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73dd8a9faab9428efa9d4c358b62b71227456131 | wikidoc | Dock4 | Dock4
Dock4, (Dedicator of cytokinesis 4) also known as DOCK4, is a large (~190 kDa) protein involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock4 activates the small G proteins Rac and Rap1.
# Discovery
Dock4 was discovered as a gene product which was disrupted during tumour progression in a murine cancer model-derived osteosarcoma cell line. Subsequent Northern blot analysis revealed high levels of Dock4 expression in skeletal muscle, prostate and ovary as well as lower levels in the heart, placenta and colon. A separate study has reported expression of a Dock4 splice variant (Dock4-Ex49) in the brain, inner ear and eye.
# Structure and function
Dock4 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
The domain arrangement of Dock4 is largely equivalent to that of Dock180 (the archetypal member of the DOCK family) and other DOCK-A/B family members (35% sequence identity with Dock180, 39% with Dock2 and 54% with Dock3). Dock4, however, contains a unique set of motifs at its proline-rich C-terminus which include a Src-binding site that is shared with CED-5, the C. elegans ortholog of mammalian DOCK proteins. Dock4 also contains a DHR2 domain (also known as Docker2 or CZH2) which is conserved among DOCK family proteins and mediates GEF-dependent functions, and a DHR1 domain (CZH1/Docker1) which has been shown to bind PtdIns(3,4,5)P3, an important step in recruitment to the plasma membrane.
# Regulation of Dock4 activity
DOCK family proteins are inefficient at promoting nucleotide exchange on their own since they appear to adopt an autoinhibitory conformation in their resting state. The adaptor protein ELMO has been shown to bind DOCK proteins and induce a conformational change which relieves the inhibition and allows G proteins access to the DHR2 domain. Binding to ELMO requires the atypical PH domain of ELMO and also involves an interaction between the N-terminal SH3 domain of DOCK and a proline-rich motif at the ELMO C-terminus. ELMO also binds the activated form of the small G protein RhoG and this has been shown to promote DOCK-dependent signalling by helping recruit the ELMO-DOCK complex to areas of high substrate availability (usually the plasma membrane). The C-terminus of DOCK proteins interacts with another adaptor protein, Crk. Dock4 undergoes RhoG/ELMO-dependent recruitment to the plasma membrane and promotes migration in fibroblasts. In rat hippocampal neurones Dock4 forms a trimeric complex with ELMO2 and CrkII which is required for the normal development of dendrites. More recently, a role has been described for Dock4 as part of the Wnt signalling pathway which regulates cell proliferation and migration. In this system Dock4 was reported to undergo phosphorylation by Glycogen synthase kinase 3 (GSK-3) which stimulated an increase in Dock4 GEF activity.
# Signalling downstream of Dock4
DOCK family proteins contribute to cell signalling by activating G proteins of the Rho family, such as Rac and Cdc42. Dock4 has also been shown to activate Rap1, a feature not reported in any of the other DOCK family proteins to date. Dock4 dependent Rac activation regulates reorganisation of the cytoskeleton and leads to the formation of membrane protrusions (e.g. lamellipodia) which are a crucial step in neuronal development and cell migration. The effect of Dock4 on the Wnt pathway appears to be mediated through Rac activation as well as through GEF-independent associations with components of the "β-catenin degradation complex".
# Dock4 in cancer
Mutations in Dock4 have been described in a number of cancers. The exact mechanism and extent to which it regulates cancer-associated signalling pathways is poorly understood thus far although a mutation in Dock4 which affects its GEF specificity has been reported to promote detachment and invasion of cancer cells. | Dock4
Dock4, (Dedicator of cytokinesis 4) also known as DOCK4, is a large (~190 kDa) protein involved in intracellular signalling networks.[1] It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock4 activates the small G proteins Rac and Rap1.
# Discovery
Dock4 was discovered as a gene product which was disrupted during tumour progression in a murine cancer model-derived osteosarcoma cell line.[2] Subsequent Northern blot analysis revealed high levels of Dock4 expression in skeletal muscle, prostate and ovary as well as lower levels in the heart, placenta and colon. A separate study has reported expression of a Dock4 splice variant (Dock4-Ex49) in the brain, inner ear and eye.[3]
# Structure and function
Dock4 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
The domain arrangement of Dock4 is largely equivalent to that of Dock180 (the archetypal member of the DOCK family) and other DOCK-A/B family members (35% sequence identity with Dock180, 39% with Dock2 and 54% with Dock3[2]). Dock4, however, contains a unique set of motifs at its proline-rich C-terminus which include a Src-binding site that is shared with CED-5, the C. elegans ortholog of mammalian DOCK proteins.[2] Dock4 also contains a DHR2 domain (also known as Docker2 or CZH2) which is conserved among DOCK family proteins and mediates GEF-dependent functions, and a DHR1 domain (CZH1/Docker1) which has been shown to bind PtdIns(3,4,5)P3,[4] an important step in recruitment to the plasma membrane.
# Regulation of Dock4 activity
DOCK family proteins are inefficient at promoting nucleotide exchange on their own since they appear to adopt an autoinhibitory conformation in their resting state. The adaptor protein ELMO has been shown to bind DOCK proteins and induce a conformational change which relieves the inhibition and allows G proteins access to the DHR2 domain.[5] Binding to ELMO requires the atypical PH domain of ELMO and also involves an interaction between the N-terminal SH3 domain of DOCK and a proline-rich motif at the ELMO C-terminus.[6] ELMO also binds the activated form of the small G protein RhoG and this has been shown to promote DOCK-dependent signalling by helping recruit the ELMO-DOCK complex to areas of high substrate availability (usually the plasma membrane).[7] The C-terminus of DOCK proteins interacts with another adaptor protein, Crk.[8][9] Dock4 undergoes RhoG/ELMO-dependent recruitment to the plasma membrane and promotes migration in fibroblasts.[10] In rat hippocampal neurones Dock4 forms a trimeric complex with ELMO2 and CrkII which is required for the normal development of dendrites.[11] More recently, a role has been described for Dock4 as part of the Wnt signalling pathway which regulates cell proliferation and migration. In this system Dock4 was reported to undergo phosphorylation by Glycogen synthase kinase 3 (GSK-3) which stimulated an increase in Dock4 GEF activity.[12]
# Signalling downstream of Dock4
DOCK family proteins contribute to cell signalling by activating G proteins of the Rho family, such as Rac and Cdc42.[13] Dock4 has also been shown to activate Rap1,[2] a feature not reported in any of the other DOCK family proteins to date. Dock4 dependent Rac activation regulates reorganisation of the cytoskeleton and leads to the formation of membrane protrusions (e.g. lamellipodia) which are a crucial step in neuronal development and cell migration.[10][11] The effect of Dock4 on the Wnt pathway appears to be mediated through Rac activation as well as through GEF-independent associations with components of the "β-catenin degradation complex".[12]
# Dock4 in cancer
Mutations in Dock4 have been described in a number of cancers.[2][14][15] The exact mechanism and extent to which it regulates cancer-associated signalling pathways is poorly understood thus far although a mutation in Dock4 which affects its GEF specificity has been reported to promote detachment and invasion of cancer cells.[2] | https://www.wikidoc.org/index.php/Dock4 | |
619decf98fd264873d8442802ae94c152c00c739 | wikidoc | Dock6 | Dock6
Dock6 (Dedicator of cytokinesis 6), also known as Zir1 is a large (~200 kDa) protein involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors which function as activators of small G proteins.
# Discovery
Dock6 was identified as one of a family of proteins which share high sequence similarity with Dock180, the archetypal member of the DOCK family. It has a similar domain arrangement to other DOCK proteins, with a DHR1 domain known in other proteins to bind phospholipids, and a DHR2 domain containing the GEF activity.
# Function
There is currently very little information about the cellular role of this protein. However, Dock6 has been reported to exhibit dual GEF specificity towards the small G proteins Rac1 and Cdc42. It is the only DOCK family member reported to activate both of these G proteins. The same study also showed that transfection of the Dock6 DHR2 domain into N1E-115 neuroblastoma cells promoted Rac- and Cdc42-dependent neurite outgrowth, although the physiological significance of this has yet to be demonstrated. | Dock6
Dock6 (Dedicator of cytokinesis 6), also known as Zir1 is a large (~200 kDa) protein involved in intracellular signalling networks.[1] It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors which function as activators of small G proteins.
# Discovery
Dock6 was identified as one of a family of proteins which share high sequence similarity with Dock180, the archetypal member of the DOCK family.[2] It has a similar domain arrangement to other DOCK proteins,[3] with a DHR1 domain known in other proteins to bind phospholipids,[4] and a DHR2 domain containing the GEF activity.[5]
# Function
There is currently very little information about the cellular role of this protein. However, Dock6 has been reported to exhibit dual GEF specificity towards the small G proteins Rac1 and Cdc42.[6] It is the only DOCK family member reported to activate both of these G proteins. The same study also showed that transfection of the Dock6 DHR2 domain into N1E-115 neuroblastoma cells promoted Rac- and Cdc42-dependent neurite outgrowth, although the physiological significance of this has yet to be demonstrated. | https://www.wikidoc.org/index.php/Dock6 | |
625df043ad51a564b58e93b742aa347f639362fd | wikidoc | Dock7 | Dock7
Dock7 (Dedicator of cytokinesis 7), also known as Zir2, is a large (~240 kDa) protein involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock7 activates isoforms of the small G protein Rac.
# Discovery
Dock7 was identified as one of a number of proteins which share high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family. Dock7 expression has been reported in neurons and in the HEK 293 cell line.
# Structure and function
Dock7 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock7 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH-PH domains known to elicit nucleotide exchange. Instead they possess a DHR2 domain which mediates G protein activation by stabilising it in its nucleotide free state. They also contain a DHR1 domain which, in many DOCK family members, interacts with phospholipids. Dock7 shares the highest level of sequence similarity with Dock6 and Dock8, the other members of the DOCK-C subfamily. However, the specificity of the Dock7 DHR2 domain appears to resemble that of DOCK-A/B subfamily proteins in that it binds Rac but not Cdc42. Many DOCK family proteins contain important structural features at their N- and C-termini, however, these regions in Dock7 are poorly characterised thus far and no such features have been identified.
# Regulation of Dock7 Activity
Many members of the DOCK family are regulated by protein-protein interactions mediated via domains at their N- and C-termini, however, the mechanisms by which Dock7 is regulated are largely unknown. There is evidence that the production of PtdIns(3,4,5)P3 by members of the Phosphoinositide 3-kinase (PI3K) family is important for efficient recruitment of Dock7 since the PI3K inhibitor LY294002 was shown to block Dock7-dependent functions in neurons. This observation is consistent with the role of the DHR1 domain in other DOCK family proteins. In neurons of the hippocampus Dock7 undergoes striking changes in subcellular localisation during the progressive stages of neuronal development, resulting in an abundance of this protein in a single neurite which goes on to form the axon of the polarised neuron.
In Schwann cells (which generate an insulating layer, known as the myelin sheath, around axons of the peripheral nervous system) Dock7 appears to be activated downstream of the neuregulin receptor ErbB2, which receives signals from the axon that induce Schwann cell proliferation, migration and myelination. ErbB2 has been shown to tyrosine phosphorylate Dock7 and thus promote Schwann cell migration.
# Signalling downstream of Dock7
DOCK proteins are known activators of small G proteins of the Rho family. A study of Dock7 in HEK 293 cells and hippocampal neurons has shown that it can bind and promote nucleotide exchange on the Rac subfamily isoforms Rac1 and Rac3. This work suggests that Dock7 is a key mediator of the process that specifies which of the many neurites will become the axon. Indeed, overexpression of Dock7 induced the formation of multiple axons and RNA interference knock-down of Dock7 prevented axon formation. In Schwann cells Dock7 was shown to regulate the activation of Cdc42 as well as Rac1 however no direct interaction between Dock7 and Cdc42 has been demonstrated. Dock7 has also been reported to interact with the TSC1-TSC2 (also known as hamartin-tuberin) complex, the normal function of which is disrupted in sufferers of Tuberous sclerosis. It was subsequently suggested that Dock7 may function as a GEF for Rheb, a small G protein that functions downstream of the TSC1-TSC2 complex. Although DOCK family proteins are generally considered as GEFs specific for Rho family G proteins Dock4 has been shown to bind and activate Rap1, which is not a member of the Rho family. This apparent promiscuity among DOCK proteins and their targets, coupled with the fact that Rheb is highly expressed in the brain means that Dock7 GEF activity towards Rheb, although not yet demonstrated, would not be surprising. | Dock7
Dock7 (Dedicator of cytokinesis 7), also known as Zir2, is a large (~240 kDa) protein involved in intracellular signalling networks.[1] It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock7 activates isoforms of the small G protein Rac.
# Discovery
Dock7 was identified as one of a number of proteins which share high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family.[2] Dock7 expression has been reported in neurons[3][4] and in the HEK 293 cell line.[5]
# Structure and function
Dock7 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock7 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH-PH domains known to elicit nucleotide exchange. Instead they possess a DHR2 domain which mediates G protein activation by stabilising it in its nucleotide free state.[6] They also contain a DHR1 domain which, in many DOCK family members, interacts with phospholipids.[7] Dock7 shares the highest level of sequence similarity with Dock6 and Dock8, the other members of the DOCK-C subfamily. However, the specificity of the Dock7 DHR2 domain appears to resemble that of DOCK-A/B subfamily proteins in that it binds Rac but not Cdc42.[3] Many DOCK family proteins contain important structural features at their N- and C-termini, however, these regions in Dock7 are poorly characterised thus far and no such features have been identified.
# Regulation of Dock7 Activity
Many members of the DOCK family are regulated by protein-protein interactions mediated via domains at their N- and C-termini,[8] however, the mechanisms by which Dock7 is regulated are largely unknown. There is evidence that the production of PtdIns(3,4,5)P3 by members of the Phosphoinositide 3-kinase (PI3K) family is important for efficient recruitment of Dock7 since the PI3K inhibitor LY294002 was shown to block Dock7-dependent functions in neurons.[3] This observation is consistent with the role of the DHR1 domain in other DOCK family proteins. In neurons of the hippocampus Dock7 undergoes striking changes in subcellular localisation during the progressive stages of neuronal development, resulting in an abundance of this protein in a single neurite which goes on to form the axon of the polarised neuron.[3]
In Schwann cells (which generate an insulating layer, known as the myelin sheath, around axons of the peripheral nervous system) Dock7 appears to be activated downstream of the neuregulin receptor ErbB2, which receives signals from the axon that induce Schwann cell proliferation, migration and myelination. ErbB2 has been shown to tyrosine phosphorylate Dock7 and thus promote Schwann cell migration.[4]
# Signalling downstream of Dock7
DOCK proteins are known activators of small G proteins of the Rho family. A study of Dock7 in HEK 293 cells and hippocampal neurons has shown that it can bind and promote nucleotide exchange on the Rac subfamily isoforms Rac1 and Rac3.[3] This work suggests that Dock7 is a key mediator of the process that specifies which of the many neurites will become the axon. Indeed, overexpression of Dock7 induced the formation of multiple axons and RNA interference knock-down of Dock7 prevented axon formation. In Schwann cells Dock7 was shown to regulate the activation of Cdc42 as well as Rac1 however no direct interaction between Dock7 and Cdc42 has been demonstrated.[4] Dock7 has also been reported to interact with the TSC1-TSC2 (also known as hamartin-tuberin) complex, the normal function of which is disrupted in sufferers of Tuberous sclerosis.[5][9] It was subsequently suggested that Dock7 may function as a GEF for Rheb, a small G protein that functions downstream of the TSC1-TSC2 complex. Although DOCK family proteins are generally considered as GEFs specific for Rho family G proteins Dock4 has been shown to bind and activate Rap1,[10] which is not a member of the Rho family. This apparent promiscuity among DOCK proteins and their targets, coupled with the fact that Rheb is highly expressed in the brain means that Dock7 GEF activity towards Rheb, although not yet demonstrated, would not be surprising. | https://www.wikidoc.org/index.php/Dock7 | |
9faedf93a39dd056bf853a79398a7f8905183538 | wikidoc | Dock8 | Dock8
DOCK8 (Dedicator of cytokinesis 8), also known as Zir3, is a large (~190 kDa) protein involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins.
# Discovery
Dock8 was identified during a yeast two hybrid (YTH) screen for proteins that interact with the Rho family small G protein Cdc42. Subsequent northern blot analysis revealed high levels of Dock8 expression in the placenta, lung, kidney and pancreas as well as lower levels in the heart, brain and skeletal muscle.
# Function
Dock8 shares the same core domain arrangement as all other DOCK proteins, with a DHR2 domain which, in other proteins, contains GEF activity and a DHR1 domain known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1 and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay. This may be due to the fact many DOCK-G protein interactions require the presence of adaptor proteins to stabilise the complex and thus facilitate nucleotide exchange.
# Clinical significance
Mutation in DOCK8 Gene is associated with the autosomal recessive form of Job's syndrome or hyper-IgE Syndrome. It is manifested in infancy and the patient survives till late childhood or adolescence. The disease is characterised by eczema, recurrent cold staphylococcal abscesses, recurrent lung infections, coarse facies (thickened skin), primary teeth remnants (2 rows of teeth present), high IgE levels and eosinophilia.
# Somatic mutations
Despite the fact that little is known about the cellular role of Dock8 its importance has been highlighted in several studies which have identified disruption of the DOCK8 gene in disease. Deletion and reduced expression of Dock8 have been reported in a human lung cancer cell line and Dock8 was also identified as a putative candidate gene associated with progression of gliomas.
# Clinical significance of germline mutations
Autosomal recessive DOCK8 deficiency is associated with a variant of combined immunodeficiency. This variant of Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 and this clinical entity is known to be due to having biallelic germline mutations in the DOCK8 gene. HIES due to DOCK8-deficiency has a distinct clinical presentation compared to other forms of HIES and in inherited in an autosomal recessive manner.
The clinical manifestations of DOCK8 immunodefiency include recurrent infections, allergies, and malignancies. Nearly all patients have recurrent or chronic upper and lower respiratory tract infections, with many requiring sinus surgery and myringotomy tube placement. Recurrent lung infections may lead to bronchiectasis or damage to the airways leaving them widened and scarred. The cutaneous or skin infections are distinctive and include severe and difficult to treat viral infections, such as herpes simplex virus, human papilloma virus, and molluscum contagiosum; bacteria such as Staphylococcus aureus; as well as fungal infections of the mouth or skin with Candida. Eczema is common, and can be quite severe and further complicated by bacterial infection. Together, these skin infections can become disfiguring.
DOCK8 immunodefiency patients frequently have allergies to many food and environmental allergens, as well as asthma. Autoimmunity has been seen in some patients, such as autoimmune hemolytic anemia, as well as vasculitis and vasculopathy. Patients are also at increased risk for developing squamous cell carcinomas and lymphoid malignancies. Some but not all lymphomas are associated with poor control of the cancer-causing virus, Epstein–Barr. These cancer risks are significant and patients should be monitored closely for signs of malignancy.
This disorder is considered a combined immunodeficiency because it includes both decreased lymphocyte numbers and defective lymphocyte function. It can also be classified as a type of autosomal recessive hyperimmunoglobulinemia E syndrome. Laboratory manifestations include progressive lymphopenia that primarily affects CD4 and CD8 T cell subsets, reduced B cell and/or NK cell counts in some patients, eosinophilia, and immunoglobulin abnormalities. Antibody responses to vaccines are frequently poor. Loss of Dock8 protein expression can be demonstrated by diagnostic intracellular flow cytometry testing.
Once a diagnosis is made, treatment is based on an individual’s clinical condition and may include medication and other strategies for managing infections, allergies, and asthma. Supportive care includes prophylactic antimicrobials, and consideration of immune globulin replacement. Interferon alpha has been used for control of serious viral infections, such as widespread warts or herpes simplex virus. Hematopoietic stem cell transplant is curative in many primary immunodeficiencies and has successfully been used for patients with DOCK8 immunodefiency. | Dock8
DOCK8 (Dedicator of cytokinesis 8), also known as Zir3, is a large (~190 kDa) protein involved in intracellular signalling networks.[1] It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins.
# Discovery
Dock8 was identified during a yeast two hybrid (YTH) screen for proteins that interact with the Rho family small G protein Cdc42.[2] Subsequent northern blot analysis revealed high levels of Dock8 expression in the placenta, lung, kidney and pancreas as well as lower levels in the heart, brain and skeletal muscle.
# Function
Dock8 shares the same core domain arrangement as all other DOCK proteins, with a DHR2 domain which, in other proteins, contains GEF activity and a DHR1 domain known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1 and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay. This may be due to the fact many DOCK-G protein interactions require the presence of adaptor proteins to stabilise the complex and thus facilitate nucleotide exchange.[3]
# Clinical significance
Mutation in DOCK8 Gene is associated with the autosomal recessive form of Job's syndrome or hyper-IgE Syndrome. It is manifested in infancy and the patient survives till late childhood or adolescence. The disease is characterised by eczema, recurrent cold staphylococcal abscesses, recurrent lung infections, coarse facies (thickened skin), primary teeth remnants (2 rows of teeth present), high IgE levels and eosinophilia.
# Somatic mutations
Despite the fact that little is known about the cellular role of Dock8 its importance has been highlighted in several studies which have identified disruption of the DOCK8 gene in disease. Deletion and reduced expression of Dock8 have been reported in a human lung cancer cell line[4] and Dock8 was also identified as a putative candidate gene associated with progression of gliomas.[5]
# Clinical significance of germline mutations
Autosomal recessive DOCK8 deficiency is associated with a variant of combined immunodeficiency. This variant of Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 [6] and this clinical entity is known to be due to having biallelic germline mutations in the DOCK8 gene.[7] HIES due to DOCK8-deficiency has a distinct clinical presentation compared to other forms of HIES and in inherited in an autosomal recessive manner.
The clinical manifestations of DOCK8 immunodefiency include recurrent infections, allergies, and malignancies. Nearly all patients have recurrent or chronic upper and lower respiratory tract infections, with many requiring sinus surgery and myringotomy tube placement. Recurrent lung infections may lead to bronchiectasis or damage to the airways leaving them widened and scarred. The cutaneous or skin infections are distinctive and include severe and difficult to treat viral infections, such as herpes simplex virus, human papilloma virus, and molluscum contagiosum; bacteria such as Staphylococcus aureus; as well as fungal infections of the mouth or skin with Candida. Eczema is common, and can be quite severe and further complicated by bacterial infection. Together, these skin infections can become disfiguring.
DOCK8 immunodefiency patients frequently have allergies to many food and environmental allergens, as well as asthma. Autoimmunity has been seen in some patients, such as autoimmune hemolytic anemia, as well as vasculitis and vasculopathy. Patients are also at increased risk for developing squamous cell carcinomas and lymphoid malignancies. Some but not all lymphomas are associated with poor control of the cancer-causing virus, Epstein–Barr. These cancer risks are significant and patients should be monitored closely for signs of malignancy.
This disorder is considered a combined immunodeficiency because it includes both decreased lymphocyte numbers and defective lymphocyte function. It can also be classified as a type of autosomal recessive hyperimmunoglobulinemia E syndrome. Laboratory manifestations include progressive lymphopenia that primarily affects CD4 and CD8 T cell subsets, reduced B cell and/or NK cell counts in some patients, eosinophilia, and immunoglobulin abnormalities. Antibody responses to vaccines are frequently poor. Loss of Dock8 protein expression can be demonstrated by diagnostic intracellular flow cytometry testing.[7]
Once a diagnosis is made, treatment is based on an individual’s clinical condition and may include medication and other strategies for managing infections, allergies, and asthma. Supportive care includes prophylactic antimicrobials, and consideration of immune globulin replacement. Interferon alpha has been used for control of serious viral infections, such as widespread warts or herpes simplex virus. Hematopoietic stem cell transplant is curative in many primary immunodeficiencies and has successfully been used for patients with DOCK8 immunodefiency. | https://www.wikidoc.org/index.php/Dock8 | |
07d3021f5220e72b8a4efe0d2422f5117f8cca1f | wikidoc | Dock9 | Dock9
Dock9 (Dedicator of cytokinesis 9), also known as Zizimin1, is a large (~230 kDa) protein involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G proteins. Dock9 activates the small G protein Cdc42.
# Discovery
Dock9 was discovered using an affinity proteomic approach designed to identify novel activators of the small G protein Cdc42 in fibroblasts. Subsequent northern blot analysis revealed that Dock9 is expressed primarily in the brain, heart, skeletal muscle, kidney, placenta and lung. Lower levels were detected in the colon, thymus, liver, small intestine and in leukocytes from peripheral blood.
# Structure and Function
Dock9 shares a similar structure of two core domains (known as DHR1 and DHR2), which are shared by all DOCK family members. The C-terminal DHR2 domain functions as an atypical GEF domain for small G proteins (see Dock180: structure and function) and the DHR1 domain is known, in some DOCK-A/B/C subfamily proteins, to be involved in their recruitment to the plasma membrane. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain that mediates their recruitment to the membrane. Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 in vitro and in vivo via its DHR2 domain. However, Dock9 adopts an autoinhibitory conformation that masks the DHR2 domain in its resting state. The mechanism by which this autoinhibition is overcome is still unclear although in some other DOCK proteins, which also undergo autoinhibition, it requires an interaction with adaptor proteins such as ELMO. Dock9 has also been reported to dimerise, under resting conditions, via its DHR2 domains and this study suggests that other DOCK family proteins may also behave in the same way. Recent analysis of a chromosomal region associated with susceptibility to bipolar disorder revealed that single nucleotide polymorphisms in the DOCK9 gene contribute to the risk and severity of this condition. | Dock9
Dock9 (Dedicator of cytokinesis 9), also known as Zizimin1, is a large (~230 kDa) protein involved in intracellular signalling networks.[1] It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G proteins. Dock9 activates the small G protein Cdc42.
# Discovery
Dock9 was discovered using an affinity proteomic approach designed to identify novel activators of the small G protein Cdc42 in fibroblasts.[2] Subsequent northern blot analysis revealed that Dock9 is expressed primarily in the brain, heart, skeletal muscle, kidney, placenta and lung. Lower levels were detected in the colon, thymus, liver, small intestine and in leukocytes from peripheral blood.
# Structure and Function
Dock9 shares a similar structure of two core domains (known as DHR1 and DHR2), which are shared by all DOCK family members. The C-terminal DHR2 domain functions as an atypical GEF domain for small G proteins (see Dock180: structure and function) and the DHR1 domain is known, in some DOCK-A/B/C subfamily proteins, to be involved in their recruitment to the plasma membrane. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain that mediates their recruitment to the membrane.[3] Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 in vitro and in vivo via its DHR2 domain.[2] However, Dock9 adopts an autoinhibitory conformation that masks the DHR2 domain in its resting state.[3] The mechanism by which this autoinhibition is overcome is still unclear although in some other DOCK proteins, which also undergo autoinhibition, it requires an interaction with adaptor proteins such as ELMO.[4][5] Dock9 has also been reported to dimerise, under resting conditions, via its DHR2 domains and this study suggests that other DOCK family proteins may also behave in the same way.[6] Recent analysis of a chromosomal region associated with susceptibility to bipolar disorder revealed that single nucleotide polymorphisms in the DOCK9 gene contribute to the risk and severity of this condition.[7] | https://www.wikidoc.org/index.php/Dock9 | |
9a4dcb8d530f1f0756b82b15d9124c8f3478558a | wikidoc | Doubt | Doubt
# Overview
Doubt, a status between belief and disbelief, involves uncertainty or distrust or lack of sureness of a fact, an action, a motive, or a decision. Doubt brings into question some notion of a perceived "reality", and may involve delaying relevant action out of concerns for mistakes or faults.
The term "to doubt" can also mean "to question one's circumstances and life-experience".
# Impact on society
Doubt sometimes tends to call on reason. It may encourage people to hesitate before acting, and/or to apply more rigorous methods. Doubt may have particular importance as leading towards disbelief.
Politics, ethics and law, faced with important decisions that often determine the course of individual life, place great importance on doubt, and often foster elaborate adversarial processes to carefully sort through all the evidence to come to a decision.
One view regards the scientific method, and to a degree all of science, as entirely motivated by doubt: rather than accepting existing theories, scientists express systematic or habitual doubt (skepticism) and devise experiments to test (and, optimally, to disprove) any theory. Some commentators Template:Who? see technology as simply the expansion of the experiments to a wider user-base, which takes real risks with it. Users may no longer doubt the applicability of the theory in play, but there remain doubts about how it interacts with the real world. The process of technology-transfer stages exploitation of science to ensure the minimization of doubt and danger.
# Psychology
PsychoanalystsTemplate:Who? often attribute doubt, which they may interpret as a symptom of a phobia emanating from the ego, to childhood, when the ego develops. Childhood experiences, these traditions maintain, can plant doubt about one's abilities and even about one's very identity. The influence of parents and other influential figures often carries heavy connotations onto the resultant self-image of the child/ego, with doubts often included in such self-portrayals.
Cognitive mental as well as more spiritual approaches abound in response to the wide variety of potential causes for doubt — sometimes seen as a "Bad Thing". Behavioral therapy, in which a person systematically asks his own mind if the doubt has any real basis, uses rational, Socratic methods. Behavioral therapists claim that any constant confirmation leads to emotional detachment from the original doubt. This method contrasts to those of say, the Buddhist faith, which involve a more esoteric approach to doubt and inaction. Buddhism sees all doubt as a negative attachment to one's perceived past and future. To let go of the personal history of one's life (affirming this release every day in meditation) plays a central role in releasing the doubts — developed in and attached to — that history. Through much spiritual exertion, one can (if desired) dispel doubt, and live "only in the present".
## Psychopathology
Many people associate "excessive" doubt with obsessive-compulsive disorder, sometimes nicknamed a "disease of doubt".
# Philosophy
Anything that is questionable or causes doubt, especially an argument or a claim.
Branches of philosophy like logic devote much effort to distinguish the dubious, the probable and the certain. Much of illogic rests on dubious assumptions, dubious data or dubious conclusions, with rhetoric, whitewashing, and deception playing their accustomed roles.
## Religion
Doubt that god(s) exist forms the basis of agnosticism — possibly definable as the belief that one cannot determine the existence of god(s) — and atheism, which can entail either not believing in god(s) or believing that no god(s) exist(s).
By extension, doubt as to the existence or intentions of the Christian God applies to doubt concerning the Christian Bible as well, bringing into question its alleged status as the word of God, and propounding alternative explanations (such as a work of mythology like Homer's ancient Greek epics the Iliad and the Odyssey). Doubt of a religion itself brings into question the truth of its set of beliefs.
Christians often debate doubt in the contexts of salvation and eventual redemption in an afterlife. This issue has become particularly important in the Protestant version of the Christian faith, which requires only acceptance of Jesus as saviour and intermediary with God for a positive outcome. The debate appears less important in most other religions and ethical traditions.
## Spirituality
In the context of spirituality, people can see doubt as the opposite of faith. If faith represents a compulsion to follow a path, doubt may block that particular path. People use doubts and faith every day to choose the life path that they follow; for example: “I doubt that laziness will help me achieve my goals.”
Doubt can serve to create individual illusions to shield the vision of an unpleasant outcome. "I doubt anyone will catch me if I rob this store." Depending upon the energy put into the doubt, when used in this way, doubt itself has little impact on events and merely blocks the individual from seeing possibilities. | Doubt
Template:Emotion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Doubt, a status between belief and disbelief, involves uncertainty or distrust or lack of sureness of a fact, an action, a motive, or a decision. Doubt brings into question some notion of a perceived "reality", and may involve delaying relevant action out of concerns for mistakes or faults.
The term "to doubt" can also mean "to question one's circumstances and life-experience".
# Impact on society
Doubt sometimes tends to call on reason. It may encourage people to hesitate before acting, and/or to apply more rigorous methods. Doubt may have particular importance as leading towards disbelief.
Politics, ethics and law, faced with important decisions that often determine the course of individual life, place great importance on doubt, and often foster elaborate adversarial processes to carefully sort through all the evidence to come to a decision.
One view regards the scientific method, and to a degree all of science, as entirely motivated by doubt: rather than accepting existing theories, scientists express systematic or habitual doubt (skepticism) and devise experiments to test (and, optimally, to disprove) any theory. Some commentators Template:Who? see technology as simply the expansion of the experiments to a wider user-base, which takes real risks with it. Users may no longer doubt the applicability of the theory in play, but there remain doubts about how it interacts with the real world. The process of technology-transfer stages exploitation of science to ensure the minimization of doubt and danger.
# Psychology
PsychoanalystsTemplate:Who? often attribute doubt, which they may interpret as a symptom of a phobia emanating from the ego, to childhood, when the ego develops. Childhood experiences, these traditions maintain, can plant doubt about one's abilities and even about one's very identity. The influence of parents and other influential figures often carries heavy connotations onto the resultant self-image of the child/ego, with doubts often included in such self-portrayals.
Cognitive mental as well as more spiritual approaches abound in response to the wide variety of potential causes for doubt — sometimes seen as a "Bad Thing". Behavioral therapy, in which a person systematically asks his own mind if the doubt has any real basis, uses rational, Socratic methods. Behavioral therapists claim that any constant confirmation leads to emotional detachment from the original doubt. This method contrasts to those of say, the Buddhist faith, which involve a more esoteric approach to doubt and inaction. Buddhism sees all doubt as a negative attachment to one's perceived past and future. To let go of the personal history of one's life (affirming this release every day in meditation) plays a central role in releasing the doubts — developed in and attached to — that history. Through much spiritual exertion, one can (if desired) dispel doubt, and live "only in the present".
## Psychopathology
Many people associate "excessive" doubt with obsessive-compulsive disorder, sometimes nicknamed a "disease of doubt".
# Philosophy
Anything that is questionable or causes doubt, especially an argument or a claim.
Branches of philosophy like logic devote much effort to distinguish the dubious, the probable and the certain. Much of illogic rests on dubious assumptions, dubious data or dubious conclusions, with rhetoric, whitewashing, and deception playing their accustomed roles.
## Religion
Doubt that god(s) exist forms the basis of agnosticism — possibly definable as the belief that one cannot determine the existence of god(s) — and atheism, which can entail either not believing in god(s) or believing that no god(s) exist(s).
By extension, doubt as to the existence or intentions of the Christian God applies to doubt concerning the Christian Bible as well, bringing into question its alleged status as the word of God, and propounding alternative explanations (such as a work of mythology like Homer's ancient Greek epics the Iliad and the Odyssey). Doubt of a religion itself brings into question the truth of its set of beliefs.
