strengthened by impurities, in particular carbon, from the smelting process. A certain proportion of carbon (between 0.002% and 2.1%) produces steel, which may be up to 1000 times harder than pure iron. Crude iron metal is produced in blast furnaces, where ore is reduced by coke to pig iron, which has a high carbon content. Further refinement with oxygen reduces the carbon content to the correct proportion to make steel. Steels and low carbon iron alloys along with other metals (alloy steels) are by far the most common metals in industrial use, due to their great range of desirable properties and the widespread abundance of iron-bearing rock.
Iron chemical compounds have many uses. Iron oxide mixed with aluminium powder can be ignited to create a thermite reaction, used in welding and purifying ores. Iron forms binary compounds with the halogens and the chalcogens. Among its organometallic compounds is ferrocene, the first sandwich compound discovered.
Iron plays an important role in biology, forming complexes with molecular oxygen in hemoglobin and myoglobin; these two compounds are common oxygen transport proteins in vertebrates. Iron is also the metal at the active site of many important redox enzymes dealing with cellular respiration and oxidation and reduction in plants and animals.
# Characteristics
## Mechanical properties
The mechanical properties of iron and its alloys can be evaluated using a variety of tests, including the Brinell test, Rockwell test and the Vickers hardness test. The data on iron is so consistent that it is often used to calibrate measurements or to compare tests. However, the mechanical properties of iron are significantly affected by the sample's purity: pure research-purpose single crystals of iron are actually softer than aluminium, and the purest industrially produced iron (99.99%) has a hardness of 20–30 Brinell. An increase in the carbon content of the iron will initially cause a significant corresponding increase in the iron's hardness and tensile strength. Maximum hardness of 65 Rc is achieved with a 0.6% carbon content, although this produces a metal with a low tensile strength.
Because of its significance for planetary cores, the physical properties of iron at high pressures and temperatures have also been studied extensively. The form of iron that is stable under standard conditions can be subjected to pressures up to ca. 15 GPa before transforming into a high-pressure form, as described in the next section.
## Phase diagram and allotropes
Iron represents an example of allotropy in a metal. There are at least four allotropic forms of iron, known as α, γ, δ, and ε; at very high pressures, some controversial experimental evidence exists for a phase β stable at very high pressures and temperatures.
As molten iron cools it crystallizes at 1538 °C into its δ allotrope, which has a body-centered cubic (bcc) crystal structure. As it cools further to 1394 °C, it changes to its γ-iron allotrope, a face-centered cubic (fcc) crystal structure, or austenite. At 912 °C and below, the crystal structure again becomes the bcc α-iron allotrope, or ferrite. Finally, at 770 °C (the Curie point, Tc) iron becomes magnetic. As the iron passes through the Curie temperature there is no change in crystalline structure, but there is a change in "domain structure", where each domain contains iron atoms with a particular electronic spin. In unmagnetized iron, all the electronic spins of the atoms within one domain are in the same direction, however, the neighboring domains point in various other directions and thus over all they cancel each other out. As a result, the iron is unmagnetized. In magnetized iron, the electronic spins of all the domains are aligned, so that the magnetic effects of neighboring domains reinforce each other. Although each domain contains billions of atoms, they are very small, about 10 micrometres across. At pressures above approximately 10 GPa and temperatures of a few hundred kelvin or less, α-iron changes into a hexagonal close-packed (hcp) structure, which is also known as ε-iron; the higher-temperature γ-phase also changes into ε-iron, but does so at higher pressure. The β-phase, if it exists, would appear at pressures of at least 50 GPa and temperatures of at least 1500 K; it has been thought to have an orthorhombic or a double hcp structure.
Iron is of greatest importance when mixed with certain other metals and with carbon to form steels. There are many types of steels, all with different properties, and an understanding of the properties of the allotropes of iron is key to the manufacture of good quality steels.
α-iron, also known as ferrite, is the most stable form of iron at normal temperatures. It is a fairly soft metal that can dissolve only a small concentration of carbon (no more than 0.021% by mass at 910 °C).
Above 912 °C and up to 1400 °C α-iron undergoes a phase transition from bcc to the fcc configuration of γ-iron, also called austenite. This is similarly soft and metallic but can dissolve considerably more carbon (as much as 2.04% by mass at 1146 °C). This form of iron is used in the type of stainless steel used for making cutlery, and hospital and food-service equipment.
The high-pressure phases of iron are important as endmember models for the solid parts of planetary cores. The inner core of the Earth is generally assumed to consist essentially of an iron-nickel alloy with ε (or β) structure.
The melting point of iron is experimentally well defined for pressures up to approximately 50 GPa. For higher pressures, different studies placed the γ-ε-liquid triple point at pressures differing by tens of gigapascals and yielded differences of more than 1000 K for the melting point. Generally speaking, molecular dynamics computer simulations of iron melting and shock wave experiments suggest higher melting points and a much steeper slope of the melting curve than static experiments carried out in diamond anvil cells.
## Isotopes
Naturally occurring iron consists of four stable isotopes: 5.845% of 54Fe, 91.754% of 56Fe, 2.119% of 57Fe and 0.282% of 58Fe. Of these stable isotopes, only 57Fe has a nuclear spin (−1⁄2). The nuclide 54Fe is predicted to undergo double beta decay, but this process had never been observed experimentally for these nuclei, and only the lower limit on the half-life was established: t1/2>3.1×1022 years.
60Fe is an extinct radionuclide of long half-life (2.6 million years). It is not found on Earth, but its ultimate decay product is the stable nuclide nickel-60.
Much of the past work on measuring the isotopic composition of Fe has focused on determining 60Fe variations due to processes accompanying nucleosynthesis (i.e., meteorite studies) and ore formation. In the last decade however, advances in mass spectrometry technology have allowed the detection and quantification of minute, naturally occurring variations in the ratios of the stable isotopes of iron. Much of this work has been driven by the Earth and planetary science communities, although applications to biological and industrial systems are beginning to emerge.
The most abundant iron isotope 56Fe is of particular interest to nuclear scientists as it represents the most common endpoint of nucleosynthesis. It is often cited, falsely, as the isotope of highest binding energy, a distinction which actually belongs to nickel-62. Since 56Ni is easily produced from lighter nuclei in the alpha process in nuclear reactions in supernovae (see silicon burning process), nickel-56 (14 alpha particles) is the endpoint of fusion chains inside extremely massive stars, since addition of another alpha particle would result in zinc-60, which requires a great deal more energy. This nickel-56, which has a half-life of about 6 days, is therefore made in quantity in these stars, but soon decays by two successive positron emissions within supernova decay products in the supernova remnant gas cloud, first to radioactive cobalt-56, and then stable iron-56. This last nuclide is therefore common in the universe, relative to other stable metals of approximately the same atomic weight.
In phases of the meteorites Semarkona and Chervony Kut a correlation between the concentration of 60Ni, the daughter product of 60Fe, and the abundance of the stable iron isotopes could be found which is evidence for the existence of 60Fe at the time of formation of the Solar System. Possibly the energy released by the decay of 60Fe contributed, together with the energy released by decay of the radionuclide 26Al, to the remelting and differentiation of asteroids after their formation 4.6 billion years ago. The abundance of 60Ni present in extraterrestrial material may also provide further insight into the origin of the Solar System and its early history.
Nuclei of iron atoms have some of the highest binding energies per nucleon, surpassed only by the nickel isotope 62Ni. This is formed by nuclear fusion in stars. Although a further tiny energy gain could be extracted by synthesizing 62Ni, conditions in stars are unsuitable for this process to be favored. Elemental distribution on Earth greatly favors iron over nickel, and also presumably in supernova element production.
Iron-56 is the heaviest stable isotope produced by the alpha process in stellar nucleosynthesis; elements heavier than iron and nickel require a supernova for their formation. Iron is the most abundant element in the core of red giants, and is the most abundant metal in iron meteorites and in the dense metal cores of planets such as Earth.
## Nucleosynthesis
Iron is created by extremely large stars with extremely hot (over 2.5 billion kelvin) cores through the silicon burning process. It is the heaviest stable element to be produced in this manner. The process starts with the second largest stable nucleus created by silicon burning, which is calcium. One stable nucleus of calcium fuses with one helium nucleus, creating unstable titanium. Before the titanium decays, it can fuse with another helium nucleus, creating unstable chromium. Before the chromium decays, it can fuse with another helium nucleus, creating unstable iron. Before the iron decays, it can fuse with another helium nucleus, creating unstable nickel-56. Any further fusion of nickel-56 consumes energy instead of producing energy, so after the production of nickel-56, the star does not produce the energy necessary to keep the core from collapsing. Eventually, the nickel-56 decays to unstable cobalt-56, which in turn decays to stable iron-56.
When the core of the star collapses, it creates a supernova. Supernovas also create additional forms of stable iron via the r-process.
## Occurrence
### Planetary occurrence
Iron is the sixth most abundant element in the Universe, and the most common refractory element. It is formed as the final exothermic stage of stellar nucleosynthesis, by silicon fusion in massive stars.
Metallic or native iron is rarely found on the surface of the Earth because it tends to oxidize, but its oxides are pervasive and represent the primary ores. While it makes up about 5% of the Earth's crust, both the Earth's inner and outer core are believed to consist largely of an iron-nickel alloy constituting 35% of the mass of the Earth as a whole. Iron is consequently the most abundant element on Earth, but only the fourth most abundant element in the Earth's crust. Most of the iron in the crust is found combined with oxygen as iron oxide minerals such as hematite (Fe2O3) and magnetite (Fe3O4). Large deposits of iron are found in banded iron formations. These geological formations are a type of rock consisting of repeated thin layers of iron oxides alternating with bands of iron-poor shale and chert. The banded iron formations were laid down in the time between 3,700 million years ago and 1,800 million years ago
About 1 in 20 meteorites consist of the unique iron-nickel minerals taenite (35–80% iron) and kamacite (90–95% iron). Although rare, iron meteorites are the main form of natural metallic iron on the Earth's surface.
The red color of the surface of Mars is derived from an iron oxide-rich regolith. This has been proven by Mössbauer spectroscopy.
### Stocks in use in society
According to the International Resource Panel's Metal Stocks in Society report, the global stock of iron in use in society is 2200 kg per capita. Much of this is in more-developed countries (7000–14000 kg per capita) rather than less-developed countries (2000 kg per capita).
# Chemistry and compounds
Iron forms compounds mainly in the +2 and +3 oxidation states. Traditionally, iron(II) compounds are called ferrous, and iron(III) compounds ferric. Iron also occurs in higher oxidation states, an example being the purple potassium ferrate (K2FeO4) which contains iron in its +6 oxidation state. Iron(IV) is a common intermediate in many biochemical oxidation reactions. Numerous organometallic compounds contain formal oxidation states of +1, 0, −1, or even −2. The oxidation states and other bonding properties are often assessed using the technique of Mössbauer spectroscopy.
There are also many mixed valence compounds that contain both iron(II) and iron(III) centers, such as magnetite and Prussian blue (Fe4(Fe6)3). The latter is used as the traditional "blue" in blueprints.
The iron compounds produced on the largest scale in industry are iron(II) sulfate (FeSO4·7H2O) and iron(III) chloride (FeCl3). The former is one of the most readily available sources of iron(II), but is less stable to aerial oxidation than Mohr's salt ((NH4)2Fe(SO4)2·6H2O). Iron(II) compounds tend to be oxidized to iron(III) compounds in the air.
Unlike many other metals, iron does not form amalgams with mercury. As a result, mercury is traded in standardized 76 pound flasks (34 kg) made of iron.
## Binary compounds
Iron reacts with oxygen in the air to form various oxide and hydroxide compounds; the most common are iron(II,III) oxide (Fe3O4), and iron(III) oxide (Fe2O3). Iron(II) oxide also exists, though it is unstable at room temperature. These oxides are the principal ores for the production of iron (see bloomery and blast furnace). They are also used in the production of ferrites, useful magnetic storage media in computers, and pigments. The best known sulfide is iron pyrite (FeS2), also known as fool's gold owing to its golden luster.
The binary ferrous and ferric halides are well known, with the exception of ferric iodide. The ferrous halides typically arise from treating iron metal with the corresponding binary halogen acid to give the corresponding hydrated salts.
Iron reacts with fluorine, chlorine, and bromine to give the corresponding ferric halides, ferric chloride being the most common:
## Coordination and organometallic compounds
Several cyanide complexes are known. The most famous example is Prussian blue, (Fe4(Fe6)3). Potassium ferricyanide and potassium ferrocyanide are also known; the formation of Prussian blue upon reaction with iron(II) and iron(III) respectively forms the basis of a "wet" chemical test. Prussian blue is also used as an antidote for thallium and radioactive caesium poisoning. Prussian blue can be used in laundry bluing to correct the yellowish tint left by ferrous salts in water.
Several carbonyl compounds of iron are known. The premier iron(0) compound is iron pentacarbonyl, Fe(CO)5, which is used to produce carbonyl iron powder, a highly reactive form of metallic iron. Thermolysis of iron pentacarbonyl gives the trinuclear cluster, triiron dodecacarbonyl. Collman's reagent, disodium tetracarbonylferrate, is a useful reagent for organic chemistry; it contains iron in the −2 oxidation state. Cyclopentadienyliron dicarbonyl dimer contains iron in the rare +1 oxidation state.
Ferrocene is an extremely stable complex. The first sandwich compound, it contains an iron(II) center with two cyclopentadienyl ligands bonded through all ten carbon atoms. This arrangement was a shocking novelty when it was first discovered, but the discovery of ferrocene has led to a new branch of organometallic chemistry. Ferrocene itself can be used as the backbone of a ligand, e.g. dppf. Ferrocene can itself be oxidized to the ferrocenium cation (Fc+); the ferrocene/ferrocenium couple is often used as a reference in electrochemistry.
# History
## Wrought iron
Iron objects of great age are much rarer than objects made of gold or silver due to the ease of corrosion of iron.Template:Sfn Beads made from meteoric iron in 3500 BCE or earlier were found in Gerzah, Egypt by G. A. Wainwright.Template:Sfn The beads contain 7.5% nickel, which is a signature of meteoric origin since iron found in the Earth's crust has very little to no nickel content. Meteoric iron was highly regarded due to its origin in the heavens and was often used to forge weapons and tools or whole specimens placed in churches.Template:Sfn Items that were likely made of iron by Egyptians date from 2500 to 3000 BCE.Template:Sfn Iron had a distinct advantage over bronze in warfare implements. It was much harder and more durable than bronze, although susceptible to rust. However, this is contested. Hittitologist Trevor Bryce argues that before advanced iron-working techniques were developed in India, meteoritic iron weapons used by early Mesopotamian armies had a tendency to shatter in combat, due to their high carbon content.
The first iron production started in the Middle Bronze Age but it took several centuries before iron displaced bronze. Samples of smelted iron from Asmar, Mesopotamia and Tall Chagar Bazaar in northern Syria were made sometime between 2700 and 3000 BCE.Template:Sfn The Hittites appear to be the first to understand the production of iron from its ores and regard it highly in their society. They began to smelt iron between 1500 and 1200 BCE and the practice spread to the rest of the Near East after their empire fell in 1180 BCE.Template:Sfn The subsequent period is called the Iron Age. Iron smelting, and thus the Iron Age, reached Europe two hundred years later and arrived in Zimbabwe, Africa by the 8th century.Template:Sfn In China, iron only appears circa 700–500 BCE. Iron smelting may have been introduced into China through Central Asia. The earliest evidence of the use of a blast furnace in China dates to the 1st century AD, and cupola furnaces were used as early as the Warring States period (403–221 BCE). Usage of the blast and cupola furnace remained widespread during the Song and Tang Dynasties.
Artifacts of smelted iron are found in India dating from 1800 to 1200 BCE, and in the Levant from about 1500 BCE (suggesting smelting in Anatolia or the Caucasus).
The Book of Genesis, fourth chapter, verse 22 contains the first mention of iron in the Old Testament of the Bible; "Tubal-cain, an instructor of every artificer in brass and iron."Template:Sfn Other verses allude to iron mining (Job 28:2), iron used as a stylus (Job 19:24), furnace (Deuteronomy 4:20), chariots (Joshua 17:16), nails (I Chron. 22:3), saws and axes (II Sam. 12:31), and cooking utensils (Ezekiel 4:3).Template:Sfn The metal is also mentioned in the New Testament, for example in Acts chapter 12 verse 10, " the iron gate that leadeth unto the city" of Antioch.Template:Sfn
Iron working was introduced to Greece in the late 11th century BCE. The spread of ironworking in Central and Western Europe is associated with Celtic expansion. According to Pliny the Elder, iron use was common in the Roman era.Template:Sfn The annual iron output of the Roman Empire is estimated at 84,750 t, while the similarly populous Han China produced around 5,000 t.
During the Industrial Revolution in Britain, Henry Cort began refining iron from pig iron to wrought iron (or bar iron) using innovative production systems. In 1783 he patented the puddling process for refining iron ore. It was later improved by others, including Joseph Hall.
## Cast iron
Cast iron was first produced in China during 5th century BCE, but was hardly in Europe until the medieval period. The earliest cast iron artifacts were discovered by archaeologists in what is now modern Luhe County, Jiangsu in China. Cast iron was used in ancient China for warfare, agriculture, and architecture. During the medieval period, means were found in Europe of producing wrought iron from cast iron (in this context known as pig iron) using finery forges. For all these processes, charcoal was required as fuel.
Medieval blast furnaces were about 10 feet (3.048 m) tall and made of fireproof brick; forced air was usually provided by hand-operated bellows. Modern blast furnaces have grown much bigger.
In 1709, Abraham Darby I established a coke-fired blast furnace to produce cast iron. The ensuing availability of inexpensive iron was one of the factors leading to the Industrial Revolution. Toward the end of the 18th century, cast iron began to replace wrought iron for certain purposes, because it was cheaper. Carbon content in iron wasn't implicated as the reason for the differences in properties of wrought iron, cast iron, and steel until the 18th century.Template:Sfn
Since iron was becoming cheaper and more plentiful, it also became a major structural material following the building of the innovative first iron bridge in 1778.
## Steel
Steel (with smaller carbon content than pig iron but more than wrought iron) was first produced in antiquity by using a bloomery. Blacksmiths in Luristan in western Iran were making good steel by 1000 BCE.Template:Sfn Then improved versions, Wootz steel by India and Damascus steel were developed around 300 BCE and 500 CE respectively. These methods were specialized, and so steel did not become a major commodity until the 1850s.
New methods of producing it by carburizing bars of iron in the cementation process were devised in the 17th century AD. In the Industrial Revolution, new methods of producing bar iron without charcoal were devised and these were later applied to produce steel. In the late 1850s, Henry Bessemer invented a new steelmaking process, involving blowing air through molten pig iron, to produce mild steel. This made steel much more economical, thereby leading to wrought iron no longer being produced.
## Foundations of modern chemistry
Antoine Lavoisier used the reaction of water steam with metallic iron inside an incandescent iron tube to produce hydrogen in his experiments leading to the demonstration of the mass conservation. Anaerobic oxidation of iron at high temperature can be schematically represented by the following reactions:
# Production of metallic iron
## Industrial routes
The production of iron or steel is a process consisting of two main stages, unless the desired product is cast iron. In the first stage pig iron is produced in a blast furnace. Alternatively, it may be directly reduced. The second stage, pig iron is converted to wrought iron or steel.
For a few limited purposes like electromagnet cores, pure iron is produced by electrolysis of a ferrous sulfate solution
### Blast furnace processing
Industrial iron production starts with iron ores, principally hematite, which has a nominal formula Fe2O3, and magnetite, with the formula Fe3O4. These ores are reduced to the metal in a carbothermic reaction, i.e. by treatment with carbon. The conversion is typically conducted in in a blast furnace at temperatures of about 2000 °C. Carbon is provided in the form of coke. The process also contains a flux such as limestone, which is used to remove silicaceous minerals in the ore, which would otherwise clog the furnace. The coke and limestone are fed into the top of the furnace, while a massive blast of heated air, about 4 tons per ton of iron, is forced into the furnace at the bottom.