Christians often debate doubt in the contexts of salvation and eventual redemption in an afterlife. This issue has become particularly important in the Protestant version of the Christian faith, which requires only acceptance of Jesus as saviour and intermediary with God for a positive outcome. The debate appears less important in most other religions and ethical traditions.
## Spirituality
In the context of spirituality, people can see doubt as the opposite of faith. If faith represents a compulsion to follow a path, doubt may block that particular path. People use doubts and faith every day to choose the life path that they follow; for example: “I doubt that laziness will help me achieve my goals.”
Doubt can serve to create individual illusions to shield the vision of an unpleasant outcome. "I doubt anyone will catch me if I rob this store." Depending upon the energy put into the doubt, when used in this way, doubt itself has little impact on events and merely blocks the individual from seeing possibilities. | https://www.wikidoc.org/index.php/Doubt | |
dc4ca8eb8f738ccc61cdd4614bd5a9038c2d6b76 | wikidoc | Doula | Doula
A doula is a non-medical assistant who provides physical, emotional and informational support in prenatal care, during childbirth and during the postpartum period.
# Etymology and history of usage
The word doula comes from Greek, and refers to a woman who personally serves as slave to another man or woman. In Greece, the word has negative connotations, denoting "slave", as some doulas have inadvertently discovered through their international social networks. For this reason, some women performing professional labor support choose to call themselves labor companions or birthworkers. Anthropologist Dana Raphael first used the term doula to refer to experienced mothers who assisted new mothers in breastfeeding and newborn care in the Philippines. Thus the term arose initially with reference to the postpartum context, and is still used in that domain. Medical researchers Marshall Klaus and John Kennell, who conducted the first of several randomized clinical trials on the medical outcomes of doula attended births, adopted the term to refer to labor support as well as prenatal and postpartum support.
# Types of doulas
Labor/birth support doulas are trained and experienced labor support persons who attend to the emotional and physical comfort needs of laboring women to smooth the labor process. They do not perform clinical tasks such as heart rate checks, or vaginal exams but rather use massage, aromatherapy, reflexology, positioning suggestions, etc., to help labor progress as well as possible. A labor/birth support doula joins a laboring woman either at her home or in hospital or birth center and remains with her until a few hours after the birth. Some doulas also offer several prenatal visits, phone support, and one postpartum meeting to ensure the mother is well informed and supported. The terms of a labor/birth doula's responsibilities are decided between the doula and the family. In addition to emotional, physical and informational support, doulas work as advocates of their client’s wishes and may assist in communicating with medical staff to obtain information for the client to make informed decisions regarding medical procedures.
Postpartum doulas are hired to support the woman after birth, usually in the family's home. They are trained to offer families evidence-based information and support on breastfeeding, emotional and physical recovery from childbirth, infant soothing and coping skills for new parents. They may also help with light housework, fix a meal and help incorporate an older child into this new experience. The terms of a postpartum doula's responsibilities are decided between the doula and the family.
Some hospitals and foundations offer program for volunteer community doulas . Volunteer doulas play an important role for women at risk for complications, and those facing financial barriers to additional labor support. These doulas will offer continuous encouragement and reassurance to laboring women. In this way, volunteer doulas can encourage mother based birth advocacy, and motivate a woman to feel in control of her pregnancy.
The doula is not meant to sideline or replace the father/significant other. Their respective roles are similar, but the differences are crucial. The father or partner may be better able to provide continuous support, but typically has little actual experience in dealing with the often-subtle forces of the labor process. Even more important, many fathers experience the birth as an emotional journey of their own and find it hard to be objective in such a situation. Studies have shown that fathers usually participate more actively during labor with the presence of a doula than without one. A responsible doula supports and encourages the father in his support style rather than replaces him.
# Labor/Births Doulas in the U.S. and Canada
In the United States and Canada, labor/birth doulas are not required to be certified, however certification is available through several different organizations . A labor doula provides:
- Continuous physical, emotional, and informational support during labor and childbirth.
- Support from a professional care provider who understands, and trusts the process of birth, and who helps facilitate the birth experience for the parents, baby, and primary care providers.
- Explanations of medical procedures and interventions;
- Emotional support;
- Advice during pregnancy;
- Exercise and physical suggestions to make pregnancy and childbirth more comfortable;
- Help with preparation of a birth plan;
- Facilitation of communication between members of laboring woman's birth team;
- Massage and other non-pharmacological pain relief measures, aromatherapy, any other non-medical comfort techniques she may be trained in;
- Positioning suggestions during labor and birth;
- Support the partner so that s/he can provide support and encouragement to the laboring woman;
- Help to avoid unnecessary interventions;
- Help with breastfeeding preparation and beginning;
- Some doulas offer a written record of the birth (birth story);
- Is present during entire labor and afterwards as long as is needed by parent(s).
## Postpartum Doulas in the U.S. and Canada
In the United States and Canada, postpartum birth doulas are not required to be certified, however certification is available through several different organizations. A postpartum doula provides:
- Assistance with breastfeeding education and offers tips and informational support
- In home support for the mother, baby and family, any where from a couple days postpartum to several months.
- Informed and helpful newborn care help and assistance.
- Support for the partner so that s/he can support and nurture the mother, and the newborn baby.
- Evidence-based information with the partner that shows how his or her role in the early weeks will have a dramatic positive effect on the family.
- May also offer help in the following areas: household care, help with childcare/sibling care, meal preparation, errand running, and other tasks that may be requested. | Doula
A doula is a non-medical assistant who provides physical, emotional and informational support in prenatal care, during childbirth and during the postpartum period.
# Etymology and history of usage
The word doula comes from Greek, and refers to a woman who personally serves as slave to another man or woman. In Greece, the word has negative connotations, denoting "slave", as some doulas have inadvertently discovered through their international social networks. For this reason, some women performing professional labor support choose to call themselves labor companions or birthworkers. Anthropologist Dana Raphael first used the term doula to refer to experienced mothers who assisted new mothers in breastfeeding and newborn care in the Philippines[citation needed]. Thus the term arose initially with reference to the postpartum context, and is still used in that domain. Medical researchers Marshall Klaus and John Kennell, who conducted the first of several randomized clinical trials on the medical outcomes of doula attended births, adopted the term to refer to labor support as well as prenatal and postpartum support.[1]
# Types of doulas
Labor/birth support doulas are trained and experienced labor support persons who attend to the emotional and physical comfort needs of laboring women to smooth the labor process. They do not perform clinical tasks such as heart rate checks, or vaginal exams but rather use massage, aromatherapy, reflexology, positioning suggestions, etc., to help labor progress as well as possible. A labor/birth support doula joins a laboring woman either at her home or in hospital or birth center and remains with her until a few hours after the birth. Some doulas also offer several prenatal visits, phone support, and one postpartum meeting to ensure the mother is well informed and supported. The terms of a labor/birth doula's responsibilities are decided between the doula and the family. In addition to emotional, physical and informational support, doulas work as advocates of their client’s wishes and may assist in communicating with medical staff to obtain information for the client to make informed decisions regarding medical procedures.
Postpartum doulas are hired to support the woman after birth, usually in the family's home. They are trained to offer families evidence-based information and support on breastfeeding, emotional and physical recovery from childbirth, infant soothing and coping skills for new parents. They may also help with light housework, fix a meal and help incorporate an older child into this new experience. The terms of a postpartum doula's responsibilities are decided between the doula and the family.
Some hospitals and foundations offer program for volunteer community doulas [1]. Volunteer doulas play an important role for women at risk for complications, and those facing financial barriers to additional labor support. These doulas will offer continuous encouragement and reassurance to laboring women. In this way, volunteer doulas can encourage mother based birth advocacy, and motivate a woman to feel in control of her pregnancy.
The doula is not meant to sideline or replace the father/significant other. Their respective roles are similar, but the differences are crucial. The father or partner may be better able to provide continuous support, but typically has little actual experience in dealing with the often-subtle forces of the labor process. Even more important, many fathers experience the birth as an emotional journey of their own and find it hard to be objective in such a situation. Studies have shown that fathers usually participate more actively during labor with the presence of a doula than without one.[citation needed] A responsible doula supports and encourages the father in his support style rather than replaces him.
# Labor/Births Doulas in the U.S. and Canada
In the United States and Canada, labor/birth doulas are not required to be certified, however certification is available [2] through several different organizations [3]. A labor doula provides:
- Continuous physical, emotional, and informational support during labor and childbirth.
- Support from a professional care provider who understands, and trusts the process of birth, and who helps facilitate the birth experience for the parents, baby, and primary care providers.
- Explanations of medical procedures and interventions;
- Emotional support;
- Advice during pregnancy;
- Exercise and physical suggestions to make pregnancy and childbirth more comfortable;
- Help with preparation of a birth plan;
- Facilitation of communication between members of laboring woman's birth team;
- Massage and other non-pharmacological pain relief measures, aromatherapy, any other non-medical comfort techniques she may be trained in;
- Positioning suggestions during labor and birth;
- Support the partner so that s/he can provide support and encouragement to the laboring woman;
- Help to avoid unnecessary interventions;
- Help with breastfeeding preparation and beginning;
- Some doulas offer a written record of the birth (birth story);
- Is present during entire labor and afterwards as long as is needed by parent(s).
## Postpartum Doulas in the U.S. and Canada
In the United States and Canada, postpartum birth doulas are not required to be certified, however certification is available through several different organizations. A postpartum doula provides:
- Assistance with breastfeeding education and offers tips and informational support
- In home support for the mother, baby and family, any where from a couple days postpartum to several months.
- Informed and helpful newborn care help and assistance.
- Support for the partner so that s/he can support and nurture the mother, and the newborn baby.
- Evidence-based information with the partner that shows how his or her role in the early weeks will have a dramatic positive effect on the family.
- May also offer help in the following areas: household care, help with childcare/sibling care, meal preparation, errand running, and other tasks that may be requested. | https://www.wikidoc.org/index.php/Doula | |
b4375aadb2af309438563c14d6225105a5c80d08 | wikidoc | Dylar | Dylar
Dylar is a fictional psychoactive drug that appears in Don DeLillo's novel White Noise.
Dylar is intended to remove the fear of death. However, the drug does not work properly and extended use sometimes results in insanity. Extended users interpret spoken words and metaphor as actual actions and events. In an instance presented in the novel, the spoken phrase "hail of bullets" causes a Dylar-using character to panic, drop to the floor and crawl to shelter.
The drug is only produced on an experimental, highly secretive basis and comes in the form of a small white pill with an insoluble polymer coating containing only a minute hole. During digestion water enters through the polymer coating and the active ingredients begin to dissolve, but can only leave the polymer coating through the tiny laser drilled hole, creating a highly controlled release of the chemical. When empty, the coating collapses in on itself and passes harmlessly out through the digestive tract. | Dylar
Dylar is a fictional psychoactive drug that appears in Don DeLillo's novel White Noise.
Dylar is intended to remove the fear of death. However, the drug does not work properly and extended use sometimes results in insanity. Extended users interpret spoken words and metaphor as actual actions and events. In an instance presented in the novel, the spoken phrase "hail of bullets" causes a Dylar-using character to panic, drop to the floor and crawl to shelter.
The drug is only produced on an experimental, highly secretive basis and comes in the form of a small white pill with an insoluble polymer coating containing only a minute hole. During digestion water enters through the polymer coating and the active ingredients begin to dissolve, but can only leave the polymer coating through the tiny laser drilled hole, creating a highly controlled release of the chemical. When empty, the coating collapses in on itself and passes harmlessly out through the digestive tract.
Template:Fictional-stub | https://www.wikidoc.org/index.php/Dylar | |
48610fc67990fdf56289067cda97713ea34b66f1 | wikidoc | EC-No | EC-No
The terms EC-No and EC# refer to the seven-digit code (sometimes called the EC number) that has been allocated by the Commission of the European Communities for commercially available chemical substances within the European Union. The European EC Number should not be confused with the Enzyme Commission EC number for enzymes.
The "EC#" designation supersedes the outmoded EINECS and ELINCS designations, and the EC# codes include those on the
so-called No-longer Polymers List, a list of substances that were on the European market between 18 September 1981 and 31 October 1993 and at the time were regarded as polymers, but are no longer regarded as such.
# Format
The EC# is made up of seven digits according to the pattern xxx-xxx-x.
EINECs numbers start with number 200-001-8.
ELINCS numbers start with 400-010-9
Numbers in the No-longer Polymers List start with 500-001-0.
The EC/EINECS/ELINCS Number may be written in a general form as:
in which R is the check digit and N represents a fundamental sequential number. The check digit is the remainder of the following sum after division by 11: | EC-No
The terms EC-No and EC# refer to the seven-digit code (sometimes called the EC number) that has been allocated by the Commission of the European Communities for commercially available chemical substances within the European Union. The European EC Number should not be confused with the Enzyme Commission EC number for enzymes.
The "EC#" designation supersedes the outmoded EINECS and ELINCS designations, and the EC# codes include those on the
so-called No-longer Polymers List, a list of substances that were on the European market between 18 September 1981 and 31 October 1993 and at the time were regarded as polymers, but are no longer regarded as such.
# Format
The EC# is made up of seven digits according to the pattern xxx-xxx-x.
EINECs numbers start with number 200-001-8.
ELINCS numbers start with 400-010-9
Numbers in the No-longer Polymers List start with 500-001-0.
The EC/EINECS/ELINCS Number may be written in a general form as:
in which R is the check digit and N represents a fundamental sequential number. The check digit is the remainder of the following sum after division by 11: | https://www.wikidoc.org/index.php/EC-No | |
238f2e230e68f62a7a6dbb2715e0464cc4fa2ab1 | wikidoc | ECGF1 | ECGF1
Thymidine phosphorylase is an enzyme that in humans is encoded by the TYMP gene.
Platelet-derived endothelial cell growth factor (ECGF1) is an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. ECGF1 has a highly restricted target cell specificity acting only on endothelial cells.
Because it limits glial cell proliferation, ECGF1 is also known as thymidine phosphorylase and as gliostatin. The ECGF1 gene contains 10 exons spanning more than 4.3 kb. Thymidine phosphorylase activity of ECGF1 in leukocytes from mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients was less than 5 percent of controls, indicating that loss-of-function mutations in thymidine phosphorylase cause MNGIE.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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} | ECGF1
Thymidine phosphorylase is an enzyme that in humans is encoded by the TYMP gene.[1][2]
Platelet-derived endothelial cell growth factor (ECGF1) is an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. ECGF1 has a highly restricted target cell specificity acting only on endothelial cells.
Because it limits glial cell proliferation, ECGF1 is also known as thymidine phosphorylase and as gliostatin. The ECGF1 gene contains 10 exons spanning more than 4.3 kb. Thymidine phosphorylase activity of ECGF1 in leukocytes from mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients was less than 5 percent of controls, indicating that loss-of-function mutations in thymidine phosphorylase cause MNGIE.[3]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/ECGF1 | |
0375d37691bd8efcb6c4fca61a440dd32bbd8493 | wikidoc | ECHS1 | ECHS1
Enoyl Coenzyme A hydratase, short chain, 1, mitochondrial, also known as ECHS1, is a human gene.
The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature.
# Structure
The ECHS1 gene is approximately 11 kb in length, and is composed of eight exons, with exons I and VIII containing the 5'- and 3'-untranslated regions, respectively. There are two major transcription start sites, located 62 and 63 bp upstream of the translation codon, were mapped by primer extension analysis. The 5'-flanking region of the ECHS1 gene is GC-rich and contains several copies of the SP1 binding motive but no typical TATA or CAAT boxes are apparent. Alu repeat elements have been identified within the region -1052/-770 relative to the cap site and in intron 7. The precursor polypeptide contains 290 amino acid residues, with an N-terminal presequence of 29 residues, a 5'-untranslated sequence of 21 bp and a 3'-untranslated sequence of 391 bp.
# Function
Enoyl-CoA hydratase (ECH) catalyzes the second step in beta-oxidation pathway of fatty acid metabolism. The enzyme is involved in the formation of a β-hydroxyacyl-CoA thioester. The two catalytic glutamic acid residues are believed to act in concert to activate a water molecule, while Gly-141 is proposed to be involved in substrate activation. There are two potent inhibitors of ECHS, which irreversibly inactivate the enzyme via covalent adduct formation.
# Clinical significance
Enoyl-CoA hydratase short chain has been confirmed to interact with STAT3, such that ECHS1 specifically represses STAT3 activity by inhibiting STAT3 phosphorylation. STAT3 can act as both an oncogene and a tumor suppressor. ECHS1 itself has shown to occur in many cancers, particularly in hypatocellular carcinoma (HCC) development; both exogenous and endogenous forms of ECHS1 bind to HBs and induce apoptosis as a result. This means that ECHS1 may be used in the future as a therapy for patients with HBV-related hepatitis or HCC. | ECHS1
Enoyl Coenzyme A hydratase, short chain, 1, mitochondrial, also known as ECHS1, is a human gene.[1]
The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature.[1]
# Structure
The ECHS1 gene is approximately 11 kb in length, and is composed of eight exons, with exons I and VIII containing the 5'- and 3'-untranslated regions, respectively. There are two major transcription start sites, located 62 and 63 bp upstream of the translation codon, were mapped by primer extension analysis. The 5'-flanking region of the ECHS1 gene is GC-rich and contains several copies of the SP1 binding motive but no typical TATA or CAAT boxes are apparent. Alu repeat elements have been identified within the region -1052/-770 relative to the cap site and in intron 7.[2] The precursor polypeptide contains 290 amino acid residues, with an N-terminal presequence of 29 residues, a 5'-untranslated sequence of 21 bp and a 3'-untranslated sequence of 391 bp.[3]
# Function
Enoyl-CoA hydratase (ECH) catalyzes the second step in beta-oxidation pathway of fatty acid metabolism. The enzyme is involved in the formation of a β-hydroxyacyl-CoA thioester. The two catalytic glutamic acid residues are believed to act in concert to activate a water molecule, while Gly-141 is proposed to be involved in substrate activation. There are two potent inhibitors of ECHS, which irreversibly inactivate the enzyme via covalent adduct formation.[4]
# Clinical significance
Enoyl-CoA hydratase short chain has been confirmed to interact with STAT3, such that ECHS1 specifically represses STAT3 activity by inhibiting STAT3 phosphorylation.[5] STAT3 can act as both an oncogene and a tumor suppressor. ECHS1 itself has shown to occur in many cancers, particularly in hypatocellular carcinoma (HCC) development;[6] both exogenous and endogenous forms of ECHS1 bind to HBs and induce apoptosis as a result. This means that ECHS1 may be used in the future as a therapy for patients with HBV-related hepatitis or HCC.[7] | https://www.wikidoc.org/index.php/ECHS1 | |
13505d0d50ab4c9ae3667151eba6184aca39b37d | wikidoc | ECSIT | ECSIT
Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT), also known as SITPEC, is a protein that in humans is encoded by the ECSIT gene. ECSIT is a cytosolic adaptor protein involved in inflammatory responses, embryonic development, and the assembly and stabilization of mitochondrial NADH:ubiquinone oxidoreductase (complex I).
# Structure
ECSIT is located on the p arm of chromosome 19 in position 13.2 and has 9 exons. The ECSIT gene produces a 49 kDa protein composed of 431 amino acids. ECSIT's interactions with p65/p50 NF-κB proteins is dependent on lysine 372 ubiquitination. ECSIT also contains an N-terminal targeting signal that causes it to localize to mitochondria where only the 45 kDa mitochondrial ECSIT is found to interact.
# Function
ECSIT has been found to play multiple roles in cell-signaling, including those that utilize Toll-like receptors (TLRs), TGF-β, and BMP. ECSIT plays a regulatory role as part of the TAK1-ECSIT-TRAF6 complex that is involved in the activation of NF-κB by the TLR4 signal and through its interactions with TRIM59 to negatively regulate NF-κB, IRF-3, and IRF-7-mediated signal pathways. Additionally, ECSIT appears to contribute to bactericidal activity in TLR signaling through its interaction with tumor necrosis factor receptor-associated factor 6 (TRAF6). Importantly, ubiquitination of ECSIT has shown itself to be necessary for the activation of p65/p50 NF-κBs in TLR4 signaling. Functioning as a scaffold protein, ECSIT is also essential for the association of RIG-I-like receptors (RIG-I or MDA5) to VISA. The bridging of these receptors to VISA is an important signaling event used in innate antiviral responses. Apart from inflammatory and immune responses, ECSIT, in its 45 kDa, mitochondrial form helps maintain assembly chaperone NDUFAF1's stable presence in the mitochondrion. Through this interaction, ECSIT is demonstrated to play an important role in NADH:ubiquinone oxidoreductase (complex I) assembly and stabilization. Finally, it is important to note that ECSIT is required for normal embryonic development.
# Interactions
ECSIT has 136 protein-protein interactions, with 53 of them being co-complex interactions. | ECSIT
Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT), also known as SITPEC, is a protein that in humans is encoded by the ECSIT gene.[1] ECSIT is a cytosolic adaptor protein involved in inflammatory responses, embryonic development, and the assembly and stabilization of mitochondrial NADH:ubiquinone oxidoreductase (complex I).[2]
# Structure
ECSIT is located on the p arm of chromosome 19 in position 13.2 and has 9 exons.[3] The ECSIT gene produces a 49 kDa protein composed of 431 amino acids.[4] ECSIT's interactions with p65/p50 NF-κB proteins is dependent on lysine 372 ubiquitination.[5] ECSIT also contains an N-terminal targeting signal that causes it to localize to mitochondria where only the 45 kDa mitochondrial ECSIT is found to interact.[2]
# Function
ECSIT has been found to play multiple roles in cell-signaling, including those that utilize Toll-like receptors (TLRs), TGF-β, and BMP. ECSIT plays a regulatory role as part of the TAK1-ECSIT-TRAF6 complex that is involved in the activation of NF-κB by the TLR4 signal and through its interactions with TRIM59 to negatively regulate NF-κB, IRF-3, and IRF-7-mediated signal pathways.[6][7] Additionally, ECSIT appears to contribute to bactericidal activity in TLR signaling through its interaction with tumor necrosis factor receptor-associated factor 6 (TRAF6). Importantly, ubiquitination of ECSIT has shown itself to be necessary for the activation of p65/p50 NF-κBs in TLR4 signaling.[5] Functioning as a scaffold protein, ECSIT is also essential for the association of RIG-I-like receptors (RIG-I or MDA5) to VISA. The bridging of these receptors to VISA is an important signaling event used in innate antiviral responses.[8] Apart from inflammatory and immune responses, ECSIT, in its 45 kDa, mitochondrial form helps maintain assembly chaperone NDUFAF1's stable presence in the mitochondrion. Through this interaction, ECSIT is demonstrated to play an important role in NADH:ubiquinone oxidoreductase (complex I) assembly and stabilization.[2] Finally, it is important to note that ECSIT is required for normal embryonic development.[1]
# Interactions
ECSIT has 136 protein-protein interactions, with 53 of them being co-complex interactions.[citation needed][9] | https://www.wikidoc.org/index.php/ECSIT | |
071b0b550c081873ff43892fe2347eba7b7a2e3c | wikidoc | EEF1D | EEF1D
Elongation factor 1-delta is a protein that in humans is encoded by the EEF1D gene.
# Function
This gene encodes a subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This subunit functions as guanine nucleotide exchange factor. It is reported that this subunit interacts with HIV-1 Tat, and thus it represses the translation of host-cell, but not HIV-1, mRNAs. Several alternatively spliced transcript variants have been found for this gene, however, the full length nature of only two variants has been determined.
# Interactions
EEF1D has been shown to interact with Glycyl-tRNA synthetase, EEF1G and KTN1, and is predicted to interact with TMEM63A. | EEF1D
Elongation factor 1-delta is a protein that in humans is encoded by the EEF1D gene.[1]
# Function
This gene encodes a subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This subunit functions as guanine nucleotide exchange factor. It is reported that this subunit interacts with HIV-1 Tat, and thus it represses the translation of host-cell, but not HIV-1, mRNAs. Several alternatively spliced transcript variants have been found for this gene, however, the full length nature of only two variants has been determined.[2]
# Interactions
EEF1D has been shown to interact with Glycyl-tRNA synthetase,[3] EEF1G[4][5] and KTN1,[6] and is predicted to interact with TMEM63A.[7] | https://www.wikidoc.org/index.php/EEF1D | |
8c7c78fb9b96cf304b8bad669ce225cb02176f12 | wikidoc | EEF2K | EEF2K
Eukaryotic elongation factor-2 kinase (eEF-2 kinase or eEF-2K), also known as calmodulin-dependent protein kinase III (CAMKIII) and calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase, is an enzyme that in humans is encoded by the EEF2K gene.
# Function
eEF-2 kinase is a highly conserved protein kinase in the calmodulin-mediated signaling pathway that links multiple up-stream signals to the regulation of protein synthesis. It phosphorylates eukaryotic elongation factor 2 (EEF2) and thus inhibits the EEF2 function.
# Activation
The activity of eEF-2K is dependent on calcium and calmodulin. Activation of eEF-2K proceeds by a sequential two-step mechanism. First, calcium-calmodulin binds with high affinity to activate the kinase domain, triggering rapid autophosphorylation of Thr-348. In the second step, autophosphorylation of Thr-348 leads to a conformational change in the kinase likely supported by the binding of phospho-Thr-348 to an allosteric phosphate binding pocket in the kinase domain. This increases the activity of eEF-2K against its substrate, elongation factor 2.
eEF-2K can gain calcium-independent activity through autophosphorylation of Ser-500. However, calmodulin must remain bound to the enzyme for its activity to be sustained.
# Clinical significance
The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.
It is also suggested that eEF-2K may play a role the rapid anti-depressant effects of ketamine through its regulation of neuronal protein synthesis.
# Cancer
eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis. | EEF2K
Eukaryotic elongation factor-2 kinase (eEF-2 kinase or eEF-2K), also known as calmodulin-dependent protein kinase III (CAMKIII) and calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase,[1] is an enzyme that in humans is encoded by the EEF2K gene.[2][3]
# Function
eEF-2 kinase is a highly conserved protein kinase in the calmodulin-mediated signaling pathway that links multiple up-stream signals to the regulation of protein synthesis. It phosphorylates eukaryotic elongation factor 2 (EEF2) and thus inhibits the EEF2 function.[2][4]
# Activation
The activity of eEF-2K is dependent on calcium and calmodulin. Activation of eEF-2K proceeds by a sequential two-step mechanism. First, calcium-calmodulin binds with high affinity to activate the kinase domain, triggering rapid autophosphorylation of Thr-348.[5][6] In the second step, autophosphorylation of Thr-348 leads to a conformational change in the kinase likely supported by the binding of phospho-Thr-348 to an allosteric phosphate binding pocket in the kinase domain. This increases the activity of eEF-2K against its substrate, elongation factor 2.[6]
eEF-2K can gain calcium-independent activity through autophosphorylation of Ser-500. However, calmodulin must remain bound to the enzyme for its activity to be sustained.[5]
# Clinical significance
The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.[2][7]
It is also suggested that eEF-2K may play a role the rapid anti-depressant effects of ketamine through its regulation of neuronal protein synthesis.[8]
# Cancer
eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis.[9][10] | https://www.wikidoc.org/index.php/EEF2K | |
6a52c5c0593a8a8dc6622f51d4a212bd16e738f5 | wikidoc | EFHC2 | EFHC2
EF-hand domain (C-terminal) containing 2 is a protein that in humans is encoded by the EFHC2 gene.
# Gene
EFHC2 is located on the negative strand (sense strand) of the X chromosome at p11.3. EFHC2 is also one of a few, select number of genes with in vitro evidence suggesting that it escapes X inactivation. EFHC2 spans 195,796 base pairs and is neighbored by NDP, the gene encoding for Norrie disease protein. Preliminary evidence based on genome wide association studies have linked a SNP in the intron between exons 13 and 14 of EFHC2 with harm avoidance.
The mRNA transcript encoding the EFHC2 protein is 3,269 base pairs. The first ninety base pairs compose the five prime untranslated region and the last 1913 base pairs compose the three prime untranslated region.
# Protein
The EFHC2 gene encodes a 749-amino acid protein which contains three DM10 domains (InterPro: IPR006602) and three calcium-binding EF-hand motifs.
The isoelectric point of EFHC2 is estimated to be 7.13 in humans. Relative to other proteins expressed in humans, EFHC2 has fewer alanine residues and a greater number of tyrosine residues and is predicted to reside in the cytoplasm.
# Tissue distribution
EFHC2 is widely expressed in the central nervous system as well as peripheral tissues.
# Clinical significance
A related protein, EFHC1 is encoded by a gene on chromosome 6. It has been suggested that both proteins are involved in the development of epilepsy and that this gene may be associated with fear recognition in individuals with Turner syndrome.
A mutation in EFHC2 which results in a serine to a tyrosine substitution at amino acid position 430 (S430Y) has been associated with juvenile myoclonic epilepsy in a male, German population. Additionally, a single nucleotide polymorphism in EFHC2 correlates to a reduced ability of Turner syndrome patients to recognize fear in facial expressions; however, these findings remain controversial.
# Conservation in other species | EFHC2
EF-hand domain (C-terminal) containing 2 is a protein that in humans is encoded by the EFHC2 gene.[1][2]
# Gene
EFHC2 is located on the negative strand (sense strand) of the X chromosome at p11.3. EFHC2 is also one of a few, select number of genes with in vitro evidence suggesting that it escapes X inactivation.[3] EFHC2 spans 195,796 base pairs and is neighbored by NDP, the gene encoding for Norrie disease protein. Preliminary evidence based on genome wide association studies have linked a SNP in the intron between exons 13 and 14 of EFHC2 with harm avoidance.[4]
The mRNA transcript encoding the EFHC2 protein is 3,269 base pairs. The first ninety base pairs compose the five prime untranslated region and the last 1913 base pairs compose the three prime untranslated region.
# Protein
The EFHC2 gene encodes a 749-amino acid protein which contains three DM10 domains (InterPro: IPR006602) and three calcium-binding EF-hand motifs.[1]
The isoelectric point of EFHC2 is estimated to be 7.13 in humans.[5] Relative to other proteins expressed in humans, EFHC2 has fewer alanine residues and a greater number of tyrosine residues and is predicted to reside in the cytoplasm.[6][7]
# Tissue distribution
EFHC2 is widely expressed in the central nervous system as well as peripheral tissues.[8]
# Clinical significance
A related protein, EFHC1 is encoded by a gene on chromosome 6. It has been suggested that both proteins are involved in the development of epilepsy[2][9] and that this gene may be associated with fear recognition in individuals with Turner syndrome.[1]
A mutation in EFHC2 which results in a serine to a tyrosine substitution at amino acid position 430 (S430Y) has been associated with juvenile myoclonic epilepsy in a male, German population.[2] Additionally, a single nucleotide polymorphism in EFHC2 correlates to a reduced ability of Turner syndrome patients to recognize fear in facial expressions;[10] however, these findings remain controversial.[11]
# Conservation in other species | https://www.wikidoc.org/index.php/EFHC2 | |
f5551f67e09b06737af0a9dd99a90bf09d191c42 | wikidoc | EGFL7 | EGFL7
EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene. Intron 7 of EGFL7 hosts the miR-126 microRNA gene.
# Gene
Epidermal Growth Factor like domain 7 (Egfl7) also known as Vascular Endothelial-statin (VE-statin) codes for a gene mostly expressed in endothelial cells. The egfl7 gene is located on chromosomes 9 and 2 in human and mouse, respectively, and is structured in 11 exons and introns, including intron-1a and 1b which are alternatively transcribed from two different promoters. These transcripts vary only in the first exon and code for the same protein which is initiated in the third exon The seventh intron of the egfl7 gene contains a miRNA site for miR-126 and miR-126.
# Protein structure and expression
The Egfl7 protein (29 kDa) is composed of several putative domains: a putative cleavable signal peptide at the N-terminal end, an EMI domain, found on extracellular matrix proteins, two EGF-like domains and a leucine and valine rich C-terminal region. The first EGF-like domain has a region similar to the DSL (Delta/Serrate/Lag-2) domain found in ligands of the Notch receptors family, the second EGF-like domain is predicted to bind Ca2+. The Eglf7 protein is secreted and associates with the blood vessel extracellular matrix.
Endothelial cell lines naturally express egfl7, on the contrary to non-endothelial cells. In endothelial cells, expression is controlled by the Erg and GATA2 transcription factors and, indirectly by Fli-1. The expression pattern of the egfl7 gene is conserved across species. Egfl7 is expressed in endothelial progenitors and in endothelial cells during embryonic and neonatal development. Expression is down-regulated in adults but is still detectable in blood vessels of lung, heart and kidney. An up-regulation of egfl7 is observed in endothelial cells during vascular remodelling tissues, such as in reproductive organs during pregnancy, in regenerating endothelium following arterial injury, in atherosclerotic plaques, and in growing tumours. Expression of egfl7 has also been reported in primordial germ cells and in adult ovaries and testes and in neurons.
## Expression in human tumours
Expression of egfl7 is endothelial cell-specific in physiological conditions, however it is aberrantly expressed by tumour cells in human cancers. In colorectal cancer, high levels of egfl7 correspond to tumours with higher pathologic stages and to the presence of lymph node metastases. Egfl7 is also over-expressed by tumour cells in human hepatocellular carcinoma and overexpression is significantly higher in tumours with multiple nodules, without capsules and with vein invasion. Levels of egfl7 are thus correlated with markers of metastasis and with poor prognosis. In glioma, egfl7 expression levels correlate with tumour grade. There is a correlation between expression of egfl7, cell proliferation and micro-vessel density.
# Function
Silencing (knockdown) of the egfl7 gene in the zebrafish inhibits vascular tubulogenesis and embryos have little or no blood circulation. They show pericardial oedema and haemorrhage. Their main blood vessels have no lumen. Although an initial gene inactivation report showed that mice which did not express egfl7 had various vascular defects, the observed phenotypes were later attributed to the concomitant inactivation of the miR-126 locus. To date, there is no phenotype associated with the loss of egfl7 in mice. Egfl7 knockout mice are phenotypically normal, viable and fertile, they have a normal vascular system. Over-expression of egfl7 specifically in endothelial cells in mice induces embryonic lethality with head haemorrhages, cardiac defects and head and yolk sac vasculature defects. In vitro, Egfl7 inhibits the formation of cord-like structure in embryonic bodies.
## Cellular migration
In vitro, the Egfl7 protein inhibits human aortic smooth muscle cells migration stimulated by PDGF-BB but has no effects on cell proliferation, suggesting that Egfl7 plays a role in vessel maturation. In contrast, Egfl7 produced in conditioned medium is a chemo-attractant for rat vascular smooth muscle cells, mouse endothelial cells and for primary mouse embryonic fibroblasts in vitro. In vitro, egfl7 knockdown in HUVEC inhibits migration, probably by blocking the Notch pathway, although other groups reported that Egfl7 has no effect on HUVEC migration.
Suppression of egfl7 expression inhibits the migration of hepatocellular carcinoma cells through an EGFR/FAK pathway. In vivo, egfl7 knockdown expression in hepatocellular carcinoma cells decreases the number of intra-hepatic and pulmonary metastases. In mice, inhibition of egfl7 in hepatocellular carcinoma cells decrease tumour growth and micro-vessel density. Over-expression of Egfl7 in tumour cells implanted in mice increases tumour growth and metastasis. Within the tumours, Egfl7 increases micro-vessel density, hypoxia, necrosis and vascular permeability.
## Inhibition of elastogenesis
Egfl7 is a natural negative regulator of vascular elastogenesis. It interacts with and inhibits the catalytic activity of LOX, preventing the crosslink of tropoelastin molecules into mature insoluble elastin.
## Inhibition of Notch pathway
Egfl7 interacts with the four Notch receptors, with Dll4, but not with jagged1. Moreover, recombinant Egfl7 competes with jagged1 or jagged2 proteins for their interaction with Notch1. Egfl7 knockdown stimulates the Notch pathway and Egfl7 over-expression inhibits the Notch pathway in HUVEC and neural stem cells.
## Inhibition of leukocyte adhesion proteins
Treatment with Egfl7 inhibits the hypoxia/re-oxygenation-induced ICAM-1 expression, NF-κB nuclear translocation and decrease of IκBα expression in human coronary artery endothelial cells (HCAEC). HCAEC treatment with recombinant egfl7 protein inhibits neutrophils adhesion onto HCAEC and NF-κB DNA-binding activity induced by calcineurin inhibition, a cornerstone of immuno-suppressive therapy after heart transplantation.
Egfl7 promotes tumour escape from immunity by repressing leukocyte adhesion molecules of tumor blood vessel endothelial cells. Endothelial cells from mice tumours over-expressing Egfl7 express much less ICAM-1, VCAM-1 and E-selectin than control tumours. Consequently, tumours over-expressing Egfl7 are much less infiltrated by immune cells. In vitro, egfl7 knockdown in HUVEC promotes expression of ICAM-1, VCAM-1 and E-selectin, and enhances the adhesion of Jurkat cells on these cells. | EGFL7
EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene.[1] Intron 7 of EGFL7 hosts the miR-126 microRNA gene.
# Gene
Epidermal Growth Factor like domain 7 (Egfl7) also known as Vascular Endothelial-statin (VE-statin) codes for a gene mostly expressed in endothelial cells.[2][3][4] The egfl7 gene is located on chromosomes 9 and 2 in human and mouse, respectively, and is structured in 11 exons and introns, including intron-1a and 1b which are alternatively transcribed from two different promoters.[2] These transcripts vary only in the first exon and code for the same protein which is initiated in the third exon [2] The seventh intron of the egfl7 gene contains a miRNA site for miR-126 and miR-126.[5]
# Protein structure and expression
The Egfl7 protein (29 kDa) is composed of several putative domains: a putative cleavable signal peptide at the N-terminal end, an EMI domain, found on extracellular matrix proteins,[6] two EGF-like domains and a leucine and valine rich C-terminal region. The first EGF-like domain has a region similar to the DSL (Delta/Serrate/Lag-2) domain found in ligands of the Notch receptors family,[7] the second EGF-like domain is predicted to bind Ca2+. The Eglf7 protein is secreted and associates with the blood vessel extracellular matrix.[2][3][4][8]
Endothelial cell lines naturally express egfl7, on the contrary to non-endothelial cells.[2][4] In endothelial cells, expression is controlled by the Erg and GATA2 transcription factors and, indirectly by Fli-1.[9] The expression pattern of the egfl7 gene is conserved across species.[3] Egfl7 is expressed in endothelial progenitors and in endothelial cells during embryonic and neonatal development. Expression is down-regulated in adults but is still detectable in blood vessels of lung, heart and kidney.[2][3][4] An up-regulation of egfl7 is observed in endothelial cells during vascular remodelling tissues, such as in reproductive organs during pregnancy, in regenerating endothelium following arterial injury, in atherosclerotic plaques, and in growing tumours.[2][3][10] Expression of egfl7 has also been reported in primordial germ cells and in adult ovaries and testes[11] and in neurons.[12]
## Expression in human tumours
Expression of egfl7 is endothelial cell-specific in physiological conditions, however it is aberrantly expressed by tumour cells in human cancers. In colorectal cancer, high levels of egfl7 correspond to tumours with higher pathologic stages and to the presence of lymph node metastases.[13] Egfl7 is also over-expressed by tumour cells in human hepatocellular carcinoma and overexpression is significantly higher in tumours with multiple nodules, without capsules and with vein invasion. Levels of egfl7 are thus correlated with markers of metastasis and with poor prognosis.[14] In glioma, egfl7 expression levels correlate with tumour grade. There is a correlation between expression of egfl7, cell proliferation and micro-vessel density.[15]
# Function
Silencing (knockdown) of the egfl7 gene in the zebrafish inhibits vascular tubulogenesis and embryos have little or no blood circulation. They show pericardial oedema and haemorrhage. Their main blood vessels have no lumen.[3] Although an initial gene inactivation report showed that mice which did not express egfl7 had various vascular defects,[16] the observed phenotypes were later attributed to the concomitant inactivation of the miR-126 locus.[5][17] To date, there is no phenotype associated with the loss of egfl7 in mice. Egfl7 knockout mice are phenotypically normal, viable and fertile, they have a normal vascular system.[5] Over-expression of egfl7 specifically in endothelial cells in mice induces embryonic lethality with head haemorrhages, cardiac defects and head and yolk sac vasculature defects.[18] In vitro, Egfl7 inhibits the formation of cord-like structure in embryonic bodies.[19]
## Cellular migration
In vitro, the Egfl7 protein inhibits human aortic smooth muscle cells migration stimulated by PDGF-BB but has no effects on cell proliferation, suggesting that Egfl7 plays a role in vessel maturation. In contrast, Egfl7 produced in conditioned medium is a chemo-attractant for rat vascular smooth muscle cells, mouse endothelial cells and for primary mouse embryonic fibroblasts in vitro.[10] In vitro, egfl7 knockdown in HUVEC inhibits migration, probably by blocking the Notch pathway,[18] although other groups reported that Egfl7 has no effect on HUVEC migration.[2][3][10][16]
Suppression of egfl7 expression inhibits the migration of hepatocellular carcinoma cells through an EGFR/FAK pathway. In vivo, egfl7 knockdown expression in hepatocellular carcinoma cells decreases the number of intra-hepatic and pulmonary metastases.[14] In mice, inhibition of egfl7 in hepatocellular carcinoma cells decrease tumour growth and micro-vessel density.[14] Over-expression of Egfl7 in tumour cells implanted in mice increases tumour growth and metastasis. Within the tumours, Egfl7 increases micro-vessel density, hypoxia, necrosis and vascular permeability.[20]
## Inhibition of elastogenesis
Egfl7 is a natural negative regulator of vascular elastogenesis. It interacts with and inhibits the catalytic activity of LOX, preventing the crosslink of tropoelastin molecules into mature insoluble elastin.[8]
## Inhibition of Notch pathway
Egfl7 interacts with the four Notch receptors, with Dll4, but not with jagged1. Moreover, recombinant Egfl7 competes with jagged1 or jagged2 proteins for their interaction with Notch1. Egfl7 knockdown stimulates the Notch pathway and Egfl7 over-expression inhibits the Notch pathway in HUVEC and neural stem cells.[12][18]
## Inhibition of leukocyte adhesion proteins
Treatment with Egfl7 inhibits the hypoxia/re-oxygenation-induced ICAM-1 expression, NF-κB nuclear translocation and decrease of IκBα expression in human coronary artery endothelial cells (HCAEC).[21] HCAEC treatment with recombinant egfl7 protein inhibits neutrophils adhesion onto HCAEC and NF-κB DNA-binding activity induced by calcineurin inhibition, a cornerstone of immuno-suppressive therapy after heart transplantation.[22]
Egfl7 promotes tumour escape from immunity by repressing leukocyte adhesion molecules of tumor blood vessel endothelial cells.[20] Endothelial cells from mice tumours over-expressing Egfl7 express much less ICAM-1, VCAM-1 and E-selectin than control tumours. Consequently, tumours over-expressing Egfl7 are much less infiltrated by immune cells. In vitro, egfl7 knockdown in HUVEC promotes expression of ICAM-1, VCAM-1 and E-selectin, and enhances the adhesion of Jurkat cells on these cells. | https://www.wikidoc.org/index.php/EGFL7 | |
e191841925f8ca8f183e62c4f3071357f8265168 | wikidoc | EGLN1 | EGLN1
Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.
# The hypoxia response
HIF-1α is a ubiquitous, constitutively synthesized transcription factor responsible for upregulating the expression of genes involved in the cellular response to hypoxia. These gene products may include proteins such as glycolytic enzymes and angiogenic growth factors. In normoxia, HIF alpha subunits are marked for the ubiquitin-proteasome degradation pathway through hydroxylation of proline-564 and proline-402 by PHD2. Prolyl hydroxylation is critical for promoting pVHL binding to HIF, which targets HIF for polyubiquitylation.
# Structure
PHD2 is a 46-kDa enzyme that consists of an N-terminal domain homologous to MYND zinc finger domains, and a C-terminal domain homologous to the 2-oxoglutarate dioxygenases. The catalytic domain consists of a double-stranded β-helix core that is stabilized by three α-helices packed along the major β-sheet. The active site, which is contained in the pocket between the β-sheets, chelates iron(II) through histidine and aspartate coordination. 2-oxoglutarate displaces a water molecule to bind iron as well. The active site is lined by hydrophobic residues, possibly because such residues are less susceptible to potential oxidative damage by reactive species leaking from the iron center.
PHD2 catalyses the hydroxylation of two sites on HIF-α, which are termed termed the N-terminal oxygen dependent degradation domain (residues 395-413, NODD) and the C-terminal oxygen dependent degradation domain (residues 556-574, CODD). These two HIF substrates are usually represented by 19 amino acid long peptides in in vitro experiments. X-ray crystallography and NMR spectroscopy showed that both peptides bind to the same binding site on PHD2, in a cleft on the PHD2 surface. An induced fit mechanism was indicated from the structure, in which residues 237-254 adopt a closed loop conformation, whilst in the structure without CODD or NODD, the same residues adopted an open finger-like conformation. Such conformational change was confirmed by NMR spectroscopy, X-ray crystallography and molecular dynamics calculations. A recent study found a second peptide binding site on PHD2 although peptide binding to this alternative site did not seem to affect the catalytic activity of the enzyme. Further studies are required to fully understand the biological significance of this second peptide binding site.
The enzyme has a high affinity for iron(II) and 2-oxoglutarate (also known as α-ketoglutarate), and forms a long-lived complex with these factors. It has been proposed that cosubstrate and iron concentrations poise the HIF hydroxylases to respond to an appropriate "hypoxic window" for a particular cell type or tissue. Studies have revealed that PHD2 has a KM for dioxygen slightly above its atmospheric concentration, and PHD2 is thought to be the most important sensor of the cell's oxygen status.
# Mechanism
The enzyme incorporates one oxygen atom from dioxygen into the hydroxylated product, and one oxygen atom into the succinate coproduct. Its interactions with HIF-1α rely on a mobile loop region that helps to enclose the hydroxylation site and helps to stabilize binding of both iron and 2-oxyglutarate. A feedback regulation mechanism that involves the displacement of HIF-1α by hydroxylated HIF-1α when 2-oxoglutarate is limiting was also proposed.
# Biological role and disease relevance
PHD2 is the primary regulator of HIF-1α steady state levels in the cell. A PHD2 knockdown showed increased levels of HIF-1α under normoxia, and an increase in HIF-1α nuclear accumulation and HIF-dependent transcription. HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines.
However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in tumor proliferation. For example, one animal study showed tumor reduction in PHD2-deficient mice through activation of antiproliferative TGF-β signaling. Other in vivo models showed tumor-suppressing activity for PHD2 in pancreatic cancer as well as liver cancer. A study of 121 human patients revealed PHD2 as a strong prognostic marker in gastric cancer, with PHD2-negative patients having shortened survival compared to PHD2-positive patients.
Recent genome-wide association studies have suggested that EGLN1 may be involved in the low hematocrit phenotype exhibited by the Tibetan population and hence that EGLN1 may play a role in the heritable adaptation of this population to live at high altitude.
# As a therapeutic target
HIF's important role as a homeostatic mediator implicates PHD2 as a therapeutic target for a range of disorders regarding angiogenesis, erythropoeisis, and cellular proliferation. There has been interest both in potentiating and inhibiting the activity of PHD2. For example, methylselenocysteine (MSC) inhibition of HIF-1α led to tumor growth inhibition in renal cell carcinoma in a PHD-dependent manner. It is thought that this phenomenon relies on PHD-stabilization, but mechanistic details of this process have not yet been investigated. On the other hand, screens of small-molecule chelators have revealed hydroxypyrones and hydroxypyridones as potential inhibitors for PHD2. Recently, dihydropyrazoles, a triazole-based small molecule, was found to be a potent inhibitor of PHD2 that is active both in vitro and in vivo. Substrate analog peptides have also been developed to exhibit inhibitory selectivity for PHD2 over factor inhibiting HIF (FIH), for which some other PHD-inhibitors show overlapping specificity. | EGLN1
Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1.[1][2][3][4] PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.
# The hypoxia response
HIF-1α is a ubiquitous, constitutively synthesized transcription factor responsible for upregulating the expression of genes involved in the cellular response to hypoxia. These gene products may include proteins such as glycolytic enzymes and angiogenic growth factors.[5] In normoxia, HIF alpha subunits are marked for the ubiquitin-proteasome degradation pathway through hydroxylation of proline-564 and proline-402 by PHD2. Prolyl hydroxylation is critical for promoting pVHL binding to HIF, which targets HIF for polyubiquitylation.[4]
# Structure
PHD2 is a 46-kDa enzyme that consists of an N-terminal domain homologous to MYND zinc finger domains, and a C-terminal domain homologous to the 2-oxoglutarate dioxygenases. The catalytic domain consists of a double-stranded β-helix core that is stabilized by three α-helices packed along the major β-sheet.[6] The active site, which is contained in the pocket between the β-sheets, chelates iron(II) through histidine and aspartate coordination. 2-oxoglutarate displaces a water molecule to bind iron as well.[7] The active site is lined by hydrophobic residues, possibly because such residues are less susceptible to potential oxidative damage by reactive species leaking from the iron center.[6]
PHD2 catalyses the hydroxylation of two sites on HIF-α, which are termed termed the N-terminal oxygen dependent degradation domain (residues 395-413, NODD) and the C-terminal oxygen dependent degradation domain (residues 556-574, CODD).[8][9] These two HIF substrates are usually represented by 19 amino acid long peptides in in vitro experiments.[10] X-ray crystallography and NMR spectroscopy showed that both peptides bind to the same binding site on PHD2, in a cleft on the PHD2 surface.[7][11] An induced fit mechanism was indicated from the structure, in which residues 237-254 adopt a closed loop conformation, whilst in the structure without CODD or NODD, the same residues adopted an open finger-like conformation.[7][11] Such conformational change was confirmed by NMR spectroscopy,[11] X-ray crystallography[7][11] and molecular dynamics calculations.[12] A recent study found a second peptide binding site on PHD2 although peptide binding to this alternative site did not seem to affect the catalytic activity of the enzyme.[13] Further studies are required to fully understand the biological significance of this second peptide binding site.
The enzyme has a high affinity for iron(II) and 2-oxoglutarate (also known as α-ketoglutarate), and forms a long-lived complex with these factors.[14] It has been proposed that cosubstrate and iron concentrations poise the HIF hydroxylases to respond to an appropriate "hypoxic window" for a particular cell type or tissue.[15] Studies have revealed that PHD2 has a KM for dioxygen slightly above its atmospheric concentration, and PHD2 is thought to be the most important sensor of the cell's oxygen status.[16]
# Mechanism
The enzyme incorporates one oxygen atom from dioxygen into the hydroxylated product, and one oxygen atom into the succinate coproduct.[17] Its interactions with HIF-1α rely on a mobile loop region that helps to enclose the hydroxylation site and helps to stabilize binding of both iron and 2-oxyglutarate.[7] A feedback regulation mechanism that involves the displacement of HIF-1α by hydroxylated HIF-1α when 2-oxoglutarate is limiting was also proposed.[18]
# Biological role and disease relevance
PHD2 is the primary regulator of HIF-1α steady state levels in the cell. A PHD2 knockdown showed increased levels of HIF-1α under normoxia, and an increase in HIF-1α nuclear accumulation and HIF-dependent transcription. HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines.[4]
However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in tumor proliferation. For example, one animal study showed tumor reduction in PHD2-deficient mice through activation of antiproliferative TGF-β signaling.[19] Other in vivo models showed tumor-suppressing activity for PHD2 in pancreatic cancer as well as liver cancer.[20][21] A study of 121 human patients revealed PHD2 as a strong prognostic marker in gastric cancer, with PHD2-negative patients having shortened survival compared to PHD2-positive patients.[22]
Recent genome-wide association studies have suggested that EGLN1 may be involved in the low hematocrit phenotype exhibited by the Tibetan population and hence that EGLN1 may play a role in the heritable adaptation of this population to live at high altitude.[23]
# As a therapeutic target
HIF's important role as a homeostatic mediator implicates PHD2 as a therapeutic target for a range of disorders regarding angiogenesis, erythropoeisis, and cellular proliferation. There has been interest both in potentiating and inhibiting the activity of PHD2.[5] For example, methylselenocysteine (MSC) inhibition of HIF-1α led to tumor growth inhibition in renal cell carcinoma in a PHD-dependent manner. It is thought that this phenomenon relies on PHD-stabilization, but mechanistic details of this process have not yet been investigated.[24] On the other hand, screens of small-molecule chelators have revealed hydroxypyrones and hydroxypyridones as potential inhibitors for PHD2.[25] Recently, dihydropyrazoles, a triazole-based small molecule, was found to be a potent inhibitor of PHD2 that is active both in vitro and in vivo.[26] Substrate analog peptides have also been developed to exhibit inhibitory selectivity for PHD2 over factor inhibiting HIF (FIH), for which some other PHD-inhibitors show overlapping specificity.[27] | https://www.wikidoc.org/index.php/EGLN1 | |
84642e7bf974bc9f0b6dbb645740a85acbb2f951 | wikidoc | EGLN2 | EGLN2
Egl nine homolog 2 is a protein that in humans is encoded by the EGLN2 gene. ELGN2 is a alpha-ketoglutarate-dependent hydroxylase, a superfamily of non-haem iron-containing proteins.
The hypoxia inducible factor (HIF) is a transcriptional complex which is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degradation by prolyl hydroxylation.
This gene encodes an enzyme responsible for this posttranslational modification. Multiple alternatively spliced variants, encoding the same protein, have been identified. | EGLN2
Egl nine homolog 2 is a protein that in humans is encoded by the EGLN2 gene.[1] ELGN2 is a alpha-ketoglutarate-dependent hydroxylase, a superfamily of non-haem iron-containing proteins.
The hypoxia inducible factor (HIF) is a transcriptional complex which is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degradation by prolyl hydroxylation.
This gene encodes an enzyme responsible for this posttranslational modification. Multiple alternatively spliced variants, encoding the same protein, have been identified.[1] | https://www.wikidoc.org/index.php/EGLN2 | |
99bd7d282d84c039be84b74b4150e665fdf4e15b | wikidoc | EHMT1 | EHMT1
Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.
# Function
The protein encoded by this gene is a histone methyltransferase that is part of the E2F6 complex, which represses transcription. The encoded protein methylates the Lys-9 position of histone H3, which tags it for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition.
# Clinical significance
Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome). | EHMT1
Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.[1]
# Function
The protein encoded by this gene is a histone methyltransferase that is part of the E2F6 complex, which represses transcription. The encoded protein methylates the Lys-9 position of histone H3, which tags it for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition.[1]
# Clinical significance
Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome).[1] | https://www.wikidoc.org/index.php/EHMT1 | |
9b6485b61a51b38e9435326f54f1e5b29a984c28 | wikidoc | EHMT2 | EHMT2
Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the EHMT2 gene. G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 (i.e., H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and HeK27me2).
# Function
A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. This gene is found near this cluster; it was mapped near the gene for C2 within a 120-kb region that included a HSP70 gene pair. These genes are all within the human major histocompatibility complex class III region. This gene was thought to be two different genes, NG36 and G9a, adjacent to each other but a recent publication shows that there is only a single gene. The protein encoded by this gene is thought to be involved in intracellular protein-protein interaction. There are three alternatively spliced transcript variants of this gene but only two are fully described.
G9a and G9a-like protein, another histone-lysine N-methyltransferase, catalyze the synthesis of H3K9me2, which is a repressive mark. G9a is an important control mechanism for epigenetic regulation within the nucleus accumbens (NAcc); reduced G9a expression in the NAcc plays a central role in mediating the development of an addiction. G9a opposes increases in ΔFosB expression via H3K9me2 and is suppressed by ΔFosB. G9a exerts opposite effects to that of ΔFosB on drug-related behavior (e.g., self-administration) and synaptic remodeling (e.g., dendritic arborization – the development of additional tree-like dendritic branches and spines) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression. G9a and ΔFosB share many of the same gene targets.
# Interactions
EHMT2 has been shown to interact with KIAA0515 and the prostate tissue associated homeodomain protein NKX3.1. | EHMT2
Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the EHMT2 gene.[1][2][3] G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 (i.e., H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and HeK27me2).[4][5]
# Function
A cluster of genes, BAT1-BAT5, has been localized in the vicinity of the genes for TNF alpha and TNF beta. This gene is found near this cluster; it was mapped near the gene for C2 within a 120-kb region that included a HSP70 gene pair. These genes are all within the human major histocompatibility complex class III region. This gene was thought to be two different genes, NG36 and G9a, adjacent to each other but a recent publication shows that there is only a single gene. The protein encoded by this gene is thought to be involved in intracellular protein-protein interaction. There are three alternatively spliced transcript variants of this gene but only two are fully described.[3]
G9a and G9a-like protein, another histone-lysine N-methyltransferase, catalyze the synthesis of H3K9me2, which is a repressive mark.[4][5][6] G9a is an important control mechanism for epigenetic regulation within the nucleus accumbens (NAcc);[7] reduced G9a expression in the NAcc plays a central role in mediating the development of an addiction.[7] G9a opposes increases in ΔFosB expression via H3K9me2 and is suppressed by ΔFosB.[7][8] G9a exerts opposite effects to that of ΔFosB on drug-related behavior (e.g., self-administration) and synaptic remodeling (e.g., dendritic arborization – the development of additional tree-like dendritic branches and spines) in the nucleus accumbens, and therefore opposes ΔFosB's function as well as increases in its expression.[7] G9a and ΔFosB share many of the same gene targets.[9]
# Interactions
EHMT2 has been shown to interact with KIAA0515 and the prostate tissue associated homeodomain protein NKX3.1.[10][11] | https://www.wikidoc.org/index.php/EHMT2 | |
32c37ed69cb1c89e69af4d2090cabadfd134959d | wikidoc | eIF-2 | eIF-2
eIF-2 (Eukaryotic Initiation Factor 2) is a heterotrimer of subunits alpha, beta, and gamma. eIF-2 mediates the binding of methionyl-tRNAimet to the ribosome in a GTP-dependent manner.
eIF-2 is released from the ribosome bound to GDP as an inactive binary complex.
To participate in another round of translation initiation, this GDP must be exchanged for GTP.
Under steady-state conditions of translation, eIF-2 must be recycled in order to participate in another round of translation initiation.
# eIF-2B
Conversion of the inactive eIF-2-GDP to the active eIF-2-GTP form is catalyzed by a guanine nucleotide exchange factor, eIF-2B.
Phosphorylation of the alpha subunit of eIF-2 inhibits translation initiation by impairing the eIF-2B-catalyzed guanine nucleotide exchange reaction. | eIF-2
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
eIF-2 (Eukaryotic Initiation Factor 2) is a heterotrimer of subunits alpha, beta, and gamma. eIF-2 mediates the binding of methionyl-tRNAimet to the ribosome in a GTP-dependent manner.
eIF-2 is released from the ribosome bound to GDP as an inactive binary complex.
To participate in another round of translation initiation, this GDP must be exchanged for GTP.
Under steady-state conditions of translation, eIF-2 must be recycled in order to participate in another round of translation initiation.
# eIF-2B
Conversion of the inactive eIF-2-GDP to the active eIF-2-GTP form is catalyzed by a guanine nucleotide exchange factor, eIF-2B.
Phosphorylation of the alpha subunit of eIF-2 inhibits translation initiation by impairing the eIF-2B-catalyzed guanine nucleotide exchange reaction. | https://www.wikidoc.org/index.php/EIF-2 | |
854c39bac81c4c5196759baf208ecf9e3b07504d | wikidoc | EIF3K | EIF3K
Eukaryotic translation initiation factor 3 subunit K (eIF3k) is a protein that in humans is encoded by the EIF3K gene.
# Function
The ~800 kDa eukaryotic initiation factor 3 (eIF3) is the largest eIF and contains at least 12 subunits, including eIF3k/EIF2S12. eIF3 plays an essential role in translation by binding directly to the 40S ribosomal subunit and promoting formation of the 43S preinitiation complex.
# Interactions
eIF3k has been shown to interact with Cyclin D3 and eIF3a. | EIF3K
Eukaryotic translation initiation factor 3 subunit K (eIF3k) is a protein that in humans is encoded by the EIF3K gene.[1][2][3]
# Function
The ~800 kDa eukaryotic initiation factor 3 (eIF3) is the largest eIF and contains at least 12 subunits, including eIF3k/EIF2S12. eIF3 plays an essential role in translation by binding directly to the 40S ribosomal subunit and promoting formation of the 43S preinitiation complex.[4][3]
# Interactions
eIF3k has been shown to interact with Cyclin D3[5] and eIF3a.[2][6] | https://www.wikidoc.org/index.php/EIF3K | |
1cca2c5054426e7e6ca7349397be8cc03bca5664 | wikidoc | eIF4A | eIF4A
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.
# Background
The mechanisms governing the basic subsistence of eukaryotic cells are immensely complex; it is therefore unsurprising that regulation occurs at a number of stages of protein synthesis – the regulation of translation has become a well-studied field. Human translational control is of increasing research interest as it has connotations in a range of diseases. Orthologs of many of the factors involved in human translation are shared by a range of eukaryotic organisms; some of which are used as model systems for the investigation of translation initiation and elongation, for example: sea urchin eggs upon fertilization, rodent brain and rabbit reticulocytes. Monod and Jacob were among the first to propose that "the synthesis of individual proteins may be provoked or suppressed within a cell, under the influence of specific external agents, and the relative rates at which different proteins may be profoundly altered, depending upon external conditions". Almost half a century after the flurry of postulations arising from the revelation of the central dogma of molecular biology, of which the preceding supposition by Monod and Jacob is an example; contemporary researchers still have much to learn about the modulation of genetic expression. Synthesis of protein from mature messenger RNA in eukaryotes is divided into translation initiation, elongation, and termination of these stages; the initiation of translation is the rate limiting step. Within the process of translation initiation; the bottleneck occurs shortly before the ribosome binds to the 5’ m7GTP facilitated by a number of proteins; it is at this stage that constrictions born of stress, amino acid starvation etc. take effect.
# Function
Eukaryotic initiation factor complex 2 (eIF2) forms a ternary complex with GTP and the initiator Met-tRNA – this process is regulated by guanine nucleotide exchange and phosphorylation and serves as the main regulatory element of the bottleneck of gene expression. Before translation can progress to the elongation stage, a number of initiation factors must facilitate the synergy of the ribosome and the mRNA and ensure that the 5’ UTR of the mRNA is sufficiently devoid of secondary structure. Binding in this way is facilitated by group 4 eukaryotic initiation factors; eIF4F has implications in the normal regulation of translation as well as the transformation and progression of cancerous cells; as such, it represents an interesting field of research.
# Mechanism
The repertoire of compounds involved in eukaryotic translation consists of initiation factor classes 1 – 6; eIF4F is responsible for the binding of capped mRNA to the 40S ribosomal subunit via eIF3. The mRNA cap is bound by eIF4E (25 kDa), eIF4G (185 kDa) acts as a scaffold for the complex whilst the ATP-dependent RNA helicase eIF4A (46 kDa) processes the secondary structure of the mRNA 5’ UTR to render it more conducive to ribosomal binding and subsequent translation. Together these three proteins are referred to as eIF4F. For maximal activity; eIF4A also requires eIF4B (80 kDa), which itself is enhanced by eIF4H (25 kDa). A study conducted by Bi et al. in wheat germ seemed to indicate that eIF4A has a higher binding affinity for ADP than ATP except in the presence of eIF4B, which increased the ATP binding affinity tenfold without affecting ADP affinity. Once bound to the 5’ cap of mRNA, this 48S complex then searches for the (usually) AUG start codon and translation begins.
# Genes
In humans, the gene encoding eIF4A isoform I has a transcript length of 1741bp, contains 11 exons, and is located on chromosome 17. The genes for human isoforms II and III reside on chromosomes 3 and 17 respectively.
# Proteins
The 407 residue, 46 kDa, protein eIF4A is the prototypical member of the DEAD box helicase family, so-called due to their conserved four-residue D-E-A-D sequence. This family of helicases is found in a range of prokaryotic and eukaryotic organisms including humans, wherein they catalyse a variety of processes including embryogenesis and RNA splicing as well as translation initiation. Crystallographic analysis of yeast eIF4A carried out by Carruthers et al. (2000) revealed that the molecule is approximately 80 Å in length and has a “dumbbell” shape where the proximal section represents an 11 residue (18 Å) linker postulated to confer a degree of flexibility and distension to the molecule in solution. eIF4A is an abundant cytoplasmic protein.
Three isoforms of eIF4A exist; I and II share 95% amino acid similarity and have been found simultaneously in rabbit reticulocyte eIF4F in a ratio of 4:1, respectively. The third isoform; eIF4A III, which shares only 65% similarity to the other isoforms is believed to be a core component of the exon junction complex involved in pre-mRNA splicing. | eIF4A
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.[1][2]
# Background
The mechanisms governing the basic subsistence of eukaryotic cells are immensely complex; it is therefore unsurprising that regulation occurs at a number of stages of protein synthesis – the regulation of translation has become a well-studied field.[3] Human translational control is of increasing research interest as it has connotations in a range of diseases.[4] Orthologs of many of the factors involved in human translation are shared by a range of eukaryotic organisms; some of which are used as model systems for the investigation of translation initiation and elongation, for example: sea urchin eggs upon fertilization,[5] rodent brain[6] and rabbit reticulocytes.[7] Monod and Jacob were among the first to propose that "the synthesis of individual proteins may be provoked or suppressed within a cell, under the influence of specific external agents, and the relative rates at which different proteins may be profoundly altered, depending upon external conditions".[8] Almost half a century after the flurry of postulations arising from the revelation of the central dogma of molecular biology, of which the preceding supposition by Monod and Jacob is an example; contemporary researchers still have much to learn about the modulation of genetic expression. Synthesis of protein from mature messenger RNA in eukaryotes is divided into translation initiation, elongation, and termination of these stages; the initiation of translation is the rate limiting step. Within the process of translation initiation; the bottleneck occurs shortly before the ribosome binds to the 5’ m7GTP facilitated by a number of proteins; it is at this stage that constrictions born of stress, amino acid starvation etc. take effect.
# Function
Eukaryotic initiation factor complex 2 (eIF2) forms a ternary complex with GTP and the initiator Met-tRNA – this process is regulated by guanine nucleotide exchange and phosphorylation and serves as the main regulatory element of the bottleneck of gene expression. Before translation can progress to the elongation stage, a number of initiation factors must facilitate the synergy of the ribosome and the mRNA and ensure that the 5’ UTR of the mRNA is sufficiently devoid of secondary structure. Binding in this way is facilitated by group 4 eukaryotic initiation factors; eIF4F has implications in the normal regulation of translation as well as the transformation and progression of cancerous cells; as such, it represents an interesting field of research.
# Mechanism
The repertoire of compounds involved in eukaryotic translation consists of initiation factor classes 1 – 6;[9] eIF4F is responsible for the binding of capped mRNA to the 40S ribosomal subunit via eIF3. The mRNA cap is bound by eIF4E (25 kDa), eIF4G (185 kDa) acts as a scaffold for the complex whilst the ATP-dependent RNA helicase eIF4A (46 kDa) processes the secondary structure of the mRNA 5’ UTR to render it more conducive to ribosomal binding and subsequent translation.[10] Together these three proteins are referred to as eIF4F. For maximal activity; eIF4A also requires eIF4B (80 kDa), which itself is enhanced by eIF4H (25 kDa).[11] A study conducted by Bi et al. in wheat germ seemed to indicate that eIF4A has a higher binding affinity for ADP than ATP except in the presence of eIF4B, which increased the ATP binding affinity tenfold without affecting ADP affinity.[12] Once bound to the 5’ cap of mRNA, this 48S complex then searches for the (usually) AUG start codon and translation begins.
# Genes
In humans, the gene encoding eIF4A isoform I has a transcript length of 1741bp, contains 11 exons, and is located on chromosome 17.[13][14] The genes for human isoforms II and III reside on chromosomes 3[15] and 17[16][17] respectively.
# Proteins
The 407 residue,[15] 46 kDa,[18] protein eIF4A is the prototypical member of the DEAD box helicase family, so-called due to their conserved four-residue D-E-A-D sequence. This family of helicases is found in a range of prokaryotic and eukaryotic organisms including humans, wherein they catalyse a variety of processes including embryogenesis and RNA splicing as well as translation initiation.[19] Crystallographic analysis of yeast eIF4A carried out by Carruthers et al. (2000)[20] revealed that the molecule is approximately 80 Å in length and has a “dumbbell” shape where the proximal section represents an 11 residue (18 Å) linker postulated to confer a degree of flexibility and distension to the molecule in solution. eIF4A is an abundant cytoplasmic protein.[21]
Three isoforms of eIF4A exist; I and II share 95% amino acid similarity and have been found simultaneously in rabbit reticulocyte eIF4F in a ratio of 4:1, respectively.[22] The third isoform; eIF4A III, which shares only 65% similarity to the other isoforms is believed to be a core component of the exon junction complex involved in pre-mRNA splicing.[23] | https://www.wikidoc.org/index.php/EIF4A | |
8ba338d293df7a9f981cfb91eb0dcdeb462274fb | wikidoc | EIF4E | EIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.