In the furnace, the coke reacts with oxygen in the air blast to produce carbon monoxide:
The carbon monoxide reduces the iron ore (in the chemical equation below, hematite) to molten iron, becoming carbon dioxide in the process:
Some iron in the high-temperature lower region of the furnace reacts directly with the coke:
The flux present to melt impurities in the ore is principally limestone (calcium carbonate) and dolomite (calcium-magnesium carbonate). Other specialized fluxes are used depending on the details of the ore. In the heat of the furnace the limestone flux decomposes to calcium oxide (also known as quicklime):
Then calcium oxide combines with silicon dioxide to form a liquid slag.
The slag melts in the heat of the furnace. In the bottom of the furnace, the molten slag floats on top of the denser molten iron, and apertures in the side of the furnace are opened to run off the iron and the slag separately. The iron, once cooled, is called pig iron, while the slag can be used as a material in road construction or to improve mineral-poor soils for agriculture
### Direct iron reduction
Owing to environmental concerns, alternative methods of processing iron have been developed. "Direct iron reduction" reduces iron ore to a powder called "sponge" iron or "direct" iron that is suitable for steelmaking. Two main reactions comprise the direct reduction process:
Natural gas is partially oxidized (with heat and a catalyst):
These gases are then treated with iron ore in a furnace, producing solid sponge iron:
Silica is removed by adding a limestone flux as described above.
### Further processes
Pig iron is not pure iron, but has 4–5% carbon dissolved in it with small amounts of other impurities like sulfur, magnesium, phosphorus and manganese. As the carbon is the major impurity, the iron (pig iron) becomes brittle and hard. This form of iron, also known as cast iron, is used to cast articles in foundries such as stoves, pipes, radiators, lamp-posts and rails.
Alternatively pig iron may be made into steel (with up to about 2% carbon) or wrought iron (commercially pure iron). Various processes have been used for this, including finery forges, puddling furnaces, Bessemer converters, open hearth furnaces, basic oxygen furnaces, and electric arc furnaces. In all cases, the objective is to oxidize some or all of the carbon, together with other impurities. On the other hand, other metals may be added to make alloy steels.
Annealing involves the heating of a piece of steel to 700–800 °C for several hours and then gradual cooling. It makes the steel softer and more workable.
## Laboratory methods
Metallic iron is generally produced in the laboratory by two methods. One route is electrolysis of ferrous chloride onto an iron cathode. The second method involves reduction of iron oxides with hydrogen gas at about 500 °C.
# Applications
## Metallurgical
Iron is the most widely used of all the metals, accounting for 95% of worldwide metal production. Its low cost and high strength make it indispensable in engineering applications such as the construction of machinery and machine tools, automobiles, the hulls of large ships, and structural components for buildings. Since pure iron is quite soft, it is most commonly combined with alloying elements to make steel.
Commercially available iron is classified based on purity and the abundance of additives. Pig iron has 3.5–4.5% carbon and contains varying amounts of contaminants such as sulfur, silicon and phosphorus. Pig iron is not a saleable product, but rather an intermediate step in the production of cast iron and steel. The reduction of contaminants in pig iron that negatively affect material properties, such as sulfur and phosphorus, yields cast iron containing 2–4% carbon, 1–6% silicon, and small amounts of manganese. It has a melting point in the range of 1420–1470 K, which is lower than either of its two main components, and makes it the first product to be melted when carbon and iron are heated together. Its mechanical properties vary greatly and depend on the form the carbon takes in the alloy.
"White" cast irons contain their carbon in the form of cementite, or iron-carbide. This hard, brittle compound dominates the mechanical properties of white cast irons, rendering them hard, but unresistant to shock. The broken surface of a white cast iron is full of fine facets of the broken iron-carbide, a very pale, silvery, shiny material, hence the appellation.
In gray iron the carbon exists as separate, fine flakes of graphite, and also renders the material brittle due to the sharp edged flakes of graphite that produce stress concentration sites within the material. A newer variant of gray iron, referred to as ductile iron is specially treated with trace amounts of magnesium to alter the shape of graphite to spheroids, or nodules, reducing the stress concentrations and vastly increasing the toughness and strength of the material.
Wrought iron contains less than 0.25% carbon but large amounts of slag that give it a fibrous characteristic. It is a tough, malleable product, but not as fusible as pig iron. If honed to an edge, it loses it quickly. Wrought iron is characterized by the presence of fine fibers of slag entrapped within the metal. Wrought iron is more corrosion resistant than steel. It has been almost completely replaced by mild steel for traditional "wrought iron" products and blacksmithing.
Mild steel corrodes more readily than wrought iron, but is cheaper and more widely available. Carbon steel contains 2.0% carbon or less, with small amounts of manganese, sulfur, phosphorus, and silicon. Alloy steels contain varying amounts of carbon as well as other metals, such as chromium, vanadium, molybdenum, nickel, tungsten, etc. Their alloy content raises their cost, and so they are usually only employed for specialist uses. One common alloy steel, though, is stainless steel. Recent developments in ferrous metallurgy have produced a growing range of microalloyed steels, also termed 'HSLA' or high-strength, low alloy steels, containing tiny additions to produce high strengths and often spectacular toughness at minimal cost.
Apart from traditional applications, iron is also used for protection from ionizing radiation. Although it is lighter than another traditional protection material, lead, it is much stronger mechanically. The attenuation of radiation as a function of energy is shown in the graph.
The main disadvantage of iron and steel is that pure iron, and most of its alloys, suffer badly from rust if not protected in some way. Painting, galvanization, passivation, plastic coating and bluing are all used to protect iron from rust by excluding water and oxygen or by cathodic protection.
## Iron compounds
Although its metallurgical role is dominant in terms of amounts, iron compounds are pervasive in industry as well being used in many niche uses. Iron catalysts are traditionally used in the Haber-Bosch Process for the production of ammonia and the Fischer-Tropsch process for conversion of carbon monoxide to hydrocarbons for fuels and lubricants. Powdered iron in an acidic solvent was used in the Bechamp reduction the reduction of nitrobenzene to aniline.
Iron(III) chloride finds use in water purification and sewage treatment, in the dyeing of cloth, as a coloring agent in paints, as an additive in animal feed, and as an etchant for copper in the manufacture of printed circuit boards. It can also be dissolved in alcohol to form tincture of iron. The other halides tend to be limited to laboratory uses.
Iron(II) sulfate is used as a precursor to other iron compounds. It is also used to reduce chromate in cement. It is used to fortify foods and treat iron deficiency anemia. These are its main uses. Iron(III) sulfate is used in settling minute sewage particles in tank water. Iron(II) chloride is used as a reducing flocculating agent, in the formation of iron complexes and magnetic iron oxides, and as a reducing agent in organic synthesis.
# Biological role
Iron is abundant in biology. Iron-proteins are found in all living organisms, ranging from the evolutionarily primitive archaea to humans. The color of blood is due to the hemoglobin, an iron-containing protein. As illustrated by hemoglobin, iron is often bound to cofactors, e.g. in hemes. The iron-sulfur clusters are pervasive and include nitrogenase, the enzymes responsible for biological nitrogen fixation. Influential theories of evolution have invoked a role for iron sulfides in the iron-sulfur world theory.
Iron is a necessary trace element found in nearly all living organisms. Iron-containing enzymes and proteins, often containing heme prosthetic groups, participate in many biological oxidations and in transport. Examples of proteins found in higher organisms include hemoglobin, cytochrome (see high-valent iron), and catalase.
## Bioinorganic compounds
The most commonly known and studied "bioinorganic" compounds of iron (i.e., iron compounds used in biology) are the heme proteins: examples are hemoglobin, myoglobin, and cytochrome P450. These compounds can transport gases, build enzymes, and be used in transferring electrons. Metalloproteins are a group of proteins with metal ion cofactors. Some examples of iron metalloproteins are ferritin and rubredoxin. Many enzymes vital to life contain iron, such as catalase, lipoxygenases, and IRE-BP.
## Health and diet
Iron is pervasive, but particularly rich sources of dietary iron include red meat, lentils, beans, poultry, fish, leaf vegetables, watercress, tofu, chickpeas, black-eyed peas, blackstrap molasses, fortified bread, and fortified breakfast cereals. Iron in low amounts is found in molasses, teff, and farina. Iron in meat (heme iron) is more easily absorbed than iron in vegetables. Although some studies suggest that heme/hemoglobin from red meat has effects which may increase the likelihood of colorectal cancer, there is still some controversy, and even a few studies suggesting that there is not enough evidence to support such claims.
Iron provided by dietary supplements is often found as iron(II) fumarate, although iron sulfate is cheaper and is absorbed equally well. Elemental iron, or reduced iron, despite being absorbed at only one third to two thirds the efficiency (relative to iron sulfate), is often added to foods such as breakfast cereals or enriched wheat flour. Iron is most available to the body when chelated to amino acids and is also available for use as a common iron supplement. Often the amino acid chosen for this purpose is the cheapest and most common amino acid, glycine, leading to "iron glycinate" supplements. The Recommended Dietary Allowance (RDA) for iron varies considerably based on age, gender, and source of dietary iron (heme-based iron has higher bioavailability). Infants may require iron supplements if they are bottle-fed cow's milk. Blood donors and pregnant women are at special risk of low iron levels and are often advised to supplement their iron intake.
## Uptake and storage
Iron acquisition poses a problem for aerobic organisms, because ferric iron is poorly soluble near neutral pH. Thus, bacteria have evolved high-affinity sequestering agents called siderophores.
After uptake, in cells, iron storage is carefully regulated; "free" iron ions do not exist as such. A major component of this regulation is the protein transferrin, which binds iron ions absorbed from the duodenum and carries it in the blood to cells. In animals, plants, and fungi, iron is often the metal ion incorporated into the heme complex. Heme is an essential component of cytochrome proteins, which mediate redox reactions, and of oxygen carrier proteins such as hemoglobin, myoglobin, and leghemoglobin.
Inorganic iron contributes to redox reactions in the iron-sulfur clusters of many enzymes, such as nitrogenase (involved in the synthesis of ammonia from nitrogen and hydrogen) and hydrogenase. Non-heme iron proteins include the enzymes methane monooxygenase (oxidizes methane to methanol), ribonucleotide reductase (reduces ribose to deoxyribose; DNA biosynthesis), hemerythrins (oxygen transport and fixation in marine invertebrates) and purple acid phosphatase (hydrolysis of phosphate esters).
Iron distribution is heavily regulated in mammals, partly because iron ions have a high potential for biological toxicity.
## Regulation of uptake
Iron uptake is tightly regulated by the human body, which has no regulated physiological means of excreting iron. Only small amounts of iron are lost daily due to mucosal and skin epithelial cell sloughing, so control of iron levels is mostly by regulating uptake.
Regulation of iron uptake is impaired in some people as a result of a genetic defect that maps to the HLA-H gene region on chromosome 6. In these people, excessive iron intake can result in iron overload disorders, such as hemochromatosis. Many people have a genetic susceptibility to iron overload without realizing it or being aware of a family history of the problem. For this reason, it is advised that people do not take iron supplements unless they suffer from iron deficiency and have consulted a doctor. Hemochromatosis is estimated to cause disease in between 0.3 and 0.8% of Caucasians.
MRI finds that iron accumulates in the hippocampus of the brains of those with Alzheimer's disease and in the substantia nigra of those with Parkinson disease.
## Bioremediation
Iron-eating bacteria live in the hulls of sunken ships such as the Titanic. The acidophile bacteria Acidithiobacillus ferrooxidans, Leptospirillum ferrooxidans, Sulfolobus spp., Acidianus brierleyi and Sulfobacillus thermosulfidooxidans can oxidize ferrous iron enzymically. A sample of the fungus Aspergillus niger was found growing from gold mining solution, and was found to contain cyano metal complexes such as gold, silver, copper iron and zinc. The fungus also plays a role in the solubilization of heavy metal sulfides.
## Permeable reactive barriers
Zerovalent iron is the main reactive material for permeable reactive barriers.
# Toxicity
Large amounts of ingested iron can cause excessive levels of iron in the blood. High blood levels of free ferrous iron react with peroxides to produce free radicals, which are highly reactive and can damage DNA, proteins, lipids, and other cellular components. Thus, iron toxicity occurs when there is free iron in the cell, which generally occurs when iron levels exceed the capacity of transferrin to bind the iron. Damage to the cells of the gastrointestinal tract can also prevent them from regulating iron absorption leading to further increases in blood levels. Iron typically damages cells in the heart, liver and elsewhere, which can cause significant adverse effects, including coma, metabolic acidosis, shock, liver failure, coagulopathy, adult respiratory distress syndrome, long-term organ damage, and even death. Humans experience iron toxicity above 20 milligrams of iron for every kilogram of mass, and 60 milligrams per kilogram is considered a lethal dose. Overconsumption of iron, often the result of children eating large quantities of ferrous sulfate tablets intended for adult consumption, is one of the most common toxicological causes of death in children under six. The Dietary Reference Intake (DRI) lists the Tolerable Upper Intake Level (UL) for adults as 45 mg/day. For children under fourteen years old the UL is 40 mg/day.
The medical management of iron toxicity is complicated, and can include use of a specific chelating agent called deferoxamine to bind and expel excess iron from the body. | Iron
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Iron is a chemical element with symbol Fe (from Template:Lang-la) and atomic number 26. It is a metal in the first transition series.[1] It is by mass the most common element on Earth, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust. Its abundance in rocky planets like Earth is due to its abundant production by fusion in high-mass stars, where the production of nickel-56 (which decays to the most common isotope of iron) is the last nuclear fusion reaction that is exothermic. Consequently, radioactive nickel is the last element to be produced before the violent collapse of a supernova scatters precursor radionuclide of iron into space.
Like other group 8 elements, iron exists in a wide range of oxidation states, −2 to +6, although +2 and +3 are the most common. Elemental iron occurs in meteoroids and other low oxygen environments, but is reactive to oxygen and water. Fresh iron surfaces appear lustrous silvery-gray, but oxidize in normal air to give hydrated iron oxides, commonly known as rust. Unlike many other metals which form passivating oxide layers, iron oxides occupy more volume than the metal and thus flake off, exposing fresh surfaces for corrosion.
Iron metal has been used since ancient times, although copper alloys, which have lower melting temperatures, were used even earlier in human history. Pure iron is relatively soft, but is unobtainable by smelting. The material is significantly hardened and strengthened by impurities, in particular carbon, from the smelting process. A certain proportion of carbon (between 0.002% and 2.1%) produces steel, which may be up to 1000 times harder than pure iron. Crude iron metal is produced in blast furnaces, where ore is reduced by coke to pig iron, which has a high carbon content. Further refinement with oxygen reduces the carbon content to the correct proportion to make steel. Steels and low carbon iron alloys along with other metals (alloy steels) are by far the most common metals in industrial use, due to their great range of desirable properties and the widespread abundance of iron-bearing rock.
Iron chemical compounds have many uses. Iron oxide mixed with aluminium powder can be ignited to create a thermite reaction, used in welding and purifying ores. Iron forms binary compounds with the halogens and the chalcogens. Among its organometallic compounds is ferrocene, the first sandwich compound discovered.
Iron plays an important role in biology, forming complexes with molecular oxygen in hemoglobin and myoglobin; these two compounds are common oxygen transport proteins in vertebrates. Iron is also the metal at the active site of many important redox enzymes dealing with cellular respiration and oxidation and reduction in plants and animals.
# Characteristics
## Mechanical properties
The mechanical properties of iron and its alloys can be evaluated using a variety of tests, including the Brinell test, Rockwell test and the Vickers hardness test. The data on iron is so consistent that it is often used to calibrate measurements or to compare tests.[3][4] However, the mechanical properties of iron are significantly affected by the sample's purity: pure research-purpose single crystals of iron are actually softer than aluminium,[2] and the purest industrially produced iron (99.99%) has a hardness of 20–30 Brinell.[5] An increase in the carbon content of the iron will initially cause a significant corresponding increase in the iron's hardness and tensile strength. Maximum hardness of 65 Rc is achieved with a 0.6% carbon content, although this produces a metal with a low tensile strength.[6]
Because of its significance for planetary cores, the physical properties of iron at high pressures and temperatures have also been studied extensively. The form of iron that is stable under standard conditions can be subjected to pressures up to ca. 15 GPa before transforming into a high-pressure form, as described in the next section.
## Phase diagram and allotropes
Iron represents an example of allotropy in a metal. There are at least four allotropic forms of iron, known as α, γ, δ, and ε; at very high pressures, some controversial experimental evidence exists for a phase β stable at very high pressures and temperatures.[7]
As molten iron cools it crystallizes at 1538 °C into its δ allotrope, which has a body-centered cubic (bcc) crystal structure. As it cools further to 1394 °C, it changes to its γ-iron allotrope, a face-centered cubic (fcc) crystal structure, or austenite. At 912 °C and below, the crystal structure again becomes the bcc α-iron allotrope, or ferrite. Finally, at 770 °C (the Curie point, Tc) iron becomes magnetic. As the iron passes through the Curie temperature there is no change in crystalline structure, but there is a change in "domain structure", where each domain contains iron atoms with a particular electronic spin. In unmagnetized iron, all the electronic spins of the atoms within one domain are in the same direction, however, the neighboring domains point in various other directions and thus over all they cancel each other out. As a result, the iron is unmagnetized. In magnetized iron, the electronic spins of all the domains are aligned, so that the magnetic effects of neighboring domains reinforce each other. Although each domain contains billions of atoms, they are very small, about 10 micrometres across.[8] At pressures above approximately 10 GPa and temperatures of a few hundred kelvin or less, α-iron changes into a hexagonal close-packed (hcp) structure, which is also known as ε-iron; the higher-temperature γ-phase also changes into ε-iron, but does so at higher pressure. The β-phase, if it exists, would appear at pressures of at least 50 GPa and temperatures of at least 1500 K; it has been thought to have an orthorhombic or a double hcp structure.[7]
Iron is of greatest importance when mixed with certain other metals and with carbon to form steels. There are many types of steels, all with different properties, and an understanding of the properties of the allotropes of iron is key to the manufacture of good quality steels.
α-iron, also known as ferrite, is the most stable form of iron at normal temperatures. It is a fairly soft metal that can dissolve only a small concentration of carbon (no more than 0.021% by mass at 910 °C).[9]
Above 912 °C and up to 1400 °C α-iron undergoes a phase transition from bcc to the fcc configuration of γ-iron, also called austenite. This is similarly soft and metallic but can dissolve considerably more carbon (as much as 2.04% by mass at 1146 °C). This form of iron is used in the type of stainless steel used for making cutlery, and hospital and food-service equipment.[8]
The high-pressure phases of iron are important as endmember models for the solid parts of planetary cores. The inner core of the Earth is generally assumed to consist essentially of an iron-nickel alloy with ε (or β) structure.
The melting point of iron is experimentally well defined for pressures up to approximately 50 GPa. For higher pressures, different studies placed the γ-ε-liquid triple point at pressures differing by tens of gigapascals and yielded differences of more than 1000 K for the melting point. Generally speaking, molecular dynamics computer simulations of iron melting and shock wave experiments suggest higher melting points and a much steeper slope of the melting curve than static experiments carried out in diamond anvil cells.[10]
## Isotopes
Naturally occurring iron consists of four stable isotopes: 5.845% of 54Fe, 91.754% of 56Fe, 2.119% of 57Fe and 0.282% of 58Fe. Of these stable isotopes, only 57Fe has a nuclear spin (−1⁄2). The nuclide 54Fe is predicted to undergo double beta decay, but this process had never been observed experimentally for these nuclei, and only the lower limit on the half-life was established: t1/2>3.1×1022 years.