# Structure and function
Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine five-prime cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs. It is a 24-kD polypeptide that exists as both a free form and as part of the eIF4F pre-initiation complex. Almost all cellular mRNA require eIF4E in order to be translated into protein. The eIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.
The other subunits of eIF4F are a 47-kD polypeptide, termed eIF4A, that possesses ATPase and RNA helicase activities, and a 220-kD scaffolding polypeptide, eIF4G.
Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an internal ribosome entry site in the RNA.
# Regulation
Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E is a potential target for transcriptional control. Regulation of eIF4E may be achieved via three distinct mechanisms: transcription, phosphorylation, and inhibitory proteins.
a. Regulation of eIF4E by Gene Expression
The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle. The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene. This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.
b. Regulation of eIF4E by Phosphorylation
Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E. Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G0 and M phase and wherein high phosphorylation is seen during G1 and S phase. This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.
c. Regulation of eIF4E by Inhibitory Proteins
Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation. Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation. Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E.
# The Role of eIF4E in Cancer
The role of eIF4E in cancer was established after Lazaris-Karatzas et al. made the discovery that overexpressing eIF4E causes tumorigenic transformation of fibroblasts. Since this initial observation, numerous groups have recapitulated these results in different cell lines. As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated.
# FMRP represses translation through EIF4E binding
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1. RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.
In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.
# Interactions
EIF4E has been shown to interact with:
- EIF4A1,
- EIF4EBP1,
- EIF4EBP2,
- EIF4EBP3,
- EIF4ENIF1,
- EIF4G1, and
- EIF4G2. | EIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.[1][2]
# Structure and function
Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine five-prime cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs. It is a 24-kD polypeptide that exists as both a free form and as part of the eIF4F pre-initiation complex.[3] Almost all cellular mRNA require eIF4E in order to be translated into protein. The eIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.
The other subunits of eIF4F are a 47-kD polypeptide, termed eIF4A,[4] that possesses ATPase and RNA helicase activities, and a 220-kD scaffolding polypeptide, eIF4G.[5][6][7]
Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an internal ribosome entry site in the RNA.
# Regulation
Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E is a potential target for transcriptional control.[8] Regulation of eIF4E may be achieved via three distinct mechanisms: transcription, phosphorylation, and inhibitory proteins.[9]
a. Regulation of eIF4E by Gene Expression
The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle.[10] The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene.[11] This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.
b. Regulation of eIF4E by Phosphorylation
Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E.[12] Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G0 and M phase and wherein high phosphorylation is seen during G1 and S phase.[13] This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.
c. Regulation of eIF4E by Inhibitory Proteins
Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation.[9] Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation.[14] Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E.[15]
# The Role of eIF4E in Cancer
The role of eIF4E in cancer was established after Lazaris-Karatzas et al. made the discovery that overexpressing eIF4E causes tumorigenic transformation of fibroblasts.[16] Since this initial observation, numerous groups have recapitulated these results in different cell lines.[17] As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated.[18]
# FMRP represses translation through EIF4E binding
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1.[19] RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.[20]
In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.[19]
# Interactions
EIF4E has been shown to interact with:
- EIF4A1,[21][22]
- EIF4EBP1,[21][22][23][24][25][26][27][28][29][30][31][32][33]
- EIF4EBP2,[24][34]
- EIF4EBP3,[35][36]
- EIF4ENIF1,[37]
- EIF4G1,[22][24][29][38][39] and
- EIF4G2.[40] | https://www.wikidoc.org/index.php/EIF4E | |
2de3cff7cbe988bb9a2627947e37f46db3a0eb7b | wikidoc | EIF4H | EIF4H
Eukaryotic translation initiation factor 4H is a protein that in humans is encoded by the EIF4H gene.
This gene encodes one of the translation initiation factors, which function to stimulate the initiation of protein synthesis at the level of mRNA utilization.
This gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Alternative splicing of this gene generates 2 transcript variants.
EIF4H appears analogous to drr-2 in C. elegans which regulates the mTOR pathway and affects longevity. | EIF4H
Eukaryotic translation initiation factor 4H is a protein that in humans is encoded by the EIF4H gene.[1][2][3]
This gene encodes one of the translation initiation factors, which function to stimulate the initiation of protein synthesis at the level of mRNA utilization.
This gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Alternative splicing of this gene generates 2 transcript variants.[3]
EIF4H appears analogous to drr-2 in C. elegans which regulates the mTOR pathway and affects longevity.[4] | https://www.wikidoc.org/index.php/EIF4H | |
ce4962efed06b1f6666a244ef8443d11414ca16c | wikidoc | EIF5A | EIF5A
Eukaryotic translation initiation factor 5A-1 is a protein that in humans is encoded by the EIF5A gene.
It is the only known protein to contain the unusual amino acid hypusine , which is synthesized on eIF5A at a specific lysine residue from the polyamine spermidine by two catalytic steps.
EF-P is the prokaryotic homolog of eIF5A, which is also modified post-translationally in a similar but distinct way. | EIF5A
Eukaryotic translation initiation factor 5A-1 is a protein that in humans is encoded by the EIF5A gene.[1]
It is the only known protein to contain the unusual amino acid hypusine [N (ε)- (4-amino-2-hydroxybutyl)-lysine], which is synthesized on eIF5A at a specific lysine residue from the polyamine spermidine by two catalytic steps.[2]
EF-P is the prokaryotic homolog of eIF5A, which is also modified post-translationally in a similar but distinct way.[3][4] | https://www.wikidoc.org/index.php/EIF5A | |
2ad3879ccfe72ef4023afb6d538a2af0e1fb353a | wikidoc | ELAC2 | ELAC2
Zinc phosphodiesterase ELAC protein 2 is an enzyme that in humans is encoded by the ELAC2 gene. on chromosome 17. It is an endonuclease thought to be involved in mitochondrial tRNA maturation,
# Function
The ELAC2 gene encodes a protein that is 92 kDa in size and is localized to the mitochondrion and the nucleus. The ELAC2 protein is a zinc phosphodiesterase, which is known to show tRNA 3'-processing endonuclease activity inside the mitochondria. Mitochondria contain their own pool of tRNAs that are involved in the protein translation of 13 subunits of the respiratory chain that are encoded by the mitochondrial genome. ELAC2 functions in the maturation of tRNA by removing a 3'-trailer (extra 3' nucleotides) from tRNA precursors, generating 3' termini of tRNAs.
The reaction leaves a 3'-hydroxy group is left at the tRNA end, and a 5'-phosphoryl group at the cleaved, trailing end. The reaction requires zinc ions as co-factors.
# Clinical significance
Variants of the ELAC2 gene are associated with prostate cancer, hereditary 2 (HPC2), a condition associated with familial cancer of the prostate. Multiple mutations including truncation and missense mutations are known to cause the disease from multiple families based on linkage analysis and positional cloning.
In addition, mutations in ELAC2 are known to cause combined oxidative phosphorylation deficiency 17 (COXPD17), a rare autosomal recessive disorder of mitochondrial functions characterized by severe hypertrophic cardiomyopathy. | ELAC2
Zinc phosphodiesterase ELAC protein 2 is an enzyme that in humans is encoded by the ELAC2 gene.[1][2][3] on chromosome 17. It is an endonuclease thought to be involved in mitochondrial tRNA maturation,
# Function
The ELAC2 gene encodes a protein that is 92 kDa in size and is localized to the mitochondrion [4] and the nucleus. The ELAC2 protein is a zinc phosphodiesterase, which is known to show tRNA 3'-processing endonuclease activity inside the mitochondria. Mitochondria contain their own pool of tRNAs that are involved in the protein translation of 13 subunits of the respiratory chain that are encoded by the mitochondrial genome. ELAC2 functions in the maturation of tRNA by removing a 3'-trailer (extra 3' nucleotides) from tRNA precursors, generating 3' termini of tRNAs.
The reaction leaves a 3'-hydroxy group is left at the tRNA end, and a 5'-phosphoryl group at the cleaved, trailing end. The reaction requires zinc ions as co-factors.
# Clinical significance
Variants of the ELAC2 gene are associated with prostate cancer, hereditary 2 (HPC2), a condition associated with familial cancer of the prostate.[5][6] Multiple mutations including truncation and missense mutations are known to cause the disease from multiple families based on linkage analysis and positional cloning.[6]
In addition, mutations in ELAC2 are known to cause combined oxidative phosphorylation deficiency 17 (COXPD17), a rare autosomal recessive disorder of mitochondrial functions characterized by severe hypertrophic cardiomyopathy.[7] | https://www.wikidoc.org/index.php/ELAC2 | |
b6119eebbb97492fc68a406b6080fcd735903b77 | wikidoc | ELMO1 | ELMO1
Engulfment and cell motility protein 1 is a protein that in humans is encoded by the ELMO1 gene. ELMO1 is located on chromosome number seven in humans and is located on chromosome number thirteen in mice.
# Structure
The human engulfment and cell motility protein 1, ELMO1, is 720 residues in length. The protein contains the following three domains:
- N-terminal Armadillo domain (residues 82-262)
- central ELMO (Engulfment and Cell Motility) domain (301-492)
- C-terminal pleckstrin homology domain (residues 527-674)
ELMO1 also has a pro-rich motif at the extreme C terminus. Secondary structure analysis has predicted that there are alpha-helical regions at both the N and C-terminus.
The structure of the pleckstrin homology domain of ELMO1 has been determine by X-ray crystallography.
# Function
The protein encoded by this gene interacts with the dedicator of cyto-kinesis 1 protein to promote phagocytosis and effect cell shape changes. Similarity to a C. elegans protein suggests that this protein may function in apoptosis and in cell migration. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.
# Interactions
ELMO1 has been shown to interact with Dock180 and HCK. ELMO1 directly interacts with the SH3 domain of HCK. The association between ELMO1 and HCK is dependent on polyproline interactions.
When ELMO1 is complexed with DOCK180, Rac GTPase-dependent biological processes are activated. The pH domain of ELMO1 functions in trans to stabilize DOCK180 and make it resistant to degradation. When ELMO1 binds to DOCK180 it relieves the steric inhibition of DOCK180 which then activates the Rac GTPase. The pro-rich motif of the C terminus on ELMO1 is essential for the binding of ELMO1 to the SH3 domain at the N terminus of DOCK180. The complex of ELMO1 and DOCK180 act as a regulator of Rac during development of a cell and cell migration. Mutation of both interaction sites for DOCK180 on ELMO1 will lead to the disruption of the ELMO1-DOCK180 complex. ELMO1 complexed with both DOCK180 and CrkII leads to maximal efficiency of phagocytosis in the cell. This complex of molecules happens upstream of Rac during phagocytosis. | ELMO1
Engulfment and cell motility protein 1 is a protein that in humans is encoded by the ELMO1 gene.[1][2] ELMO1 is located on chromosome number seven in humans and is located on chromosome number thirteen in mice.
# Structure
The human engulfment and cell motility protein 1, ELMO1, is 720 residues in length. The protein contains the following three domains:
- N-terminal Armadillo domain (residues 82-262)
- central ELMO (Engulfment and Cell Motility) domain (301-492)
- C-terminal pleckstrin homology domain (residues 527-674)
ELMO1 also has a pro-rich motif at the extreme C terminus. Secondary structure analysis has predicted that there are alpha-helical regions at both the N and C-terminus.[3]
The structure of the pleckstrin homology domain of ELMO1 has been determine by X-ray crystallography.[3]
# Function
The protein encoded by this gene interacts with the dedicator of cyto-kinesis 1 protein to promote phagocytosis and effect cell shape changes. Similarity to a C. elegans protein suggests that this protein may function in apoptosis and in cell migration. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.[2]
# Interactions
ELMO1 has been shown to interact with Dock180[1][4] and HCK. ELMO1 directly interacts with the SH3 domain of HCK. The association between ELMO1 and HCK is dependent on polyproline interactions.[5]
When ELMO1 is complexed with DOCK180, Rac GTPase-dependent biological processes are activated. The pH domain of ELMO1 functions in trans to stabilize DOCK180 and make it resistant to degradation. When ELMO1 binds to DOCK180 it relieves the steric inhibition of DOCK180 which then activates the Rac GTPase. The pro-rich motif of the C terminus on ELMO1 is essential for the binding of ELMO1 to the SH3 domain at the N terminus of DOCK180.[3] The complex of ELMO1 and DOCK180 act as a regulator of Rac during development of a cell and cell migration. Mutation of both interaction sites for DOCK180 on ELMO1 will lead to the disruption of the ELMO1-DOCK180 complex. ELMO1 complexed with both DOCK180 and CrkII leads to maximal efficiency of phagocytosis in the cell. This complex of molecules happens upstream of Rac during phagocytosis.[1] | https://www.wikidoc.org/index.php/ELMO1 | |
c85535f16d43b639a758c5303b9d4cc3ae7741af | wikidoc | EMSAM | EMSAM
EMSAM® (selegiline transdermal system) is a transdermal patch using the monoamine oxidase inhibitor (MAOI) selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment of major depessive disorder. On February 28, 2006 the FDA approved EMSAM for the treatment of clinical depression.
# Inception & Development
EMSAM's development was spearheaded by Alexander J. Bodkin, M.D.
, Director of the Clinical Psychopharmacology Research Program at McLean Hospital in Belmont MA, in conjunction with Harvard Medical School.
Currently, it is the only MAOI on the market used in the treatment of depression, that is absorbed through the skin into the blood stream and thereby to the central nervous system.
The patch "is a matrix containing three layers consisting of a backing, an... adhesive drug layer, and a release liner that is placed against the skin." The primary advantage of delivering selegiline in this manner is to bypass the gastrointestinal tract and liver, specifically the small intenstine, thereby avoiding the chance of hypertensive crisis (very high spike in blood pressure possibly leading to stroke).
"Despite long-standing concerns over hypertensive reactions,... (MAOIs) have grown in popularity... (and) the risk of hypertensive episodes is less than 1%."
# Food Intake Restrictions
The dietary problem was first discovered by a neurologist whose wife was taking an MAO inhibitor. After eating hard cheese, which is rich in tyramine, she would get severe headaches; thus, her husband's discovery of these spikes in blood pressure. For this reason, the crisis is still called the "cheese syndrome", even though other foods can cause the same problem.
When an MAOI is taken orally, and an individual ingests such tyramine rich foods, the body can not properly regulate the additional tyramine. Therefore, dietary modifications are necessary.
Foods containing considerable amounts of tyramine include: air dried, aged and fermented meats, sausages and salamis; pickled herring; any spoiled or improperly stored meat, poultry and fish; spoiled or improperly stored animal livers; broad bean pods (fava beans); all tap beers, and other beers that have not been pasteurized; concentrated yeast extract (such as Marmite); most soybean products (including soy sauce and tofu); aged cheeses(not processed cheese); sauerkraut; and over-the-counter supplements containing tyramine.
# EMSAM Advantages
Due mainly to the availiability of the newer SSRIs and SNRIs, which are viewed to have more medically benign side effects in the treatment of depression, psychopharmacologists and psychiatrists have avoided prescribing MAOIs
because of the possibility of hypertensive crisis. With EMSAM, taken at the lowest dose of 6 mg every 24 hours, no dietary modifications are required by the FDA
In addition to the lack of dietary restrictions at the 6mg/24h dose, EMSAM offers another benefit. It is a continuous delivery system, keeping the medication at a steady level in the body over time. Generally, oral medication can not keep a steady dose in the blood stream.
EMSAM is also valuable in the treatment of depression that is not alleviated by the more commonly used selective serotonin reuptake inhibitors(SSRIs), dual serotonin and norepinephrine reupatake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).
# Usage
The patch is changed once daily. There may be a reaction to the adhesive on the skin at the site of application. Patients are encouraged to use an adhesive remover: usually mineral oil, Vaseline® or an over-the-counter product such as dermatology recommended TRIAD® brand adhesive tape remover pads. A new patch is placed on a different site. The combination of adhesive remover, and placing each patch on a new area of skin, is to discourage any dermatological reason for discontinuance of the patch.
Using rubbing alcohol or hydrogen peroxide to clean the skin of oils and dirt before applying a patch can increase the likelihood of proper attachment for the duration of each 24 hour period. Immediately after applying a patch it can be helpful to use the pressure and body heat of the palm of the hand to enhance proper adhesive contact.
All of the dietary restrictions are currently required by the FDA, as a precaution, at the higher 9 mg/24h and 12 mg/24h doses of EMSAM.
# Medication Interactions
Over-the-counter items that can not be used while on EMSAM include: St. John's Wort; products containing dextromethorphan such as cough and cold preparations; decongestant medicines; and diet pills or herbal weight loss products. Caffeine and chocolate can only be consumed in small amounts.
There are prescription medications that can not be taken while using EMSAM, and for 2 weeks after stopping EMSAM. Some medications must not be taken for 1 week (or more) before an individual can start using EMSAM.
Medications that can not be taken because they can cause serotonin syndrome
include: (SSRIs), (SNRIs), (TCAs), other MAOIs, mirtazapine, bupropion, meperidine, analgesics such as tramadol, methadone, propoxyphene, cyclobezaprine and oral selegiline.
The use of EMSAM is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). Carbamazepine and oxcarbazepine are also contraindicated.
Patients taking EMSAM should not undergo elective surgery requiring general anesthesia or be given local anesthesia containing sympathomimetic vasoconstrictors.
# EMSAM Name Origin, Manufacturer & Distributor
The acronym EMSAM is derived from the names Emily and Samuel. They are the children of Mel Sharoky, M.D., CEO of EMSAM's manufacturer, Somerset Pharmaceuticals, Inc., The prescription medication is distributed by Bristol-Myers Squibb out of Princeton NJ | EMSAM
EMSAM® (selegiline transdermal system) is a transdermal patch using the monoamine oxidase inhibitor (MAOI) selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment of major depessive disorder.[1] On February 28, 2006 the FDA approved EMSAM for the treatment of clinical depression.
[2]
[3]
[4]
# Inception & Development
EMSAM's development was spearheaded by Alexander J. Bodkin, M.D.
[5], Director of the Clinical Psychopharmacology Research Program at McLean Hospital in Belmont MA, in conjunction with Harvard Medical School. [4]
[6]
[7]
[8] Currently, it is the only MAOI on the market used in the treatment of depression, that is absorbed through the skin into the blood stream and thereby to the central nervous system.
The patch "is a matrix containing three layers consisting of a backing, an... adhesive drug layer, and a release liner that is placed against the skin."[1] The primary advantage of delivering selegiline in this manner is to bypass the gastrointestinal tract and liver, specifically the small intenstine, thereby avoiding the chance of hypertensive crisis (very high spike in blood pressure possibly leading to stroke).[1]
[9]
[10]
"Despite long-standing concerns over hypertensive reactions,... (MAOIs) have grown in popularity... (and) the risk of hypertensive episodes is less than 1%."[11]
# Food Intake Restrictions
The dietary problem was first discovered by a neurologist whose wife was taking an MAO inhibitor. After eating hard cheese, which is rich in tyramine, she would get severe headaches; thus, her husband's discovery of these spikes in blood pressure. For this reason, the crisis is still called the "cheese syndrome", even though other foods can cause the same problem.
When an MAOI is taken orally, and an individual ingests such tyramine rich foods, the body can not properly regulate the additional tyramine. Therefore, dietary modifications are necessary.
Foods containing considerable amounts of tyramine include: air dried, aged and fermented meats, sausages and salamis; pickled herring; any spoiled or improperly stored meat, poultry and fish; spoiled or improperly stored animal livers; broad bean pods (fava beans); all tap beers, and other beers that have not been pasteurized; concentrated yeast extract (such as Marmite); most soybean products (including soy sauce and tofu); aged cheeses(not processed cheese); sauerkraut; and over-the-counter supplements containing tyramine.
[7]
[12]
[13][14][15]
# EMSAM Advantages
Due mainly to the availiability of the newer SSRIs and SNRIs, which are viewed to have more medically benign side effects in the treatment of depression, psychopharmacologists and psychiatrists have avoided prescribing MAOIs[1][11]
[16]
[17]
because of the possibility of hypertensive crisis. With EMSAM, taken at the lowest dose of 6 mg every 24 hours, no dietary modifications are required by the FDA
In addition to the lack of dietary restrictions at the 6mg/24h dose, EMSAM offers[10] another benefit. It is a continuous delivery system, keeping the medication at a steady level in the body over time.[18] Generally, oral medication can not keep a steady dose in the blood stream.
EMSAM is also valuable in the treatment of depression that is not alleviated by the more commonly used selective serotonin reuptake inhibitors(SSRIs), dual serotonin and norepinephrine reupatake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).
# Usage
The patch is changed once daily. There may be a reaction to the adhesive on the skin at the site of application.[19] Patients are encouraged to use an adhesive remover: usually mineral oil, Vaseline® or an over-the-counter product such as dermatology recommended TRIAD® brand adhesive tape remover pads. A new patch is placed on a different site. The combination of adhesive remover, and placing each patch on a new area of skin, is to discourage any dermatological reason for discontinuance of the patch.
Using rubbing alcohol or hydrogen peroxide to clean the skin of oils and dirt before applying a patch can increase the likelihood of proper attachment for the duration of each 24 hour period. Immediately after applying a patch it can be helpful to use the pressure and body heat of the palm of the hand to enhance proper adhesive contact.
All of the dietary restrictions are currently required by the FDA, as a precaution, at the higher 9 mg/24h and 12 mg/24h doses of EMSAM.[20]
# Medication Interactions
Over-the-counter items that can not be used while on EMSAM include: St. John's Wort; products containing dextromethorphan such as cough and cold preparations; decongestant medicines; and diet pills or herbal weight loss products. Caffeine and chocolate can only be consumed in small amounts.
There are prescription medications that can not be taken while using EMSAM, and for 2 weeks after stopping EMSAM.[4] Some medications must not be taken for 1 week (or more) before an individual can start using EMSAM.
Medications that can not be taken because they can cause serotonin syndrome [21]
include: (SSRIs), (SNRIs), (TCAs), other MAOIs, mirtazapine, bupropion, meperidine, analgesics such as tramadol, methadone, propoxyphene, cyclobezaprine and oral selegiline.[4]
The use of EMSAM is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). Carbamazepine and oxcarbazepine are also contraindicated.[4]
Patients taking EMSAM should not undergo elective surgery requiring general anesthesia or be given local anesthesia containing sympathomimetic vasoconstrictors.[4]
# EMSAM Name Origin, Manufacturer & Distributor
The acronym EMSAM is derived from the names Emily and Samuel. They are the children of Mel Sharoky, M.D., CEO of EMSAM's manufacturer, Somerset Pharmaceuticals, Inc.,[22] The prescription medication is distributed by Bristol-Myers Squibb out of Princeton NJ
# External links
- Everything You Ever Wanted to Know about EMSAM and more. [4]
- FDA Approves Emsam (selegiline) as First Drug Patch for Depression. |[5]
- Andrew Bridges, Associated Press (2006). "Skin patch for mood disorders approved". The Boston Globe March 01, 2006 |[6]
- Bodkin JA, Amsterdam JD (2002). "Transdermal Selegiline in Major Depression: A Double-Blind, Placebo-Controlled, Parallel-Group Study in Outpatients". American Journal of Psychiatry 159:1869-1875,November 20
- Bristol-Myers Squibb Company EMSAM® information for U.S. residents only. [7]
- Hitti, Miranda (reviewed bt Chang, M.D. Louise) (28-02-2006). ""FDA OKs Patch to Treat Depression,
Using EMSAM in Lower Doses May Avoid Concerns About Drug Interactions"". Medicine Net.com. Text "[[8]]" ignored (help); Text "WebMD, Inc. " ignored (help); line feed character in |title= at position 36 (help); Check date values in: |date= (help)CS1 maint: Multiple names: authors list (link) .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}
- Tong TG, Saklad SR (1994). "What foods you should avoid on MAOIs" (MAO-I's Dietary Restrictions) [9]
- Walker SE, Shulman KI, Tailor SA, Gardner D (October 1996). "Tyramine Content of Previously Restricted Foods in Monoamine Oxidase Inhibitor Diets". Journal of Clinical Psychopharmacology © Williams & Wilkins. All Rights Reserved. (5): 383–388. PMID 8889911. Unknown parameter |Volume= ignored (|volume= suggested) (help)CS1 maint: Multiple names: authors list (link) [10]
- William J. Cromie (November 7, 2002). "Bodkin is patching up depression". Harvard University Gazette (photo of Dr. Bodkin displaying patch.)[11]
- Feiger AD, Rickels K, Rynn MA, Zimbroff DL, Robinson DS (2006). "Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial". J Clin Psychiatry Sep; 67(9): 1354-61. [12]
- Framton JE, Plosker GL (2007). "Selegiline transdermal system: in the treatment of major depressive disorder". Drugs 67(2): 257-65; discussion 266-7. [13]
- Patkar AA, Pae CU, Masand PS (2006). "Transdermal selegiline: the new generation of monoamine oxidase inhibitors". CNS Spectrums May;11(5): 363-75. [14]
- Patkar AA, Pae CU, Zarzar M (2007). "Transdermal selegiline." Drugs of Today (Barcelona, Spain) Jun; 43(6): 361-77. [15]
- NIH Medication Information: EMSAM.
- NIH Medline Information: Serotonin Syndrome | https://www.wikidoc.org/index.php/EMSAM | |
9d2fa524a2fe75606cb3e40a2d5c2824fd51dd8a | wikidoc | ENDOG | ENDOG
Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson’s disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.
# Structure
The enzyme encoded by this gene is a member of the conserved DNA/RNA non-specific ββα-Me-finger nuclease family and possesses a unique site selectivity of poly(dG).poly(dC) sequences in double-stranded DNA. The protein is initially synthesized as an inactive 33-kDa precursor. This precursor is activated by proteolytic cleavage of the mitochondrial targeting sequence, thus producing a mature 28-kDa enzyme that is translocated to the mitochondrial intermembrane space, where it forms an active homodimer. The H-N-N motif (His-141, Asn-163, Asn-172) is crucial for the protein's catalytic function and substrate specificity, and the His-141 amino acid is necessary for magnesium coordination. The amino acid Asn-251 also appears to be catalytic, and Glu-271 appears to be another magnesium ligand, but both are located far from the H-N-N motif and, thus, their interactions are unclear.
# Function
The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrial intermembrane space. The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA.
In some apoptotic pathways, EndoG is released from the mitochondrion and migrates to the nucleus, where it degrades chromatin with the help of other nuclear proteins. In one such pathway, caspase-independent apoptosis, the E3 ligase C-terminal of Hsc-70 interacting protein (CHIP), a regulator of EndoG expression, functions as a protective mechanism against oxidative stress. Under normal conditions, EndoG remains bound to Hsp70 and CHIP; however, when undergoing oxidative stress, EndoG dissociates from Hsp70 and CHIP and translocates to the nucleus, where it degrades DNA to effect apoptosis. Therefore, maintaining low levels of EndoG could prevent cell death caused by stress conditions. In epithelial cells, the nuclear localization and proapoptotic function of EndoG leads it to play a role in cell senescence.
In addition to DNA degradation, EndoG also stimulates inhibitors of apoptosis proteins (IAPs) to target proteins for proteasomal degradation.
# Clinical significance
The Endonuclase G enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling. Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The BNIP3 pathway involves mitochondrial release and nuclear translocation of the endonuclease G. It is not clear, however, that how BNIP3 interacts with mitochondria. It has been shown that BNIP3 interacts with the voltage-dependent anion channel (VDAC) to directly induce mitochondrial release and nuclear translocation of EndonucleaseG. Data has identified VDAC as an interacting partner of BNIP3 and provide direct evidence to support that EndoG is a mediator of the BNIP3 cell death pathway. Most notably, Enodnuclease G is pivotal during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society. During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. More recently, Endonuclease G is considered a determinant of cardiac hypertrophy. A link has been established between Endonuclease G and mitochondrial function during cardiac hypertrophy, partly through the effects of Endo G on Mfn2 and Jp2, and revealed a role for Endonuclease G in the crosstalk between the processes controlled by Mfn2 and Jp2 in maladaptive cardiac hypertrophy.
Previous studies reported greater efficacy of anticancer drugs when used in conjunction with high EndoG levels. Thus, regulators of EndoG, such as CHIP, could serve as therapeutic targets for oxidative stress-induced cell death in cancer and aging. Through its association with cell senescence in epithelial cells, EndoG may also contribute to age-related vascular diseases such as arteriosclerosis. Similarly, myonuclear localization of EndoG is correlated with atrophied aging skeletal muscle, leading to increased apoptotic signaling and muscle mass loss. EndoG has also been implicated in Parkinson’s disease (PD), as it induces DNA fragmentation in neurons when translocated from the mitochondria to nuclei. This mechanism involves the kynurenine pathway and the permeability transition pore; as such, targeting molecules in this pathway could prevent EndoG-mediated cell death and effectively help treat PD in patients. Similarly, EndoG knockdown in mice mitigated injurious insults; thus, therapeutic strategies to inhibit or silence EndoG could help protect tissues during injury and disease. So far, two EndoG inhibitors, PNR-3-80 (5-((1-(2-naphthoyl)-5-chloro-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione) and PNR-3-82 (5-((1-(2-naphthoyl)-5-methoxy-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, have been tested and confirmed.
# Interactions | ENDOG
Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene.[1][2] This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress.[3] As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson’s disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.[3][4]
# Structure
The enzyme encoded by this gene is a member of the conserved DNA/RNA non-specific ββα-Me-finger nuclease family and possesses a unique site selectivity of poly(dG).poly(dC) sequences in double-stranded DNA. The protein is initially synthesized as an inactive 33-kDa precursor. This precursor is activated by proteolytic cleavage of the mitochondrial targeting sequence, thus producing a mature 28-kDa enzyme that is translocated to the mitochondrial intermembrane space, where it forms an active homodimer.[5][6][7] The H-N-N motif (His-141, Asn-163, Asn-172) is crucial for the protein's catalytic function and substrate specificity, and the His-141 amino acid is necessary for magnesium coordination. The amino acid Asn-251 also appears to be catalytic, and Glu-271 appears to be another magnesium ligand, but both are located far from the H-N-N motif and, thus, their interactions are unclear.[7]
# Function
The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrial intermembrane space.[2][8] The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA.[2]
In some apoptotic pathways, EndoG is released from the mitochondrion and migrates to the nucleus, where it degrades chromatin with the help of other nuclear proteins.[3][5][7] In one such pathway, caspase-independent apoptosis, the E3 ligase C-terminal of Hsc-70 interacting protein (CHIP), a regulator of EndoG expression, functions as a protective mechanism against oxidative stress. Under normal conditions, EndoG remains bound to Hsp70 and CHIP; however, when undergoing oxidative stress, EndoG dissociates from Hsp70 and CHIP and translocates to the nucleus, where it degrades DNA to effect apoptosis. Therefore, maintaining low levels of EndoG could prevent cell death caused by stress conditions.[9] In epithelial cells, the nuclear localization and proapoptotic function of EndoG leads it to play a role in cell senescence.[6]
In addition to DNA degradation, EndoG also stimulates inhibitors of apoptosis proteins (IAPs) to target proteins for proteasomal degradation.[10]
# Clinical significance
The Endonuclase G enzyme is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.[11] Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[12] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The BNIP3 pathway involves mitochondrial release and nuclear translocation of the endonuclease G.[13][14] It is not clear, however, that how BNIP3 interacts with mitochondria. It has been shown that BNIP3 interacts with the voltage-dependent anion channel (VDAC) to directly induce mitochondrial release and nuclear translocation of EndonucleaseG. Data has identified VDAC as an interacting partner of BNIP3 and provide direct evidence to support that EndoG is a mediator of the BNIP3 cell death pathway.[15] Most notably, Enodnuclease G is pivotal during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a heart attack (also known as ischemic heart disease). Ischemic heart disease, which results from an occlusion of one of the major coronary arteries, is currently still the leading cause of morbidity and mortality in western society.[16][17] During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. More recently, Endonuclease G is considered a determinant of cardiac hypertrophy. A link has been established between Endonuclease G and mitochondrial function during cardiac hypertrophy, partly through the effects of Endo G on Mfn2 and Jp2, and revealed a role for Endonuclease G in the crosstalk between the processes controlled by Mfn2 and Jp2 in maladaptive cardiac hypertrophy.[18]
Previous studies reported greater efficacy of anticancer drugs when used in conjunction with high EndoG levels. Thus, regulators of EndoG, such as CHIP, could serve as therapeutic targets for oxidative stress-induced cell death in cancer and aging.[9] Through its association with cell senescence in epithelial cells, EndoG may also contribute to age-related vascular diseases such as arteriosclerosis.[6] Similarly, myonuclear localization of EndoG is correlated with atrophied aging skeletal muscle, leading to increased apoptotic signaling and muscle mass loss. EndoG has also been implicated in Parkinson’s disease (PD), as it induces DNA fragmentation in neurons when translocated from the mitochondria to nuclei. This mechanism involves the kynurenine pathway and the permeability transition pore; as such, targeting molecules in this pathway could prevent EndoG-mediated cell death and effectively help treat PD in patients.[4] Similarly, EndoG knockdown in mice mitigated injurious insults; thus, therapeutic strategies to inhibit or silence EndoG could help protect tissues during injury and disease. So far, two EndoG inhibitors, PNR-3-80 (5-((1-(2-naphthoyl)-5-chloro-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione) and PNR-3-82 (5-((1-(2-naphthoyl)-5-methoxy-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, have been tested and confirmed.[5]
# Interactions | https://www.wikidoc.org/index.php/ENDOG | |
0d178586f01ce3e223d98675054a8cdac61a0a48 | wikidoc | ENOX2 | ENOX2
ENOX2 is a gene located on the long arm of the X chromosome in humans. The gene encodes the protein Ecto-NOX disulfide-thiol exchanger 2, a member of the NOX family of NADPH oxidases.