60Fe is an extinct radionuclide of long half-life (2.6 million years).[11] It is not found on Earth, but its ultimate decay product is the stable nuclide nickel-60.
Much of the past work on measuring the isotopic composition of Fe has focused on determining 60Fe variations due to processes accompanying nucleosynthesis (i.e., meteorite studies) and ore formation. In the last decade however, advances in mass spectrometry technology have allowed the detection and quantification of minute, naturally occurring variations in the ratios of the stable isotopes of iron. Much of this work has been driven by the Earth and planetary science communities, although applications to biological and industrial systems are beginning to emerge.[12]
The most abundant iron isotope 56Fe is of particular interest to nuclear scientists as it represents the most common endpoint of nucleosynthesis. It is often cited, falsely, as the isotope of highest binding energy, a distinction which actually belongs to nickel-62.[13] Since 56Ni is easily produced from lighter nuclei in the alpha process in nuclear reactions in supernovae (see silicon burning process), nickel-56 (14 alpha particles) is the endpoint of fusion chains inside extremely massive stars, since addition of another alpha particle would result in zinc-60, which requires a great deal more energy. This nickel-56, which has a half-life of about 6 days, is therefore made in quantity in these stars, but soon decays by two successive positron emissions within supernova decay products in the supernova remnant gas cloud, first to radioactive cobalt-56, and then stable iron-56. This last nuclide is therefore common in the universe, relative to other stable metals of approximately the same atomic weight.
In phases of the meteorites Semarkona and Chervony Kut a correlation between the concentration of 60Ni, the daughter product of 60Fe, and the abundance of the stable iron isotopes could be found which is evidence for the existence of 60Fe at the time of formation of the Solar System. Possibly the energy released by the decay of 60Fe contributed, together with the energy released by decay of the radionuclide 26Al, to the remelting and differentiation of asteroids after their formation 4.6 billion years ago. The abundance of 60Ni present in extraterrestrial material may also provide further insight into the origin of the Solar System and its early history.[14]
Nuclei of iron atoms have some of the highest binding energies per nucleon, surpassed only by the nickel isotope 62Ni. This is formed by nuclear fusion in stars. Although a further tiny energy gain could be extracted by synthesizing 62Ni, conditions in stars are unsuitable for this process to be favored. Elemental distribution on Earth greatly favors iron over nickel, and also presumably in supernova element production.[15]
Iron-56 is the heaviest stable isotope produced by the alpha process in stellar nucleosynthesis; elements heavier than iron and nickel require a supernova for their formation. Iron is the most abundant element in the core of red giants, and is the most abundant metal in iron meteorites and in the dense metal cores of planets such as Earth.
## Nucleosynthesis
Iron is created by extremely large stars with extremely hot (over 2.5 billion kelvin) cores through the silicon burning process. It is the heaviest stable element to be produced in this manner. The process starts with the second largest stable nucleus created by silicon burning, which is calcium. One stable nucleus of calcium fuses with one helium nucleus, creating unstable titanium. Before the titanium decays, it can fuse with another helium nucleus, creating unstable chromium. Before the chromium decays, it can fuse with another helium nucleus, creating unstable iron. Before the iron decays, it can fuse with another helium nucleus, creating unstable nickel-56. Any further fusion of nickel-56 consumes energy instead of producing energy, so after the production of nickel-56, the star does not produce the energy necessary to keep the core from collapsing. Eventually, the nickel-56 decays to unstable cobalt-56, which in turn decays to stable iron-56.
When the core of the star collapses, it creates a supernova. Supernovas also create additional forms of stable iron via the r-process.
## Occurrence
### Planetary occurrence
Iron is the sixth most abundant element in the Universe, and the most common refractory element.[16] It is formed as the final exothermic stage of stellar nucleosynthesis, by silicon fusion in massive stars.
Metallic or native iron is rarely found on the surface of the Earth because it tends to oxidize, but its oxides are pervasive and represent the primary ores. While it makes up about 5% of the Earth's crust, both the Earth's inner and outer core are believed to consist largely of an iron-nickel alloy constituting 35% of the mass of the Earth as a whole. Iron is consequently the most abundant element on Earth, but only the fourth most abundant element in the Earth's crust.[17][18] Most of the iron in the crust is found combined with oxygen as iron oxide minerals such as hematite (Fe2O3) and magnetite (Fe3O4). Large deposits of iron are found in banded iron formations. These geological formations are a type of rock consisting of repeated thin layers of iron oxides alternating with bands of iron-poor shale and chert. The banded iron formations were laid down in the time between 3,700 million years ago and 1,800 million years ago[19][20]
About 1 in 20 meteorites consist of the unique iron-nickel minerals taenite (35–80% iron) and kamacite (90–95% iron). Although rare, iron meteorites are the main form of natural metallic iron on the Earth's surface.[21]
The red color of the surface of Mars is derived from an iron oxide-rich regolith. This has been proven by Mössbauer spectroscopy.[22]
### Stocks in use in society
According to the International Resource Panel's Metal Stocks in Society report, the global stock of iron in use in society is 2200 kg per capita. Much of this is in more-developed countries (7000–14000 kg per capita) rather than less-developed countries (2000 kg per capita).
# Chemistry and compounds
Iron forms compounds mainly in the +2 and +3 oxidation states. Traditionally, iron(II) compounds are called ferrous, and iron(III) compounds ferric. Iron also occurs in higher oxidation states, an example being the purple potassium ferrate (K2FeO4) which contains iron in its +6 oxidation state. Iron(IV) is a common intermediate in many biochemical oxidation reactions.[23][24] Numerous organometallic compounds contain formal oxidation states of +1, 0, −1, or even −2. The oxidation states and other bonding properties are often assessed using the technique of Mössbauer spectroscopy.[25]
There are also many mixed valence compounds that contain both iron(II) and iron(III) centers, such as magnetite and Prussian blue (Fe4(Fe[CN]6)3).[24] The latter is used as the traditional "blue" in blueprints.[26]
The iron compounds produced on the largest scale in industry are iron(II) sulfate (FeSO4·7H2O) and iron(III) chloride (FeCl3). The former is one of the most readily available sources of iron(II), but is less stable to aerial oxidation than Mohr's salt ((NH4)2Fe(SO4)2·6H2O). Iron(II) compounds tend to be oxidized to iron(III) compounds in the air.[24]
Unlike many other metals, iron does not form amalgams with mercury. As a result, mercury is traded in standardized 76 pound flasks (34 kg) made of iron.[27]
## Binary compounds
Iron reacts with oxygen in the air to form various oxide and hydroxide compounds; the most common are iron(II,III) oxide (Fe3O4), and iron(III) oxide (Fe2O3). Iron(II) oxide also exists, though it is unstable at room temperature. These oxides are the principal ores for the production of iron (see bloomery and blast furnace). They are also used in the production of ferrites, useful magnetic storage media in computers, and pigments. The best known sulfide is iron pyrite (FeS2), also known as fool's gold owing to its golden luster.[24]
The binary ferrous and ferric halides are well known, with the exception of ferric iodide. The ferrous halides typically arise from treating iron metal with the corresponding binary halogen acid to give the corresponding hydrated salts.[24]
Iron reacts with fluorine, chlorine, and bromine to give the corresponding ferric halides, ferric chloride being the most common:
## Coordination and organometallic compounds
Several cyanide complexes are known. The most famous example is Prussian blue, (Fe4(Fe[CN]6)3). Potassium ferricyanide and potassium ferrocyanide are also known; the formation of Prussian blue upon reaction with iron(II) and iron(III) respectively forms the basis of a "wet" chemical test.[24] Prussian blue is also used as an antidote for thallium and radioactive caesium poisoning.[28][29] Prussian blue can be used in laundry bluing to correct the yellowish tint left by ferrous salts in water.
Several carbonyl compounds of iron are known. The premier iron(0) compound is iron pentacarbonyl, Fe(CO)5, which is used to produce carbonyl iron powder, a highly reactive form of metallic iron. Thermolysis of iron pentacarbonyl gives the trinuclear cluster, triiron dodecacarbonyl. Collman's reagent, disodium tetracarbonylferrate, is a useful reagent for organic chemistry; it contains iron in the −2 oxidation state. Cyclopentadienyliron dicarbonyl dimer contains iron in the rare +1 oxidation state.[30]
Ferrocene is an extremely stable complex. The first sandwich compound, it contains an iron(II) center with two cyclopentadienyl ligands bonded through all ten carbon atoms. This arrangement was a shocking novelty when it was first discovered,[31] but the discovery of ferrocene has led to a new branch of organometallic chemistry. Ferrocene itself can be used as the backbone of a ligand, e.g. dppf. Ferrocene can itself be oxidized to the ferrocenium cation (Fc+); the ferrocene/ferrocenium couple is often used as a reference in electrochemistry.[32]
# History
## Wrought iron
Iron objects of great age are much rarer than objects made of gold or silver due to the ease of corrosion of iron.Template:Sfn Beads made from meteoric iron in 3500 BCE or earlier were found in Gerzah, Egypt by G. A. Wainwright.Template:Sfn The beads contain 7.5% nickel, which is a signature of meteoric origin since iron found in the Earth's crust has very little to no nickel content. Meteoric iron was highly regarded due to its origin in the heavens and was often used to forge weapons and tools or whole specimens placed in churches.Template:Sfn Items that were likely made of iron by Egyptians date from 2500 to 3000 BCE.Template:Sfn Iron had a distinct advantage over bronze in warfare implements. It was much harder and more durable than bronze, although susceptible to rust. However, this is contested. Hittitologist Trevor Bryce argues that before advanced iron-working techniques were developed in India, meteoritic iron weapons used by early Mesopotamian armies had a tendency to shatter in combat, due to their high carbon content.[33]
The first iron production started in the Middle Bronze Age but it took several centuries before iron displaced bronze. Samples of smelted iron from Asmar, Mesopotamia and Tall Chagar Bazaar in northern Syria were made sometime between 2700 and 3000 BCE.Template:Sfn The Hittites appear to be the first to understand the production of iron from its ores and regard it highly in their society. They began to smelt iron between 1500 and 1200 BCE and the practice spread to the rest of the Near East after their empire fell in 1180 BCE.Template:Sfn The subsequent period is called the Iron Age. Iron smelting, and thus the Iron Age, reached Europe two hundred years later and arrived in Zimbabwe, Africa by the 8th century.Template:Sfn In China, iron only appears circa 700–500 BCE.[34] Iron smelting may have been introduced into China through Central Asia.[35] The earliest evidence of the use of a blast furnace in China dates to the 1st century AD,[36] and cupola furnaces were used as early as the Warring States period (403–221 BCE).[37] Usage of the blast and cupola furnace remained widespread during the Song and Tang Dynasties.[38]
Artifacts of smelted iron are found in India dating from 1800 to 1200 BCE,[39] and in the Levant from about 1500 BCE (suggesting smelting in Anatolia or the Caucasus).[40][41]
The Book of Genesis, fourth chapter, verse 22 contains the first mention of iron in the Old Testament of the Bible; "Tubal-cain, an instructor of every artificer in brass and iron."Template:Sfn Other verses allude to iron mining (Job 28:2), iron used as a stylus (Job 19:24), furnace (Deuteronomy 4:20), chariots (Joshua 17:16), nails (I Chron. 22:3), saws and axes (II Sam. 12:31), and cooking utensils (Ezekiel 4:3).Template:Sfn The metal is also mentioned in the New Testament, for example in Acts chapter 12 verse 10, "[Peter passed through] the iron gate that leadeth unto the city" of Antioch.Template:Sfn
Iron working was introduced to Greece in the late 11th century BCE.[42] The spread of ironworking in Central and Western Europe is associated with Celtic expansion. According to Pliny the Elder, iron use was common in the Roman era.Template:Sfn The annual iron output of the Roman Empire is estimated at 84,750 t,[43] while the similarly populous Han China produced around 5,000 t.[44]
During the Industrial Revolution in Britain, Henry Cort began refining iron from pig iron to wrought iron (or bar iron) using innovative production systems. In 1783 he patented the puddling process for refining iron ore. It was later improved by others, including Joseph Hall.
## Cast iron
Cast iron was first produced in China during 5th century BCE,[45] but was hardly in Europe until the medieval period.[46][47] The earliest cast iron artifacts were discovered by archaeologists in what is now modern Luhe County, Jiangsu in China. Cast iron was used in ancient China for warfare, agriculture, and architecture.[48] During the medieval period, means were found in Europe of producing wrought iron from cast iron (in this context known as pig iron) using finery forges. For all these processes, charcoal was required as fuel.
Medieval blast furnaces were about 10 feet (3.048 m) tall and made of fireproof brick; forced air was usually provided by hand-operated bellows.[47] Modern blast furnaces have grown much bigger.
In 1709, Abraham Darby I established a coke-fired blast furnace to produce cast iron. The ensuing availability of inexpensive iron was one of the factors leading to the Industrial Revolution. Toward the end of the 18th century, cast iron began to replace wrought iron for certain purposes, because it was cheaper. Carbon content in iron wasn't implicated as the reason for the differences in properties of wrought iron, cast iron, and steel until the 18th century.Template:Sfn
Since iron was becoming cheaper and more plentiful, it also became a major structural material following the building of the innovative first iron bridge in 1778.
## Steel
Steel (with smaller carbon content than pig iron but more than wrought iron) was first produced in antiquity by using a bloomery. Blacksmiths in Luristan in western Iran were making good steel by 1000 BCE.Template:Sfn Then improved versions, Wootz steel by India and Damascus steel were developed around 300 BCE and 500 CE respectively. These methods were specialized, and so steel did not become a major commodity until the 1850s.[49]
New methods of producing it by carburizing bars of iron in the cementation process were devised in the 17th century AD. In the Industrial Revolution, new methods of producing bar iron without charcoal were devised and these were later applied to produce steel. In the late 1850s, Henry Bessemer invented a new steelmaking process, involving blowing air through molten pig iron, to produce mild steel. This made steel much more economical, thereby leading to wrought iron no longer being produced.[50]
## Foundations of modern chemistry
Antoine Lavoisier used the reaction of water steam with metallic iron inside an incandescent iron tube to produce hydrogen in his experiments leading to the demonstration of the mass conservation. Anaerobic oxidation of iron at high temperature can be schematically represented by the following reactions:
# Production of metallic iron
## Industrial routes
The production of iron or steel is a process consisting of two main stages, unless the desired product is cast iron. In the first stage pig iron is produced in a blast furnace. Alternatively, it may be directly reduced. The second stage, pig iron is converted to wrought iron or steel.
For a few limited purposes like electromagnet cores, pure iron is produced by electrolysis of a ferrous sulfate solution
### Blast furnace processing
Industrial iron production starts with iron ores, principally hematite, which has a nominal formula Fe2O3, and magnetite, with the formula Fe3O4. These ores are reduced to the metal in a carbothermic reaction, i.e. by treatment with carbon. The conversion is typically conducted in in a blast furnace at temperatures of about 2000 °C. Carbon is provided in the form of coke. The process also contains a flux such as limestone, which is used to remove silicaceous minerals in the ore, which would otherwise clog the furnace. The coke and limestone are fed into the top of the furnace, while a massive blast of heated air, about 4 tons per ton of iron,[47] is forced into the furnace at the bottom.
In the furnace, the coke reacts with oxygen in the air blast to produce carbon monoxide:
The carbon monoxide reduces the iron ore (in the chemical equation below, hematite) to molten iron, becoming carbon dioxide in the process:
Some iron in the high-temperature lower region of the furnace reacts directly with the coke:
The flux present to melt impurities in the ore is principally limestone (calcium carbonate) and dolomite (calcium-magnesium carbonate). Other specialized fluxes are used depending on the details of the ore. In the heat of the furnace the limestone flux decomposes to calcium oxide (also known as quicklime):
Then calcium oxide combines with silicon dioxide to form a liquid slag.
The slag melts in the heat of the furnace. In the bottom of the furnace, the molten slag floats on top of the denser molten iron, and apertures in the side of the furnace are opened to run off the iron and the slag separately. The iron, once cooled, is called pig iron, while the slag can be used as a material in road construction or to improve mineral-poor soils for agriculture[47]
### Direct iron reduction
Owing to environmental concerns, alternative methods of processing iron have been developed. "Direct iron reduction" reduces iron ore to a powder called "sponge" iron or "direct" iron that is suitable for steelmaking.[47] Two main reactions comprise the direct reduction process:
Natural gas is partially oxidized (with heat and a catalyst):
These gases are then treated with iron ore in a furnace, producing solid sponge iron:
Silica is removed by adding a limestone flux as described above.
### Further processes
Pig iron is not pure iron, but has 4–5% carbon dissolved in it with small amounts of other impurities like sulfur, magnesium, phosphorus and manganese. As the carbon is the major impurity, the iron (pig iron) becomes brittle and hard. This form of iron, also known as cast iron, is used to cast articles in foundries such as stoves, pipes, radiators, lamp-posts and rails.
Alternatively pig iron may be made into steel (with up to about 2% carbon) or wrought iron (commercially pure iron). Various processes have been used for this, including finery forges, puddling furnaces, Bessemer converters, open hearth furnaces, basic oxygen furnaces, and electric arc furnaces. In all cases, the objective is to oxidize some or all of the carbon, together with other impurities. On the other hand, other metals may be added to make alloy steels.
Annealing involves the heating of a piece of steel to 700–800 °C for several hours and then gradual cooling. It makes the steel softer and more workable.
## Laboratory methods
Metallic iron is generally produced in the laboratory by two methods. One route is electrolysis of ferrous chloride onto an iron cathode. The second method involves reduction of iron oxides with hydrogen gas at about 500 °C.[51]
# Applications
## Metallurgical
Iron is the most widely used of all the metals, accounting for 95% of worldwide metal production.[citation needed] Its low cost and high strength make it indispensable in engineering applications such as the construction of machinery and machine tools, automobiles, the hulls of large ships, and structural components for buildings. Since pure iron is quite soft, it is most commonly combined with alloying elements to make steel.
Commercially available iron is classified based on purity and the abundance of additives. Pig iron has 3.5–4.5% carbon[53] and contains varying amounts of contaminants such as sulfur, silicon and phosphorus. Pig iron is not a saleable product, but rather an intermediate step in the production of cast iron and steel. The reduction of contaminants in pig iron that negatively affect material properties, such as sulfur and phosphorus, yields cast iron containing 2–4% carbon, 1–6% silicon, and small amounts of manganese. It has a melting point in the range of 1420–1470 K, which is lower than either of its two main components, and makes it the first product to be melted when carbon and iron are heated together. Its mechanical properties vary greatly and depend on the form the carbon takes in the alloy.
"White" cast irons contain their carbon in the form of cementite, or iron-carbide. This hard, brittle compound dominates the mechanical properties of white cast irons, rendering them hard, but unresistant to shock. The broken surface of a white cast iron is full of fine facets of the broken iron-carbide, a very pale, silvery, shiny material, hence the appellation.
In gray iron the carbon exists as separate, fine flakes of graphite, and also renders the material brittle due to the sharp edged flakes of graphite that produce stress concentration sites within the material. A newer variant of gray iron, referred to as ductile iron is specially treated with trace amounts of magnesium to alter the shape of graphite to spheroids, or nodules, reducing the stress concentrations and vastly increasing the toughness and strength of the material.
Wrought iron contains less than 0.25% carbon but large amounts of slag that give it a fibrous characteristic.[53] It is a tough, malleable product, but not as fusible as pig iron. If honed to an edge, it loses it quickly. Wrought iron is characterized by the presence of fine fibers of slag entrapped within the metal. Wrought iron is more corrosion resistant than steel. It has been almost completely replaced by mild steel for traditional "wrought iron" products and blacksmithing.
Mild steel corrodes more readily than wrought iron, but is cheaper and more widely available. Carbon steel contains 2.0% carbon or less,[54] with small amounts of manganese, sulfur, phosphorus, and silicon. Alloy steels contain varying amounts of carbon as well as other metals, such as chromium, vanadium, molybdenum, nickel, tungsten, etc. Their alloy content raises their cost, and so they are usually only employed for specialist uses. One common alloy steel, though, is stainless steel. Recent developments in ferrous metallurgy have produced a growing range of microalloyed steels, also termed 'HSLA' or high-strength, low alloy steels, containing tiny additions to produce high strengths and often spectacular toughness at minimal cost.
Apart from traditional applications, iron is also used for protection from ionizing radiation. Although it is lighter than another traditional protection material, lead, it is much stronger mechanically. The attenuation of radiation as a function of energy is shown in the graph.
The main disadvantage of iron and steel is that pure iron, and most of its alloys, suffer badly from rust if not protected in some way. Painting, galvanization, passivation, plastic coating and bluing are all used to protect iron from rust by excluding water and oxygen or by cathodic protection.
## Iron compounds
Although its metallurgical role is dominant in terms of amounts, iron compounds are pervasive in industry as well being used in many niche uses. Iron catalysts are traditionally used in the Haber-Bosch Process for the production of ammonia and the Fischer-Tropsch process for conversion of carbon monoxide to hydrocarbons for fuels and lubricants.[55] Powdered iron in an acidic solvent was used in the Bechamp reduction the reduction of nitrobenzene to aniline.[56]
Iron(III) chloride finds use in water purification and sewage treatment, in the dyeing of cloth, as a coloring agent in paints, as an additive in animal feed, and as an etchant for copper in the manufacture of printed circuit boards.[57] It can also be dissolved in alcohol to form tincture of iron. The other halides tend to be limited to laboratory uses.
Iron(II) sulfate is used as a precursor to other iron compounds. It is also used to reduce chromate in cement. It is used to fortify foods and treat iron deficiency anemia. These are its main uses. Iron(III) sulfate is used in settling minute sewage particles in tank water. Iron(II) chloride is used as a reducing flocculating agent, in the formation of iron complexes and magnetic iron oxides, and as a reducing agent in organic synthesis.
# Biological role
Iron is abundant in biology.[58][59] Iron-proteins are found in all living organisms, ranging from the evolutionarily primitive archaea to humans. The color of blood is due to the hemoglobin, an iron-containing protein. As illustrated by hemoglobin, iron is often bound to cofactors, e.g. in hemes. The iron-sulfur clusters are pervasive and include nitrogenase, the enzymes responsible for biological nitrogen fixation. Influential theories of evolution have invoked a role for iron sulfides in the iron-sulfur world theory.
Iron is a necessary trace element found in nearly all living organisms. Iron-containing enzymes and proteins, often containing heme prosthetic groups, participate in many biological oxidations and in transport. Examples of proteins found in higher organisms include hemoglobin, cytochrome (see high-valent iron), and catalase.[60]
## Bioinorganic compounds
The most commonly known and studied "bioinorganic" compounds of iron (i.e., iron compounds used in biology) are the heme proteins: examples are hemoglobin, myoglobin, and cytochrome P450. These compounds can transport gases, build enzymes, and be used in transferring electrons. Metalloproteins are a group of proteins with metal ion cofactors. Some examples of iron metalloproteins are ferritin and rubredoxin. Many enzymes vital to life contain iron, such as catalase, lipoxygenases, and IRE-BP.
## Health and diet
Iron is pervasive, but particularly rich sources of dietary iron include red meat, lentils, beans, poultry, fish, leaf vegetables, watercress, tofu, chickpeas, black-eyed peas, blackstrap molasses, fortified bread, and fortified breakfast cereals. Iron in low amounts is found in molasses, teff, and farina. Iron in meat (heme iron) is more easily absorbed than iron in vegetables.[61] Although some studies suggest that heme/hemoglobin from red meat has effects which may increase the likelihood of colorectal cancer,[62][63] there is still some controversy,[64] and even a few studies suggesting that there is not enough evidence to support such claims.[65]
Iron provided by dietary supplements is often found as iron(II) fumarate, although iron sulfate is cheaper and is absorbed equally well. Elemental iron, or reduced iron, despite being absorbed at only one third to two thirds the efficiency (relative to iron sulfate),[66] is often added to foods such as breakfast cereals or enriched wheat flour. Iron is most available to the body when chelated to amino acids[67] and is also available for use as a common iron supplement. Often the amino acid chosen for this purpose is the cheapest and most common amino acid, glycine, leading to "iron glycinate" supplements.[68] The Recommended Dietary Allowance (RDA) for iron varies considerably based on age, gender, and source of dietary iron (heme-based iron has higher bioavailability).[69] Infants may require iron supplements if they are bottle-fed cow's milk.[70] Blood donors and pregnant women are at special risk of low iron levels and are often advised to supplement their iron intake.[71]
## Uptake and storage
Iron acquisition poses a problem for aerobic organisms, because ferric iron is poorly soluble near neutral pH. Thus, bacteria have evolved high-affinity sequestering agents called siderophores.[72][73][74]
After uptake, in cells, iron storage is carefully regulated; "free" iron ions do not exist as such. A major component of this regulation is the protein transferrin, which binds iron ions absorbed from the duodenum and carries it in the blood to cells.[75] In animals, plants, and fungi, iron is often the metal ion incorporated into the heme complex. Heme is an essential component of cytochrome proteins, which mediate redox reactions, and of oxygen carrier proteins such as hemoglobin, myoglobin, and leghemoglobin.
Inorganic iron contributes to redox reactions in the iron-sulfur clusters of many enzymes, such as nitrogenase (involved in the synthesis of ammonia from nitrogen and hydrogen) and hydrogenase. Non-heme iron proteins include the enzymes methane monooxygenase (oxidizes methane to methanol), ribonucleotide reductase (reduces ribose to deoxyribose; DNA biosynthesis), hemerythrins (oxygen transport and fixation in marine invertebrates) and purple acid phosphatase (hydrolysis of phosphate esters).
Iron distribution is heavily regulated in mammals, partly because iron ions have a high potential for biological toxicity.[76]
## Regulation of uptake
Iron uptake is tightly regulated by the human body, which has no regulated physiological means of excreting iron. Only small amounts of iron are lost daily due to mucosal and skin epithelial cell sloughing, so control of iron levels is mostly by regulating uptake.[77]
Regulation of iron uptake is impaired in some people as a result of a genetic defect that maps to the HLA-H gene region on chromosome 6. In these people, excessive iron intake can result in iron overload disorders, such as hemochromatosis. Many people have a genetic susceptibility to iron overload without realizing it or being aware of a family history of the problem. For this reason, it is advised that people do not take iron supplements unless they suffer from iron deficiency and have consulted a doctor. Hemochromatosis is estimated to cause disease in between 0.3 and 0.8% of Caucasians.[78]
MRI finds that iron accumulates in the hippocampus of the brains of those with Alzheimer's disease and in the substantia nigra of those with Parkinson disease.[79]
## Bioremediation
Iron-eating bacteria live in the hulls of sunken ships such as the Titanic.[80] The acidophile bacteria Acidithiobacillus ferrooxidans, Leptospirillum ferrooxidans, Sulfolobus spp., Acidianus brierleyi and Sulfobacillus thermosulfidooxidans can oxidize ferrous iron enzymically.[81] A sample of the fungus Aspergillus niger was found growing from gold mining solution, and was found to contain cyano metal complexes such as gold, silver, copper iron and zinc. The fungus also plays a role in the solubilization of heavy metal sulfides.[82]
## Permeable reactive barriers
Zerovalent iron is the main reactive material for permeable reactive barriers.[83]
# Toxicity
Template:NFPA 704
Large amounts of ingested iron can cause excessive levels of iron in the blood. High blood levels of free ferrous iron react with peroxides to produce free radicals, which are highly reactive and can damage DNA, proteins, lipids, and other cellular components. Thus, iron toxicity occurs when there is free iron in the cell, which generally occurs when iron levels exceed the capacity of transferrin to bind the iron. Damage to the cells of the gastrointestinal tract can also prevent them from regulating iron absorption leading to further increases in blood levels. Iron typically damages cells in the heart, liver and elsewhere, which can cause significant adverse effects, including coma, metabolic acidosis, shock, liver failure, coagulopathy, adult respiratory distress syndrome, long-term organ damage, and even death.[84] Humans experience iron toxicity above 20 milligrams of iron for every kilogram of mass, and 60 milligrams per kilogram is considered a lethal dose.[85] Overconsumption of iron, often the result of children eating large quantities of ferrous sulfate tablets intended for adult consumption, is one of the most common toxicological causes of death in children under six.[85] The Dietary Reference Intake (DRI) lists the Tolerable Upper Intake Level (UL) for adults as 45 mg/day. For children under fourteen years old the UL is 40 mg/day.
The medical management of iron toxicity is complicated, and can include use of a specific chelating agent called deferoxamine to bind and expel excess iron from the body.[84][86][87] | https://www.wikidoc.org/index.php/Carbonyl_iron | |
42874bf86acaea1cd994a67167b2a558231cccb6 | wikidoc | Cash | Cash
Cash usually refers to money in the form of liquid currency, such as banknotes or coins.
Sometimes used as a street name or slang for Fentanyl.
# Etymology
The English word cash is of the French caisse, itself a borrowing of the Provençal caissa. That Provençal word is a derivative of the Latin capsa (box, chest), most likely by way of an unattested Vulgar Latin form *capsea; Spanish caja and Portuguese caixa are their respective languages' reflexes.
From the original sense of a box or a chest, the word came to refer to a sum of money such as was or might be contained in one, and eventually to specie or, with the elimination of metallic standards, banknotes. In this sense, it is used in contrast to credit or other financial instruments.
The word "cash" can also be traced back to: Sanskrit karsa, a weight of gold or silver but akin to Old Persian karsha-, a weight. a unit of value equivalent to one cash coin.
# Historical usage in Asia
The word was formerly used also to refer to certain low-value coins used in South and East Asia. This sense derives from the Tamil kāsu, a South Indian monetary unit. The early European representations of this Tamil word, including Portuguese caxa and English cass, merged the existing words caixa and cash, which had similar connections with money. In the pre-1818 South Indian monetary system, the cash was the basic coin, with 80 cash equalling a fanam and 42 fanams equalling a star pagoda worth roughly 7s. 8d.
This assimilated Tamil word was then applied to various other coins with which European traders came into contact, including the famous holed cash coins of China, the Chinese cash. Also called wén, these coins were commonly strung on cords for use in larger transactions; 1000 equalled a tael.
In bookkeeping and finance, cash refers to a current asset account, as opposed to long term assets such as property plant and equipment.
Cash is commonly defined as money in the form of bills or coin, legal tender.
- ↑ Jump up to: 1.0 1.1 "Cash, n.1". OED Online..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Bloch, Oscar, and Walther von Warthburg (Dirs.) (2002). "Caisse". Dictionnaire étymologique de la langue française (1er édition «Quadrige» ed.). Paris: Presses universitaires de France.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 3.0 3.1 "Cash, n.2". OED Online. | Cash
Cash usually refers to money in the form of liquid currency, such as banknotes or coins.
Sometimes used as a street name or slang for Fentanyl.
# Etymology
The English word cash is of the French caisse, itself a borrowing of the Provençal caissa. That Provençal word is a derivative of the Latin capsa (box, chest), most likely by way of an unattested Vulgar Latin form *capsea; Spanish caja and Portuguese caixa are their respective languages' reflexes.[1]
[2]
From the original sense of a box or a chest, the word came to refer to a sum of money such as was or might be contained in one, and eventually to specie or, with the elimination of metallic standards, banknotes.[1] In this sense, it is used in contrast to credit or other financial instruments.
The word "cash" can also be traced back to: Sanskrit karsa, a weight of gold or silver but akin to Old Persian karsha-, a weight. a unit of value equivalent to one cash coin.
# Historical usage in Asia
The word was formerly used also to refer to certain low-value coins used in South and East Asia. This sense derives from the Tamil kāsu, a South Indian monetary unit. The early European representations of this Tamil word, including Portuguese caxa and English cass, merged the existing words caixa and cash, which had similar connections with money. In the pre-1818 South Indian monetary system, the cash was the basic coin, with 80 cash equalling a fanam and 42 fanams equalling a star pagoda worth roughly 7s. 8d.[3]
This assimilated Tamil word was then applied to various other coins with which European traders came into contact, including the famous holed cash coins of China, the Chinese cash. Also called wén, these coins were commonly strung on cords for use in larger transactions; 1000 equalled a tael.[3]
In bookkeeping and finance, cash refers to a current asset account, as opposed to long term assets such as property plant and equipment.
Cash is commonly defined as money in the form of bills or coin, legal tender.
- ↑ Jump up to: 1.0 1.1 "Cash, n.1". OED Online..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Bloch, Oscar, and Walther von Warthburg (Dirs.) (2002). "Caisse". Dictionnaire étymologique de la langue française (1er édition «Quadrige» ed.). Paris: Presses universitaires de France.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 3.0 3.1 "Cash, n.2". OED Online. | https://www.wikidoc.org/index.php/Cash | |
8c63258b28ce8dee6a2d2c88ea54861fbf24344d | wikidoc | Scar | Scar
# Overview
Scars are areas of fibrous tissue that replace normal skin (or other tissue) after injury. A scar results from the biologic process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound (e.g. after accident, disease, or surgery) results in some degree of scarring.
Scar tissue is not identical to the tissue which it replaces and is usually of inferior functional quality. For example, scars in the skin are less resistant to ultraviolet radiation, and sweat glands and hair follicles do not grow back within scar tissue. A myocardial infarction, commonly known as a heart attack, causes scar formation in the heart muscle which leads to loss of muscular power and possibly heart failure. However, there are some tissues (e.g. bone) which can heal without any structural or functional deterioration, and in fact bone tissue may be structurally stronger after a break.
The word scar was derived from the Greek word eschara, meaning place of fire (fireplace).
# How scarring occurs
A scar is a natural part of the healing process. Skin scars occur when the deep, thick layer of skin (the dermis) is damaged. The worse the damage is, the worse the scar will be.
Most skin scars are flat, pale and leave a trace of the original injury which caused them. The redness that often follows an injury to the skin is not a scar, and is generally not permanent. The time it takes for it to go away may, however, range from a few days to, in some serious and rare cases, several years. Various treatments can speed up the process in serious cases.
Scars form differently based on the location of the injury on the body and the age of the person who was injured.
To mend the damage, the body has to lay down new collagen fibres (a naturally occurring protein which is produced by the body).
This process results in a fortuna scar. Because the body cannot re-build the tissue exactly as it was, the new scar tissue will have a different texture and quality than the surrounding normal tissue. An injury does not become a scar until the wound has completely healed.
Transforming Growth Factors (TGF) play a critical role in scar development and current research is investigating the manipulation of these TGFs for drug development to prevent scarring from the emergency (and rather inappropriate) adult wound healing process.
## Abnormal scars
Two types of scars are the result of the body overproducing collagen, which causes the scar to be raised above the surrounding skin. Hypertrophic scars take the form of a red raised lump on the skin, but do not grow beyond the boundaries of the original wound, and they often improve in appearance after a few years. Keloid scars are a more serious form of scarring, because they can carry on growing indefinitely into a large, tumorous (although benign) growth.
Both hypertrophic and keloid scars are more common on younger and darker-skinned people. They can occur on anyone, but some people have a genetic susceptibility to these types of scarring. They can be caused by surgery, an accident, or sometimes by acne. Keloid scars can also develop from body piercings. In some people, keloid scars form spontaneously.
Although they can be a cosmetic problem, keloid scars are only inert masses of collagen and therefore completely harmless, painless, and non-contagious. They tend to be most common on the shoulders and chest. Keloid scars are most common among people of Asian or African descent.
Alternately, a scar can take the form of a sunken recess in the skin, which has a pitted appearance. These are caused when underlying structures supporting the skin, such as fat or muscle, are lost. This type of scarring is commonly associated with acne, but can be caused by chickenpox, surgery or an accident.
Scars can also take the form of stretched skin. These are caused when the skin is stretched rapidly (for instance during pregnancy, significant weight gain or adolescent growth spurts), or when skin is put under tension during the healing process, (usually near joints). This type of scar usually improves in appearance after a few years.
# Treatments for skin scars
No scar can ever be completely removed. They will always leave a trace, but their appearance can be improved by a number of means, including:
## Surgery
Scars, such as acne scars, can be cut out and stitched up, a process called scar revision.
## Laser surgery & resurfacing
The use of lasers on scars is experimental treatment, the safety or effectiveness of which has not yet been proven.
The redness of scars may be reduced by treatment with a vascular laser. It has been theorized that removing layers of skin with a carbon dioxide laser may help flatten scars, although this treatment is still highly experimental.
The Fraxel laser was recently FDA approved for the treatment of acne scars.
## Steroid injections
A long term course of steroid injections under medical supervision, into the scar may help flatten and soften the appearance of keloid or hypertrophic scars.
The steroid is injected into the scar itself; since very little is absorbed into the blood stream, side effects of this treatment are minor. This treatment is repeated at 4-6 week intervals.
## Pressure garments
Pressure garments should be used only under supervision by a medical professional. They are most often used for burn scars that cover a large area, this treatment is only effective on recent scars.
Pressure garments are usually custom-made from elastic materials, and fit tightly around the scarring. They work best when they are worn 24 hours a day for six to twelve months.
It is believed that they work by applying constant pressure to surface blood vessels and eventually causing scars to flatten and become softer.
## Radiotherapy
Low-dose, superficial radiotherapy, is used to prevent re-occurrence of severe keloid and hypertrophic scarring. It is usually effective, but only used in extreme cases due to the risk of long-term side effects.
## Dermabrasion
Dermabrasion involves the removal of the surface of the skin with specialist equipment and usually involves a general anaesthetic. It is useful with raised scars, but is less effective when the scar is sunken below the surrounding skin.
## Collagen injections
Collagen injections can be used to raise sunken scars to the level of surrounding skin. Its effects are however temporary, and it needs to be regularly repeated. There is also a risk in some people of an allergic reaction.
## Other treatments
There are also a number of gel sheets available which are usually made from silicone, which can help to flatten and soften raised scars if worn regularly. Silicone, pressure, occlusion, topical cortisone and vitamin E have all been shown to decrease the collagen that forms scars. Patches and pads help but are unsightly so people tend to quit. Chemical peels performed by a dermatologist using glycolic acid can be used to minimize acne scarring.
# Intentional scarring
The permanence of scarring has led to its intentional use as a form of body art within some cultures and subcultures (see scarification). Evidence of ritual scarring practices can be found in many tribes and cultures worldwide. | Scar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Scars are areas of fibrous tissue that replace normal skin (or other tissue) after injury. A scar results from the biologic process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound (e.g. after accident, disease, or surgery) results in some degree of scarring.
Scar tissue is not identical to the tissue which it replaces and is usually of inferior functional quality. For example, scars in the skin are less resistant to ultraviolet radiation, and sweat glands and hair follicles do not grow back within scar tissue. A myocardial infarction, commonly known as a heart attack, causes scar formation in the heart muscle which leads to loss of muscular power and possibly heart failure. However, there are some tissues (e.g. bone) which can heal without any structural or functional deterioration, and in fact bone tissue may be structurally stronger after a break.
The word scar was derived from the Greek word eschara, meaning place of fire (fireplace).
# How scarring occurs
A scar is a natural part of the healing process. Skin scars occur when the deep, thick layer of skin (the dermis) is damaged. The worse the damage is, the worse the scar will be.
Most skin scars are flat, pale and leave a trace of the original injury which caused them. The redness that often follows an injury to the skin is not a scar, and is generally not permanent. The time it takes for it to go away may, however, range from a few days to, in some serious and rare cases, several years. Various treatments can speed up the process in serious cases.
Scars form differently based on the location of the injury on the body and the age of the person who was injured.
To mend the damage, the body has to lay down new collagen fibres (a naturally occurring protein which is produced by the body).