Ecto-NOX disulfide-thiol exchanger 2 is a growth-related cell surface protein. It was identified because it reacts with the monoclonal antibody K1 in cells, such as the ovarian carcinoma line OVCAR-3, also expressing the CAKI surface glycoprotein. The encoded protein has two enzymatic activities: catalysis of hydroquinone or NADH oxidation, and protein disulfide interchange. The two activities alternate with a period length of about 24 minutes. The encoded protein also displays prion-like properties. Two transcript variants encoding different isoforms have been found for this gene.
# Gene Location
The human ENOX2 gene is located on the long (q) arm of the X chromosome in humans, at region 2 band 6 sub band 1, from base pair 130,622,330 to 130,903,317 (build GRCh38.p7) (map). The gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, and zebrafish.
# Function
ENOX2 and related NOX proteins exhibit two distinct oscillating functions: the oxidation of NADH to NAD+ and a protein disulfide isomerase-like activity, unprecedented in the biochemical literature. Regarding NADH oxidation, the protein has a specific activity of 10-20µmol/min/mg of protein with a turnover number of 200-500. The oscillations are independent of temperature, with a period of 24 minutes, completing 60 cycles in a 24-hour day. The period of oscillation changes to 22 and 26 minutes in the cancer related (tNOX) and age-related (arNOX) forms respectively. This regular oscillation is attributed to the maintenance of biological clock
## Interactions
NADH activity of ENOX2 has been shown to be stimulated by various hormones and growth factors, including insulin, EGF, transferrin, lactoferrin, vasopressin and glucagon. This stimulation is not seen in protein samples recovered from cancer cells, suggesting the regular NADH oxidase activity of ENOX2 is decoupled in cancer. ENOX2 also has a number of protein-protein interactions, with ENOX1 and SOX2, among others.
## Cell Growth
Numerous studies in the 1990s correlated NADH oxidase activity with cell growth. Conditions which stimulated cell growth also stimulated NADH oxidase activity and conditions that inhibited cell growth inhibited NADH oxidase activity. Further experimental evidence showed that the rate of cell enlargement oscillates within the 24 minute oscillation of ENOX function. Maximum cell growth rates correspond to the portion of the ENOX cycle involved in protein dulsulfide bridge formation. Theories suggest that ENOX is responsible for the breakup and formation of disulfide bonds in membrane proteins, thus maximum cell growth coincides with maximum protein disulfide interchange activity.
# Role In Disease
## Cancer
The cancer associated, drug responsive variant of ENOX, tNOX, arises as a splice variant and is found on the cell surface of human cancers. tNOX exhibits a periodicity of 22 minutes, compared to the native 24 minutes and can be inhibited by a number of anticancer drugs, without affecting the native ENOX. These properties of tNOX are being used to develop early detection and intervention mechanisms for human cancers. | ENOX2
ENOX2 is a gene located on the long arm of the X chromosome in humans.[1] The gene encodes the protein Ecto-NOX disulfide-thiol exchanger 2, a member of the NOX family of NADPH oxidases.[2][3][4]
Ecto-NOX disulfide-thiol exchanger 2 is a growth-related cell surface protein. It was identified because it reacts with the monoclonal antibody K1 in cells, such as the ovarian carcinoma line OVCAR-3, also expressing the CAKI surface glycoprotein.[2] The encoded protein has two enzymatic activities: catalysis of hydroquinone or NADH oxidation, and protein disulfide interchange. The two activities alternate with a period length of about 24 minutes. The encoded protein also displays prion-like properties. Two transcript variants encoding different isoforms have been found for this gene.[5]
# Gene Location
The human ENOX2 gene is located on the long (q) arm of the X chromosome in humans, at region 2 band 6 sub band 1, from base pair 130,622,330 to 130,903,317 (build GRCh38.p7) (map). The gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, and zebrafish.[1]
# Function
ENOX2 and related NOX proteins exhibit two distinct oscillating functions: the oxidation of NADH to NAD+ and a protein disulfide isomerase-like activity, unprecedented in the biochemical literature.[4][6][7][8] Regarding NADH oxidation, the protein has a specific activity of 10-20µmol/min/mg of protein with a turnover number of 200-500.[9][10] The oscillations are independent of temperature, with a period of 24 minutes, completing 60 cycles in a 24-hour day.[6][8] The period of oscillation changes to 22 and 26 minutes in the cancer related (tNOX) and age-related (arNOX) forms respectively.[4] This regular oscillation is attributed to the maintenance of biological clock[4][11]
## Interactions
NADH activity of ENOX2 has been shown to be stimulated by various hormones and growth factors, including insulin, EGF, transferrin, lactoferrin, vasopressin and glucagon.[12] This stimulation is not seen in protein samples recovered from cancer cells, suggesting the regular NADH oxidase activity of ENOX2 is decoupled in cancer.[12] ENOX2 also has a number of protein-protein interactions, with ENOX1 and SOX2, among others.[13]
## Cell Growth
Numerous studies in the 1990s correlated NADH oxidase activity with cell growth.[4] Conditions which stimulated cell growth also stimulated NADH oxidase activity and conditions that inhibited cell growth inhibited NADH oxidase activity. Further experimental evidence showed that the rate of cell enlargement oscillates within the 24 minute oscillation of ENOX function.[14] Maximum cell growth rates correspond to the portion of the ENOX cycle involved in protein dulsulfide bridge formation.[15] Theories suggest that ENOX is responsible for the breakup and formation of disulfide bonds in membrane proteins, thus maximum cell growth coincides with maximum protein disulfide interchange activity.[4]
# Role In Disease
## Cancer
The cancer associated, drug responsive variant of ENOX, tNOX, arises as a splice variant and is found on the cell surface of human cancers.[4][16] tNOX exhibits a periodicity of 22 minutes, compared to the native 24 minutes and can be inhibited by a number of anticancer drugs, without affecting the native ENOX.[4] These properties of tNOX are being used to develop early detection and intervention mechanisms for human cancers.[17] | https://www.wikidoc.org/index.php/ENOX2 | |
3ca1b2eb42b191975689f8b3efd0d58e924faef3 | wikidoc | ENPP3 | ENPP3
Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 is an enzyme that in humans is encoded by the ENPP3 gene.
# Function
The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells.
This protein has also been used in conjunction with CD63 as a marker for activated basophils in the Basophil Activation Test for IgE mediated allergic reactions. | ENPP3
Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 is an enzyme that in humans is encoded by the ENPP3 gene.[1][2]
# Function
The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells.[2]
This protein has also been used in conjunction with CD63 as a marker for activated basophils in the Basophil Activation Test for IgE mediated allergic reactions.[3] | https://www.wikidoc.org/index.php/ENPP3 | |
414b1ee0c250cbee506bd000188025e24ea21d79 | wikidoc | ENPP7 | ENPP7
Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene.
# History
ENPP7 is a new name for an old enzyme whose activity was originally identified in 1969 by Nilsson as a type of sphingomyelinase that hydrolyses sphingomyelin to ceramide in the intestinal tract. The enzyme was then purified and characterized by Duan et al. and named alkaline sphingomyelinase (alk-SMase), as the optimal pH of the enzyme was 9.0 and its main substrate is sphingomyelin. Most previous studies used the name of alk-SMase for this protein. The name of ENPP7 was created based on the results of cloning studies which show that alk-SMase shares no structural similarities with either acid or neutral SMase but belongs to the family of ecto nucleotide pyrophosphatase/phosphodiesterase (ENPP). As a new addition to the family it is therefore called ENPP7 or NPP7. A 3D homology model of ENPP7 was recently constructed using the crystal structural of an NPP member in bacteria as a template.
# Tissue distribution
Differing from other ENPP members, ENPP7 seems only expressed in the intestinal mucosa in many species and additionally in human liver. In the intestinal tract, ENPP7 activity is low in the duodenum and colon but high in the middle of the jejunum. As an ecto enzyme, ENPP7 is located on the surface of the intestinal mucosa and is released in the lumen by bile salt and pancreatic trypsin. The enzyme expressed in human liver is released in the bile and delivered to the intestine.
The activity of ENPP7 depends specifically on two types of primary bile salts, taurocholate (TC) and taurochenodeoxycholate (TCDC) at critical micelle concentrations. Other detergents, such as CHAPS and Triton X-100 have no stimulatory effects rather inhibitory effects, indicating a biologic interaction between bile salts and the enzyme. Unlike acid and neutral SMases in the intestinal tract that are rapidly inactivated by pancreatic trypsin, alk-SMase is resistant to trypsin digestion. Thus ENPP7 is active in the intestinal lumen and is transported along the intestinal tract. Significant activity can be detected in the faeces.
The substrates of ENPP family vary greatly. Some have activity against nucleotides, some have activity against phospholipid and lysophospholipids. ENPP7 is the only enzyme that has a type of phospholipase C activity against sphingomyelin.
# Physiological functions and clinical implications
ENPP7 is the key enzyme in the gut that digests sphingomyelin. Sphingomyelin is a lipid constituent of cell membrane, and a dietary component being particularly abundant in milk, cheese, egg, and meat. Digestion of sphingomyelin mainly occurs in the middle part of the small intestine, where ENPP7 is abundant, indicating a role of the enzyme in sphingomyelin digestion. Recent studies on ENPP7 knockout mice clearly showed that digestion of sphingomyelin and generation of ceramide is severely affected in ENPP7 deficiency mice. ENPP7 is fully developed in the intestine before birth, which gives the infant ability to digest sphingomyelin in the milk.
The daily intake of sphingomyelin for human with Western diet is about 300 mg. Under physiological conditions, only part of the sphingomyelin can be digested and absorbed. The limitation is thought to be caused by several factors that are present in the intestine such as cholesterol, phospholipids, fat and high concentrations of bile salts. It is thus understandable why SM digestion occurs most effectively in the low part of the small intestine, where most fat, phospholipids, and bile salt have been absorbed or up taken. It is also understandable that considerable amount of dietary sphingomyelin is delivered into the colon and excreted in the feces.
ENPP7 may have important roles in preventing tumorigenesis in the intestinal tract, as ceramide, the product of sphingomyelin hydrolysis, can inhibit cell proliferation and stimulate cell differentiation and apoptosis. Animal studies showed that supplement of SM or ceramide in the diet may inhibit the development of colon cancer. Of particular interest is that the activity of ENPP7 is significantly decreased in human colorectal adenoma and carcinoma as well as in the feces of the cancer patients. The decrease is caused by expression of a few mutant forms of ENPP7, which lack exon 4, resulting in total inactivation of the enzyme, as found in human colon and liver cancer cells.
Besides sphingomyelin, ENPP7 can also degrade and inactivate platelet-activating factor (PAF), which is proinflammatory, indicating that ENPP7 may also have antiinflammatory effects. Rectal administration of recombinant ENPP7 has been shown to improve ulcerative colitis in an animal study, and patients with chronic ulcerative colitis are associated with a reduced ENPP7 activity.
ENPP7 may also affect cholesterol absorption. In the intestinal tract cholesterol and sphingomyelin are co-exiting in plasma membrane and in lipid vesicles, liposomes and micelles. The two molecules form a stable complex via van der Waals forces. Cholesterol absorption can be inhibited by supplementation of sphingomyelin in the diet. Milk sphingomyelin seems more potent than egg sphingomyelin, indicating that the inhibition is related to the degree of the saturation and the length of sphingomyelin. Recent studies further showed that formation of ceramide by ENPP7 in the gut enhanced sphingomyelin-induced inhibition of cholesterol, indicating regulatory roles of ENPP7 in cholesterol absorption.
# Regulation
The expression of ENPP7 can be modified by dietary factors. High fat diet (53% energy) greatly reduces ENPP7 activities and enzyme protein in the intestinal mucosa by 50%. On the other hand, water-soluble fiber psyllium was shown to increase both the activities and protein of ENPP7 in the colon of mice. Sphingomyelin can also increase the levels of ENPP7 after a long term of administration. Besides, ursodeoxycholic acid and probiotic VSL#3 may stimulate the expression of ENPP7 in the intestine. | ENPP7
Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (E-NPP 7) also known as alkaline sphingomyelin phosphodiesterase (Alk-SMase) or intestinal alkaline sphingomyelinase is an enzyme that in humans is encoded by the ENPP7 gene.[1][2]
# History
ENPP7 is a new name for an old enzyme whose activity was originally identified in 1969 by Nilsson as a type of sphingomyelinase that hydrolyses sphingomyelin to ceramide in the intestinal tract.[3] The enzyme was then purified and characterized by Duan et al. and named alkaline sphingomyelinase (alk-SMase), as the optimal pH of the enzyme was 9.0 and its main substrate is sphingomyelin.[4][5] Most previous studies used the name of alk-SMase for this protein. The name of ENPP7 was created based on the results of cloning studies which show that alk-SMase shares no structural similarities with either acid or neutral SMase but belongs to the family of ecto nucleotide pyrophosphatase/phosphodiesterase (ENPP).[1][6] As a new addition to the family it is therefore called ENPP7 or NPP7. A 3D homology model of ENPP7 was recently constructed using the crystal structural of an NPP member in bacteria as a template.[7][8][unreliable source?]
# Tissue distribution
Differing from other ENPP members, ENPP7 seems only expressed in the intestinal mucosa in many species and additionally in human liver. In the intestinal tract, ENPP7 activity is low in the duodenum and colon but high in the middle of the jejunum.[9] As an ecto enzyme, ENPP7 is located on the surface of the intestinal mucosa and is released in the lumen by bile salt and pancreatic trypsin.[10][11] The enzyme expressed in human liver is released in the bile and delivered to the intestine.
The activity of ENPP7 depends specifically on two types of primary bile salts, taurocholate (TC) and taurochenodeoxycholate (TCDC) at critical micelle concentrations.[12] Other detergents, such as CHAPS and Triton X-100 have no stimulatory effects rather inhibitory effects, indicating a biologic interaction between bile salts and the enzyme. Unlike acid and neutral SMases in the intestinal tract that are rapidly inactivated by pancreatic trypsin,[9] alk-SMase is resistant to trypsin digestion.[11] Thus ENPP7 is active in the intestinal lumen and is transported along the intestinal tract. Significant activity can be detected in the faeces.
The substrates of ENPP family vary greatly. Some have activity against nucleotides, some have activity against phospholipid and lysophospholipids.[13] ENPP7 is the only enzyme that has a type of phospholipase C activity against sphingomyelin.
# Physiological functions and clinical implications
ENPP7 is the key enzyme in the gut that digests sphingomyelin. Sphingomyelin is a lipid constituent of cell membrane, and a dietary component being particularly abundant in milk, cheese, egg, and meat.[14] Digestion of sphingomyelin mainly occurs in the middle part of the small intestine, where ENPP7 is abundant, indicating a role of the enzyme in sphingomyelin digestion.[15] Recent studies on ENPP7 knockout mice clearly showed that digestion of sphingomyelin and generation of ceramide is severely affected in ENPP7 deficiency mice. ENPP7 is fully developed in the intestine before birth,[16][17] which gives the infant ability to digest sphingomyelin in the milk.
The daily intake of sphingomyelin for human with Western diet is about 300 mg. Under physiological conditions, only part of the sphingomyelin can be digested and absorbed.[18] The limitation is thought to be caused by several factors that are present in the intestine such as cholesterol, phospholipids, fat and high concentrations of bile salts.[19] It is thus understandable why SM digestion occurs most effectively in the low part of the small intestine, where most fat, phospholipids, and bile salt have been absorbed or up taken. It is also understandable that considerable amount of dietary sphingomyelin is delivered into the colon and excreted in the feces.[15][20][21]
ENPP7 may have important roles in preventing tumorigenesis in the intestinal tract, as ceramide, the product of sphingomyelin hydrolysis, can inhibit cell proliferation and stimulate cell differentiation and apoptosis. Animal studies showed that supplement of SM or ceramide in the diet may inhibit the development of colon cancer.[22] Of particular interest is that the activity of ENPP7 is significantly decreased in human colorectal adenoma and carcinoma as well as in the feces of the cancer patients.[23][24][25] The decrease is caused by expression of a few mutant forms of ENPP7, which lack exon 4, resulting in total inactivation of the enzyme, as found in human colon and liver cancer cells.[12][26][27]
Besides sphingomyelin, ENPP7 can also degrade and inactivate platelet-activating factor (PAF), which is proinflammatory, indicating that ENPP7 may also have antiinflammatory effects.[28] Rectal administration of recombinant ENPP7 has been shown to improve ulcerative colitis in an animal study,[29] and patients with chronic ulcerative colitis are associated with a reduced ENPP7 activity.[30]
ENPP7 may also affect cholesterol absorption. In the intestinal tract cholesterol and sphingomyelin are co-exiting in plasma membrane and in lipid vesicles, liposomes and micelles. The two molecules form a stable complex via van der Waals forces. Cholesterol absorption can be inhibited by supplementation of sphingomyelin in the diet.[31] Milk sphingomyelin seems more potent than egg sphingomyelin, indicating that the inhibition is related to the degree of the saturation and the length of sphingomyelin.[32] Recent studies further showed that formation of ceramide by ENPP7 in the gut enhanced sphingomyelin-induced inhibition of cholesterol,[33] indicating regulatory roles of ENPP7 in cholesterol absorption.
# Regulation
The expression of ENPP7 can be modified by dietary factors. High fat diet (53% energy) greatly reduces ENPP7 activities and enzyme protein in the intestinal mucosa by 50%.[34] On the other hand, water-soluble fiber psyllium was shown to increase both the activities and protein of ENPP7 in the colon of mice.[34] Sphingomyelin can also increase the levels of ENPP7 after a long term of administration.[35] Besides, ursodeoxycholic acid and probiotic VSL#3 may stimulate the expression of ENPP7 in the intestine.[36][37] | https://www.wikidoc.org/index.php/ENPP7 | |
dbbbdeb3ee161e7668e450146a22eebad43c5de6 | wikidoc | EP300 | EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2. This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16.
# Function
p300 HAT functions as histone acetyltransferase that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.
p300 HAT contains a bromodomain which is involved in IL6 signaling.:3.1
This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.
# Mechanism
The p300 protein carries out its function of activating transcription by binding to transcription factors, and the transcription machinery. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction domain (RID), the KIX domain (CREB and MYB interaction domain), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.
# Clinical significance
Mutations in the EP300 gene are responsible for a small percentage of cases of Rubinstein-Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development.
Chromosomal rearrangements involving chromosome 22 have rarely been associated with certain types of cancer. These rearrangements, called translocations, disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosomes 8 and 22 in several people with a cancer of blood cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer.
Mutations in the EP300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.
# Interactions
EP300 has been shown to interact with:
- BCL3,
- BRCA1,
- CDX2,
- CEBPB,
- CITED1,
- CITED2,
- DDX5,
- DTX1,
- EID1,
- ELK1,
- ESR1,
- FEN1,
- GPS2,
- HIF1A,
- HNF1A,
- HNRPU,
- ING4,
- ING5,
- IRF2,
- LEF1,
- MAF,
- MAML1,
- MEF2C,
- MEF2D,
- MYBL2,
- Mdm2,
- MyoD,
- MEF2A,
- NCOA6,
- NFATC2,
- NPAS2,
- P53,
- PAX6,
- PCNA,
- PROX1,
- PTMA,
- PPARA,
- PPARG,
- RORA,
- RELA,
- SMAD1,
- SMAD2,
- SMAD7,
- SNIP1,
- SS18,
- STAT3,
- STAT6,
- TAL1,
- TCF3,
- TFAP2A,
- TGS1,
- TRERF1,
- TSG101,
- THRA,
- TWIST1,
- YY1, and
- Zif268. | EP300
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene.[1] It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2. This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16.
# Function
p300 HAT functions as histone acetyltransferase[2] that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.
p300 HAT contains a bromodomain which is involved in IL6 signaling.[3]:3.1
This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.[4]
# Mechanism
The p300 protein carries out its function of activating transcription by binding to transcription factors, and the transcription machinery. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction domain (RID), the KIX domain (CREB and MYB interaction domain), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.[5]
# Clinical significance
Mutations in the EP300 gene are responsible for a small percentage of cases of Rubinstein-Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development.
Chromosomal rearrangements involving chromosome 22 have rarely been associated with certain types of cancer. These rearrangements, called translocations, disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosomes 8 and 22 in several people with a cancer of blood cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer.
Mutations in the EP300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.
# Interactions
EP300 has been shown to interact with:
- BCL3,[6]
- BRCA1,[7][8]
- CDX2,[9]
- CEBPB,[10]
- CITED1,[11]
- CITED2,[12][13][14][15]
- DDX5,[16]
- DTX1,[17]
- EID1,[18][19]
- ELK1,[20]
- ESR1,[7][21][22]
- FEN1,[23]
- GPS2,[24]
- HIF1A,[25][26]
- HNF1A,[27]
- HNRPU,[28]
- ING4,[29]
- ING5,[29]
- IRF2,[30]
- LEF1,[31]
- MAF,[32]
- MAML1,[33][34]
- MEF2C,[35]
- MEF2D,[36][37]
- MYBL2,[38]
- Mdm2,[39]
- MyoD,[35][40]
- MEF2A,[41]
- NCOA6,[42]
- NFATC2,[43]
- NPAS2,[44]
- P53,[39][45][46][47][48]
- PAX6,[9]
- PCNA,[49]
- PROX1,[32]
- PTMA,[50]
- PPARA,[51][52]
- PPARG,[21][53]
- RORA,[40]
- RELA,[54][55]
- SMAD1,[56][57]
- SMAD2,[58][59]
- SMAD7,[60]
- SNIP1,[61]
- SS18,[62]
- STAT3,[57]
- STAT6,[63]
- TAL1,[64]
- TCF3,[65]
- TFAP2A,[13]
- TGS1,[66]
- TRERF1,[67]
- TSG101,[68]
- THRA,[41]
- TWIST1,[69]
- YY1,[70][71] and
- Zif268.[72] | https://www.wikidoc.org/index.php/EP300 | |
ff4454dd6d4002d2459ce5c8f88a152cbfd7a3eb | wikidoc | EPAS1 | EPAS1
Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2alpha)) is a protein that in humans is encoded by the EPAS1 gene. It is a type of hypoxia-inducible factor, a group of transcription factors involved in body response to oxygen level. The gene is active under low oxygen condition called hypoxia. It is also important in the development of the heart, and maintaining catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.
However, a special version (allele) of EPAS1 produces EPAS1 which is responsible for high-altitude adaptation in humans. It is known that the variant gene confers increased athletic performance in some people, and hence it is dubbed the "super athlete gene".
# Function
The EPAS1 gene encodes half of a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall (hypoxia). The encoded protein contains a basic helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. EPAS 1 is involved in the development of the embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. It is essential in maintaining catecholamine homeostasis and protection against heart failure during early embryonic development.
Catecholamines include epinephrine and norepinephrine. It is important for the production of catecholamines to remain in homeostatic conditions so that both the delicate fetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control of cardiac output by increasing the fetal heart rate.
# Alleles
Tibetans carry a high proportion of an allele that improves oxygen transport. The beneficial allele is also found in the extinct Denisovan genome, suggesting that it arose in them and entered the modern human population by hybridization.
The Tibetan Mastiff also received a variant of the allele by interbreeding with the native Tibetan wolf.
# Clinical significance
Mutations in EPAS1 gene are related to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense mutations that locate in the primary hydroxylation site of HIF-2α, which disrupt the protein hydroxylation/degradation mechanism, and leads to protein stabilization and pseudohypoxic signaling. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.
Mutations in this gene are associated with erythrocytosis familial type 4, pulmonary hypertension and chronic mountain sickness. There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet. The effect is most profound among the Tibetans living in the Himalayas at an altitude of about 4,000 metres above sea level, the environment of which is intolerable to other human populations due to 40% less atmospheric oxygen. The Tibetans suffer no health problems associated with altitude sickness, but instead produce low levels of blood pigment (haemoglobin) sufficient for less oxygen, more elaborate blood vessels, have lower infant mortality, and are heavier at birth.
EPAS1 is useful in high altitudes as a short term adaptive response. However, EPAS1 can also cause excessive production of red blood cells leading to chronic mountain sickness that can lead to death and inhibited reproductive abilities. Some mutations that increase its expression are associated with increased hypertension and stroke at low altitude, with symptoms similar to mountain sickness. People permanently living at high altitudes might experience selection of EPAS1 to reduce the fitness consequences of excessive red blood cell production.
# Interactions
EPAS1 has been shown to interact with aryl hydrocarbon receptor nuclear translocator and ARNTL. | EPAS1
Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2alpha)) is a protein that in humans is encoded by the EPAS1 gene. It is a type of hypoxia-inducible factor, a group of transcription factors involved in body response to oxygen level.[1][2][3][4] The gene is active under low oxygen condition called hypoxia. It is also important in the development of the heart, and maintaining catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.
However, a special version (allele) of EPAS1 produces EPAS1 which is responsible for high-altitude adaptation in humans.[5][6] It is known that the variant gene confers increased athletic performance in some people, and hence it is dubbed the "super athlete gene".[7]
# Function
The EPAS1 gene encodes half of a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall (hypoxia). The encoded protein contains a basic helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. EPAS 1 is involved in the development of the embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. It is essential in maintaining catecholamine homeostasis and protection against heart failure during early embryonic development.[4]
Catecholamines include epinephrine and norepinephrine. It is important for the production of catecholamines to remain in homeostatic conditions so that both the delicate fetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control of cardiac output by increasing the fetal heart rate.[8]
# Alleles
Tibetans carry a high proportion of an allele that improves oxygen transport. The beneficial allele is also found in the extinct Denisovan genome, suggesting that it arose in them and entered the modern human population by hybridization.[9]
The Tibetan Mastiff also received a variant of the allele by interbreeding with the native Tibetan wolf.[10]
# Clinical significance
Mutations in EPAS1 gene are related to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense mutations that locate in the primary hydroxylation site of HIF-2α, which disrupt the protein hydroxylation/degradation mechanism, and leads to protein stabilization and pseudohypoxic signaling. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.[11][12]
Mutations in this gene are associated with erythrocytosis familial type 4,[4] pulmonary hypertension and chronic mountain sickness.[13] There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet.[5][6][14] The effect is most profound among the Tibetans living in the Himalayas at an altitude of about 4,000 metres above sea level, the environment of which is intolerable to other human populations due to 40% less atmospheric oxygen. The Tibetans suffer no health problems associated with altitude sickness, but instead produce low levels of blood pigment (haemoglobin) sufficient for less oxygen, more elaborate blood vessels,[15] have lower infant mortality,[16] and are heavier at birth.[17]
EPAS1 is useful in high altitudes as a short term adaptive response. However, EPAS1 can also cause excessive production of red blood cells leading to chronic mountain sickness that can lead to death and inhibited reproductive abilities. Some mutations that increase its expression are associated with increased hypertension and stroke at low altitude, with symptoms similar to mountain sickness. People permanently living at high altitudes might experience selection of EPAS1 to reduce the fitness consequences of excessive red blood cell production.[14]
# Interactions
EPAS1 has been shown to interact with aryl hydrocarbon receptor nuclear translocator[18] and ARNTL.[19] | https://www.wikidoc.org/index.php/EPAS1 | |
8ddb5ce8baa8b92830869f01f1c15c073bbe5d9b | wikidoc | EPHB3 | EPHB3
Ephrin type-B receptor 3 is a protein that in humans is encoded by the EPHB3 gene.
# Function
Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene is a receptor for ephrin-B family members.
# Interactions
EPHB3 has been shown to interact with MLLT4 and RAS p21 protein activator 1. | EPHB3
Ephrin type-B receptor 3 is a protein that in humans is encoded by the EPHB3 gene.[1][2]
# Function
Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene is a receptor for ephrin-B family members.[2]
# Interactions
EPHB3 has been shown to interact with MLLT4[3] and RAS p21 protein activator 1.[4] | https://www.wikidoc.org/index.php/EPHB3 | |
702b516ab0d9b50b8717c1618a6558c319bfb929 | wikidoc | EPHX1 | EPHX1
Epoxide hydrolase 1 is an enzyme encoded by the EPHX1 gene in humans.
# Function
Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.
# Discovery
Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver and later also purified from human liver and characterized. EPHX1 belongs to the family of α/β hydrolases and converts epoxides to diols.
# Tissue distribution
EPHX1 protein can be found predominantly in membrane fraction of the endoplasmic reticulum of eucaryotic cells. Its expression in mammals is generally the highest in the liver, followed by adrenal gland, lung, kidney, lung, and intestine. It was found also in bronchial epithelial cells and upper gastrointestinal tract. EPHX1 expression is individually variable among humans and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.
# Gene structure and ontology
Human EPHX1 orthologues were found in 127 organisms. Human microsomal epoxide hydrolase is coded by EPHX1 gene located on chromosome 1 (1q42.12). Three transcription variants differing in the 5´-untranslated region have been identified with length of 455 amino acids.
# Function
Conversion of epoxides to trans-dihydrodiols presents prototypical EPHX1 reaction. EPHX1 has broad substrate specificity. EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc., but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.
EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes. Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates. EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid and may play an important role in the endocannabinoid signaling pathway.
# Clinical significance
Mutations in EPHX1 have been linked with preeclampsia, elevated blood levels of bile salts (i.e. hypercholanemia), Fetal hydantoin syndrome, and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied. Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro and their combination was used for deduction of EPHX1 activity. However, their functional effect was not confirmed in human liver microsomes.
Due to the EPHX1 role in metabolism of procarcinogens and existence of gene variations with functional effect a number of association studies has been conducted. Significant associations between EPHX1 SNPs and risk of lung, upper aerodigestive tract, breast, and ovarian cancers have been observed in various populations. Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer. Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well ). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .
Recent meta-analysis comprising 8,259 patients with chronic obstructive pulmonary disease (COPD) and 42,883 controls reported that the predicted slow activity EPHX1 phenotype is a significant risk factor for COPD in Caucasian, but not in Asian population. Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease, methamphetamine-induced drug dependence, and cerebral metabolism of epoxyeicosatrienoic acids was suggested. Modulation of metabolism of epoxyeicosatrienoic acids by EPHX1 may interfere with, e.g., signal transmission of neurons, vasodilation, cardiovascular homeostasis, and inflammation. Transformation of the current knowledge about EPHX1 into clinical applications is, however, limited by the lack of crystal structure of the enzyme and by the complex relations between its genotype and phenotype.
# Notes | EPHX1
Epoxide hydrolase 1 is an enzyme encoded by the EPHX1 gene in humans.[1][2]
# Function
Epoxide hydrolase plays an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons.[2]
# Discovery
Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver [3] and later also purified from human liver and characterized.[4] EPHX1 belongs to the family of α/β hydrolases [5] and converts epoxides to diols.[6]
# Tissue distribution
EPHX1 protein can be found predominantly in membrane fraction of the endoplasmic reticulum of eucaryotic cells. Its expression in mammals is generally the highest in the liver, followed by adrenal gland, lung, kidney, lung, and intestine.[7] It was found also in bronchial epithelial cells [8] and upper gastrointestinal tract.[9] EPHX1 expression is individually variable among humans [10] and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.[11]
# Gene structure and ontology
Human EPHX1 orthologues were found in 127 organisms. Human microsomal epoxide hydrolase is coded by EPHX1 gene located on chromosome 1 (1q42.12).[12][13][14] Three transcription variants differing in the 5´-untranslated region have been identified with length of 455 amino acids.
# Function
Conversion of epoxides to trans-dihydrodiols presents prototypical EPHX1 reaction.[6] EPHX1 has broad substrate specificity.[15][16] EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc.,[17] but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.[18][19]
EPHX1 mediates the sodium-dependent transport of bile acids into hepatocytes.[20] Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates.[21][22] EPHX1 also metabolizes endocannabinoid 2-arachidonoylglycerol to arachidonic acid[23] and may play an important role in the endocannabinoid signaling pathway.
# Clinical significance
Mutations in EPHX1 have been linked with preeclampsia,[24][25] elevated blood levels of bile salts (i.e. hypercholanemia),[26] Fetal hydantoin syndrome,[27] and diphenylhydantoin toxicity. Functional single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied.[28] Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro [29] and their combination was used for deduction of EPHX1 activity.[30] However, their functional effect was not confirmed in human liver microsomes.[31]
Due to the EPHX1 role in metabolism of procarcinogens and existence of gene variations with functional effect a number of association studies has been conducted. Significant associations between EPHX1 SNPs and risk of lung, upper aerodigestive tract, breast, and ovarian cancers have been observed in various populations.[32][33][34][35][36] Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer.[37][38][39] Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well [40][41]). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .[42]
Recent meta-analysis comprising 8,259 patients with chronic obstructive pulmonary disease (COPD) and 42,883 controls reported that the predicted slow activity EPHX1 phenotype is a significant risk factor for COPD in Caucasian, but not in Asian population.[43] Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease,[44] methamphetamine-induced drug dependence,[45] and cerebral metabolism of epoxyeicosatrienoic acids [46] was suggested. Modulation of metabolism of epoxyeicosatrienoic acids by EPHX1 may interfere with, e.g., signal transmission of neurons, vasodilation, cardiovascular homeostasis, and inflammation. Transformation of the current knowledge about EPHX1 into clinical applications is, however, limited by the lack of crystal structure of the enzyme and by the complex relations between its genotype and phenotype.
# Notes | https://www.wikidoc.org/index.php/EPHX1 | |
741f9a60ed504a0643e1f7792f65629aaba59d92 | wikidoc | EPS15 | EPS15
Epidermal growth factor receptor substrate 15 is a protein that in humans is encoded by the EPS15 gene.
# Function
This gene encodes a protein that is part of the EGFR pathway. The protein is present at clathrin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.
# Model organisms
Model organisms have been used in the study of EPS15 function. A conditional knockout mouse line, called Eps15tm1a(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 six tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant animals had a decreased mean corpuscular hemoglobin concentration.
# Interactions
EPS15 has been shown to interact with:
- CRK
- EPN1,
- HGS,
- HRB, and
- REPS2. | EPS15
Epidermal growth factor receptor substrate 15 is a protein that in humans is encoded by the EPS15 gene.[1]
# Function
This gene encodes a protein that is part of the EGFR pathway. The protein is present at clathrin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.[2]
# Model organisms
Model organisms have been used in the study of EPS15 function. A conditional knockout mouse line, called Eps15tm1a(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—at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty six tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant animals had a decreased mean corpuscular hemoglobin concentration.[5]
# Interactions
EPS15 has been shown to interact with:
- CRK[13]
- EPN1,[14]
- HGS,[15][16]
- HRB,[17] and
- REPS2.[18] | https://www.wikidoc.org/index.php/EPS15 | |
d5513ef097634e5406049f9b2eb0188c2504aae3 | wikidoc | ERAP1 | ERAP1
Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator, also known as endoplasmic reticulum aminopeptidase 1 (ARTS-1), is a protein which in humans is encoded by the ARTS-1 gene.