This process results in a fortuna scar. Because the body cannot re-build the tissue exactly as it was, the new scar tissue will have a different texture and quality than the surrounding normal tissue. An injury does not become a scar until the wound has completely healed.
Transforming Growth Factors (TGF) play a critical role in scar development and current research is investigating the manipulation of these TGFs for drug development to prevent scarring from the emergency (and rather inappropriate) adult wound healing process.
## Abnormal scars
Two types of scars are the result of the body overproducing collagen, which causes the scar to be raised above the surrounding skin. Hypertrophic scars take the form of a red raised lump on the skin, but do not grow beyond the boundaries of the original wound, and they often improve in appearance after a few years. Keloid scars are a more serious form of scarring, because they can carry on growing indefinitely into a large, tumorous (although benign) growth.
Both hypertrophic and keloid scars are more common on younger and darker-skinned people. They can occur on anyone, but some people have a genetic susceptibility to these types of scarring. They can be caused by surgery, an accident, or sometimes by acne. Keloid scars can also develop from body piercings. In some people, keloid scars form spontaneously.
Although they can be a cosmetic problem, keloid scars are only inert masses of collagen and therefore completely harmless, painless, and non-contagious. They tend to be most common on the shoulders and chest. Keloid scars are most common among people of Asian or African descent.
Alternately, a scar can take the form of a sunken recess in the skin, which has a pitted appearance. These are caused when underlying structures supporting the skin, such as fat or muscle, are lost. This type of scarring is commonly associated with acne, but can be caused by chickenpox, surgery or an accident.
Scars can also take the form of stretched skin. These are caused when the skin is stretched rapidly (for instance during pregnancy, significant weight gain or adolescent growth spurts), or when skin is put under tension during the healing process, (usually near joints). This type of scar usually improves in appearance after a few years.
# Treatments for skin scars
No scar can ever be completely removed. They will always leave a trace, but their appearance can be improved by a number of means, including:
## Surgery
Scars, such as acne scars, can be cut out and stitched up, a process called scar revision.
## Laser surgery & resurfacing
The use of lasers on scars is experimental treatment, the safety or effectiveness of which has not yet been proven.
The redness of scars may be reduced by treatment with a vascular laser. It has been theorized that removing layers of skin with a carbon dioxide laser may help flatten scars, although this treatment is still highly experimental.
The Fraxel laser was recently FDA approved for the treatment of acne scars.
## Steroid injections
A long term course of steroid injections under medical supervision, into the scar may help flatten and soften the appearance of keloid or hypertrophic scars.
The steroid is injected into the scar itself; since very little is absorbed into the blood stream, side effects of this treatment are minor. This treatment is repeated at 4-6 week intervals.
## Pressure garments
Pressure garments should be used only under supervision by a medical professional. They are most often used for burn scars that cover a large area, this treatment is only effective on recent scars.
Pressure garments are usually custom-made from elastic materials, and fit tightly around the scarring. They work best when they are worn 24 hours a day for six to twelve months.
It is believed that they work by applying constant pressure to surface blood vessels and eventually causing scars to flatten and become softer.
## Radiotherapy
Low-dose, superficial radiotherapy, is used to prevent re-occurrence of severe keloid and hypertrophic scarring. It is usually effective, but only used in extreme cases due to the risk of long-term side effects.
## Dermabrasion
Dermabrasion involves the removal of the surface of the skin with specialist equipment and usually involves a general anaesthetic. It is useful with raised scars, but is less effective when the scar is sunken below the surrounding skin.
## Collagen injections
Collagen injections can be used to raise sunken scars to the level of surrounding skin. Its effects are however temporary, and it needs to be regularly repeated. There is also a risk in some people of an allergic reaction.
## Other treatments
There are also a number of gel sheets available which are usually made from silicone, which can help to flatten and soften raised scars if worn regularly. Silicone, pressure, occlusion, topical cortisone and vitamin E have all been shown to decrease the collagen that forms scars. Patches and pads help but are unsightly so people tend to quit. Chemical peels performed by a dermatologist using glycolic acid can be used to minimize acne scarring.
# Intentional scarring
The permanence of scarring has led to its intentional use as a form of body art within some cultures and subcultures (see scarification). Evidence of ritual scarring practices can be found in many tribes and cultures worldwide. | https://www.wikidoc.org/index.php/Cicatricial | |
4e66644c6f0ba3ca421167e2ea3cf510e9d32400 | wikidoc | Gene | Gene
A gene is a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and/or other functional sequence regions. The physical development and phenotype of organisms can be thought of as a product of genes interacting with each other and with the environment. A concise definition of a gene, taking into account complex patterns of regulation and transcription, genic conservation and non-coding RNA genes, has been proposed by Gerstein et al. "A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products".
Colloquially, the term gene is often used to refer to an inheritable trait which is usually accompanied by a phenotype as in ("tall genes" or "bad genes") -- the proper scientific term for this is allele.
In cells, genes consist of a long strand of DNA that contains a promoter, which controls the activity of a gene, and coding and non-coding sequence. Coding sequence determines what the gene produces, while non-coding sequence can regulate the conditions of gene expression. When a gene is active, the coding and non-coding sequence is copied in a process called transcription, producing an RNA copy of the gene's information. This RNA can then direct the synthesis of proteins via the genetic code. But some RNAs are used directly, for example as part of the ribosome. These molecules resulting from gene expression, whether RNA or protein, are known as gene products.
Genes often contain regions that do not encode products, but regulate gene expression. The genes of eukaryotic organisms can contain regions called introns that are removed from the messenger RNA in a process called splicing. The regions encoding gene products are called exons. In eukaryotes, a single gene can encode multiple proteins, which are produced through the creation of different arrangements of exons through alternative splicing. In prokaryotes (bacteria and archaea), introns are less common and genes often contain a single uninterrupted stretch of DNA, called a cistron, that codes for a product. Prokaryotic genes are often arranged in groups called operons with promoter and operator sequences that regulate transcription of a single long RNA. This RNA contains multiple coding sequences. Each coding sequence is preceded by a Shine-Dalgarno sequence that ribosomes recognize.
The total set of genes in an organism is known as its genome. An organism's genome size is generally lower in prokaryotes, both in number of base pairs and number of genes, than even single-celled eukaryotes. However, there is no clear relationship between genome sizes and complexity in eukaryotic organisms. One of the largest known genomes belongs to the single-celled amoeba Amoeba dubia, with over 670 billion base pairs, some 200 times larger than the human genome. The estimated number of genes in the human genome has been repeatedly revised downward since the completion of the Human Genome Project; current estimates place the human genome at just under 3 billion base pairs and about 20,000–25,000 genes. A recent Science article gives a number of 20,488 protein-coding genes, with perhaps 100 more yet to be discovered. The gene density of a genome is a measure of the number of genes per million base pairs (called a megabase, Mb); prokaryotic genomes have much higher gene densities than eukaryotes. The gene density of the human genome is roughly 12–15 genes per megabase pair.
# History
The existence of genes was first suggested by Gregor Mendel (1822-1884), who, in the 1860s, studied inheritance in pea plants and hypothesized a factor that conveys traits from parent to offspring. He spent over 10 years of his life on one experiment. Although he did not use the term gene, he explained his results in terms of inherited characteristics. Mendel was also the first to hypothesize independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the difference between what would later be described as genotype and phenotype. Mendel's concept was given a name by Hugo de Vries in 1889, who, at that time probably unaware of Mendel's work, in his book Intracellular Pangenesis coined the term "pangen" for "the smallest particle one hereditary characteristic". Wilhelm Johannsen abbreviated this term to "gene" ("gen" in Danish and German) two decades later.
In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, Thomas Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes occupy specific locations on the chromosome. With this knowledge, Morgan and his students began the first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed that genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse.
In 1941,George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused errors in certain steps in metabolic pathways. This showed that specific genes code for specific proteins, leading to the "one gene, one enzyme" hypothesis. Oswald Avery, Collin Macleod, and Maclyn McCarty showed in 1944 that DNA holds the gene's information. In 1953, James D. Watson and Francis Crick demonstrated the molecular structure of DNA. Together, these discoveries established the central dogma of molecular biology, which states that proteins are translated from RNA which is transcribed from DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses.
In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein. Richard J. Roberts and Phillip Sharp discovered in 1977 that genes can be split into segments. This leads to the idea that one gene can make several proteins. Recently (as of 2003-2006), biological results let the notion of gene appear more slippery. In particular, genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long continuum".
# Mendelian inheritance and classical genetics
Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would later become known as Chromosomes had been observed separating out during cell division by Wilhelm Hofmeister as early as 1848. The idea that chromosomes were the carriers of inheritance was expressed in 1883 by Wilhelm Roux. The modern conception of the gene originated with work by Gregor Mendel, a 19th century Augustinian monk who systematically studied heredity in pea plants. Mendel's work was the first to illustrate particulate inheritance, or the theory that inherited traits are passed from one generation to the next in discrete units that interact in well-defined ways. Danish botanist Wilhelm Johannsen coined the word "gene" in 1909 to describe these fundamental physical and functional units of heredity, while the related word genetics was first used by William Bateson in 1905. The word was derived from Hugo De Vries' 1889 term pangen for the same concept, itself a derivative of the word pangenesis coined by Darwin (1868). The word pangenesis is made from the Greek words pan (a prefix meaning "whole", "encompassing") and genesis ("birth") or genos ("origin").
According to the theory of Mendelian inheritance, variations in phenotype - the observable physical and behavioral characteristics of an organism - are due to variations in genotype, or the organism's particular set of genes, each of which specifies a particular trait. Different forms of a gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the pea plants Mendel worked on, along with many plants and animals, have two alleles for each trait, one inherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait, while recessive alleles give rise to their corresponding phenotype only when paired with another copy of the same allele. For example, if the allele specifying tall stems in pea plants is dominant over the allele specifying short stems, then pea plants that inherit one tall allele from one parent and one short allele from the other parent will also have tall stems. Mendel's work found that alleles assort independently in the production of gametes, or germ cells, ensuring variation in the next generation.
Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which proposes that the traits of the parents blend or mix in a smooth, continuous gradient in the offspring. Although Mendel's work was largely unrecognized after its first publication in 1866, it was rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak, who had reached similar conclusions from their own research. However, these scientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.
A series of subsequent discoveries led to the realization decades later that chromosomes within cells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), a polymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance are encoded. The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary synthesis.
# Physical definitions
The vast majority of living organisms encode their genes in long strands of DNA. DNA consists of a chain made from four types of nucleotide subunits: adenine, cytosine, guanine, and thymine. Each nucleotide subunit consists of three components: a phosphate group, a deoxyribose sugar ring, and a nucleobase. Thus, nucleotides in DNA or RNA are typically called 'bases'; consequently they are commonly referred to simply by their purine or pyrimidine original base components adenine, cytosine, guanine, thymine. Adenine and guanine are purines and cytosine and thymine are pyrimidines. The most common form of DNA in a cell is in a double helix structure, in which two individual DNA strands twist around each other in a right-handed spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine pairs with thymine (each pair contains one purine and one pyrimidine). The base pairing between guanine and cytosine forms three hydrogen bonds, while the base pairing between adenine and thymine forms two hydrogen bonds. The two strands in a double helix must therefore be complementary, that is, their bases must align such that the adenines of one strand are paired with the thymines of the other strand, and so on.
Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose, this is known as the 3' end of the molecule. The other end contains an exposed phosphate group, this is the 5' end. The directionality of DNA is vitally important to many cellular processes, since double helices are necessarily directional (a strand running 5'-3' pairs with a complementary strand running 3'-5') and processes such as DNA replication occur in only one direction. All nucleic acid synthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile.
The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons, which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms.
## RNA genes and genomes
In some cases, RNA is an intermediate product in the process of manufacturing proteins from genes. However, for other gene sequences, the RNA molecules are the actual functional products. For example, RNAs known as ribozymes are capable of enzymatic function, and miRNAs have a regulatory role. The DNA sequences from which such RNAs are transcribed are known as RNA genes.
Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized.
In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mouse. Mice with a loss-of-function mutation in the gene Kit have white tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The research team traced this effect back to mutated Kit RNA. While RNA is common as genetic storage material in viruses, in mammals in particular RNA inheritance has been observed very rarely.
## Functional structure of a gene
All genes have regulatory regions in addition to regions that explicitly code for a protein or RNA product. A regulatory region shared by almost all genes is known as the promoter, which provides a position that is recognized by the transcription machinery when a gene is about to be transcribed and expressed. A gene can have more than one promoter, resulting in RNAs that differ in how far they extend in the 5' end. Although promoter regions have a consensus sequence that is the most common sequence at this position, some genes have "strong" promoters that bind the transcription machinery well, and others have "weak" promoters that bind poorly. These weak promoters usually permit a lower rate of transcription than the strong promoters, because the transcription machinery binds to them and initiates transcription less frequently. Other possible regulatory regions include enhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream" — that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters.
Many prokaryotic genes are organized into operons, or groups of genes whose products have related functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribed only one at a time, but may include long stretches of DNA called introns which are transcribed but never translated into protein (they are spliced out before translation). Splicing can also occur in prokaryotic genes, but is less common than in eukaryotes.
## Chromosomes
The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes; the region of the chromosome at which a particular gene is located is called its locus. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. Prokaryotes - bacteria and archaea - typically store their genomes on a single large, circular chromosome, sometimes supplemented by additional small circles of DNA called plasmids, which usually encode only a few genes and are easily transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer.
Although some simple eukaryotes also possess plasmids with small numbers of genes, the majority of eukaryotic genes are stored on multiple linear chromosomes, which are packed within the nucleus in complex with storage proteins called histones. The manner in which DNA is stored on the histone, as well as chemical modifications of the histone itself, are regulatory mechanisms governing whether a particular region of DNA is accessible for gene expression. The ends of eukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres, which do not code for any gene product but are present to prevent degradation of coding and regulatory regions during DNA replication. The length of the telomeres tends to decrease each time the genome is replicated in preparation for cell division; the loss of telomeres has been proposed as an explanation for cellular senescence, or the loss of the ability to divide, and by extension for the aging process in organisms.
While the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, while the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function. However it now appears that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be being expressed, so the term "junk DNA" may be a misnomer.
# Gene expression
In all organisms, there are two major steps separating a protein-coding gene from its protein: first, the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA), and second, it must be translated from mRNA to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule itself is called a gene product.
## Genetic code
File:Rna-codons-protein.png
The genetic code is the set of rules by which a gene is translated into a functional protein. Each gene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA) strand; a correspondence between nucleotides, the basic building blocks of genetic material, and amino acids, the basic building blocks of proteins, must be established for genes to be successfully translated into functional proteins. Sets of three nucleotides, known as codons, each correspond to a specific amino acid or to a signal; three codons are known as "stop codons" and, instead of specifying a new amino acid, alert the translation machinery that the end of the gene has been reached. There are 64 possible codons (four possible nucleotides at each of three positions, hence 43 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms.
## Transcription
The process of genetic transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. The DNA strand whose sequence matches that of the RNA is known as the coding strand and the strand from which the RNA was synthesized is the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5' direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation is the blocking or sequestering of the promoter region, either by tight binding by repressor molecules that physically block the polymerase, or by organizing the DNA so that the promoter region is not accessible.
In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes, transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNA molecule produced by the polymerase is known as the primary transcript and must undergo post-transcriptional modifications before being exported to the cytoplasm for translation. The splicing of introns present within the transcribed region is a modification unique to eukaryotes; alternative splicing mechanisms can result in mature transcripts from the same gene having different sequences and thus coding for different proteins. This is a major form of regulation in eukaryotic cells.
## Translation
Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads; the tRNA is also covalently attached to the amino acid specified by the complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the ribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus. During and after its synthesis, the new protein must fold to its active three-dimensional structure before it can carry out its cellular function.
# DNA replication and inheritance
The growth, development, and reproduction of organisms relies on cell division, or the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication. The copies are made by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Because the DNA double helix is held together by base pairing, the sequence of one strand completely specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.
After DNA replication is complete, the cell must physically separate the two copies of the genome and divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, while the process of segregating chromosomes and splitting the cytoplasm occurs during M phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common, which results in asymmetrical portions of cytoplasm in the two daughter cells.
## Molecular inheritance
The duplication and transmission of genetic material from one generation of cells to the next is the basis for molecular inheritance, and the link between the classical and molecular pictures of genes. Organisms inherit the characteristics of their parents because the cells of the offspring contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene. The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell that once again has a diploid number of genes - each with one copy from the mother and one copy from the father.
During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of DNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids are the same, but results in reassortment of otherwise linked alleles if they are different. The Mendelian principle of independent assortment asserts that each of a parent's two genes for each trait will sort independently into gametes; which allele an organism inherits for one trait is unrelated to which allele it inherits for another trait. This is in fact only true for genes that do not reside on the same chromosome, or are located very far from one another on the same chromosome. The closer two genes lie on the same chromosome, the more closely they will be associated in gametes and the more often they will appear together; genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. This is known as genetic linkage.
## Mutation
DNA replication is for the most part extremely accurate, with an error rate per site of around 10-6 to 10-10 in eukaryotes. Rare, spontaneous alterations in the base sequence of a particular gene arise from a number of sources, such as errors in DNA replication and the aftermath of DNA damage. These errors are called mutations. The cell contains many DNA repair mechanisms for preventing mutations and maintaining the integrity of the genome; however, in some cases — such as breaks in both DNA strands of a chromosome — repairing the physical damage to the molecule is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of the protein for which they code; for example, the codons UCU and UUC both code for serine, so the U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are most often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's fitness.
Mutations propagated to the next generation lead to variations within a species' population. Variants of a single gene are known as alleles, and differences in alleles may give rise to differences in traits. Although it is rare for the variants in a single gene to have clearly distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants. However, this does not imply that the wild-type allele is the ancestor from which the mutants are descended.
# Genome
## Chromosomal organization
The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes called chromosomes. Extrachromosomal DNA is present in many prokaryotes and some simple eukaryotes as small, circular pieces of DNA called plasmids, which usually contain only a few genes each. Generally, regulatory regions and junk DNA are considered to be part of an organism's genome, but structural regions such as telomeres are not. The location (or locus) of a gene and the chromosome on which it is situated is in a sense arbitrary. Genes that appear together on the chromosomes of one species, such as humans, may appear on separate chromosomes in another species, such as mice. Two genes positioned near one another on a chromosome may encode proteins that figure in the same cellular process or in completely unrelated processes. As an example of the former, many of the genes involved in spermatogenesis reside together on the Y chromosome.
Many species carry more than one copy of their genome within each of their somatic cells. Cells or organisms with only one copy of each gene are called haploid; those with two copies are called diploid; and those with more than two copies are called polyploid. When more than one copy is present, the two copies are not necessarily identical; in sexually reproducing organisms, one copy is normally inherited from each parent. The copies may contain distinct DNA sequences encoding distinct alleles.
## Composition of the genome
Typical numbers of genes and size of genomes vary widely among organisms, even those that are fairly closely evolutionarily related. Although it was believed before the completion of the Human Genome Project that the human genome would contain many more genes than simpler animals such as mice or fruit flies, the completion of the project has revealed that the human genome has an unexpectedly low gene density. Estimates of the number of genes in a genome are difficult to compile because they depend on gene finding algorithms that search for patterns resembling those present in known genes, such as open reading frames, promoter regions with sequences resembling the consensus promoter sequence, and related regulatory regions such as TATA boxes in eukaryotes. Gene finding is less reliable in eukaryotic than in prokaryotic genomes due to the presence of non-coding DNA such as introns and pseudogenes. Computational gene finding methods are still significantly more reliable than earlier techniques that required mapping the locations of specific mutations that gave rise to distinguishable alleles.
In most eukaryotic species, very little of the DNA in the genome encodes proteins, and the genes may be separated by vast regions of non-coding DNA, much of which has been labeled "junk DNA" due to its apparent lack of function in the modern organism. A commonly studied type of "junk DNA" is the pseudogenes, or region of non-coding DNA that resembles expressed genes but usually lacks appropriate promoters and other control sequences; such regions are hypothesized to be the results of gene duplication events in a lineage's evolutionary past. Moreover, the genes are often fragmented internally by non-coding sequences called introns, which can be many times longer than the coding sequence but are spliced during post-transcriptional modification of pre-mRNA.
## Genetic and genomic nomenclature
Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique and each gene is only given one approved gene symbol. It is necessary to provide a unique symbol for each gene so that people can talk about them. This also facilitates electronic data retrieval from publications. In preference each symbol maintains parallel construction in different members of a gene family and can be used in other species, especially the mouse.
# Evolutionary concept of a gene
George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when we are talking about natural selection favoring some genes. The definition is: "that which segregates and recombines with appreciable frequency." According to this definition, even an asexual genome could be considered a gene, insofar that it have an appreciable permanency through many generations.
The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit.
Richard Dawkins' The Selfish Gene and The Extended Phenotype defended the idea that the gene is the only replicator in living systems. This means that only genes transmit their structure largely intact and are potentially immortal in the form of copies. So, genes should be the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection by describing life as a river of compatible genes flowing through geological time. Scoop up a bucket of genes from the river of genes, and we have an organism serving as temporary bodies or survival machines. A river of genes may fork into two branches representing two non-interbreeding species as a result of geographical separation.
# Gene targeting and implications
Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and provides the mouse models for studying the roles of individual genes in embryonic development, human disorders, aging and diseases. The mouse models, where one or more of its genes are deactivated or made inoperable, are called knockout mice. Since the first reports in which homologous recombination in embryonic stem cells was used to generate gene-targeted mice, gene targeting has proven to be a powerful means of precisely manipulating the mammalian genome, producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.
Gene targeting strategies have been expanded to all kinds of modifications, including point mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It is predicted that the ability to generate mouse models with predictable phenotypes will have a major impact on studies of all phases of development, immunology, neurobiology, oncology, physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species from which totipotent embryonic stem cells can be established, and therefore may offer a potential to the improvement of domestic animals and plants.
# Changing concept
The concept of the gene has changed considerably (see history section). Originally considered a "unit of inheritance" to a usually DNA-based unit that can exert its effects on the organism through RNA or protein products. It was also previously believed that one gene makes one protein; this concept has been overthrown by the discovery of alternative splicing and trans-splicing.
And the definition of gene is still changing. The first cases of RNA-based inheritance have been discovered in mammals. In plants, cases of traits reappearing after several generations of absence have led researchers to hypothesise RNA-directed overwriting of genomic DNA. Evidence is also accumulating that the control regions of a gene do not necessarily have to be close to the coding sequence on the linear molecule or even on the same chromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.
The concept that genes are clearly delimited is also being eroded. There is evidence for fused proteins stemming from two adjacent genes that can produce two separate protein products. While it is not clear whether these fusion proteins are functional, the phenomena is more frequent than previously thought. Even more ground-breaking than the discovery of fused genes is the observation that some proteins can be composed of exons from far away regions and even different chromosomes. This new data has led to an updated, and probably tentative, definition of a gene as "a union of genomic sequences encoding a coherent set of potentially overlapping functional products." This new definition categorizes genes by functional products, whether they be proteins or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as gene-associated regions. | Gene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
A gene is a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and/or other functional sequence regions.[1][2] The physical development and phenotype of organisms can be thought of as a product of genes interacting with each other and with the environment.[3] A concise definition of a gene, taking into account complex patterns of regulation and transcription, genic conservation and non-coding RNA genes, has been proposed by Gerstein et al.[4] "A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products".
Colloquially, the term gene is often used to refer to an inheritable trait which is usually accompanied by a phenotype as in ("tall genes" or "bad genes") -- the proper scientific term for this is allele.
In cells, genes consist of a long strand of DNA that contains a promoter, which controls the activity of a gene, and coding and non-coding sequence. Coding sequence determines what the gene produces, while non-coding sequence can regulate the conditions of gene expression. When a gene is active, the coding and non-coding sequence is copied in a process called transcription, producing an RNA copy of the gene's information. This RNA can then direct the synthesis of proteins via the genetic code. But some RNAs are used directly, for example as part of the ribosome. These molecules resulting from gene expression, whether RNA or protein, are known as gene products.
Genes often contain regions that do not encode products, but regulate gene expression. The genes of eukaryotic organisms can contain regions called introns that are removed from the messenger RNA in a process called splicing. The regions encoding gene products are called exons. In eukaryotes, a single gene can encode multiple proteins, which are produced through the creation of different arrangements of exons through alternative splicing. In prokaryotes (bacteria and archaea), introns are less common and genes often contain a single uninterrupted stretch of DNA, called a cistron, that codes for a product. Prokaryotic genes are often arranged in groups called operons with promoter and operator sequences that regulate transcription of a single long RNA. This RNA contains multiple coding sequences. Each coding sequence is preceded by a Shine-Dalgarno sequence that ribosomes recognize.
The total set of genes in an organism is known as its genome. An organism's genome size is generally lower in prokaryotes, both in number of base pairs and number of genes, than even single-celled eukaryotes. However, there is no clear relationship between genome sizes and complexity in eukaryotic organisms. One of the largest known genomes belongs to the single-celled amoeba Amoeba dubia, with over 670 billion base pairs, some 200 times larger than the human genome.[5] The estimated number of genes in the human genome has been repeatedly revised downward since the completion of the Human Genome Project; current estimates place the human genome at just under 3 billion base pairs and about 20,000–25,000 genes.[6] A recent Science article gives a number of 20,488 protein-coding genes, with perhaps 100 more yet to be discovered.[7] The gene density of a genome is a measure of the number of genes per million base pairs (called a megabase, Mb); prokaryotic genomes have much higher gene densities than eukaryotes. The gene density of the human genome is roughly 12–15 genes per megabase pair.[8]
# History
The existence of genes was first suggested by Gregor Mendel (1822-1884), who, in the 1860s, studied inheritance in pea plants and hypothesized a factor that conveys traits from parent to offspring. He spent over 10 years of his life on one experiment. Although he did not use the term gene, he explained his results in terms of inherited characteristics. Mendel was also the first to hypothesize independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the difference between what would later be described as genotype and phenotype. Mendel's concept was given a name by Hugo de Vries in 1889, who, at that time probably unaware of Mendel's work, in his book Intracellular Pangenesis coined the term "pangen" for "the smallest particle [representing] one hereditary characteristic".[9] Wilhelm Johannsen abbreviated this term to "gene" ("gen" in Danish and German) two decades later.
In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, Thomas Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes occupy specific locations on the chromosome. With this knowledge, Morgan and his students began the first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed that genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse.
In 1941,George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused errors in certain steps in metabolic pathways. This showed that specific genes code for specific proteins, leading to the "one gene, one enzyme" hypothesis.[10] Oswald Avery, Collin Macleod, and Maclyn McCarty showed in 1944 that DNA holds the gene's information. In 1953, James D. Watson and Francis Crick demonstrated the molecular structure of DNA. Together, these discoveries established the central dogma of molecular biology, which states that proteins are translated from RNA which is transcribed from DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses.
In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.[11] Richard J. Roberts and Phillip Sharp discovered in 1977 that genes can be split into segments. This leads to the idea that one gene can make several proteins. Recently (as of 2003-2006), biological results let the notion of gene appear more slippery. In particular, genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long continuum".[1]
# Mendelian inheritance and classical genetics
Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would later become known as Chromosomes had been observed separating out during cell division by Wilhelm Hofmeister as early as 1848. The idea that chromosomes were the carriers of inheritance was expressed in 1883 by Wilhelm Roux. The modern conception of the gene originated with work by Gregor Mendel, a 19th century Augustinian monk who systematically studied heredity in pea plants. Mendel's work was the first to illustrate particulate inheritance, or the theory that inherited traits are passed from one generation to the next in discrete units that interact in well-defined ways. Danish botanist Wilhelm Johannsen coined the word "gene" in 1909 to describe these fundamental physical and functional units of heredity,[12] while the related word genetics was first used by William Bateson in 1905.[10] The word was derived from Hugo De Vries' 1889 term pangen for the same concept,[9] itself a derivative of the word pangenesis coined by Darwin (1868).[13] The word pangenesis is made from the Greek words pan (a prefix meaning "whole", "encompassing") and genesis ("birth") or genos ("origin").
According to the theory of Mendelian inheritance, variations in phenotype - the observable physical and behavioral characteristics of an organism - are due to variations in genotype, or the organism's particular set of genes, each of which specifies a particular trait. Different forms of a gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the pea plants Mendel worked on, along with many plants and animals, have two alleles for each trait, one inherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait, while recessive alleles give rise to their corresponding phenotype only when paired with another copy of the same allele. For example, if the allele specifying tall stems in pea plants is dominant over the allele specifying short stems, then pea plants that inherit one tall allele from one parent and one short allele from the other parent will also have tall stems. Mendel's work found that alleles assort independently in the production of gametes, or germ cells, ensuring variation in the next generation.
Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which proposes that the traits of the parents blend or mix in a smooth, continuous gradient in the offspring. Although Mendel's work was largely unrecognized after its first publication in 1866, it was rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak, who had reached similar conclusions from their own research. However, these scientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.
A series of subsequent discoveries led to the realization decades later that chromosomes within cells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), a polymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance are encoded. The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary synthesis.
# Physical definitions
The vast majority of living organisms encode their genes in long strands of DNA. DNA consists of a chain made from four types of nucleotide subunits: adenine, cytosine, guanine, and thymine. Each nucleotide subunit consists of three components: a phosphate group, a deoxyribose sugar ring, and a nucleobase. Thus, nucleotides in DNA or RNA are typically called 'bases'; consequently they are commonly referred to simply by their purine or pyrimidine original base components adenine, cytosine, guanine, thymine. Adenine and guanine are purines and cytosine and thymine are pyrimidines. The most common form of DNA in a cell is in a double helix structure, in which two individual DNA strands twist around each other in a right-handed spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine pairs with thymine (each pair contains one purine and one pyrimidine). The base pairing between guanine and cytosine forms three hydrogen bonds, while the base pairing between adenine and thymine forms two hydrogen bonds. The two strands in a double helix must therefore be complementary, that is, their bases must align such that the adenines of one strand are paired with the thymines of the other strand, and so on.
Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose, this is known as the 3' end of the molecule. The other end contains an exposed phosphate group, this is the 5' end. The directionality of DNA is vitally important to many cellular processes, since double helices are necessarily directional (a strand running 5'-3' pairs with a complementary strand running 3'-5') and processes such as DNA replication occur in only one direction. All nucleic acid synthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile.
The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons, which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms.
## RNA genes and genomes
In some cases, RNA is an intermediate product in the process of manufacturing proteins from genes. However, for other gene sequences, the RNA molecules are the actual functional products. For example, RNAs known as ribozymes are capable of enzymatic function, and miRNAs have a regulatory role. The DNA sequences from which such RNAs are transcribed are known as RNA genes.
Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized.
In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mouse. Mice with a loss-of-function mutation in the gene Kit have white tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The research team traced this effect back to mutated Kit RNA.[14] While RNA is common as genetic storage material in viruses, in mammals in particular RNA inheritance has been observed very rarely.
## Functional structure of a gene
All genes have regulatory regions in addition to regions that explicitly code for a protein or RNA product. A regulatory region shared by almost all genes is known as the promoter, which provides a position that is recognized by the transcription machinery when a gene is about to be transcribed and expressed. A gene can have more than one promoter, resulting in RNAs that differ in how far they extend in the 5' end.[15] Although promoter regions have a consensus sequence that is the most common sequence at this position, some genes have "strong" promoters that bind the transcription machinery well, and others have "weak" promoters that bind poorly. These weak promoters usually permit a lower rate of transcription than the strong promoters, because the transcription machinery binds to them and initiates transcription less frequently. Other possible regulatory regions include enhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream" — that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters.
Many prokaryotic genes are organized into operons, or groups of genes whose products have related functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribed only one at a time, but may include long stretches of DNA called introns which are transcribed but never translated into protein (they are spliced out before translation). Splicing can also occur in prokaryotic genes, but is less common than in eukaryotes.[16]
## Chromosomes
The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes; the region of the chromosome at which a particular gene is located is called its locus. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. Prokaryotes - bacteria and archaea - typically store their genomes on a single large, circular chromosome, sometimes supplemented by additional small circles of DNA called plasmids, which usually encode only a few genes and are easily transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer.
Although some simple eukaryotes also possess plasmids with small numbers of genes, the majority of eukaryotic genes are stored on multiple linear chromosomes, which are packed within the nucleus in complex with storage proteins called histones. The manner in which DNA is stored on the histone, as well as chemical modifications of the histone itself, are regulatory mechanisms governing whether a particular region of DNA is accessible for gene expression. The ends of eukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres, which do not code for any gene product but are present to prevent degradation of coding and regulatory regions during DNA replication. The length of the telomeres tends to decrease each time the genome is replicated in preparation for cell division; the loss of telomeres has been proposed as an explanation for cellular senescence, or the loss of the ability to divide, and by extension for the aging process in organisms.[17]
While the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, while the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function.[6] However it now appears that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be being expressed, so the term "junk DNA" may be a misnomer.[2]
# Gene expression
In all organisms, there are two major steps separating a protein-coding gene from its protein: first, the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA), and second, it must be translated from mRNA to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule itself is called a gene product.
## Genetic code
File:Rna-codons-protein.png
The genetic code is the set of rules by which a gene is translated into a functional protein. Each gene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA) strand; a correspondence between nucleotides, the basic building blocks of genetic material, and amino acids, the basic building blocks of proteins, must be established for genes to be successfully translated into functional proteins. Sets of three nucleotides, known as codons, each correspond to a specific amino acid or to a signal; three codons are known as "stop codons" and, instead of specifying a new amino acid, alert the translation machinery that the end of the gene has been reached. There are 64 possible codons (four possible nucleotides at each of three positions, hence 43 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms.
## Transcription
The process of genetic transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. The DNA strand whose sequence matches that of the RNA is known as the coding strand and the strand from which the RNA was synthesized is the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5' direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation is the blocking or sequestering of the promoter region, either by tight binding by repressor molecules that physically block the polymerase, or by organizing the DNA so that the promoter region is not accessible.
In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes, transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNA molecule produced by the polymerase is known as the primary transcript and must undergo post-transcriptional modifications before being exported to the cytoplasm for translation. The splicing of introns present within the transcribed region is a modification unique to eukaryotes; alternative splicing mechanisms can result in mature transcripts from the same gene having different sequences and thus coding for different proteins. This is a major form of regulation in eukaryotic cells.
## Translation
Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads; the tRNA is also covalently attached to the amino acid specified by the complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the ribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus. During and after its synthesis, the new protein must fold to its active three-dimensional structure before it can carry out its cellular function.
# DNA replication and inheritance
The growth, development, and reproduction of organisms relies on cell division, or the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication. The copies are made by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Because the DNA double helix is held together by base pairing, the sequence of one strand completely specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.[8]
After DNA replication is complete, the cell must physically separate the two copies of the genome and divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, while the process of segregating chromosomes and splitting the cytoplasm occurs during M phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common, which results in asymmetrical portions of cytoplasm in the two daughter cells.
## Molecular inheritance
The duplication and transmission of genetic material from one generation of cells to the next is the basis for molecular inheritance, and the link between the classical and molecular pictures of genes. Organisms inherit the characteristics of their parents because the cells of the offspring contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene. The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell that once again has a diploid number of genes - each with one copy from the mother and one copy from the father.
During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of DNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids are the same, but results in reassortment of otherwise linked alleles if they are different. The Mendelian principle of independent assortment asserts that each of a parent's two genes for each trait will sort independently into gametes; which allele an organism inherits for one trait is unrelated to which allele it inherits for another trait. This is in fact only true for genes that do not reside on the same chromosome, or are located very far from one another on the same chromosome. The closer two genes lie on the same chromosome, the more closely they will be associated in gametes and the more often they will appear together; genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. This is known as genetic linkage.
## Mutation
DNA replication is for the most part extremely accurate, with an error rate per site of around 10-6 to 10-10 in eukaryotes.[8] Rare, spontaneous alterations in the base sequence of a particular gene arise from a number of sources, such as errors in DNA replication and the aftermath of DNA damage. These errors are called mutations. The cell contains many DNA repair mechanisms for preventing mutations and maintaining the integrity of the genome; however, in some cases — such as breaks in both DNA strands of a chromosome — repairing the physical damage to the molecule is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of the protein for which they code; for example, the codons UCU and UUC both code for serine, so the U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are most often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's fitness.
Mutations propagated to the next generation lead to variations within a species' population. Variants of a single gene are known as alleles, and differences in alleles may give rise to differences in traits. Although it is rare for the variants in a single gene to have clearly distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants. However, this does not imply that the wild-type allele is the ancestor from which the mutants are descended.
# Genome
## Chromosomal organization
The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes called chromosomes. Extrachromosomal DNA is present in many prokaryotes and some simple eukaryotes as small, circular pieces of DNA called plasmids, which usually contain only a few genes each. Generally, regulatory regions and junk DNA are considered to be part of an organism's genome, but structural regions such as telomeres are not. The location (or locus) of a gene and the chromosome on which it is situated is in a sense arbitrary. Genes that appear together on the chromosomes of one species, such as humans, may appear on separate chromosomes in another species, such as mice. Two genes positioned near one another on a chromosome may encode proteins that figure in the same cellular process or in completely unrelated processes. As an example of the former, many of the genes involved in spermatogenesis reside together on the Y chromosome.
Many species carry more than one copy of their genome within each of their somatic cells. Cells or organisms with only one copy of each gene are called haploid; those with two copies are called diploid; and those with more than two copies are called polyploid. When more than one copy is present, the two copies are not necessarily identical; in sexually reproducing organisms, one copy is normally inherited from each parent. The copies may contain distinct DNA sequences encoding distinct alleles.
## Composition of the genome
Typical numbers of genes and size of genomes vary widely among organisms, even those that are fairly closely evolutionarily related. Although it was believed before the completion of the Human Genome Project that the human genome would contain many more genes than simpler animals such as mice or fruit flies, the completion of the project has revealed that the human genome has an unexpectedly low gene density.[6] Estimates of the number of genes in a genome are difficult to compile because they depend on gene finding algorithms that search for patterns resembling those present in known genes, such as open reading frames, promoter regions with sequences resembling the consensus promoter sequence, and related regulatory regions such as TATA boxes in eukaryotes. Gene finding is less reliable in eukaryotic than in prokaryotic genomes due to the presence of non-coding DNA such as introns and pseudogenes.[18] Computational gene finding methods are still significantly more reliable than earlier techniques that required mapping the locations of specific mutations that gave rise to distinguishable alleles.[8]
In most eukaryotic species, very little of the DNA in the genome encodes proteins, and the genes may be separated by vast regions of non-coding DNA, much of which has been labeled "junk DNA" due to its apparent lack of function in the modern organism. A commonly studied type of "junk DNA" is the pseudogenes, or region of non-coding DNA that resembles expressed genes but usually lacks appropriate promoters and other control sequences; such regions are hypothesized to be the results of gene duplication events in a lineage's evolutionary past.[19] Moreover, the genes are often fragmented internally by non-coding sequences called introns, which can be many times longer than the coding sequence but are spliced during post-transcriptional modification of pre-mRNA.
## Genetic and genomic nomenclature
Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique and each gene is only given one approved gene symbol. It is necessary to provide a unique symbol for each gene so that people can talk about them. This also facilitates electronic data retrieval from publications. In preference each symbol maintains parallel construction in different members of a gene family and can be used in other species, especially the mouse.