Endoplasmic reticulum amino peptidase 1 is active in the endoplasmic reticulum, which is involved in protein processing and transport. This protein is an aminopeptidase, which is an enzyme that cleaves peptides at the N-terminal into smaller fragments called amino acids.
# Nomenclature
ARTS1 is also known as:
- ER aminopeptidase 1 (ERAP1) the name accepted by the Hugo Gene Nomenclature Committee
- ER aminopeptidase associated with antigen processing (ERAAP) in mice
- Adipocyte-derived leucine aminopeptidase (ALAP)
- Puromycin-insensitive leucine aminopeptidase (PILS-AP)
# Function
ERAP1 has two major functions in the immune system:
- First, ERAP1 cleaves several proteins called cytokine receptors on the surface of cells. Cleaving these receptors reduces their ability to transmit chemical signals into the cell, which affects the process of inflammation.
- Second, ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto major histocompatibility complex (MHC) class I. These peptides are attached to MHC class I in the endoplasmic reticulum and exported to the cell surface, where they are displayed to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct.
ARTS-1 is a member of the M1 family of zinc metallopeptidases which acts as an aminopeptidase that degrades oligopeptides by cleavage starting at the amino terminus. One of the functions of aminopeptidases is to degrade potentially toxic peptides in the cytosol.
ARTS-1 is a transmembrane protein that is localized to the endoplasmic reticulum. It has been implicated in the following functions:
- Shedding of various cytokine receptors and decoy receptors
- Trimming of antigenic peptides before binding to MHC class I, affecting antigen presentation to cytotoxic T lymphocytes
- Stimulation of phagocytosis upon release by macrophages
# Clinical significance
Aminopeptidases play a role in the metabolism of several peptides that may be involved in blood pressure and the pathogenesis of essential hypertension. Mutations in the ARTS-1 have been linked to an increased risk of ankylosing spondylitis but only in HLA-B27 positive patients.
The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene. | ERAP1
Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator, also known as endoplasmic reticulum aminopeptidase 1 (ARTS-1), is a protein which in humans is encoded by the ARTS-1 gene.[1]
Endoplasmic reticulum amino peptidase 1 is active in the endoplasmic reticulum, which is involved in protein processing and transport. This protein is an aminopeptidase, which is an enzyme that cleaves peptides at the N-terminal into smaller fragments called amino acids.
# Nomenclature
ARTS1 is also known as:
- ER aminopeptidase 1 (ERAP1) the name accepted by the Hugo Gene Nomenclature Committee[2]
- ER aminopeptidase associated with antigen processing (ERAAP) in mice [3]
- Adipocyte-derived leucine aminopeptidase (ALAP)
- Puromycin-insensitive leucine aminopeptidase (PILS-AP)
# Function
ERAP1 has two major functions in the immune system:
- First, ERAP1 cleaves several proteins called cytokine receptors on the surface of cells. Cleaving these receptors reduces their ability to transmit chemical signals into the cell, which affects the process of inflammation.
- Second, ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto major histocompatibility complex (MHC) class I. These peptides are attached to MHC class I in the endoplasmic reticulum and exported to the cell surface, where they are displayed to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct.[4]
ARTS-1 is a member of the M1 family of zinc metallopeptidases which acts as an aminopeptidase that degrades oligopeptides by cleavage starting at the amino terminus. One of the functions of aminopeptidases is to degrade potentially toxic peptides in the cytosol.[1]
ARTS-1 is a transmembrane protein that is localized to the endoplasmic reticulum. It has been implicated in the following functions:
- Shedding of various cytokine receptors and decoy receptors
- Trimming of antigenic peptides before binding to MHC class I, affecting antigen presentation to cytotoxic T lymphocytes
- Stimulation of phagocytosis upon release by macrophages[5]
# Clinical significance
Aminopeptidases play a role in the metabolism of several peptides that may be involved in blood pressure and the pathogenesis of essential hypertension.[1] Mutations in the ARTS-1 have been linked to an increased risk of ankylosing spondylitis but only in HLA-B27 positive patients.[6]
The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[1] | https://www.wikidoc.org/index.php/ERAP1 | |
6c641bdf95e7398f90f8a969c029d35021ea3f87 | wikidoc | ERBB3 | ERBB3
Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene.
ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. The kinase-impaired ErbB3 is known to form active heterodimers with other members of the ErbB family, most notably the ligand binding-impaired ErbB2.
# Gene and expression
The human ERBB3 gene is located on the long arm of chromosome 12 (12q13). It is encoded by 23,651 base pairs and translates into 1342 amino acids.
During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium. ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system.
# Structure
ErbB3, like the other members of the ErbB receptor tyrosine kinase family, consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains four subdomains (I-IV). Subdomains I and III are leucine-rich and are primarily involved in ligand binding. Subdomains II and IV are cysteine-rich and most likely contribute to protein conformation and stability through the formation of disulfide bonds. Subdomain II also contains the dimerization loop required for dimer formation. The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain.
Unliganded receptor adopts a conformation that inhibits dimerization. Binding of neuregulin to the ligand binding subdomains (I and III) induces a conformational change in ErbB3 that causes the protrusion of the dimerization loop in subdomain II, activating the protein for dimerization.
# Function
ErbB3 has been shown to bind the ligands heregulin and NRG-2. Ligand binding causes a change in conformation that allows for dimerization, phosphorylation, and activation of signal transduction. ErbB3 can heterodimerize with any of the other three ErbB family members. The theoretical ErbB3 homodimer would be non-functional because the kinase-impaired protein requires transphosphorylation by its binding partner to be active.
Unlike the other ErbB receptor tyrosine kinase family members which are activated through autophosphorylation upon ligand binding, ErbB3 was found to be kinase impaired, having only 1/1000 the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins. Therefore, ErbB3 must act as an allosteric activator.
## Interaction with ErbB2
The ErbB2-ErbB3 dimer is considered the most active of the possible ErbB dimers, in part because ErbB2 is the preferred dimerization partner of all the ErbB family members, and ErbB3 is the preferred partner of ErbB2. This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ. There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands.
## Activation of the PI3K/Akt pathway
The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K. ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K, a function not found in either EGFR or ErbB2.
# Role in cancer
While no evidence has been found that ErbB3 overexpression, constitutive activation, or mutation alone is oncogenic, the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis.
ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to:
- HER2 inhibitors in HER2+ breast cancers
- anti-estrogen therapy in ER+ breast cancers
- EGFR inhibitors in lung and head and neck cancers
- hormones in prostate cancers
- IGF1R inhibitors in hepatomas
- BRAF inhibitors in melanoma
ErbB2 overexpression may promote the formation of active heterodimers with ErbB3 and other ErbB family members without the need for ligand binding, resulting in weak but constitutive signaling activity.
# Role in normal development
ERBB3 is expressed in the mesenchyme of the endocardial cushion, which will later develop into the valves of the heart. ErbB3 null mouse embryos show severely underdeveloped atrioventricular valves, leading to death at embryonic day 13.5. Although this function of ErbB3 depends on neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue.
ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system and neural crest derivatives such as Schwann cells. | ERBB3
Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene.
ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. The kinase-impaired ErbB3 is known to form active heterodimers with other members of the ErbB family, most notably the ligand binding-impaired ErbB2.
# Gene and expression
The human ERBB3 gene is located on the long arm of chromosome 12 (12q13). It is encoded by 23,651 base pairs and translates into 1342 amino acids.[1]
During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium.[2] ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system.[3]
# Structure
ErbB3, like the other members of the ErbB receptor tyrosine kinase family, consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains four subdomains (I-IV). Subdomains I and III are leucine-rich and are primarily involved in ligand binding. Subdomains II and IV are cysteine-rich and most likely contribute to protein conformation and stability through the formation of disulfide bonds. Subdomain II also contains the dimerization loop required for dimer formation.[4] The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain.[5]
Unliganded receptor adopts a conformation that inhibits dimerization. Binding of neuregulin to the ligand binding subdomains (I and III) induces a conformational change in ErbB3 that causes the protrusion of the dimerization loop in subdomain II, activating the protein for dimerization.[5]
# Function
ErbB3 has been shown to bind the ligands heregulin[6] and NRG-2.[7] Ligand binding causes a change in conformation that allows for dimerization, phosphorylation, and activation of signal transduction. ErbB3 can heterodimerize with any of the other three ErbB family members. The theoretical ErbB3 homodimer would be non-functional because the kinase-impaired protein requires transphosphorylation by its binding partner to be active.[5]
Unlike the other ErbB receptor tyrosine kinase family members which are activated through autophosphorylation upon ligand binding, ErbB3 was found to be kinase impaired, having only 1/1000 the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins.[8] Therefore, ErbB3 must act as an allosteric activator.
## Interaction with ErbB2
The ErbB2-ErbB3 dimer is considered the most active of the possible ErbB dimers, in part because ErbB2 is the preferred dimerization partner of all the ErbB family members, and ErbB3 is the preferred partner of ErbB2.[9] This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ.[10] There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands.[11][12]
## Activation of the PI3K/Akt pathway
The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K.[13] ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K,[10] a function not found in either EGFR or ErbB2.
# Role in cancer
While no evidence has been found that ErbB3 overexpression, constitutive activation, or mutation alone is oncogenic,[14] the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis.[15][16]
ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to:
- HER2 inhibitors in HER2+ breast cancers[17]
- anti-estrogen therapy in ER+ breast cancers[18][19]
- EGFR inhibitors in lung and head and neck cancers[20][21]
- hormones in prostate cancers[22]
- IGF1R inhibitors in hepatomas[23]
- BRAF inhibitors in melanoma[24]
ErbB2 overexpression may promote the formation of active heterodimers with ErbB3 and other ErbB family members without the need for ligand binding, resulting in weak but constitutive signaling activity.[10]
# Role in normal development
ERBB3 is expressed in the mesenchyme of the endocardial cushion, which will later develop into the valves of the heart. ErbB3 null mouse embryos show severely underdeveloped atrioventricular valves, leading to death at embryonic day 13.5. Although this function of ErbB3 depends on neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue.[25]
ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system[26] and neural crest derivatives such as Schwann cells.[27] | https://www.wikidoc.org/index.php/ERBB3 | |
ac2c02c5666f2374f87a838629fa6c227b1f8601 | wikidoc | ERBB4 | ERBB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.
# Function
Receptor tyrosine-protein kinase erbB-4 is a receptor tyrosine kinase that is a member of the epidermal growth factor receptor subfamily. ERBB4 is a single-pass type I transmembrane protein with multiple furin-like cysteine rich domains, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins-2 and -3, heparin-binding EGF-like growth factor and betacellulin. Ligand binding induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment.
# Clinical significance
Mutations in this gene have been associated with cancer. Other single-nucleotide polymorphisms and a risk haplotype have been linked to schizophrenia. Single-nucleotide polymorphisms in ERBB4 have also been found in a study of patients with familial amyotrophic lateral sclerosis type 19.
# Interactions
ERBB4 has been shown to interact with:
- DLG4
- NRG1,
- STAT5A, and
- YAP1. | ERBB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene.[1][2] Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.[3]
# Function
Receptor tyrosine-protein kinase erbB-4 is a receptor tyrosine kinase that is a member of the epidermal growth factor receptor subfamily. ERBB4 is a single-pass type I transmembrane protein with multiple furin-like cysteine rich domains, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins-2 and -3, heparin-binding EGF-like growth factor and betacellulin. Ligand binding induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment.[3]
# Clinical significance
Mutations in this gene have been associated with cancer.[3] Other single-nucleotide polymorphisms and a risk haplotype have been linked to schizophrenia.[4] Single-nucleotide polymorphisms in ERBB4 have also been found in a study of patients with familial amyotrophic lateral sclerosis type 19.[5]
# Interactions
ERBB4 has been shown to interact with:
- DLG4[6][7]
- NRG1,
- STAT5A,[8][9] and
- YAP1.[10] | https://www.wikidoc.org/index.php/ERBB4 | |
abc27b12bc640106afc8b0156f5c0528ad952d87 | wikidoc | ERCC1 | ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER). The ERCC1-XPF nuclease also functions in pathways to repair double-strand breaks in DNA, and in the repair of “crosslink” damage that harmfully links the two DNA strands.
Cells with disabling mutations in ERCC1 are more sensitive than normal to particular DNA damaging agents, including ultraviolet (UV) radiation and to chemicals that cause crosslinking between DNA strands. Genetically engineered mice with disabling mutations in ERCC1 have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging. Complete deletion of ERCC1 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC1. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC1. When the normal genes are absent, these mutations can lead to human syndromes, including Cockayne syndrome (CS) and COFS.
ERCC1 and ERCC4 are the gene names assigned in mammalian genomes, including the human genome (Homo sapiens). Similar genes with similar functions are found in all eukaryotic organisms.
# Gene
The genomic DNA for ERCC1 was the first human DNA repair gene to be isolated by molecular cloning. The original method was by transfer of fragments of the human genome to ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells. Reflecting this cross-species genetic complementation method, the gene was called “Excision repair cross-complementing 1”. Multiple independent complementation groups of Chinese hamster ovary (CHO) cells were isolated, and this gene restored UV resistance to cells of complementation group 1.
The human ERCC1 gene encodes the ERCC1 protein of 297 amino acids with a molecular mass of about 32,500 daltons.
Genes similar to ERCC1 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD10 in the budding yeast Saccharomyces cerevisiae, and swi10+ in the fission yeast Schizosaccharomyces pombe.
# Protein
One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.
The ERCC4/XPF protein consists of two conserved domains separated by a less conserved region in the middle. The N-terminal region has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase. The C-terminal region of XPF includes the active site residues for nuclease activity. Most of the ERCC1 protein is related at the sequence level to the C-terminus of the XPF protein, but residues in the nuclease domain are not present. A DNA binding “helix-hairpin-helix” domain at the C-terminus of each protein.
By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.
# Structure-specific nuclease
The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away. This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.
The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins. There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.
Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution. DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.
## Nucleotide excision repair
During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion. During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.
## DNA double-strand break repair
Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA. Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function. The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tail is also needed in a mechanistically distinct subpathway of non-homologous end-joining, dependent on the Ku proteins. Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.
## DNA interstrand crosslink repair
Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks. Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF. Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair may involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.
# Clinical significance
## Cerebro-oculo-facio-skeletal syndrome
A few patients with severely disabling ERCC1 mutations that cause cerebro-oculo-facio-skeletal syndrome (COFS) have been reported. COFS syndrome is a rare recessive disorder in which affected individuals undergo rapid neurologic decline and indications of accelerated aging. A very severe case of such disabling mutations is F231L mutation in the tandem helix-hairpin-helix domain of ERCC1 at its interface with XPF. It is shown that this single mutation is very important for the stability of the ERCC1-XPF complex. This Phenylalanine residue is assisting ERCC1 to accommodate a key Phenylalanine residue from XPF (F894) and the mutation (F231L) disturbs this accommodating function. As a consequence, F894 protrudes out of the interface and the mutant complex is dissociating faster compared to the native one. The life span of patients with such mutations is often around 1–2 years.
## Cockayne syndrome
One Cockayne syndrome (CS) type II patient designated CS20LO exhibited a homozygous mutation in exon 7 of ERCC1, producing a F231L mutation.
## Relevance in chemotherapy
Measuring ERCC1 activity may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 activity. Nucleotide excision repair (NER) is the primary DNA repair mechanism that removes the therapeutic platinum-DNA adducts from the tumor DNA. ERCC1 activity levels, being an important part of the NER common final pathway, may serve as a marker of general NER throughput. This has been suggested for patients with gastric, ovarian, colorectal and bladder cancers. In Non-small cell lung carcinoma (NSCLC), surgically removed tumors that receive no further therapy have a better survival if ERCC1-positive than if ERCC1-negative. Thus ERCC1 positivity is a favorable prognostic marker, referring to how the disease will proceed if not further treated. ERCC1-positive NSCLC tumors do not benefit from adjuvant platinum chemotherapy. However, ERCC1-negative NSCLC tumors, prognostically worse without treatment, derive substantial benefit from adjuvant cisplatin-based chemotherapy. High ERCC1 is thus a negative predictive marker, referring to how it will respond to a specific type of treatment.
ERCC1 genotyping in humans has shown significant polymorphism at codon 118. These polymorphisms may have differential effects on platinum and mitomycin damage.
## Deficiency in cancer
ERCC1 protein expression is reduced or absent in 84% to 100% of colorectal cancers, and the promoter of ERCC1 is methylated in 38% of gliomas, resulting in reduced mRNA and protein expression. The promoter of ERCC1 was located in the DNA 5 kilobases upstream of the protein coding region. Frequencies of epigenetic reductions of nine other DNA repair genes have been evaluated in various cancers and range from 2% (OGG1 in papillary thyroid cancer) to 88% and 90% (MGMT in gastric and colon cancers, respectively). Thus, reduction of protein expression of ERCC1 in 84% to 100% of colon cancers indicates that reduced ERCC1 is one of the most frequent reductions of a DNA repair gene observed in a cancer. Deficiency in ERCC1 protein expression appears to be an early event in colon carcinogenesis, since ERCC1 was found to be deficient in 40% of the crypts within 10 cm on each side of colonic adenocarcinomas (within the early field defects from which the cancers likely arose).
Cadmium (Cd) and its compounds are well-known human carcinogens. During Cd-induced malignant transformation, the promoter regions of ERCC1, as well as of hMSH2, XRCC1, and hOGG1, were heavily methylated and both the messenger RNA and proteins of these DNA repair genes were progressively reduced. DNA damage also increased with Cd-induced transformation. Reduction of protein expression of ERCC1 in progression to sporadic cancer is unlikely to be due to mutation. While germ line (familial) mutations in DNA repair genes cause a high risk of cancer (see inherited impairment in DNA repair increases cancer risk), somatic mutations in DNA repair genes, including ERCC1, only occur at low levels in sporadic (non-familial) cancers.
Control of ERCC1 protein level occurred at the translational level. In addition to the wild-type sequence, three splice variants of mRNA ERCC1 exist. ERCC1 mRNA is also found to have either wild-type or three alternative transcription start points. Neither the level of overall mRNA transcription, splice variation nor transcription start point of mRNA correlates with protein level of ERCC1. The rate of ERCC1 protein turnover also does not correlate with ERCC1 protein level. A translational level control of ERCC1, due to a microRNA (miRNA), has been shown during HIV viral infection. A trans-activation response element (TAR) miRNA, coded for by the HIV virus, down-regulates ERCC1 protein expression. TAR miRNA allows ERCC1 mRNA to be transcribed, but acts at the p-body level to prevent translation of ERCC1 protein. (A p-body is a cytoplasmic granule “processing body” that interacts with miRNAs to repress translation or trigger degradation of target RNAs.) In breast cancer cell lines, almost one third (55/167) of miRNA promoters were targets for aberrant methylation (epigenetic repression). In breast cancers themselves, methylation of let-7a-3/let-7b miRNA in particular was found. This indicates that let-7a-3/let-7b can be epigenetically repressed.
Repression of let-7a can cause repression of ERCC1 expression through an intermediary step involving the HMGA2 gene. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present. (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are chromatin architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing local DNA conformation. Regulation is achieved by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. Hypermethylation of the promoter for let-7a miRNA reduces its expression and this allows hyperexpression of HMGA2. Hyperexpression of HMGA2 can then reduce expression of ERCC1.
Thus, there are three mechanisms that may be responsible for the low level of protein expression of ERCC1 in 84% to 100% of sporadic colon cancers. From results in gliomas and in cadmium carcinogenesis, methylation of the ERCC1 promoter may be a factor. One or more miRNAs that repress ERCC1 may be a factor. And epigenetically reduced let-7a miRNA allowing hyperexpression of HMGA2 could also reduce protein expression of ERCC1 in colon cancers. Which epigenetic mechanism occurs most frequently, or whether multiple epigenetic mechanisms reduce ERCC1 protein expression in colon cancers has not been determined.
# Accelerated aging
DNA repair-deficient Ercc1 mutant mice show numerous features of accelerated aging, and have a limited lifespan. Accelerated aging in the mutant involves various organs. Ercc1 mutant mice are deficient in several DNA repair processes including transcription-coupled DNA repair. This deficiency prevents resumption of RNA synthesis on the template DNA strand subsequent to it receiving a transcription-blocking DNA damage. Such blockages of transcription appear to promote premature aging, particularly in non-proliferating or slowly proliferating organs such as the nervous system, liver and kidney (see DNA damage theory of aging).
When Ercc1 mutant mice were subjected to dietary restriction their response closely resembled the beneficial response to dietary restriction of wild-type mice. Dietary restriction extended the lifespan of the Ercc1 mutant mice from 10 to 35 weeks for males and from 13 to 39 weeks for females. It appears that in Ercc1 mutant mice dietary restriction while delaying aging also attenuates accumulation of genome-wide DNA damage and preserves transcriptional output, likely contributing to improved cell viability.
# Spermatogenesis and oogenesis
Both male and female Ercc1-deficient mice are infertile. The DNA repair function of Ercc1 appears to be required in both male and female germ cells at all stages of their maturation. The testes of Ercc1-deficient mice have an increased level of 8-oxoguanine in their DNA, suggesting that Ercc1 may have a role in removing oxidative DNA damages.
# Notes | ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene.[1] Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.[2][3]
Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER). The ERCC1-XPF nuclease also functions in pathways to repair double-strand breaks in DNA, and in the repair of “crosslink” damage that harmfully links the two DNA strands.
Cells with disabling mutations in ERCC1 are more sensitive than normal to particular DNA damaging agents, including ultraviolet (UV) radiation and to chemicals that cause crosslinking between DNA strands. Genetically engineered mice with disabling mutations in ERCC1 have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging.[4] Complete deletion of ERCC1 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC1. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC1. When the normal genes are absent, these mutations can lead to human syndromes, including Cockayne syndrome (CS) and COFS.
ERCC1 and ERCC4 are the gene names assigned in mammalian genomes, including the human genome (Homo sapiens). Similar genes with similar functions are found in all eukaryotic organisms.
# Gene
The genomic DNA for ERCC1 was the first human DNA repair gene to be isolated by molecular cloning. The original method was by transfer of fragments of the human genome to ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells.[5] Reflecting this cross-species genetic complementation method, the gene was called “Excision repair cross-complementing 1”. Multiple independent complementation groups of Chinese hamster ovary (CHO) cells were isolated,[6] and this gene restored UV resistance to cells of complementation group 1.
The human ERCC1 gene encodes the ERCC1 protein of 297 amino acids with a molecular mass of about 32,500 daltons.
Genes similar to ERCC1 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD10 in the budding yeast Saccharomyces cerevisiae, and swi10+ in the fission yeast Schizosaccharomyces pombe.
# Protein
One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.[5]
The ERCC4/XPF protein consists of two conserved domains separated by a less conserved region in the middle. The N-terminal region has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase.[7] The C-terminal region of XPF includes the active site residues for nuclease activity.[8] Most of the ERCC1 protein is related at the sequence level to the C-terminus of the XPF protein,[9] but residues in the nuclease domain are not present. A DNA binding “helix-hairpin-helix” domain at the C-terminus of each protein.
By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.
# Structure-specific nuclease
The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away.[10] This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.[11]
The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins.[12] There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.
Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution.[12] DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.
## Nucleotide excision repair
During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion.[10] During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.
## DNA double-strand break repair
Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA.[13][14] Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function.[15][16] The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tail is also needed in a mechanistically distinct subpathway of non-homologous end-joining, dependent on the Ku proteins.[17] Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.[18]
## DNA interstrand crosslink repair
Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks.[19] Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF.[20][21] Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair may involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.[22][23]
# Clinical significance
## Cerebro-oculo-facio-skeletal syndrome
A few patients with severely disabling ERCC1 mutations that cause cerebro-oculo-facio-skeletal syndrome (COFS) have been reported.[4][24] COFS syndrome is a rare recessive disorder in which affected individuals undergo rapid neurologic decline and indications of accelerated aging. A very severe case of such disabling mutations is F231L mutation in the tandem helix-hairpin-helix domain of ERCC1 at its interface with XPF.[24][25] It is shown that this single mutation is very important for the stability of the ERCC1-XPF complex. This Phenylalanine residue is assisting ERCC1 to accommodate a key Phenylalanine residue from XPF (F894) and the mutation (F231L) disturbs this accommodating function. As a consequence, F894 protrudes out of the interface and the mutant complex is dissociating faster compared to the native one.[25] The life span of patients with such mutations is often around 1–2 years.[24]
## Cockayne syndrome
One Cockayne syndrome (CS) type II patient designated CS20LO exhibited a homozygous mutation in exon 7 of ERCC1, producing a F231L mutation.[26]
## Relevance in chemotherapy
Measuring ERCC1 activity may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 activity. Nucleotide excision repair (NER) is the primary DNA repair mechanism that removes the therapeutic platinum-DNA adducts from the tumor DNA. ERCC1 activity levels, being an important part of the NER common final pathway, may serve as a marker of general NER throughput. This has been suggested for patients with gastric,[27] ovarian, colorectal and bladder cancers.[28] In Non-small cell lung carcinoma (NSCLC), surgically removed tumors that receive no further therapy have a better survival if ERCC1-positive than if ERCC1-negative. Thus ERCC1 positivity is a favorable prognostic marker, referring to how the disease will proceed if not further treated. ERCC1-positive NSCLC tumors do not benefit from adjuvant platinum chemotherapy. However, ERCC1-negative NSCLC tumors, prognostically worse without treatment, derive substantial benefit from adjuvant cisplatin-based chemotherapy. High ERCC1 is thus a negative predictive marker, referring to how it will respond to a specific type of treatment.[29][30]
ERCC1 genotyping in humans has shown significant polymorphism at codon 118.[31] These polymorphisms may have differential effects on platinum and mitomycin damage.[31]
## Deficiency in cancer
ERCC1 protein expression is reduced or absent in 84% to 100% of colorectal cancers,[32][33] and the promoter of ERCC1 is methylated in 38% of gliomas, resulting in reduced mRNA and protein expression.[34] The promoter of ERCC1 was located in the DNA 5 kilobases upstream of the protein coding region.[34] Frequencies of epigenetic reductions of nine other DNA repair genes have been evaluated in various cancers and range from 2% (OGG1 in papillary thyroid cancer) to 88% and 90% (MGMT in gastric and colon cancers, respectively). Thus, reduction of protein expression of ERCC1 in 84% to 100% of colon cancers indicates that reduced ERCC1 is one of the most frequent reductions of a DNA repair gene observed in a cancer.[35] Deficiency in ERCC1 protein expression appears to be an early event in colon carcinogenesis, since ERCC1 was found to be deficient in 40% of the crypts within 10 cm on each side of colonic adenocarcinomas (within the early field defects from which the cancers likely arose).[32]
Cadmium (Cd) and its compounds are well-known human carcinogens. During Cd-induced malignant transformation, the promoter regions of ERCC1, as well as of hMSH2, XRCC1, and hOGG1, were heavily methylated and both the messenger RNA and proteins of these DNA repair genes were progressively reduced.[36] DNA damage also increased with Cd-induced transformation.[36] Reduction of protein expression of ERCC1 in progression to sporadic cancer is unlikely to be due to mutation. While germ line (familial) mutations in DNA repair genes cause a high risk of cancer (see inherited impairment in DNA repair increases cancer risk), somatic mutations in DNA repair genes, including ERCC1, only occur at low levels in sporadic (non-familial) cancers.[37]
Control of ERCC1 protein level occurred at the translational level. In addition to the wild-type sequence, three splice variants of mRNA ERCC1 exist.[38] ERCC1 mRNA is also found to have either wild-type or three alternative transcription start points. Neither the level of overall mRNA transcription, splice variation nor transcription start point of mRNA correlates with protein level of ERCC1. The rate of ERCC1 protein turnover also does not correlate with ERCC1 protein level. A translational level control of ERCC1, due to a microRNA (miRNA), has been shown during HIV viral infection. A trans-activation response element (TAR) miRNA, coded for by the HIV virus, down-regulates ERCC1 protein expression.[39] TAR miRNA allows ERCC1 mRNA to be transcribed, but acts at the p-body level to prevent translation of ERCC1 protein. (A p-body is a cytoplasmic granule “processing body” that interacts with miRNAs to repress translation or trigger degradation of target RNAs.) In breast cancer cell lines, almost one third (55/167) of miRNA promoters were targets for aberrant methylation (epigenetic repression).[40] In breast cancers themselves, methylation of let-7a-3/let-7b miRNA in particular was found. This indicates that let-7a-3/let-7b can be epigenetically repressed.
Repression of let-7a can cause repression of ERCC1 expression through an intermediary step involving the HMGA2 gene. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present.[41] (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are chromatin architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing local DNA conformation. Regulation is achieved by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors.[42] HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression.[43] Hypermethylation of the promoter for let-7a miRNA reduces its expression and this allows hyperexpression of HMGA2. Hyperexpression of HMGA2 can then reduce expression of ERCC1.
Thus, there are three mechanisms that may be responsible for the low level of protein expression of ERCC1 in 84% to 100% of sporadic colon cancers. From results in gliomas and in cadmium carcinogenesis, methylation of the ERCC1 promoter may be a factor. One or more miRNAs that repress ERCC1 may be a factor. And epigenetically reduced let-7a miRNA allowing hyperexpression of HMGA2 could also reduce protein expression of ERCC1 in colon cancers. Which epigenetic mechanism occurs most frequently, or whether multiple epigenetic mechanisms reduce ERCC1 protein expression in colon cancers has not been determined.[35]
# Accelerated aging
DNA repair-deficient Ercc1 mutant mice show numerous features of accelerated aging, and have a limited lifespan.[44] Accelerated aging in the mutant involves various organs. Ercc1 mutant mice are deficient in several DNA repair processes including transcription-coupled DNA repair. This deficiency prevents resumption of RNA synthesis on the template DNA strand subsequent to it receiving a transcription-blocking DNA damage. Such blockages of transcription appear to promote premature aging, particularly in non-proliferating or slowly proliferating organs such as the nervous system, liver and kidney[45] (see DNA damage theory of aging).
When Ercc1 mutant mice were subjected to dietary restriction their response closely resembled the beneficial response to dietary restriction of wild-type mice. Dietary restriction extended the lifespan of the Ercc1 mutant mice from 10 to 35 weeks for males and from 13 to 39 weeks for females.[44] It appears that in Ercc1 mutant mice dietary restriction while delaying aging also attenuates accumulation of genome-wide DNA damage and preserves transcriptional output, likely contributing to improved cell viability.[44]
# Spermatogenesis and oogenesis
Both male and female Ercc1-deficient mice are infertile.[46] The DNA repair function of Ercc1 appears to be required in both male and female germ cells at all stages of their maturation. The testes of Ercc1-deficient mice have an increased level of 8-oxoguanine in their DNA, suggesting that Ercc1 may have a role in removing oxidative DNA damages.
# Notes | https://www.wikidoc.org/index.php/ERCC1 | |
28b7a69f9a14087851f743fe35de07bea66cdcd0 | wikidoc | ERCC2 | ERCC2
ERCC2, or XPD is a protein involved in transcription-coupled nucleotide excision repair.
The XPD (ERCC2) gene encodes for a 2.3-kb mRNA containing 22 exons and 21 introns. The XPD protein is a 760 amino acids polypeptide with a size of 87kDa. Defects in this gene can result in three different disorders: the cancer-prone syndrome xeroderma pigmentosum complementation group D, photosensitive trichothiodystrophy, and Cockayne syndrome.
Just like XPB, XPD is also a part of human transcriptional initiation factor TFIIH and has ATP-dependent helicase activity. It belongs to the RAD3/XPD subfamily of helicases.
XPD is essential for the viability of cells. Deletion of XPD in mice is embryonic lethal.
# Consequences of mutations in ERCC2
The ERCC2/XPD protein participates in nucleotide excision repair (NER), and is employed in unwinding the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different damages that distort normal base pairing. Such damages include bulky chemical adducts, UV-induced pyrimidine dimers, and several forms of oxidative damage. Mutations in the ERCC2/XPD gene can lead to various syndromes, either xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or a combination of XP and TTD (XPTTD), or a combination of XP and Cockayne syndrome (XPCS). TTD and CS both display features of premature aging. These features may include sensorineural deafness, retinal degeneration, white matter hypomethylation, central nervous system calcification, reduced stature, and cachexia (loss of subcutaneous fat tissue). XPCS and TTD fibroblasts from ERCC2/XPD mutant human and mouse show evidence of defective repair of oxidative DNA damages that may underlie the segmental progeroid (premature aging) symptoms (see DNA damage theory of aging).
# Interactions
ERCC2 has been shown to interact with:
- ERCC5,
- GTF2H1,
- GTF2H2, and
- XPB.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..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} | ERCC2
ERCC2, or XPD is a protein involved in transcription-coupled nucleotide excision repair.
The XPD (ERCC2) gene encodes for a 2.3-kb mRNA containing 22 exons and 21 introns. The XPD protein is a 760 amino acids polypeptide with a size of 87kDa. Defects in this gene can result in three different disorders: the cancer-prone syndrome xeroderma pigmentosum complementation group D, photosensitive trichothiodystrophy, and Cockayne syndrome.[1]
Just like XPB, XPD is also a part of human transcriptional initiation factor TFIIH and has ATP-dependent helicase activity.[2] It belongs to the RAD3/XPD subfamily of helicases.
XPD is essential for the viability of cells. Deletion of XPD in mice is embryonic lethal.
# Consequences of mutations in ERCC2
The ERCC2/XPD protein participates in nucleotide excision repair (NER), and is employed in unwinding the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different damages that distort normal base pairing. Such damages include bulky chemical adducts, UV-induced pyrimidine dimers, and several forms of oxidative damage. Mutations in the ERCC2/XPD gene can lead to various syndromes, either xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or a combination of XP and TTD (XPTTD), or a combination of XP and Cockayne syndrome (XPCS).[3] TTD and CS both display features of premature aging. These features may include sensorineural deafness, retinal degeneration, white matter hypomethylation, central nervous system calcification, reduced stature, and cachexia (loss of subcutaneous fat tissue).[3][4] XPCS and TTD fibroblasts from ERCC2/XPD mutant human and mouse show evidence of defective repair of oxidative DNA damages that may underlie the segmental progeroid (premature aging) symptoms[5] (see DNA damage theory of aging).
# Interactions
ERCC2 has been shown to interact with:
- ERCC5,[6]
- GTF2H1,[7][8]
- GTF2H2,[9][10] and
- XPB.[7][6][11][12]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/ERCC2 | |
019cdfec8b9a2aebb3e5838ac891d1b78d6275ba | wikidoc | ERCC4 | ERCC4
ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
The nuclease enzyme ERCC1-XPF cuts specific structures of DNA. Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER). The ERCC1-XPF nuclease also functions in pathways to repair double-strand breaks in DNA, and in the repair of "crosslink" damage that harmfully links the two DNA strands.
Cells with disabling mutations in ERCC4 are more sensitive than normal to particular DNA damaging agents, including ultraviolet radiation and to chemicals that cause crosslinking between DNA strands. Genetically engineered mice with disabling mutations in ERCC4 also have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging. Complete deletion of ERCC4 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC4. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC4. When the normal genes are absent, these mutations can lead to human syndromes, including xeroderma pigmentosum, Cockayne syndrome and Fanconi anemia.
ERCC1 and ERCC4 are the human gene names and Ercc1 and Ercc4 are the analogous mammalian gene names. Similar genes with similar functions are found in all eukaryotic organisms.
# Gene
The human ERCC4 gene can correct the DNA repair defect in specific ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells. Multiple independent complementation groups of Chinese hamster ovary (CHO) cells have been isolated, and this gene restored UV resistance to cells of complementation group 4. Reflecting this cross-species genetic complementation method, the gene was called "Excision repair cross-complementing 4"
The human ERCC4 gene encodes the XPF protein of 916 amino acids with a molecular mass of about 104,000 daltons.
Genes similar to ERCC4 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD1 in the budding yeast Saccharomyces cerevisiae, and rad16+ in the fission yeast Schizosaccharomyces pombe.
# Protein
One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.
The ERCC4/XPF protein consists of two conserved areas separated by a less conserved region in the middle. The N-terminal area has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase. The C-terminal region of XPF includes the active site residues for nuclease activity. (Figure 1).
Most of the ERCC1 protein is related at the sequence level to the C terminus of the XPF protein., but residues in the nuclease domain are not present. A DNA binding "helix-hairpin-helix" domain at the C-terminus of each protein.
By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.
# Structure-specific nuclease
The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away (Figure 2). This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.
The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins. There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.
Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution. DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.
## Nucleotide excision repair (NER)
During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a site of DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion. During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.
## DNA double-strand break (DSB) repair
Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA. Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function. The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tails is also needed in a mechanistically distinct subpathway of non-homologous end-joining, independent of the Ku proteins Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.
## Interstrand crosslinks repair
Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks (ICL) Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF. Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair my involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.
# Clinical significance
## Xeroderma pigmentosum (XP)
Some individuals with the rare inherited syndrome xeroderma pigmentosum have mutations in ERCC4. These patients are classified as XP complementation group F (XP-F). Diagnostic features of XP are dry scaly skin, abnormal skin pigmentation in sun-exposed areas and severe photosensitivity, accompanied by a great than 1000-fold increased risk of developing UV radiation-induced skin cancers.
## Cockayne syndrome (CS)
Most XP-F patients show moderate symptoms of XP, but a few show additional symptoms of Cockayne syndrome. Cockayne syndrome (CS) patients exhibit photosensitivity, and also exhibit developmental defects and neurological symptoms.
Mutations in the ERCC4 gene can result in the very rare XF-E syndrome. These patients have characteristics of XP and CS, as well as additional neurologic, hepatobiliary, musculoskeletal and hematopoietic symptoms.
## Fanconi anemia
Several human patients with symptoms of Fanconi anemia (FA) have causative mutations in the ERCC4 gene. Fanconi anemia is a complex disease, involving major hematopoietic symptoms. A characteristic feature of FA is the hypersensitivity to agents that cause interstrand DNA crosslinks. FA patients with ERCC4 mutations have been classified as belonging to Fanconi anemia complementation group P (FANCP).
# ERCC4 (XPF) in the normal colon
ERCC4 (XPF) is normally expressed at a high level in cell nuclei within the inner surface of the colon (see image, panel C). The inner surface of the colon is lined with simple columnar epithelium with invaginations. The invaginations are called intestinal glands or colon crypts. The colon crypts are shaped like microscopic thick walled test tubes with a central hole down the length of the tube (the crypt lumen). Crypts are about 75 to 110 cells long. DNA repair, involving high expression of ERCC4 (XPF), PMS2 and ERCC1 proteins, appears to be very active in colon crypts in normal, non-neoplastic colon epithelium.
Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later. There are 5 to 6 stem cells at the bases of the crypts. There are about 10 million crypts along the inner surface of the average human colon. If the stem cells at the base of the crypt express ERCC4 (XPF), generally all several thousand cells of the crypt will also express ERCC4 (XPF). This is indicated by the brown color seen by immunostaining of ERCC4 (XPF) in almost all the cells in the crypt in panel C of the image in this section. A similar expression of PMS2 and ERCC1 occurs in the thousands of cells in each normal colonic crypt.
The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color. Nuclei of cells in the lamina propria, cells which are below and surround the epithelial crypts, largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). In addition, cells at the very tops of the crypts stained for PMS2 (panel A) or ERCC4 (XPF) (panel C) have low levels of these DNA repair proteins, so that such cells show the blue-gray DNA stain as well.
# ERCC4 (XPF) deficiency in the colon epithelium adjacent to and within cancers
ERCC4 (XPF) is deficient in about 55% of colon cancers, and in about 40% of the colon crypts in the epithelium within 10 cm adjacent to the cancers (in the field defects from which the cancers likely arose). When ERCC4 (XPF) is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and PMS2 as well, as illustrated in the image in this section. Deficiencies in ERCC1 (XPF) in colon epithelium appear to be due to epigenetic repression. A deficiency of ERCC4 (XPF) would lead to reduced repair of DNA damages. As indicated by Harper and Elledge, defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer. The frequent epigenetic reduction in ERCC4 (XPF) in field defects surrounding colon cancers as well as in cancers (along with epigenetic reductions in ERCC1 and PMS2) indicate that such reductions may often play a central role in progression to colon cancer.
Although epigenetic reductions in ERCC4 (XPF) expression are frequent in human colon cancers, mutations in ERCC4 (XPF) are rare in humans. However, a mutation in ERCC4 (XPF) causes patients to be prone to skin cancer. An inherited polymorphism in ERCC4 (XPF) appears to be important in breast cancer as well. These infrequent mutational alterations underscore the likely role of ERCC4 (XPF) deficiency in progression to cancer.
# Notes | ERCC4
ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.[1][2]
The nuclease enzyme ERCC1-XPF cuts specific structures of DNA. Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER). The ERCC1-XPF nuclease also functions in pathways to repair double-strand breaks in DNA, and in the repair of "crosslink" damage that harmfully links the two DNA strands.
Cells with disabling mutations in ERCC4 are more sensitive than normal to particular DNA damaging agents, including ultraviolet radiation and to chemicals that cause crosslinking between DNA strands. Genetically engineered mice with disabling mutations in ERCC4 also have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging.[3] Complete deletion of ERCC4 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC4. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC4. When the normal genes are absent, these mutations can lead to human syndromes, including xeroderma pigmentosum, Cockayne syndrome and Fanconi anemia.
ERCC1 and ERCC4 are the human gene names and Ercc1 and Ercc4 are the analogous mammalian gene names. Similar genes with similar functions are found in all eukaryotic organisms.
# Gene
The human ERCC4 gene can correct the DNA repair defect in specific ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells.[4] Multiple independent complementation groups of Chinese hamster ovary (CHO) cells have been isolated,[5] and this gene restored UV resistance to cells of complementation group 4. Reflecting this cross-species genetic complementation method, the gene was called "Excision repair cross-complementing 4"[6]
The human ERCC4 gene encodes the XPF protein of 916 amino acids with a molecular mass of about 104,000 daltons.
Genes similar to ERCC4 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD1 in the budding yeast Saccharomyces cerevisiae, and rad16+ in the fission yeast Schizosaccharomyces pombe.
# Protein
One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.[4]
The ERCC4/XPF protein consists of two conserved areas separated by a less conserved region in the middle. The N-terminal area has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase.[7] The C-terminal region of XPF includes the active site residues for nuclease activity.[8] (Figure 1).
Most of the ERCC1 protein is related at the sequence level to the C terminus of the XPF protein.,[9] but residues in the nuclease domain are not present. A DNA binding "helix-hairpin-helix" domain at the C-terminus of each protein.
By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.
# Structure-specific nuclease
The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away[10] (Figure 2). This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.[11]
The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins.[12][13] There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.
Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution.[12] DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.
## Nucleotide excision repair (NER)
During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a site of DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion.[10] During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.
## DNA double-strand break (DSB) repair
Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA.[14][15] Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function.[16][17] The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tails is also needed in a mechanistically distinct subpathway of non-homologous end-joining, independent of the Ku proteins[18][19] Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.[20]
## Interstrand crosslinks repair
Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks (ICL)[21] Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF.[22][23] Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair my involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.[24][25]
# Clinical significance
## Xeroderma pigmentosum (XP)
Some individuals with the rare inherited syndrome xeroderma pigmentosum have mutations in ERCC4. These patients are classified as XP complementation group F (XP-F). Diagnostic features of XP are dry scaly skin, abnormal skin pigmentation in sun-exposed areas and severe photosensitivity, accompanied by a great than 1000-fold increased risk of developing UV radiation-induced skin cancers.[1]
## Cockayne syndrome (CS)
Most XP-F patients show moderate symptoms of XP, but a few show additional symptoms of Cockayne syndrome.[26] Cockayne syndrome (CS) patients exhibit photosensitivity, and also exhibit developmental defects and neurological symptoms.[1][3]
Mutations in the ERCC4 gene can result in the very rare XF-E syndrome.[27] These patients have characteristics of XP and CS, as well as additional neurologic, hepatobiliary, musculoskeletal and hematopoietic symptoms.
## Fanconi anemia
Several human patients with symptoms of Fanconi anemia (FA) have causative mutations in the ERCC4 gene. Fanconi anemia is a complex disease, involving major hematopoietic symptoms. A characteristic feature of FA is the hypersensitivity to agents that cause interstrand DNA crosslinks. FA patients with ERCC4 mutations have been classified as belonging to Fanconi anemia complementation group P (FANCP).[26][28]
# ERCC4 (XPF) in the normal colon
ERCC4 (XPF) is normally expressed at a high level in cell nuclei within the inner surface of the colon (see image, panel C). The inner surface of the colon is lined with simple columnar epithelium with invaginations. The invaginations are called intestinal glands or colon crypts. The colon crypts are shaped like microscopic thick walled test tubes with a central hole down the length of the tube (the crypt lumen). Crypts are about 75 to 110 cells long. DNA repair, involving high expression of ERCC4 (XPF), PMS2 and ERCC1 proteins, appears to be very active in colon crypts in normal, non-neoplastic colon epithelium.
Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later.[30] There are 5 to 6 stem cells at the bases of the crypts.[30] There are about 10 million crypts along the inner surface of the average human colon.[29] If the stem cells at the base of the crypt express ERCC4 (XPF), generally all several thousand cells of the crypt will also express ERCC4 (XPF). This is indicated by the brown color seen by immunostaining of ERCC4 (XPF) in almost all the cells in the crypt in panel C of the image in this section. A similar expression of PMS2 and ERCC1 occurs in the thousands of cells in each normal colonic crypt.
The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color. Nuclei of cells in the lamina propria, cells which are below and surround the epithelial crypts, largely show hematoxylin blue-gray color and have little expression of PMS2, ERCC1 or ERCC4 (XPF). In addition, cells at the very tops of the crypts stained for PMS2 (panel A) or ERCC4 (XPF) (panel C) have low levels of these DNA repair proteins, so that such cells show the blue-gray DNA stain as well.[29]
# ERCC4 (XPF) deficiency in the colon epithelium adjacent to and within cancers
ERCC4 (XPF) is deficient in about 55% of colon cancers, and in about 40% of the colon crypts in the epithelium within 10 cm adjacent to the cancers (in the field defects from which the cancers likely arose).[29] When ERCC4 (XPF) is reduced in colonic crypts in a field defect, it is most often associated with reduced expression of DNA repair enzymes ERCC1 and PMS2 as well, as illustrated in the image in this section. Deficiencies in ERCC1 (XPF) in colon epithelium appear to be due to epigenetic repression.[29] A deficiency of ERCC4 (XPF) would lead to reduced repair of DNA damages. As indicated by Harper and Elledge,[31] defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer. The frequent epigenetic reduction in ERCC4 (XPF) in field defects surrounding colon cancers as well as in cancers (along with epigenetic reductions in ERCC1 and PMS2) indicate that such reductions may often play a central role in progression to colon cancer.
Although epigenetic reductions in ERCC4 (XPF) expression are frequent in human colon cancers, mutations in ERCC4 (XPF) are rare in humans.[32] However, a mutation in ERCC4 (XPF) causes patients to be prone to skin cancer.[32] An inherited polymorphism in ERCC4 (XPF) appears to be important in breast cancer as well.[33] These infrequent mutational alterations underscore the likely role of ERCC4 (XPF) deficiency in progression to cancer.
# Notes | https://www.wikidoc.org/index.php/ERCC4 | |
353ca2408c2ee3d232339dbfd972167065a0290b | wikidoc | ERCC5 | ERCC5
DNA repair protein complementing XP-G cells is a protein that in humans is encoded by the ERCC5 gene.
Excision repair cross-complementing rodent repair deficiency, complementation group 5 (xeroderma pigmentosum, complementation group G) is involved in excision repair of UV-induced DNA damage. Mutations cause Cockayne syndrome, which is characterized by severe growth defects, mental retardation, and cachexia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been described, but the biological validity of all variants has not been determined.
Mutations in ERCC5 cause arthrogryposis .
XPG is a structure specific endonuclease that incises DNA at the 3’ side of the damaged nucleotide during nucleotide excision repair.
# Syndromes
Mutational defects in the Ercc5(Xpg) gene can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or in combination with the severe neurodevelopmental disorder Cockayne syndrome (CS) or the infantile lethal cerebro-oculo-facio-skeletal syndrome.
# Mouse model
An Ercc5(Xpg) mutant mouse model presented features of premature aging including cachexia and osteoporosis with pronounced degenerative phenotypes in both liver and brain. These mutant mice developed a multi-system premature aging degenerative phenotype that appears to strengthen the link between DNA damage and aging. (see DNA damage theory of aging).
Dietary restriction, which extends lifespan of wild-type mice, also substantially increased the lifespan of Ercc5(Xpg) mutant mice. Dietary restriction of the mutant mice, while delaying aging, also appeared to slow the accumulation of genome wide DNA damage and to preserve transcriptional output, thus contributing to improved cell viability.
# Interactions
ERCC5 has been shown to interact with ERCC2. | ERCC5
DNA repair protein complementing XP-G cells is a protein that in humans is encoded by the ERCC5 gene.[1][2]
Excision repair cross-complementing rodent repair deficiency, complementation group 5 (xeroderma pigmentosum, complementation group G) is involved in excision repair of UV-induced DNA damage. Mutations cause Cockayne syndrome, which is characterized by severe growth defects, mental retardation, and cachexia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been described, but the biological validity of all variants has not been determined.[2]
Mutations in ERCC5 cause arthrogryposis .[3]
XPG is a structure specific endonuclease that incises DNA at the 3’ side of the damaged nucleotide during nucleotide excision repair.
# Syndromes
Mutational defects in the Ercc5(Xpg) gene can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or in combination with the severe neurodevelopmental disorder Cockayne syndrome (CS) or the infantile lethal cerebro-oculo-facio-skeletal syndrome.[4]
# Mouse model
An Ercc5(Xpg) mutant mouse model presented features of premature aging including cachexia and osteoporosis with pronounced degenerative phenotypes in both liver and brain.[4] These mutant mice developed a multi-system premature aging degenerative phenotype that appears to strengthen the link between DNA damage and aging.[4] (see DNA damage theory of aging).
Dietary restriction, which extends lifespan of wild-type mice, also substantially increased the lifespan of Ercc5(Xpg) mutant mice.[5] Dietary restriction of the mutant mice, while delaying aging, also appeared to slow the accumulation of genome wide DNA damage and to preserve transcriptional output, thus contributing to improved cell viability.
# Interactions
ERCC5 has been shown to interact with ERCC2.[6] | https://www.wikidoc.org/index.php/ERCC5 | |
c35a61ed1dd1637854e68c14d14d6c9e762272f0 | wikidoc | ERCC6 | ERCC6
DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.
Having 1 or more copies of a mutated ERCC6 causes Cockayne syndrome, type II.
# Function
DNA can be damaged by ultraviolet radiation, toxins, radioactive substances, and reactive biochemical intermediates like free radicals. The ERCC6 protein is involved in repairing the genome when specific genes undergoing transcription (dubbed active genes) are inoperative; as such, CSB serves as a transcription-coupled excision repair protein, being one of the fundamental enzymes in active gene repair.
# Structure and Mechanism
CSB has been found to exhibit ATPase properties; there are contradictory publications regarding the effect of ATP concentration on CSB's activity. The most recent evidence suggests that ADP/AMP allosterically regulate CSB. As such, it has been speculated that CSB may promote protein complex formation at repair sites subject to the ATP to ADP charge ratio.
Conservation of helicase motifs in eukaryote CSB is evident; all seven major domains of the protein are conserved among numerous RNA and DNA helicases. Detailed structural analysis of CSB has been performed; motifs I, Ia, II, and III are collectively called domain 1, while motifs IV, V, and VI comprise domain 2. These domains wrap around an interdomain cleft involved in ATP binding and hydrolysis. Motifs III and IV are in close proximity to the active site; hence, residues in these regions stabilize ATP/ADP binding via hydrogen bonding. Domain 2 has been proposed to affect DNA binding after induced conformational changes stemming from ATP hydrolysis. Specific residues involved in gene binding have yet to be identified.
The evolutionary roots of CSB has led some to contend that it exhibits helicase activity. Evidence for the helicase properties of CSB is highly disputed; yet, it has been found the protein participates in intracellular trafficking, a traditional role of helicases. The complex interactions between DNA repair proteins suggest that eukaryote CSB upholds some but not all of the functions of its prokaryotic precursors.
# Interactions
CSB has been shown to interact with P53.
CSB has been shown to act as chromatin remodeling factor for RNA Polymerase II. When RNA Polymerase II is stalled by a mistake in the genome, CSB remodels the DNA double helix so as to allow access by repair enzymes to the lesion.
CSB is involved in the base excision repair (BER) pathway. This is due to demonstrated interactions with human AP endonuclease, though interactions between recombinant CSB and E. coli endonuclease IV as well as human N-terminus AP endonuclease fragments have not been observed in vitro. Specifically, CSB stimulates the AP site incision activity of AP endonuclease independent of ATP.
In addition to the BER pathway, CSB is heavily integrated in the nucleotide excision repair (NER) pathway. While BER utilizes glycosylases to recognize and correct non-bulky lesions, NER is particularly versatile in repairing DNA damaged by UV radiation via the removal of oxidized bases. CSB's role in NER is best manifested by interactions with T cell receptors, in which protein collaboration is key in effective antigen binding.
# Neurogenesis and Neural Differentiation
ERCC6 knockout within human neural progenitor cells has been shown to decrease both neurogenesis and neural differentiation. Both mechanisms are key in brain development, explaining characteristic cognitive deficiencies of Cockayne syndrome - such as stunted development of the nervous system - that otherwise do not seem related to symptoms like photosensitivity and hearing loss.
# Cockayne syndrome
In humans, Cockayne syndrome (CS) is a rare autosomal recessive leukodystrophy (associated with the degradation of white matter). CS arises from germ line mutations in either of two genes, CSA(ERCC8) or CSB(ERCC6). About two thirds of CS patients have a mutation in the CSB(ERCC6) gene. Mutations in ERCC6 that lead to CS deal with both the size of the protein as well as the specific amino acid residues utilized in biosynthesis. Patients exhibiting type II CS often have shortened and/or misfolded CSB that disrupt gene expression and transcription. The characteristic biological effect of malfunctioning ERCC6 is nerve cell death, resulting in premature aging and growth defects.
The extent to which malfunctioning CSB hinders oxidative repair heavily influences patients' neurological functioning. The two subforms of the disorder (the latter of which corresponds to ERCC6 defects) - CS-A and CS-B - both cause problems in the oxidative repair, though CS-B patients more often exhibit nerve system problems stemming from damage to this pathway. Most type II CS patients exhibit photosensitivity as per the heavily oxidative properties of UV light.
# DNA repair
CSB and CSA proteins are considered to function in transcription coupled nucleotide excision repair (TC-NER). CSB and CSA deficient cells are unable to preferentially repair UV-induced cyclobutane pyrimidine dimers in actively transcribed genes, consistent with a failed TC-NER response. CSB also accumulates at sites of DNA double-strand breaks in a transcription dependent manner and influences double-strand break repair. CSB protein facilitates homologous recombinational repair of double-strand breaks and represses non-homologous end joining.
In a damaged cell, the CSB protein localizes to sites of DNA damage. CSB recruitment to damaged sites is influenced by the type of DNA damage and is, most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damages. The CSB protein interacts with SNM1A(DCLRE1A) protein, a 5’- 3’ exonuclease, to promote the removal of DNA interstrand croslinks.
# Implications in cancer
Single-nucleotide polymorphisms in the ERCC6 gene have been correlated with significantly increased risk of certain forms of cancer. A specific mutation at the 1097 position (M1097V) as well as polymorphisms at amino acid residue 1413 have been associated with heightened risk of bladder cancer for experimental subjects in Taiwan; moreover, M1097V has been argued to play a key role in pathogenesis. Rs1917799 polymorphism has been associated with increased risk of gastric cancer for Chinese experimental subjects, and mutations at codon 399 have been correlated to the onset of oral cancers among Taiwanese patients. Another study found a diverse set of mutations in the ERCC6 gene among Chinese lung cancer patients versus the general population (in terms of statistical significance), but failed to identify specific polymorphisms correlated with the patients' illness.
Faulty DNA repair is implicated causally in tumor development due to malfunctioning proteins' inability to correct genes responsible for apoptosis and cell growth. Yet, the vast majority of studies regarding the effects of ERCC6 knockout or mutations on cancer are based upon statistical correlations of available patient data as opposed to mechanistic analysis of in vivo cancer onset. Hence, confounding based on protein-protein, protein-substrate, and/or substrate-substrate interactions disallows conclusions positing mutations in ERCC6 cause cancer on an individual basis. | ERCC6
DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene.[1][2][3] The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.[4]
Having 1 or more copies of a mutated ERCC6 causes Cockayne syndrome, type II.
# Function
DNA can be damaged by ultraviolet radiation, toxins, radioactive substances, and reactive biochemical intermediates like free radicals. The ERCC6 protein is involved in repairing the genome when specific genes undergoing transcription (dubbed active genes) are inoperative; as such, CSB serves as a transcription-coupled excision repair protein, being one of the fundamental enzymes in active gene repair.[4]
# Structure and Mechanism
CSB has been found to exhibit ATPase properties; there are contradictory publications regarding the effect of ATP concentration on CSB's activity.[5] The most recent evidence suggests that ADP/AMP allosterically regulate CSB.[3] As such, it has been speculated that CSB may promote protein complex formation at repair sites subject to the ATP to ADP charge ratio.
Conservation of helicase motifs in eukaryote CSB is evident; all seven major domains of the protein are conserved among numerous RNA and DNA helicases. Detailed structural analysis of CSB has been performed; motifs I, Ia, II, and III are collectively called domain 1, while motifs IV, V, and VI comprise domain 2. These domains wrap around an interdomain cleft involved in ATP binding and hydrolysis. Motifs III and IV are in close proximity to the active site; hence, residues in these regions stabilize ATP/ADP binding via hydrogen bonding.[6] Domain 2 has been proposed to affect DNA binding after induced conformational changes stemming from ATP hydrolysis. Specific residues involved in gene binding have yet to be identified.[7]
The evolutionary roots of CSB has led some to contend that it exhibits helicase activity.[8] Evidence for the helicase properties of CSB is highly disputed; yet, it has been found the protein participates in intracellular trafficking, a traditional role of helicases. The complex interactions between DNA repair proteins suggest that eukaryote CSB upholds some but not all of the functions of its prokaryotic precursors.[9]
# Interactions
CSB has been shown to interact with P53.[10][11]
CSB has been shown to act as chromatin remodeling factor for RNA Polymerase II. When RNA Polymerase II is stalled by a mistake in the genome, CSB remodels the DNA double helix so as to allow access by repair enzymes to the lesion.[12]
CSB is involved in the base excision repair (BER) pathway. This is due to demonstrated interactions with human AP endonuclease, though interactions between recombinant CSB and E. coli endonuclease IV as well as human N-terminus AP endonuclease fragments have not been observed in vitro. Specifically, CSB stimulates the AP site incision activity of AP endonuclease independent of ATP.[13]
In addition to the BER pathway, CSB is heavily integrated in the nucleotide excision repair (NER) pathway. While BER utilizes glycosylases to recognize and correct non-bulky lesions, NER is particularly versatile in repairing DNA damaged by UV radiation via the removal of oxidized bases. CSB's role in NER is best manifested by interactions with T cell receptors, in which protein collaboration is key in effective antigen binding.[14]
# Neurogenesis and Neural Differentiation
ERCC6 knockout within human neural progenitor cells has been shown to decrease both neurogenesis and neural differentiation. Both mechanisms are key in brain development, explaining characteristic cognitive deficiencies of Cockayne syndrome - such as stunted development of the nervous system - that otherwise do not seem related to symptoms like photosensitivity and hearing loss.[15]
# Cockayne syndrome
In humans, Cockayne syndrome (CS) is a rare autosomal recessive leukodystrophy (associated with the degradation of white matter). CS arises from germ line mutations in either of two genes, CSA(ERCC8) or CSB(ERCC6). About two thirds of CS patients have a mutation in the CSB(ERCC6) gene.[16] Mutations in ERCC6 that lead to CS deal with both the size of the protein as well as the specific amino acid residues utilized in biosynthesis. Patients exhibiting type II CS often have shortened and/or misfolded CSB that disrupt gene expression and transcription. The characteristic biological effect of malfunctioning ERCC6 is nerve cell death, resulting in premature aging and growth defects.[4]
The extent to which malfunctioning CSB hinders oxidative repair heavily influences patients' neurological functioning. The two subforms of the disorder (the latter of which corresponds to ERCC6 defects) - CS-A and CS-B - both cause problems in the oxidative repair, though CS-B patients more often exhibit nerve system problems stemming from damage to this pathway. Most type II CS patients exhibit photosensitivity as per the heavily oxidative properties of UV light.[17][18]
# DNA repair
CSB and CSA proteins are considered to function in transcription coupled nucleotide excision repair (TC-NER). CSB and CSA deficient cells are unable to preferentially repair UV-induced cyclobutane pyrimidine dimers in actively transcribed genes, consistent with a failed TC-NER response.[19] CSB also accumulates at sites of DNA double-strand breaks in a transcription dependent manner and influences double-strand break repair.[20] CSB protein facilitates homologous recombinational repair of double-strand breaks and represses non-homologous end joining.[20]
In a damaged cell, the CSB protein localizes to sites of DNA damage. CSB recruitment to damaged sites is influenced by the type of DNA damage and is, most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damages.[16] The CSB protein interacts with SNM1A(DCLRE1A) protein, a 5’- 3’ exonuclease, to promote the removal of DNA interstrand croslinks.[21]
# Implications in cancer
Single-nucleotide polymorphisms in the ERCC6 gene have been correlated with significantly increased risk of certain forms of cancer. A specific mutation at the 1097 position (M1097V) as well as polymorphisms at amino acid residue 1413 have been associated with heightened risk of bladder cancer for experimental subjects in Taiwan; moreover, M1097V has been argued to play a key role in pathogenesis.[22] Rs1917799 polymorphism has been associated with increased risk of gastric cancer for Chinese experimental subjects,[23] and mutations at codon 399 have been correlated to the onset of oral cancers among Taiwanese patients.[24] Another study found a diverse set of mutations in the ERCC6 gene among Chinese lung cancer patients versus the general population (in terms of statistical significance), but failed to identify specific polymorphisms correlated with the patients' illness.[25]
Faulty DNA repair is implicated causally in tumor development due to malfunctioning proteins' inability to correct genes responsible for apoptosis and cell growth. Yet, the vast majority of studies regarding the effects of ERCC6 knockout or mutations on cancer are based upon statistical correlations of available patient data as opposed to mechanistic analysis of in vivo cancer onset. Hence, confounding based on protein-protein, protein-substrate, and/or substrate-substrate interactions disallows conclusions positing mutations in ERCC6 cause cancer on an individual basis. | https://www.wikidoc.org/index.php/ERCC6 | |
6115532515452fe2c191c2dcfcddc4e927faf050 | wikidoc | PDIA3 | PDIA3
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.
# Structure
The PDIA3 protein consists of four thioredoxin-like domains: a, b, b′, and a′. The a and a′ domains have Cys-Gly-His-Cys active site motifs (C57-G58-H59-C60 and C406-G407-H408-C409) and are catalytically active. The bb′ domains contain a CNX binding site, which is composed of positively charged, highly conserved residues (K214, K274, and R282) that interact with the negatively charged residues of the CNX P domain. The b′ domain comprises the majority of the binding site, but the β4-β5 loop of the b domain provides additional contact (K214) to strengthen the interaction. A transient disulfide bond forms between the N-terminal cysteine in the catalytic motif and a substrate, but in a step called "escape pathway", the bond is disrupted as the C-terminal cysteine attacks the N-terminal cysteine to release the substrate.
# Function
The PDIA3 protein is a thiol oxidoreductase that has protein disulfide isomerase activity. PDIA3 is also part of the major histocompatibility complex (MHC) class I peptide loading complex, which is essential for formation of the final antigen conformation and export from the endoplasmic reticulum to the cell surface. This protein of the endoplasmic reticulum interacts with lectin chaperones such as calreticulin and CNX in order to modulate the folding of proteins that are newly synthesized. It is believed that PDIA3 plays a role in protein folding by promoting the formation of disulfide bonds, and that CNX facilitates the positioning substrates next to the catalytic cysteines. This function allows it to serve as a redox sensor by activating mTORC1, which then mediates mTOR complex assembly to adapt cells to oxidative damage. Thus, PDIA3 regulates cell growth and death according to oxygen concentrations, such as in the hypoxic microenvironment of bones. Additionally, PDIA3 activates cell anchorage in bones by associating with cell division and cytoskeleton proteins, such as beta-actin and vimentin, to form a complex which controls TUBB3 folding and proper attachment of the microtubules to the kinetochore. PDIA3 also plays a role in cytokine-dependent signal transduction, including STAT3 signaling.
# Clinical significance
It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical cancer. It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line. PDIA3 is also involved in bone metastasis, which is the most common source of distant relapse in breast cancer. In addition to cancer, overexpression of PDIA3 is linked to renal fibrosis, which is characterized by excess synthesis and secretion of ECM leading to ER stress.
# Interactions
It has been demonstrated that PDIA3 interacts with:
- BACE1,
- ERP27,
- tapasin,
- CRT, and
- CNX. | PDIA3
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme.[1][2][3] This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.[4]
# Structure
The PDIA3 protein consists of four thioredoxin-like domains: a, b, b′, and a′. The a and a′ domains have Cys-Gly-His-Cys active site motifs (C57-G58-H59-C60 and C406-G407-H408-C409) and are catalytically active.[5][6] The bb′ domains contain a CNX binding site, which is composed of positively charged, highly conserved residues (K214, K274, and R282) that interact with the negatively charged residues of the CNX P domain. The b′ domain comprises the majority of the binding site, but the β4-β5 loop of the b domain provides additional contact (K214) to strengthen the interaction.[6] A transient disulfide bond forms between the N-terminal cysteine in the catalytic motif and a substrate, but in a step called "escape pathway", the bond is disrupted as the C-terminal cysteine attacks the N-terminal cysteine to release the substrate.[5]
# Function
The PDIA3 protein is a thiol oxidoreductase that has protein disulfide isomerase activity.[3][5] PDIA3 is also part of the major histocompatibility complex (MHC) class I peptide loading complex, which is essential for formation of the final antigen conformation and export from the endoplasmic reticulum to the cell surface.[5][7] This protein of the endoplasmic reticulum interacts with lectin chaperones such as calreticulin and CNX in order to modulate the folding of proteins that are newly synthesized. It is believed that PDIA3 plays a role in protein folding by promoting the formation of disulfide bonds, and that CNX facilitates the positioning substrates next to the catalytic cysteines.[4][5] This function allows it to serve as a redox sensor by activating mTORC1, which then mediates mTOR complex assembly to adapt cells to oxidative damage. Thus, PDIA3 regulates cell growth and death according to oxygen concentrations, such as in the hypoxic microenvironment of bones. Additionally, PDIA3 activates cell anchorage in bones by associating with cell division and cytoskeleton proteins, such as beta-actin and vimentin, to form a complex which controls TUBB3 folding and proper attachment of the microtubules to the kinetochore. PDIA3 also plays a role in cytokine-dependent signal transduction, including STAT3 signaling.[8]
# Clinical significance
It has been demonstrated that the downregulation of ERp57 expression is correlated with poor prognosis in early-stage cervical cancer.[9] It has also been demonstrated that ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line.[10] PDIA3 is also involved in bone metastasis, which is the most common source of distant relapse in breast cancer.[8] In addition to cancer, overexpression of PDIA3 is linked to renal fibrosis, which is characterized by excess synthesis and secretion of ECM leading to ER stress.[11]
# Interactions
It has been demonstrated that PDIA3 interacts with:
- BACE1,[12]
- ERP27,[13]
- tapasin,[12][6]
- CRT,[12] and
- CNX.[5][12][6] | https://www.wikidoc.org/index.php/ERP57 | |
9ca87a36cacd5f02999737280eccef90472302b4 | wikidoc | ETFDH | ETFDH
Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.
# Function
Electron-transferring-flavoprotein dehydrogenase in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with type II glutaric aciduria.
# Structure
The ETFDH gene is located on the q arm of chromosome 4 in position 32.1 and has 13 exons spanning 36,613 base pairs. The protein is synthesized as a 67-kDa precursor which is targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane. This 64-kDA mature form is a monomer integrated into the mitochondrial inner membrane, containing a 4Fe-4S cluster and 1 molecule of FAD.
# Function
This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains. It accepts electrons from ETF and reduces ubiquinone.
# Clinical Significance
Mutations in the ETFDH can cause glutaric aciduria 2C (GA2C), an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids.