# Evolutionary concept of a gene
George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when we are talking about natural selection favoring some genes. The definition is: "that which segregates and recombines with appreciable frequency." According to this definition, even an asexual genome could be considered a gene, insofar that it have an appreciable permanency through many generations.
The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit.
Richard Dawkins' The Selfish Gene and The Extended Phenotype defended the idea that the gene is the only replicator in living systems. This means that only genes transmit their structure largely intact and are potentially immortal in the form of copies. So, genes should be the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection by describing life as a river of compatible genes flowing through geological time. Scoop up a bucket of genes from the river of genes, and we have an organism serving as temporary bodies or survival machines. A river of genes may fork into two branches representing two non-interbreeding species as a result of geographical separation.
# Gene targeting and implications
Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and provides the mouse models for studying the roles of individual genes in embryonic development, human disorders, aging and diseases. The mouse models, where one or more of its genes are deactivated or made inoperable, are called knockout mice. Since the first reports in which homologous recombination in embryonic stem cells was used to generate gene-targeted mice,[20] gene targeting has proven to be a powerful means of precisely manipulating the mammalian genome, producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.[21][22]
Gene targeting strategies have been expanded to all kinds of modifications, including point mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It is predicted that the ability to generate mouse models with predictable phenotypes will have a major impact on studies of all phases of development, immunology, neurobiology, oncology, physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species from which totipotent embryonic stem cells can be established, and therefore may offer a potential to the improvement of domestic animals and plants.[22][23]
# Changing concept
The concept of the gene has changed considerably (see history section). Originally considered a "unit of inheritance" to a usually DNA-based unit that can exert its effects on the organism through RNA or protein products. It was also previously believed that one gene makes one protein; this concept has been overthrown by the discovery of alternative splicing and trans-splicing.[10]
And the definition of gene is still changing. The first cases of RNA-based inheritance have been discovered in mammals.[14] In plants, cases of traits reappearing after several generations of absence have led researchers to hypothesise RNA-directed overwriting of genomic DNA.[24] Evidence is also accumulating that the control regions of a gene do not necessarily have to be close to the coding sequence on the linear molecule or even on the same chromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.[25]
The concept that genes are clearly delimited is also being eroded. There is evidence for fused proteins stemming from two adjacent genes that can produce two separate protein products. While it is not clear whether these fusion proteins are functional, the phenomena is more frequent than previously thought.[26] Even more ground-breaking than the discovery of fused genes is the observation that some proteins can be composed of exons from far away regions and even different chromosomes.[27][2] This new data has led to an updated, and probably tentative, definition of a gene as "a union of genomic sequences encoding a coherent set of potentially overlapping functional products."[10] This new definition categorizes genes by functional products, whether they be proteins or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as gene-associated regions.[10] | https://www.wikidoc.org/index.php/Cistron | |
31cfd9de9117d55620b7253676bf3c63e3e850ff | wikidoc | ClpX | ClpX
ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial is an enzyme that in humans is encoded by the CLPX gene. This protein is a member of the family of AAA Proteins (AAA+ ATPase) and is to form the protein complex of Clp protease (Endopeptidase Clp).
# Structure
## Protein Structure
The knowledge of human ClpX protein are majorly based on the investigations on E. Coli protein. The monomer of ClpX protein in E. Coli contains a N-terminal domain and a AAA+ module which consists of a large and a small AAA+ domain.
## Complex Assembly
During protease Clp complex assembly, the ClpX subunits form a hexameric ring structure. According to the orientation of ClpX subunits within the ring structure, these subunits can be categorized into two classes: "loadable" subunit (L subunit) and "unloadable" subunit (U subunit). In L subunit, the large and small AAA+ domain form a cleft for nucleotide ATP or ADP binding. However, the large and small AAA+ domains in U subunit rotate ~ 80°, which prevents nucleotide binding. The L and U subunits form a "L-L-U-L-L-U" pattern when they assemble into a hexameric ring, which has the maximum capacity to bind four ATP or ADP. Electro-microscopy (EM) studies showed that ClpX ring structures stack coaxially on either one side or both side of ClpP tetradecamer complex to form ClpXP protease complexes. ATP binding can stabilize the association between ClpX and ClpP ring structures.
# Function
ClpX is an ATP-dependent chaperone that can recognize protein substrates by binding to protein degradation tags. These tags can be short unstructured peptide sequences (e.g., ssrA-tag in E coli). As an essential component of ClpP protease complex, ClpX recruits degradable substrates and unfolds their tertiary structure, which requires energy provided by ATP hydrolysis. Subsequently, these ClpX Chaperons transfer protein substrates into the proteolytic chamber formed by ClpP tetradecamer.
# Clinical Significance
In mammals, ClpXP protease is a pivotal contributor to mitochondrial protein quality control. A compromised ClpXP function usually leads to the accumulation of damaged proteins and mitochondrial dysfunctions, which believes to be potential causes for neurodegenerative diseases and aging. | ClpX
ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial is an enzyme that in humans is encoded by the CLPX gene. This protein is a member of the family of AAA Proteins (AAA+ ATPase) and is to form the protein complex of Clp protease (Endopeptidase Clp).
# Structure
## Protein Structure
The knowledge of human ClpX protein are majorly based on the investigations on E. Coli protein. The monomer of ClpX protein in E. Coli contains a N-terminal domain and a AAA+ module which consists of a large and a small AAA+ domain.[1]
## Complex Assembly
During protease Clp complex assembly, the ClpX subunits form a hexameric ring structure. According to the orientation of ClpX subunits within the ring structure, these subunits can be categorized into two classes: "loadable" subunit (L subunit) and "unloadable" subunit (U subunit). In L subunit, the large and small AAA+ domain form a cleft for nucleotide ATP or ADP binding. However, the large and small AAA+ domains in U subunit rotate ~ 80°, which prevents nucleotide binding. The L and U subunits form a "L-L-U-L-L-U" pattern when they assemble into a hexameric ring, which has the maximum capacity to bind four ATP or ADP.[2] Electro-microscopy (EM) studies showed that ClpX ring structures stack coaxially on either one side or both side of ClpP tetradecamer complex to form ClpXP protease complexes. ATP binding can stabilize the association between ClpX and ClpP ring structures.
# Function
ClpX is an ATP-dependent chaperone that can recognize protein substrates by binding to protein degradation tags. These tags can be short unstructured peptide sequences (e.g., ssrA-tag in E coli). As an essential component of ClpP protease complex, ClpX recruits degradable substrates and unfolds their tertiary structure, which requires energy provided by ATP hydrolysis. Subsequently, these ClpX Chaperons transfer protein substrates into the proteolytic chamber formed by ClpP tetradecamer.
# Clinical Significance
In mammals, ClpXP protease is a pivotal contributor to mitochondrial protein quality control. A compromised ClpXP function usually leads to the accumulation of damaged proteins and mitochondrial dysfunctions, which believes to be potential causes for neurodegenerative diseases and aging.[3] | https://www.wikidoc.org/index.php/ClpX | |
96644f9130cee216e82471abc10283d14adb7286 | wikidoc | Cmax | Cmax
# Overview
Cmax is a term used in pharmacokinetics refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose. Cmax is the opposite of Cmin, which is the minimum (or trough) concentration that a drug achieves after dosing.
Tmax is the term used in pharmacokinetics to describe the time at which the Cmax is observed.
After an intravenous administration, Cmax and Tmax are closely dependent on the experimental protocol, since the concentrations are always decreasing after the dose. But after oral administration,Cmax and Tmax are dependent on the extent, and the rate of drug absorption and the disposition profile of the drug. They could be used to characterize the properties of different formulations in the same subject.
Short term drug side effects are most likely to occur at or near the Cmax whereas the therapeutic effect of drug with sustained duration of action usually occurs at concentrations slightly above the Cmin.
The Cmax is often measured in an effort to show bioequivalence between a generic and innovator drug product. According to FDA, drug quality BA (bioavailability) and BE (bioequivalence) rely on pharmacokinetic measures such as AUC and Cmax that are reflective of systemic exposure. | Cmax
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Overview
Cmax is a term used in pharmacokinetics refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose. Cmax is the opposite of Cmin, which is the minimum (or trough) concentration that a drug achieves after dosing.[1]
Tmax is the term used in pharmacokinetics to describe the time at which the Cmax is observed.[2]
After an intravenous administration, Cmax and Tmax are closely dependent on the experimental protocol, since the concentrations are always decreasing after the dose. But after oral administration,Cmax and Tmax are dependent on the extent, and the rate of drug absorption and the disposition profile of the drug. They could be used to characterize the properties of different formulations in the same subject.[3]
Short term drug side effects are most likely to occur at or near the Cmax whereas the therapeutic effect of drug with sustained duration of action usually occurs at concentrations slightly above the Cmin.
The Cmax is often measured in an effort to show bioequivalence between a generic and innovator drug product.[4] According to FDA, drug quality BA (bioavailability) and BE (bioequivalence) rely on pharmacokinetic measures such as AUC and Cmax that are reflective of systemic exposure.[5] | https://www.wikidoc.org/index.php/Cmax | |
0c666a9c01b21b856f3601c566185b9fb441cf02 | wikidoc | Coca | Coca
Coca is a plant in the family Erythroxylaceae, native to north-western South America. The plant plays a significant role in traditional Andean culture. It is used by Andean cultures such as the Quechuas of Peru as a messenger from the Gods, but is best-known in most of the world for the stimulant drug cocaine that is chemically extracted from its new fresh leaf tips in a similar fashion to tea bush harvesting. Unprocessed coca leaves are also commonly used in the Andean countries to make a herbal tea with mild stimulant effects similar to strong coffee.
The plant resembles a blackthorn bush, and grows to a height of 2–3 m (7–10 ft). The branches are straight, and the leaves, which have a green tint, are thin, opaque, oval, more or less tapering at the extremities. A marked characteristic of the leaf is an areolated portion bounded by two longitudinal curved lines, one line on each side of the midrib, and more conspicuous on the under face of the leaf.
The flowers are small, and disposed in little clusters on short stalks; the corolla is composed of five yellowish-white petals, the anthers are heart-shaped, and the pistil consists of three carpels united to form a three-chambered ovary. The flowers mature into red berries.
The leaves are sometimes eaten by the larvae of the moth Eloria noyesi.
# Species and classification
There are twelve main species and varieties. Two subspecies, Erythroxylum coca var. coca and E. coca var. ipadu, are almost indistinguishable phenotypically; a related high cocaine-bearing species has two subspecies, E. novogranatense var. novogranatense and E. novogranatense var. truxillense that are phenotypically similar, but morphologically distinguishable. Under the older Cronquist system of classifying flowering plants, this was placed in an order Linales; more modern systems place it in the order Malpighiales.
# Cultivation and uses
Coca is traditionally cultivated in the lower altitudes of the eastern slopes of the Andes, or the highlands depending on the species grown. Since ancient times, its leaves have been used as a stimulant by some of the Andean people of Peru, Colombia, Ecuador, Venezuela, Bolivia, where unprocessed coca remains legal and popular today as a common herbal tea with mild stimulant effects. In the highlands, coca tea and chewed leaves are used as a breathing aid to combat the effects of altitude sickness.
Coca leaf is the raw material for the manufacture of the drug cocaine, a powerful stimulant and anaesthetic extracted chemically from large quantities of coca leaves. Today, cocaine is best known as an illegal recreational drug popular in Europe and North America. Cocaine was often sold as a patent medicine in the late 19th and early 20th centuries before its proscription, and cocaine remains legal (though uncommon and highly regulated) for medical use as a local anaesthetic in many jurisdictions, used particularly for dental, throat, and nasal surgery. See cocaine.
Though legal and traditionally well-established within the local societies, the unrestricted cultivation of coca in the Andes has been opposed since the 1980s by the United States government because the leaf can be refined into cocaine destined for the recreational drug market, which is illegal in most countries. The money derived from cocaine sales has been used by both left-wing and right-wing insurgent and paramilitary groups in the Andes to finance their operations, contributing significantly to political instability. The United States government has thus funded coca-eradication programs in Andean countries as a matter of policy, ranging from involuntary aerial spraying of herbicides on coca crops to programs designed to encourage local farmers to grow alternate crops.
Good fresh samples of the dried leaves are uncurled, are of a deep green on the upper, and a grey-green on the lower surface, and have a strong tea-like odor; when chewed they produce a pleasurable numbness in the mouth, and have a pleasant, pungent taste. They are traditionally chewed with lime to increase the release of cocaine from the leaf. Bad specimens, usually old or stale leaves, have a camphoraceous smell and a brownish colour, and lack the pungent taste.
The seeds are sown from December to January in small plots (almacigas) sheltered from the sun, and the young plants when at 40–60 cm in height are placed in final planting holes (aspi), or if the ground is level, in furrows (uachos) in carefully weeded soil. The plants thrive best in hot, damp and humid situations, such as the clearings of forests; but the leaves most preferred are obtained in drier localities, on the sides of hills. The leaves are gathered from plants varying in age from one and a half to upwards of forty years, but only the new fresh growth is harvested. They are considered ready for plucking when they break on being bent. The first and most abundant harvest is in March, after the rains; the second is at the end of June, the third in October or November. The green leaves (matu) are spread in thin layers on coarse woollen cloths and dried in the sun; they are then packed in sacks, which must be kept dry in order to preserve the quality of the leaves.
## Pharmacological aspects
The pharmacologically active ingredient of coca is the alkaloid cocaine which is found in the amount of about 0.2% in fresh leaves. Besides cocaine, the coca leaf contains a number of other alkaloids, including Methylecgonine cinnamate, Benzoylecgonine, Truxilline, Hydroxytropacocaine, Tropacocaine, Ecgonine, Cuscohygrine, Dihydrocuscohygrine, Nicotine and Hygrine. Some of these non-psychoactive chemicals are still used for the flavouring of Coca-Cola. When chewed, Coca acts as a stimulant to help suppress hunger sensations, thirst, and fatigue. The LD50 of coca extract is 3,450 mg/kg, however, the LD50 of the extract based on its cocaine content is 31.4 mg/kg.
## History
The chewing of coca leaves is generally agreed to date back at least to the sixth century A.D. Moche period, and the subsequent Inca period, based on mummies found with a supply of coca leaves, pottery depicting the characteristic cheek bulge of a coca chewer, spatulas for extracting alkali and figured bags for coca leaves and lime made from precious metals, and gold representations of coca in special gardens of the Inca in Cuzco Coca chewing may originally have been limited to the eastern Andes before its introduction to the Incas. As the plant was viewed as having a divine origin, its cultivation became subject to a state monopoly and its use restricted to nobles and a few favored classes (court orators, couriers, favored public workers, and the army) by the rule of the Topa Inca (1471-1493). As the Incan empire declined, the drug became more widely available. After some deliberation, Philip II of Spain issued a decree recognizing the drug as essential to the well-being of the Andean Indians but urging missionaries to end its religious use. The Spanish are believed to have effectively encouraged use of coca by an increasing majority of the population to increase their labor output and tolerance for starvation, but it is not clear that this was planned deliberately.
Traditional medical uses of coca were foremost as a stimulant to overcome exhaustion, hunger, and thirst. It also was used as an anaesthetic to alleviate the pain of rheumatism, wounds and sores, broken bones, sore eyes, childbirth, and during trephining operations on the skull. Because cocaine constricts blood vessels, the action of coca also served to oppose bleeding, and coca seeds were used for nosebleeds. Indigenous use of coca was also reported as a treatment for malaria, ulcers, asthma, to improve digestion, to guard against bowel laxity, as an aphrodisiac, and credited with improving longevity. European manufacturers of patent medicines eventually claimed an even wider variety of applications, and ultimately the plant was marketed to the public at large in soft drinks such as Coca-cola.
Typical coca consumption is about two ounces per day, and contemporary methods are believed to be unchanged from ancient times. Coca is kept in a woven pouch (chuspa or huallqui). A few leaves are chosen to form a quid (acullico) held between the mouth and gums. The consumer carefully uses a wooden stick (formerly, often a spatula of precious metal) to transfer an alkaline component into the quid without touching his flesh with the corrosive substance. The alkali component, usually kept in a gourd (ishcupuro or poporo), can be made by burning limestone to form unslaked quicklime, burning quinoa stalks, or the bark from certain trees, and may be called ilipta, tocra or mambe depending on its composition.
The practice of chewing coca was most likely originally a simple matter of survival. The coca leaf contains many essential nutrients in addition to its more well-known mood-altering alkaloid. It is rich in protein and vitamins, and it grows in regions where other food sources are scarce. The boost in energy and strength provided by the cocaine in coca leaves was also very functional in an area where oxygen is scarce and extensive walking is essential. This was also used to alleviate the feeling of hunger, sleepiness and headaches linked to altitude and other altitude sicknesses. The coca plant was so central to the world-view of the Yunga and Aymara tribes of South America that time and distance were often measured in "cocada", the 45-minute intervals at which fresh lumps of coca would be taken, or the distance one could travel in that period. In testament of the significance of coca to indigenous cultures, it is widely believed that the word "coca" originally meant "plant."
Coca was also a vital part of the religious cosmology of the Andean tribes in the pre-Inca period as well as throughout the Inca Empire (Tahuantinsuyu). Coca was historically employed as an offering to the Sun, or to produce smoke at the great sacrifices; and the priests, it was believed, must chew it during the performance of religious ceremonies, otherwise the gods would not be appeased.
## Traditional uses
The activity of chewing coca is called mambear, chacchar or acullicar, borrowed from Quechua, or in Bolivia, picchar, derived from the Aymara language. The Spanish masticar is also frequently used, along with the slang term "bolear," derived from the word "bola" or ball of coca pouched in the cheek while chewing. Doing so usually causes users to feel a tingling and numbing sensation in their mouths, similar to receiving Novocaine during a dental procedure. Even today, chewing coca leaves is a common sight in indigenous communities across the central Andean region, particularly in places like the mountains of Bolivia, where the cultivation and consumption of coca is as much a part of the national culture similar to chicha, like wine is to France or beer is to Germany. It also serves as a powerful symbol of indigenous cultural and religious identity, amongst a diversity of indigenous nations throughout South America. Bags of coca leaves are sold in local markets and by street vendors. Commercially manufactured coca teas are also available in most stores and supermarkets, including upscale suburban supermarkets.
Coca is still chewed in the traditional way, with a tiny quantity of ilucta added to the coca leaves; it softens their astringent flavor and activates the alkaloids. Other names for this basifying substance are llipta in Peru and the Spanish word lejía, lye in English. Many of these materials are salty in flavor, but there are variations. The most common base in the La Paz area of Bolivia is a product known as lejía dulce (sweet lye) which is made from quinoa ashes mixed with anise and cane sugar, forming a soft black putty with a sweet and pleasing licorice flavor. In some places, baking soda is used under the name bico.
Coca is still held in veneration among some of the indigenous and mestizo peoples of Peru, Bolivia, Ecuador, Colombia and northern Argentina and Chile. It is believed by the miners of Cerro de Pasco to soften the veins of ore, if masticated (chewed) and thrown upon them (see also Cocomama). Coca leaves play a crucial part in offerings to the apus (mountains), Inti (the sun), or Pachamama (the earth). Coca leaves are often read in a form of divination analogous to reading tea leaves in other cultures.
In the Sierra Nevada de Santa Marta, on the Caribbean Coast of Colombia, coca is consumed by the Kogi, Arhuaco & Wiwa by using a special gadget called poporo. The poporo is the mark of manhood, but it is a female symbolic sex. It represents the womb and the stick is a phallic symbol. The movements of the stick in the poporo symbolize the sexual act. For a man the poporo is a good companion which means "food", "woman", "memory" and "meditation". Women are prohibited from using coca. It is important to stress that poporo is the symbol of manhood. But it is the woman who gives men their manhood. When the boy is ready to be married, his mother will initiate him in the use of the coca. This act of initiation is carefully supervised by the mama, a traditional leader.
Mate de coca, sometimes called "coca tea", is a tisane made from the leaves of the Coca plant (Eritroxilécea). The consumption of coca tea is a common occurrence in many South American countries. Coca tea is also used for medicinal and religious purposes by many indigenous tribes in the Andes. On the "Inca Trail" to Macchu Picchu, guides also serve coca tea with every meal because it is widely believed that it alleviates the symptoms of mild altitude sickness. And traditionally, official governmental persons travelling to La Paz in Bolivia are greeted by a mate de coca. News reports noted that Princess Anne and the late Pope John Paul II drank the beverage during visits to the region. Recently (June 24 2007) chairman of Microsoft Corp. and multi-billionaire, Bill Gates drank Coca Tea in The Inti Raymi or Sun festival in Cusco Peru, which begins at Coricancha temple and ends at the Sacsayhuamán fortress, takes place every June 24. The event, with the participation of 600 actors, is to commemorate the the ancient Incan ritual in which the Sun God was worshipped.
## International use
Coca has a long history of export and use around the world—legal and illegal. Modern export of processed coca (as cocaine) to global markets is well documented, and coca leaves are exported for coca tea, as a food additive (Coca-Cola), and for medical use. Several pipes taken from Shakespeare's residence and dated to the seventeenth century have shown evidence of cocaine. Queen Victoria of England was also a cocaine user. The drug was first introduced to Europe in the 16th century.
In recent times, the governments of several South American countries, such as Peru, Bolivia and Venezuela, have defended and championed the traditional use of coca, as well as the modern uses of the leaf and its extracts in household products such as teas and toothpaste. Alan Garcia, president of Peru, has recommended its use in salads and other edible preparations.
## Industrial use
Coca is used industrially in the cosmetics and food industries. The Coca-Cola Company used to buy 115 tons of coca leaf from Peru and 105 tons from Bolivia per year, which it has used as a flavouring ingredient in its Coca-Cola formula. Coca is sold to the pharmaceutical industry where it is used for various anaesthetics. Coca is used to produce Coca tea by Enaco S.A. (National Company of the Coca) a government enterprise in Peru.
In Colombia, the Paeces, a Tierradentro (Cauca) indigenous community, started in December 2005 to produce a drink called "Coca Sek." The production method belongs to the resguardos of Calderas (Inzá) and takes about 150 kg of coca per 3,000 produced bottles.
## Literary References
One of the best known examples of coca's reference in literature is Patrick O'Brian's character, Stephen Maturin. In many of the more than twenty book series, a.k.a. Aubrey-Maturin series, Maturin expounds the benefits of coca. However, the reader is made aware of the truly addictive effects of the drug when rats, who have found the coca (Erythroxylum coca) and become seriously addicted, scourge the ship looking for it.
# Legality
## International
Article 26 of the Single Convention on Narcotic Drugs states:
- If a Party permits the cultivation of the coca bush, it shall apply thereto and to coca leaves the system of controls as provided in article 23 respecting the control of the opium poppy, but as regards paragraph 2 (d) of that article, the requirements imposed on the Agency therein referred to shall be only to take physical possession of the crops as soon as possible after the end of the harvest.
- The Parties shall so far as possible enforce the uprooting of all coca bushes which grow wild. They shall destroy the coca bushes if illegally cultivated.
The Article 23 controls referred to in paragraph 1 are rules requiring opium-, coca-, and cannabis-cultivating nations to designate an agency to regulate said cultivation and take physical possession of the crops as soon as possible after harvest. Article 27 states that "The Parties may permit the use of coca leaves for the preparation of a flavouring agent, which shall not contain any alkaloids, and, to the extent necessary for such use, may permit the production, import, export, trade in and possession of such leaves". This provision is designed to accommodate Coca-Cola and other producers of coca products.
In Bolivia, the president Evo Morales (elected in December, 2005), a former coca growers union leader, has promised to legalize the cultivation and traditional use of coca. Morales asserts that "coca no es cocaína"—the coca leaf is not cocaine. During his speech to the General Assembly of the United Nations on 19 September 2006, he held a coca leaf in his hand to demonstrate its innocuity.
In Hong Kong, Coca leaves are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purporses. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined HK$10,000. The penalty for trafficking or manufacturing the substance is a HK$5,000,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$1,000,000 fine and/or 7 years of imprisonment.
In Peru, private companies already manufacture coca leaf products.
More recently, coca has been reintroduced to the U.S. as a flavoring agent in the herbal liquer Agwa. Coca Leaf Tea is also currently for sale on Amazon.com through an independent distributor. | Coca
Coca is a plant in the family Erythroxylaceae, native to north-western South America. The plant plays a significant role in traditional Andean culture. It is used by Andean cultures such as the Quechuas of Peru as a messenger from the Gods, but is best-known in most of the world for the stimulant drug cocaine that is chemically extracted from its new fresh leaf tips in a similar fashion to tea bush harvesting. Unprocessed coca leaves are also commonly used in the Andean countries to make a herbal tea with mild stimulant effects similar to strong coffee.
The plant resembles a blackthorn bush, and grows to a height of 2–3 m (7–10 ft). The branches are straight, and the leaves, which have a green tint, are thin, opaque, oval, more or less tapering at the extremities. A marked characteristic of the leaf is an areolated portion bounded by two longitudinal curved lines, one line on each side of the midrib, and more conspicuous on the under face of the leaf.
The flowers are small, and disposed in little clusters on short stalks; the corolla is composed of five yellowish-white petals, the anthers are heart-shaped, and the pistil consists of three carpels united to form a three-chambered ovary. The flowers mature into red berries.
The leaves are sometimes eaten by the larvae of the moth Eloria noyesi.
# Species and classification
There are twelve main species and varieties. Two subspecies, Erythroxylum coca var. coca and E. coca var. ipadu, are almost indistinguishable phenotypically; a related high cocaine-bearing species has two subspecies, E. novogranatense var. novogranatense and E. novogranatense var. truxillense that are phenotypically similar, but morphologically distinguishable. Under the older Cronquist system of classifying flowering plants, this was placed in an order Linales; more modern systems place it in the order Malpighiales.
# Cultivation and uses
Coca is traditionally cultivated in the lower altitudes of the eastern slopes of the Andes, or the highlands depending on the species grown. Since ancient times, its leaves have been used as a stimulant by some of the Andean people of Peru, Colombia, Ecuador, Venezuela, Bolivia, where unprocessed coca remains legal and popular today as a common herbal tea with mild stimulant effects. In the highlands, coca tea and chewed leaves are used as a breathing aid to combat the effects of altitude sickness.
Coca leaf is the raw material for the manufacture of the drug cocaine, a powerful stimulant and anaesthetic extracted chemically from large quantities of coca leaves. Today, cocaine is best known as an illegal recreational drug popular in Europe and North America. Cocaine was often sold as a patent medicine in the late 19th and early 20th centuries before its proscription, and cocaine remains legal (though uncommon and highly regulated) for medical use as a local anaesthetic in many jurisdictions, used particularly for dental, throat, and nasal surgery. See cocaine.
Though legal and traditionally well-established within the local societies, the unrestricted cultivation of coca in the Andes has been opposed since the 1980s by the United States government because the leaf can be refined into cocaine destined for the recreational drug market, which is illegal in most countries. The money derived from cocaine sales has been used by both left-wing and right-wing insurgent and paramilitary groups in the Andes to finance their operations, contributing significantly to political instability. The United States government has thus funded coca-eradication programs in Andean countries as a matter of policy, ranging from involuntary aerial spraying of herbicides on coca crops to programs designed to encourage local farmers to grow alternate crops.
Good fresh samples of the dried leaves are uncurled, are of a deep green on the upper, and a grey-green on the lower surface, and have a strong tea-like odor; when chewed they produce a pleasurable numbness in the mouth, and have a pleasant, pungent taste. They are traditionally chewed with lime to increase the release of cocaine from the leaf. Bad specimens, usually old or stale leaves, have a camphoraceous smell and a brownish colour, and lack the pungent taste.
The seeds are sown from December to January in small plots (almacigas) sheltered from the sun, and the young plants when at 40–60 cm in height are placed in final planting holes (aspi), or if the ground is level, in furrows (uachos) in carefully weeded soil. The plants thrive best in hot, damp and humid situations, such as the clearings of forests; but the leaves most preferred are obtained in drier localities, on the sides of hills. The leaves are gathered from plants varying in age from one and a half to upwards of forty years, but only the new fresh growth is harvested. They are considered ready for plucking when they break on being bent. The first and most abundant harvest is in March, after the rains; the second is at the end of June, the third in October or November. The green leaves (matu) are spread in thin layers on coarse woollen cloths and dried in the sun; they are then packed in sacks, which must be kept dry in order to preserve the quality of the leaves.
## Pharmacological aspects
The pharmacologically active ingredient of coca is the alkaloid cocaine which is found in the amount of about 0.2% in fresh leaves. Besides cocaine, the coca leaf contains a number of other alkaloids, including Methylecgonine cinnamate, Benzoylecgonine, Truxilline, Hydroxytropacocaine, Tropacocaine, Ecgonine, Cuscohygrine, Dihydrocuscohygrine, Nicotine and Hygrine. Some of these non-psychoactive chemicals are still used for the flavouring of Coca-Cola. When chewed, Coca acts as a stimulant to help suppress hunger sensations, thirst, and fatigue. The LD50 of coca extract is 3,450 mg/kg, however, the LD50 of the extract based on its cocaine content is 31.4 mg/kg.
## History
The chewing of coca leaves is generally agreed to date back at least to the sixth century A.D. Moche period, and the subsequent Inca period, based on mummies found with a supply of coca leaves, pottery depicting the characteristic cheek bulge of a coca chewer, spatulas for extracting alkali and figured bags for coca leaves and lime made from precious metals, and gold representations of coca in special gardens of the Inca in Cuzco[1][2] Coca chewing may originally have been limited to the eastern Andes before its introduction to the Incas. As the plant was viewed as having a divine origin, its cultivation became subject to a state monopoly and its use restricted to nobles and a few favored classes (court orators, couriers, favored public workers, and the army) by the rule of the Topa Inca (1471-1493). As the Incan empire declined, the drug became more widely available. After some deliberation, Philip II of Spain issued a decree recognizing the drug as essential to the well-being of the Andean Indians but urging missionaries to end its religious use. The Spanish are believed to have effectively encouraged use of coca by an increasing majority of the population to increase their labor output and tolerance for starvation, but it is not clear that this was planned deliberately.
Traditional medical uses of coca were foremost as a stimulant to overcome exhaustion, hunger, and thirst. It also was used as an anaesthetic to alleviate the pain of rheumatism, wounds and sores, broken bones, sore eyes, childbirth, and during trephining operations on the skull. Because cocaine constricts blood vessels, the action of coca also served to oppose bleeding, and coca seeds were used for nosebleeds. Indigenous use of coca was also reported as a treatment for malaria, ulcers, asthma, to improve digestion, to guard against bowel laxity, as an aphrodisiac, and credited with improving longevity. European manufacturers of patent medicines eventually claimed an even wider variety of applications, and ultimately the plant was marketed to the public at large in soft drinks such as Coca-cola.
Typical coca consumption is about two ounces per day, and contemporary methods are believed to be unchanged from ancient times. Coca is kept in a woven pouch (chuspa or huallqui). A few leaves are chosen to form a quid (acullico) held between the mouth and gums. The consumer carefully uses a wooden stick (formerly, often a spatula of precious metal) to transfer an alkaline component into the quid without touching his flesh with the corrosive substance. The alkali component, usually kept in a gourd (ishcupuro or poporo), can be made by burning limestone to form unslaked quicklime, burning quinoa stalks, or the bark from certain trees, and may be called ilipta, tocra or mambe depending on its composition.[1][2]
The practice of chewing coca was most likely originally a simple matter of survival. The coca leaf contains many essential nutrients in addition to its more well-known mood-altering alkaloid. It is rich in protein and vitamins, and it grows in regions where other food sources are scarce. The boost in energy and strength provided by the cocaine in coca leaves was also very functional in an area where oxygen is scarce and extensive walking is essential. This was also used to alleviate the feeling of hunger, sleepiness and headaches linked to altitude and other altitude sicknesses. The coca plant was so central to the world-view of the Yunga and Aymara tribes of South America that time and distance were often measured in "cocada", the 45-minute intervals at which fresh lumps of coca would be taken, or the distance one could travel in that period. In testament of the significance of coca to indigenous cultures, it is widely believed that the word "coca" originally meant "plant."
Coca was also a vital part of the religious cosmology of the Andean tribes in the pre-Inca period as well as throughout the Inca Empire (Tahuantinsuyu). Coca was historically employed as an offering to the Sun, or to produce smoke at the great sacrifices; and the priests, it was believed, must chew it during the performance of religious ceremonies, otherwise the gods would not be appeased.
## Traditional uses
The activity of chewing coca is called mambear, chacchar or acullicar, borrowed from Quechua, or in Bolivia, picchar, derived from the Aymara language. The Spanish masticar is also frequently used, along with the slang term "bolear," derived from the word "bola" or ball of coca pouched in the cheek while chewing. Doing so usually causes users to feel a tingling and numbing sensation in their mouths, similar to receiving Novocaine during a dental procedure. Even today, chewing coca leaves is a common sight in indigenous communities across the central Andean region, particularly in places like the mountains of Bolivia, where the cultivation and consumption of coca is as much a part of the national culture similar to chicha, like wine is to France or beer is to Germany. It also serves as a powerful symbol of indigenous cultural and religious identity, amongst a diversity of indigenous nations throughout South America. Bags of coca leaves are sold in local markets and by street vendors. Commercially manufactured coca teas are also available in most stores and supermarkets, including upscale suburban supermarkets.
Coca is still chewed in the traditional way, with a tiny quantity of ilucta added to the coca leaves; it softens their astringent flavor and activates the alkaloids. Other names for this basifying substance are llipta in Peru and the Spanish word lejía, lye in English. Many of these materials are salty in flavor, but there are variations. The most common base in the La Paz area of Bolivia is a product known as lejía dulce (sweet lye) which is made from quinoa ashes mixed with anise and cane sugar, forming a soft black putty with a sweet and pleasing licorice flavor. In some places, baking soda is used under the name bico.
Coca is still held in veneration among some of the indigenous and mestizo peoples of Peru, Bolivia, Ecuador, Colombia and northern Argentina and Chile. It is believed by the miners of Cerro de Pasco to soften the veins of ore, if masticated (chewed) and thrown upon them (see also Cocomama). Coca leaves play a crucial part in offerings to the apus (mountains), Inti (the sun), or Pachamama (the earth). Coca leaves are often read in a form of divination analogous to reading tea leaves in other cultures.
In the Sierra Nevada de Santa Marta, on the Caribbean Coast of Colombia, coca is consumed by the Kogi, Arhuaco & Wiwa by using a special gadget called poporo. The poporo is the mark of manhood, but it is a female symbolic sex. It represents the womb and the stick is a phallic symbol. The movements of the stick in the poporo symbolize the sexual act. For a man the poporo is a good companion which means "food", "woman", "memory" and "meditation". Women are prohibited from using coca. It is important to stress that poporo is the symbol of manhood. But it is the woman who gives men their manhood. When the boy is ready to be married, his mother will initiate him in the use of the coca. This act of initiation is carefully supervised by the mama, a traditional leader.
Mate de coca, sometimes called "coca tea", is a tisane made from the leaves of the Coca plant (Eritroxilécea). The consumption of coca tea is a common occurrence in many South American countries. Coca tea is also used for medicinal and religious purposes by many indigenous tribes in the Andes. On the "Inca Trail" to Macchu Picchu, guides also serve coca tea with every meal because it is widely believed that it alleviates the symptoms of mild altitude sickness. And traditionally, official governmental persons travelling to La Paz in Bolivia are greeted by a mate de coca. News reports noted that Princess Anne and the late Pope John Paul II drank the beverage during visits to the region. Recently (June 24 2007) chairman of Microsoft Corp. and multi-billionaire, Bill Gates drank Coca Tea in The Inti Raymi or Sun festival in Cusco Peru, which begins at Coricancha temple and ends at the Sacsayhuamán fortress, takes place every June 24. The event, with the participation of 600 actors, is to commemorate the the ancient Incan ritual in which the Sun God was worshipped.
## International use
Coca has a long history of export and use around the world—legal and illegal. Modern export of processed coca (as cocaine) to global markets is well documented, and coca leaves are exported for coca tea, as a food additive (Coca-Cola), and for medical use. Several pipes taken from Shakespeare's residence and dated to the seventeenth century have shown evidence of cocaine. Queen Victoria of England was also a cocaine user. The drug was first introduced to Europe in the 16th century.
In recent times, the governments of several South American countries, such as Peru, Bolivia and Venezuela, have defended and championed the traditional use of coca, as well as the modern uses of the leaf and its extracts in household products such as teas and toothpaste. Alan Garcia, president of Peru, has recommended its use in salads and other edible preparations. [1]
## Industrial use
Coca is used industrially in the cosmetics and food industries. The Coca-Cola Company used to buy 115 tons of coca leaf from Peru and 105 tons from Bolivia per year, which it has used as a flavouring ingredient in its Coca-Cola formula. [2][3] Coca is sold to the pharmaceutical industry where it is used for various anaesthetics. Coca is used to produce Coca tea by Enaco S.A. (National Company of the Coca) a government enterprise in Peru.[4] [5]
In Colombia, the Paeces, a Tierradentro (Cauca) indigenous community, started in December 2005 to produce a drink called "Coca Sek." The production method belongs to the resguardos of Calderas (Inzá) and takes about 150 kg of coca per 3,000 produced bottles.
## Literary References
One of the best known examples of coca's reference in literature is Patrick O'Brian's character, Stephen Maturin. In many of the more than twenty book series, a.k.a. Aubrey-Maturin series, Maturin expounds the benefits of coca. However, the reader is made aware of the truly addictive effects of the drug when rats, who have found the coca (Erythroxylum coca) and become seriously addicted, scourge the ship looking for it.
# Legality
## International
Article 26 of the Single Convention on Narcotic Drugs states:
- If a Party permits the cultivation of the coca bush, it shall apply thereto and to coca leaves the system of controls as provided in article 23 respecting the control of the opium poppy, but as regards paragraph 2 (d) of that article, the requirements imposed on the Agency therein referred to shall be only to take physical possession of the crops as soon as possible after the end of the harvest.
- The Parties shall so far as possible enforce the uprooting of all coca bushes which grow wild. They shall destroy the coca bushes if illegally cultivated.
The Article 23 controls referred to in paragraph 1 are rules requiring opium-, coca-, and cannabis-cultivating nations to designate an agency to regulate said cultivation and take physical possession of the crops as soon as possible after harvest. Article 27 states that "The Parties may permit the use of coca leaves for the preparation of a flavouring agent, which shall not contain any alkaloids, and, to the extent necessary for such use, may permit the production, import, export, trade in and possession of such leaves". This provision is designed to accommodate Coca-Cola and other producers of coca products.
In Bolivia, the president Evo Morales (elected in December, 2005), a former coca growers union leader, has promised to legalize the cultivation and traditional use of coca. Morales asserts that "coca no es cocaína"—the coca leaf is not cocaine. During his speech to the General Assembly of the United Nations on 19 September 2006, he held a coca leaf in his hand to demonstrate its innocuity.[6]
In Hong Kong, Coca leaves are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purporses. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined HK$10,000. The penalty for trafficking or manufacturing the substance is a HK$5,000,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$1,000,000 fine and/or 7 years of imprisonment.
In Peru, private companies already manufacture coca leaf products.
More recently, coca has been reintroduced to the U.S. as a flavoring agent in the herbal liquer Agwa. Coca Leaf Tea is also currently for sale on Amazon.com through an independent distributor. | https://www.wikidoc.org/index.php/Coca |
Subsets and Splits