A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ETFDH gene, causes increased production of reactive oxygen species (ROS) and shortened neurites in cells expressing this mutant compared to wild type cells. Suberic acid, an accumulated intermediate metabolite in dehydrogenase deficiency, can significantly impair neurite outgrowth in NSC34 cells. This shortening of neurites can be restored by riboflavin, carnitine, or Coenzyme Q10 supplements.
# Interactions
The encoded protein interacts with MYH7B, LINC00174, LINC00574, Homeobox protein goosecoid-2, AIRE, OTX1, Keratin-associated protein 13-2, Keratin-associated protein 11-1, TRIM69, Zinc finger protein 581, and COX6B1. | ETFDH
Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.[1]
# Function
Electron-transferring-flavoprotein dehydrogenase in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with type II glutaric aciduria.[1]
# Structure
The ETFDH gene is located on the q arm of chromosome 4 in position 32.1 and has 13 exons spanning 36,613 base pairs.[2][3] The protein is synthesized as a 67-kDa precursor which is targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.[1] This 64-kDA mature form is a monomer integrated into the mitochondrial inner membrane, containing a 4Fe-4S cluster and 1 molecule of FAD.[3]
# Function
This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains.[3] It accepts electrons from ETF and reduces ubiquinone.[4][5]
# Clinical Significance
Mutations in the ETFDH can cause glutaric aciduria 2C (GA2C), an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids.[4][5]
A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ETFDH gene, causes increased production of reactive oxygen species (ROS) and shortened neurites in cells expressing this mutant compared to wild type cells. Suberic acid, an accumulated intermediate metabolite in dehydrogenase deficiency, can significantly impair neurite outgrowth in NSC34 cells. This shortening of neurites can be restored by riboflavin, carnitine, or Coenzyme Q10 supplements.[6]
# Interactions
The encoded protein interacts with MYH7B, LINC00174, LINC00574, Homeobox protein goosecoid-2, AIRE, OTX1, Keratin-associated protein 13-2, Keratin-associated protein 11-1, TRIM69, Zinc finger protein 581, and COX6B1.[7] | https://www.wikidoc.org/index.php/ETFDH | |
c15f614b1a81ea7df07a56f3e7533ba0b2896d04 | wikidoc | ETHE1 | ETHE1
Protein ETHE1, mitochondrial, also known as "ethylmalonic encephalopathy 1 protein" and "per sulfide dioxygenase", is a protein that in humans is encoded by the ETHE1 gene located on chromosome 19.
# Structure
The human ETHE1 gene consists of 7 exons and encodes for a protein that is approximately 27 kDa in size.
# Function
This gene encodes a protein that is expressed in the thyroid.
The ETHE1 protein is thought to localize primarily to the mitochondrial matrix and functions as a sulfur dioxygenase. Sulfur deoxygenates are proteins that function in sulfur metabolism. The ETHE1 protein is thought to catalyze the following reaction:
and requires iron and possibly glutathione as cofactors. The physiological substrate of ETHE1 is thought to be glutathione persulfide, an intermediate metabolite involved in hydrogen sulfide degradation.
# Clinical significance
Mutations in ETHE1 gene are thought to cause ethylmalonic encephalopathy, a rare inborn error of metabolism. Patients carrying ETHE1 mutations have been found to exhibit lower activity of ETHE1 and affinity for the ETHE1 substrate. Mouse models of Ethe1 genetic ablation likewise exhibited reduced sulfide dioxygenase catabolism and cranial features of ethylmalonic encephalopathy. Decrease in sulfide dioxygenase activity results in abnormal catabolism of hydrogen sulfide, an gas-phase signaling molecule in the central nervous system, whose accumulation is thought to inhibit cytochrome c oxidase activity in the respiratory chain of the mitochondrion. However, other metabolic pathways may also be involved that could exert a modulatory effect on hydrogen sulfide toxicity.
# Interactions
ETHE1 has been shown to interact with RELA. | ETHE1
Protein ETHE1, mitochondrial, also known as "ethylmalonic encephalopathy 1 protein" and "per sulfide dioxygenase", is a protein that in humans is encoded by the ETHE1 gene located on chromosome 19.[1]
# Structure
The human ETHE1 gene consists of 7 exons and encodes for a protein that is approximately 27 kDa in size.
# Function
This gene encodes a protein that is expressed in the thyroid.[1]
The ETHE1 protein is thought to localize primarily to the mitochondrial matrix [2][3] and functions as a sulfur dioxygenase. Sulfur deoxygenates are proteins that function in sulfur metabolism. The ETHE1 protein is thought to catalyze the following reaction:
and requires iron[4] and possibly glutathione[4] as cofactors. The physiological substrate of ETHE1 is thought to be glutathione persulfide,[4] an intermediate metabolite involved in hydrogen sulfide degradation.
# Clinical significance
Mutations in ETHE1 gene are thought to cause ethylmalonic encephalopathy,[3][5] a rare inborn error of metabolism. Patients carrying ETHE1 mutations have been found to exhibit lower activity of ETHE1 and affinity for the ETHE1 substrate.[4] Mouse models of Ethe1 genetic ablation likewise exhibited reduced sulfide dioxygenase catabolism and cranial features of ethylmalonic encephalopathy.[2] Decrease in sulfide dioxygenase activity results in abnormal catabolism of hydrogen sulfide, an gas-phase signaling molecule in the central nervous system,[4] whose accumulation is thought to inhibit cytochrome c oxidase activity in the respiratory chain of the mitochondrion.[2] However, other metabolic pathways may also be involved that could exert a modulatory effect on hydrogen sulfide toxicity.[6]
# Interactions
ETHE1 has been shown to interact with RELA.[7] | https://www.wikidoc.org/index.php/ETHE1 | |
1cb5a1a6b76ad9ecda481640f1eb2593a103acc3 | wikidoc | EVI5L | EVI5L
EVI5L (Ecotropic Viral Integration Site 5-Like) is a protein that in humans is encoded by the EVI5L gene. EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity. Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.
# Gene
The EVI5L gene is 34,701 base pairs long and has an unprocessed mRNA that is 3,756 nucleotides in length. It consists of 19 exons that encode for an 805 amino acid protein.
## Locus
EVI5L is located on the short arm (p) of chromosome 19 in region 1, band 3, and sub-band 2 (19p13.2) starting at 7,830,275 base pairs and ending at 7,864,976 base pairs. It is encoded for on the plus strand. It is located near the CLEC4M (C-type lectin domain family 4, member M) gene, which is involved in peptide antigen transport.
# Homology and Evolution
## Homologous domains
EVI5L contains a RAB-GAP TBC domain, which is involved with regulating membrane trafficking by cycling between inactive (GDP-bound) and active (GTP-bound) conformations. It also has the apolipophorin-III and tetratricopeptide repeat (TPR) domains. Apolipophorin-III play vital roles in the transport of lipids and lipoprotein metabolism, while TPR mediates protein-protein interactions and the assembly of multi protein complexes. These three domains are highly conserved in EVI5L orthologs.
## Paralogs
There are 7 moderately related proteins in humans that are paralogous to the RAB-GAP TBC domain of EVI5L. All of these proteins are in the guanosine nucleotide-binding protein family
## Orthologs
There are 63 orthologs of EVI5L that have been identified including mammals, birds, reptiles, and fish. EVI5L is highly conserved among its orthologs but is not present in insects, plants, bacteria, archea or protists.
## Homologs
The following table lists the homologs of EVI5L:
# Protein
The protein of EVI5L consists of 805 amino acid residues. The molecular weight of the mature protein is 92.5 kdal with an isoelectric point of 5.05. EVI5L has an unusually large amount of glutamic acid residues, compared to similar proteins. Most of the protein is neutral, with no positive charge, negative charge, or mixed charge clusters. It has a very small negative hydrophobicity (-0.597019). EVI5L is a soluble protein that localizes in the nucleus. It contains no signal peptide, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus. There is no transmembrane domain in EVI5L.
## Isoforms
EVI5L has two isoforms produced by alternative splicing. Isoform 2 is missing in-frame exon 11, making it shorter (794 amino acids).
## Post-Translational Modifications
Post translational modifications of EVI5L that are evolutionarily conserved in majority of the orthologs include glycosylation (C-mannosylation), glycation, phosphorylation (non-kinase and kinase specific), and sumoylation. There is also one leucine-rich nuclear export signal.
## Secondary Structure
The entire secondary structure of EVI5L is made up of alpha helices, with no beta sheets present. This is also true for EVI5Ls closest structural paralog, RABGAP1L.
# Expression
## Promoter
The predicted promoter for the EVI5L gene spans 664 base pairs from 7,910,867 to 7,911,530 with a predicted transcriptional start site that is 114 base pairs and spans from 7,911,346 to 7,911,460. The promoter region and beginning of the EVI5L gene (7,910,997 to 7,911,843) is not conserved past primates. This region was used to determine transcription factor interactions.
Some of the main transcription factors predicted to bind to the promoter includes: activator-, mediator- and TBP-dependent core promoter element for RNA polymerase II transcription from TATA-less promoters, p53 tumor suppressor, brachyury gene, mesoderm developmental factor, EGR/nerve growth factor induced protein C & related factors, and GLI zinc finger family.
## Expression
Expression data from expressed sequence tag mapping, microarray and in situ hybridization shows EVI5L has ubiquitously low expression. However, it has slightly higher expression in the testis and fetal brain.
# Function and Biochemistry
The exact function of EVI5L is unknown. Given this, the paralogs of the gene are associated with starvation-induced autophagosome formation and trafficking and translocation of GLUT4-containing vesicles. Therefore, EVI5L is predicted to target endocytic vesicles.
# Interacting Proteins
EVI5L has been shown to interact with NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18 and SRPK2 (serine/threonine-protein kinase 2). NUDT18 is a member of the Nudix hydrolase family. Nudix hydrolases eliminate potentially toxic nucleotide metabolites from the cell and regulate the concentrations and availability of many different nucleotide substrates, cofactors, and signaling molecules. SRPK2 is a Serine/arginine rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing.
# Clinical significance
Zebrafish deficient for Rab23 or its GTPase-activating protein, EVI5L, exhibit abnormal heart formation. This is attributed to the requirement of RAB23 in the differentiation of cardiac progenitor cells. RAB23 is required for normal development of the brain, spinal cord and heart, and without EVI5L to activate RAB23, abnormal formation of these organs ensues. | EVI5L
EVI5L (Ecotropic Viral Integration Site 5-Like) is a protein that in humans is encoded by the EVI5L gene.[1] EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity.[2][3] Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.[4]
# Gene
The EVI5L gene is 34,701 base pairs long and has an unprocessed mRNA that is 3,756 nucleotides in length. It consists of 19 exons that encode for an 805 amino acid protein.[5]
## Locus
EVI5L is located on the short arm (p) of chromosome 19 in region 1, band 3, and sub-band 2 (19p13.2) starting at 7,830,275 base pairs and ending at 7,864,976 base pairs. It is encoded for on the plus strand. It is located near the CLEC4M (C-type lectin domain family 4, member M) gene, which is involved in peptide antigen transport.[6]
# Homology and Evolution
## Homologous domains
EVI5L contains a RAB-GAP TBC domain, which is involved with regulating membrane trafficking by cycling between inactive (GDP-bound) and active (GTP-bound) conformations.[7] It also has the apolipophorin-III and tetratricopeptide repeat (TPR) domains. Apolipophorin-III play vital roles in the transport of lipids and lipoprotein metabolism,[8] while TPR mediates protein-protein interactions and the assembly of multi protein complexes.[9] These three domains are highly conserved in EVI5L orthologs.
## Paralogs
There are 7 moderately related proteins in humans that are paralogous to the RAB-GAP TBC domain of EVI5L. All of these proteins are in the guanosine nucleotide-binding protein family[10]
## Orthologs
There are 63[11] orthologs of EVI5L that have been identified including mammals, birds, reptiles, and fish.[12] EVI5L is highly conserved among its orthologs but is not present in insects, plants, bacteria, archea or protists.
## Homologs
The following table lists the homologs of EVI5L:
# Protein
The protein of EVI5L consists of 805[13] amino acid residues. The molecular weight of the mature protein is 92.5 kdal with an isoelectric point of 5.05. EVI5L has an unusually large amount of glutamic acid residues, compared to similar proteins. Most of the protein is neutral, with no positive charge, negative charge, or mixed charge clusters.[14] It has a very small negative hydrophobicity (-0.597019). EVI5L is a soluble protein[15] that localizes in the nucleus.[16] It contains no signal peptide, no mitochondrial targeting motifs and no peroxisomal targeting signal in the C-terminus. There is no transmembrane domain in EVI5L.[17]
## Isoforms
EVI5L has two isoforms produced by alternative splicing. Isoform 2 is missing in-frame exon 11, making it shorter (794 amino acids).[18]
## Post-Translational Modifications
Post translational modifications of EVI5L that are evolutionarily conserved in majority of the orthologs include glycosylation (C-mannosylation),[19] glycation,[20] phosphorylation (non-kinase and kinase specific),[21][22] and sumoylation.[23] There is also one leucine-rich nuclear export signal.[24]
## Secondary Structure
The entire secondary structure of EVI5L is made up of alpha helices, with no beta sheets present.[25][26] This is also true for EVI5Ls closest structural paralog, RABGAP1L.[27]
# Expression
## Promoter
The predicted promoter for the EVI5L gene spans 664 base pairs from 7,910,867 to 7,911,530 with a predicted transcriptional start site that is 114 base pairs and spans from 7,911,346 to 7,911,460.[28] The promoter region and beginning of the EVI5L gene (7,910,997 to 7,911,843) is not conserved past primates. This region was used to determine transcription factor interactions.
Some of the main transcription factors predicted to bind to the promoter includes: activator-, mediator- and TBP-dependent core promoter element for RNA polymerase II transcription from TATA-less promoters, p53 tumor suppressor, brachyury gene, mesoderm developmental factor, EGR/nerve growth factor induced protein C & related factors, and GLI zinc finger family.[29]
## Expression
Expression data from expressed sequence tag mapping, microarray and in situ hybridization shows EVI5L has ubiquitously low expression.[30][31][32] However, it has slightly higher expression in the testis and fetal brain.
# Function and Biochemistry
The exact function of EVI5L is unknown. Given this, the paralogs of the gene are associated with starvation-induced autophagosome formation and trafficking and translocation of GLUT4-containing vesicles.[33][34] Therefore, EVI5L is predicted to target endocytic vesicles.
# Interacting Proteins
EVI5L has been shown to interact with NUDT18 (nucleoside diphosphate linked moiety X)-type motif 18[35] and SRPK2 (serine/threonine-protein kinase 2).[36] NUDT18 is a member of the Nudix hydrolase family. Nudix hydrolases eliminate potentially toxic nucleotide metabolites from the cell and regulate the concentrations and availability of many different nucleotide substrates, cofactors, and signaling molecules.[37] SRPK2 is a Serine/arginine rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing.[38]
# Clinical significance
Zebrafish deficient for Rab23 or its GTPase-activating protein, EVI5L, exhibit abnormal heart formation. This is attributed to the requirement of RAB23 in the differentiation of cardiac progenitor cells. RAB23 is required for normal development of the brain, spinal cord and heart, and without EVI5L to activate RAB23, abnormal formation of these organs ensues.[39] | https://www.wikidoc.org/index.php/EVI5L | |
0c65df914aeb4372709ac91872b3acaeadc78186 | wikidoc | Echis | Echis
Echis is a genus of venomous vipers found in the dry regions of Africa, the Middle East, India and Sri Lanka. These snakes are quick-tempered and strike readily, which, combined with a virulent hemotoxic venom, makes them very dangerous, despite their small size. They also have a characteristic threat display, rubbing sections of their body together to produce a "sizzling" warning sound. The name Echis is a Greek word that means "viper." Eight species are currently recognized.
# Description
Relatively small in size with adults never larger than about 90 cm in length (E. pyramidum).
The head is short, wide, pear-shaped and distinct from the neck. The snout is short and rounded, while the eyes are relatively large and set well forward. The crown is covered with small, irregular, imbricate scales, which may be either smooth or keeled.
The body is moderately slender and cylindrical. The dorsal scales are mostly keeled. However, the scales on the lower flanks stick out at a distinct 45-degree angle and have a central ridge, or keel, that is serrated (hence the common name). The tail is short and the subcaudals single.
# Geographic range
India and Sri Lanka, parts of the Middle East and Africa north of the equator.
# Behavior
All members of this genus have a distinctive threat display, which involves forming a series of parallel C-shaped coils and rubbing them together to produce a sizzling sound, rather like water on a hot plate. The proper term for this is stridulation. As they become more agitated, this stridulating behavior becomes faster and louder. It is postulated that this display evolved as a means of limiting water loss, such as might occur when hissing. However, some authors describe this display as being accompanied by loud hissing.
These snakes are very aggressive and will strike vigorously from the position described above. When doing so, they may overbalance and end up moving towards their aggressor as a result; most unusual behavior for a snake.
# Feeding
Little is known about the eating habits of some species, but of others the diet is reported to be extremely varied, and may include items such as locusts, beetles, worms, slugs, spiders, scorpions, centipedes, solifugids, frogs, toads, reptiles (including other snakes), small mammals and birds.
# Reproduction
Most Echis species, such as those found in Africa, are oviparous, while others, such as those in India, are viviparous.
# Venom
Bites from Echis species probably result in more deaths than from any other species. The genus is recognized as medically significant in many tropical rural areas. They may be small, but they are very aggressive, quick to strike and possess an extremely virulent hemotoxic venom. There seems to be no significant correlation between the length of the specimen and the symptomology signs that occur in humans. Most victims are bitten after dark when these snakes are active.
Most of these species have venom that contains factors that can cause a consumption coagulopathy and defibrination which may persist for days to weeks. This may result in bleeding anywhere in the body, including the possibility of an intracranial hemorrhage. The latter classically occurs a few days following the bite.
Venom toxicity varies among the different species, geographic locations, individual specimens, sexes, over the seasons, different milkings, and of course the method of injection (SC, IM, IP, IV). Consequently, the LD50 values for Echis venom differ significantly. In mice the intravenous LD50 ranges from 2.3 mg/kg (U.S. Navy, 1991), to 24.1 mg/kg (Christensen, 1955) to 0.44-0.48 mg/kg (Cloudsley-Thompson, 1988). In humans, the lethal dose is estimated to be 3-5 mg (Minton, 1967). Latifi (1991) notes that venom from females was more than twice as toxic on average than venom from males.
The amount of venom produced also varies. Reported yields include 20-35 mg of dried venom from specimens 41-56 cm in length (Minton 1974, U.S. Navy, 1991), 6-48 mg (16 mg average) from Iranian specimens (Latifi, 1991) and 13-35 mg of dried venom from animals from various other localities (Boquet, 1967). Yield varies seasonally, as well as between the sexes: the most venom is produced during the summer months and males produce more than females.
# Species
*) Not including the nominate subspecies (typical form).
T) Type species.
# Taxonomy
Some sources also mention several other species:
- E. omanensis, Babocsay 2004. A new species found in the United Arab Emirates and east Oman.
- E. khosatzkii, Cherlin 1990. Found in Oman and Yemen. Considered a synonym of E. pyramidum.
- E. multisquamatus, Cherlin 1981. Described here as E. carinatus multisquamatus.
# Trivia
- A saw scaled viper of the genus Echis may be responsible for biblical claims of a fiery flying serpent. | Echis
Echis is a genus of venomous vipers found in the dry regions of Africa, the Middle East, India and Sri Lanka. These snakes are quick-tempered and strike readily, which, combined with a virulent hemotoxic venom, makes them very dangerous, despite their small size. They also have a characteristic threat display, rubbing sections of their body together to produce a "sizzling" warning sound.[3] The name Echis is a Greek word that means "viper."[4][5] Eight species are currently recognized.[6]
# Description
Relatively small in size with adults never larger than about 90 cm in length (E. pyramidum).[2]
The head is short, wide, pear-shaped and distinct from the neck. The snout is short and rounded, while the eyes are relatively large and set well forward. The crown is covered with small, irregular, imbricate scales, which may be either smooth or keeled.[3]
The body is moderately slender and cylindrical. The dorsal scales are mostly keeled. However, the scales on the lower flanks stick out at a distinct 45-degree angle and have a central ridge, or keel, that is serrated (hence the common name). The tail is short and the subcaudals single.[3]
# Geographic range
India and Sri Lanka, parts of the Middle East and Africa north of the equator.[1]
# Behavior
All members of this genus have a distinctive threat display, which involves forming a series of parallel C-shaped coils and rubbing them together to produce a sizzling sound, rather like water on a hot plate.[3][2] The proper term for this is stridulation.[7] As they become more agitated, this stridulating behavior becomes faster and louder. It is postulated that this display evolved as a means of limiting water loss, such as might occur when hissing.[3] However, some authors describe this display as being accompanied by loud hissing.[7]
These snakes are very aggressive and will strike vigorously from the position described above. When doing so, they may overbalance and end up moving towards their aggressor as a result; most unusual behavior for a snake.[2]
# Feeding
Little is known about the eating habits of some species, but of others the diet is reported to be extremely varied, and may include items such as locusts, beetles, worms, slugs, spiders, scorpions, centipedes, solifugids, frogs, toads, reptiles (including other snakes), small mammals and birds.[3][2]
# Reproduction
Most Echis species, such as those found in Africa, are oviparous, while others, such as those in India, are viviparous.[2][3]
# Venom
Bites from Echis species probably result in more deaths than from any other species. The genus is recognized as medically significant in many tropical rural areas. They may be small, but they are very aggressive, quick to strike and possess an extremely virulent hemotoxic venom. There seems to be no significant correlation between the length of the specimen and the symptomology signs that occur in humans. Most victims are bitten after dark when these snakes are active.[3]
Most of these species have venom that contains factors that can cause a consumption coagulopathy and defibrination which may persist for days to weeks. This may result in bleeding anywhere in the body, including the possibility of an intracranial hemorrhage. The latter classically occurs a few days following the bite.[8]
Venom toxicity varies among the different species, geographic locations, individual specimens, sexes, over the seasons, different milkings, and of course the method of injection (SC, IM, IP, IV). Consequently, the LD50 values for Echis venom differ significantly. In mice the intravenous LD50 ranges from 2.3 mg/kg (U.S. Navy, 1991), to 24.1 mg/kg (Christensen, 1955) to 0.44-0.48 mg/kg (Cloudsley-Thompson, 1988). In humans, the lethal dose is estimated to be 3-5 mg (Minton, 1967). Latifi (1991) notes that venom from females was more than twice as toxic on average than venom from males.[3]
The amount of venom produced also varies. Reported yields include 20-35 mg of dried venom from specimens 41-56 cm in length (Minton 1974, U.S. Navy, 1991), 6-48 mg (16 mg average) from Iranian specimens (Latifi, 1991) and 13-35 mg of dried venom from animals from various other localities (Boquet, 1967). Yield varies seasonally, as well as between the sexes: the most venom is produced during the summer months and males produce more than females.[3]
# Species
*) Not including the nominate subspecies (typical form).
T) Type species.
# Taxonomy
Some sources also mention several other species:[9][3][10]
- E. omanensis, Babocsay 2004. A new species found in the United Arab Emirates and east Oman.
- E. khosatzkii, Cherlin 1990. Found in Oman and Yemen. Considered a synonym of E. pyramidum.
- E. multisquamatus, Cherlin 1981. Described here as E. carinatus multisquamatus.
# Trivia
- A saw scaled viper of the genus Echis may be responsible for biblical claims of a fiery flying serpent.[11] | https://www.wikidoc.org/index.php/Echis | |
46512d680a46dee6f88165e422e762bb20074c77 | wikidoc | Edema | Edema
Synonyms and keywords: oedema or œdema
# Overview
Edema (American English), formerly known as dropsy or hydropsy, is the increase of interstitial fluid in any organ — swelling. Generally, the amount of interstitial fluid is in the balance of homeostasis. Increased secretion of fluid into the interstitium or impaired removal of this fluid may cause edema. Cutaneous edema is referred to as "pitting" when, after pressure is applied to a small area, the indentation persists after the release of the pressure.
# Classification
Edema can be classified into pitting edema and non piting edema. Peripheral pitting edema is the more common type, resulting from water retention. It can be caused by systemic diseases, pregnancy in some women, either directly or as a result of heart failure, or local conditions such as varicose veins, thrombophlebitis, insect bites, and dermatitis. Non-pitting edema is observed when the indentation does not persist. It is associated with such conditions as lymphedema, lipedema, and myxedema.
# Pathophysiology
Generation of interstitial fluid is regulated by the Starling equation of tissue fluid which states that it depends on the balance of osmotic pressure and of hydrostatic pressure which act in opposite directions across the semipermeable capillary walls. Consequently, anything that increases oncotic pressure outside blood vessels (for example inflammation), or reduces oncotic pressure in the blood (states of low plasma osmolality, for example cirrhosis) will cause edema. Increased hydrostatic pressure inside the blood vessel (for example in heart failure) will have the same effect. If the permeability of the capillary walls increases, more fluid will tend to escape out of the capillary, as can happen when there is inflammation.
# Causes
Causes of edema can be grouped by its extension as generalized and localized edema. Other way to classify it is by its primary mechanism: Increased capillary hydraulic pressure, hypoalbuminemia, increased capillary permeability, lymphatic obstruction or increased interstitial oncotic pressure.
## Life Threatening Causes
Life threatening causes of edema are:
- Acute kidney failure
- Acute pulmonary edema
- Adult respiratory distress syndrome
- Anaphylaxis
- Anthrax
- Burns
- Eclampsia
- Ischemic heart disease
- Sepsis
## Common Causes
- Cirrhosis
- Drugs
- Heart failure
- Nephrotic syndrome and other forms of renal disease
- Pregnancy
- Premenstrual edema
- Venous insufficiency
## Causes by Organ System
## Causes in Alphabetical Order
- Aagenaes syndrome
- Acanthocheilonemiasis
- Acute altitude sickness
- Acute glomerulonephritis
- Acute infantile hemorrhagic oedema
- Acute pulmonary edema
- Acute renal failure
- Adult respiratory distress syndrome
- Aldesleukin
- Alitretinoin
- Allergic reaction
- Alpha1 blockers
- Amlodipine
- Amnion rupture sequence
- Anaphylaxis
- Andersen disease
- Androgens
- Angioimmunoblastic T-cell lymphoma
- Anthrax
- Aorta-pulmonary artery fistula
- Aortic coarctation
- Aplasia cutis congenital - intestinal lymphangiectasia
- Aromatase inhibitors
- Aspirin
- Aspirin
- Autoimmune disease (juvenile idiopathic arthritis & Crohn's disease)
- Azficel-T
- Bicalutamide
- Bone marrow failure
- Boston ivy poisoning
- Bronchogenic carcinoma
- Burns
- C1 esterase inhibitor deficiency
- Cachexia
- Calcium channel blockers
- Capillary leak syndromes
- Carbenoxolone
- Carcinoid tumours and carcinoid syndrome
- Cardiomyopathy - hearing loss, type t-RNA lysine gene mutation
- Cefaclor
- Cetrorelix
- Chagas disease
- Chlordiazepoxide
- Chronic kidney disease
- chronic venous insufficiency - post-thrombotic syndrome
- Cirrhosis
- Cisplatin
- Classical hodgkin disease
- Combined oxidative phosphorylation deficiency 5
- Congenital disorder of glycosylation type 1h
- Conivaptan
- Conjugated estrogens
- Crizotinib
- Cushing disease
- Cystic fibrosis
- Danazol
- Decreased cardiac output
- Deep vein thrombosis
- Deserpidine
- Desmopressin
- Desogestrel and ethinyl estradiol
- Dexamethasone
- Dextrocardia-bronchiectasis-sinusitis
- Diabetes mellitus
- Diazoxide
- Dihydropyridine calcium channel blockers
- Dilated cardiomyopathy
- Diltiazem
- Distichiasis
- Docetaxel
- Early hepatic cirrhosis
- Eclampsia
- Ectodermal dysplasia - arthrogryposis - diabetes mellitus
- Eosinophilic gastroenteritis
- Encephalopathy progressive - optic atrophy
- Eosinophilia-myalgia syndrome
- Eosinophilic enteropathy, pattern II
- Epidemic dropsy
- Erythroderma
- Essential mixed cryoglobulinemia
- Estramustine
- Estrogen dependent hereditary angioedema
- Estrogens
- Ethynodiol diacetate and ethinyl estradiol
- Excessive dieting
- Felbamate
- Felodipine
- Fludrocortisone
- Flurbiprofen
- Fructose-1-phosphate aldolase deficiency, hereditary
- Fungemia
- Gabapentin
- Gallium nitrate
- Gastritis, familial giant hypertrophic
- Gestrinone
- Ginseng overuse
- Glomerular disease
- Glucocorticoids
- Glufosinate
- Gold salts
- Goldberg syndrome
- Goodpasture's syndrome
- Granulomatous lymphangitis
- Heart failure
- Hemangiomatosis, familial pulmonary capillary
- Hemolytic disease of the newborn
- Hepatic failure
- Hepatic venous obstruction
- Hepatitis
- Hepatorenal tyrosinemia
- Hereditary angioedema
- Hydralazine
- Hydrocortisone
- Hydroxyprogesterone caproate
- Hypernatremia
- Hypertensive heart disease
- Hypoproteinaemia
- Hypothyroidism
- Ichthyosis congenita
- Imatinib mesylate
- Indomethacin
- Inflammation or sepsis
- Inherited hemolytic-uremic syndrome
- Insulins
- Interleukin 11
- Interleukin-2 therapy
- Intestinal capillariasis
- Irons-bhan syndrome
- Ischemic heart disease
- Isradipine
- Jacobs syndrome
- Junin virus
- Kawasaki disease
- Kwashiorkor
- Leg injury
- Lenalidomide
- Letterer-siwe disease
- Lidocaine (cream)
- Lidocaine (ointment)
- Lipoprotein glomerulopathy
- Liver disease
- Liver failure
- Lymph node dissection
- Lymphadenitis
- Lymphangiomatosis, pulmonary
- Lymphatic filariasis
- Lymphedema praecox
- Malabsorption syndrome
- Malignant ascites
- Malnutrition
- Mefenamic acid
- Membranoproliferative glomerulonephritis
- Ménétrier's disease
- Mesangiocapillary glomerulonephritis type I
- Mesangiocapillary glomerulonephritis type III
- Methysergide
- Microcephaly -- microphthalmos -- blindness
- Milroy's disease
- Minoxidil
- Mitral valve disease
- Mixed cellularity hodgkin's disease
- Monosomy 3p14 p11
- Multiple joint dislocations -- metaphyseal dysplasia
- Nabilone
- Nephritis
- Nephrosis, idiopathic form, familiar
- Nephrotic syndrome
- Neu-laxova syndrome
- Nevus of ota retinitis pigmentosa
- Nifedipine
- Nilutamide
- Nitrendipine
- Nodal enlargement due to malignancy
- Nodular sclerosing hodgkin's lymphoma
- Non-diarrheal (d-) HUS syndrome
- Nondihydropyridine calcium channel blockers
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Noonan syndrome
- Nutritional deficiency
- Obal syndrome
- Opitz-Reynolds-Fitzgerald syndrome
- Ovarian hyperstimulation syndrome
- Oxandrolone
- Oxaprozin
- Palifermin
- Pegaspargase
- Penciclovir
- Pergolide
- Phenylbutazone
- Pimavanserin
- Pinacidil
- Pioglitazone
- Plasmodium malariae
- Plasmodium ovale
- POEMS syndrome
- Polyarteritis nodosa
- Post-streptococcal glomerulonephritis
- Pramipexole
- Prednisolone
- Pre-eclampsia
- Pregabalin
- Pregnancy and premenstrual edema
- Pregnancy
- Primary biliary cirrhosis
- Progestins
- Protein deficiency
- Protein losing enteropathy
- Proximal spinal muscular atrophy
- Pulmonary lymphangiectasia, congenital
- Recurring airway infection
- Refeeding edema
- Renal disease
- Renal failure
- Reserpine
- Rheumatic fever
- Rofecoxib
- Ropinirole
- Sargramostim
- Schneckenbecken dysplasia
- Siltuximab
- Sinecatechins
- Single ventricular heart
- Sleeping sickness (east african)
- Sleeping sickness (west african)
- Sodium overload
- Sodium phenylbutyrate
- Spinal muscular atrophy, type I
- St. Anthony's fire
- Streptozocin
- Sympatholytics
- Tamoxifen
- Tang His Ryu syndrome
- Temsirolimus
- Terconazole
- Testosterone
- Thiamine deficiency
- Thiazolidinediones
- Thyroid disorders
- Tiagabine
- Tolmetin
- Trauma
- Trichinosis
- Tricuspid atresia
- Tricuspid valve diseases
- Turner syndrome
- Type IV glycogen storage disease
- Tyrosinemia
- Uhl anomaly
- Varicose veins
- Vasodilators
- Venous stenosis
- Venous thrombosis
- Vitamin E deficiency
- Von Willebrand factor
- Waldmann disease
- Water intoxication
- Whipple's disease
- X chromosome, duplication xq13 1 q21 1
- X chromosome, monosomy xp22 pter
- X chromosome, monosomy xq28
- X chromosome, trisomy 26-28
- X chromosome, trisomy xp3
- X chromosome, trisomy xpter xq13
- X chromosome, trisomy xq
- X chromosome, trisomy xq25
- Yellow nail syndrome
# Organ-Specific Edema
Edema of specific organs (cerebral edema, pulmonary edema, macular edema, pedal edema) may also occur, each with different specific causes to peripheral edema, but all based on the same principles. Ascites is effectively edema within the peritoneal cavity, as pleural effusions are effectively edema in the pleural cavity. Causes of edema which are generalized to the whole body can cause edema in multiple organs and peripherally. For example, severe heart failure can cause peripheral edema, pulmonary edema, pleural effusions and ascites.
Common and usually harmless appearances of cutaneous edema are observed with mosquito bites and skin contact with certain plants (urticaria).
Edema may be found in the eyes after corrective surgery or procedures of that nature. | Edema
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Martin Nino, M.D. [2]
Synonyms and keywords: oedema or œdema
# Overview
Edema (American English), formerly known as dropsy or hydropsy, is the increase of interstitial fluid in any organ — swelling. Generally, the amount of interstitial fluid is in the balance of homeostasis. Increased secretion of fluid into the interstitium or impaired removal of this fluid may cause edema. Cutaneous edema is referred to as "pitting" when, after pressure is applied to a small area, the indentation persists after the release of the pressure.
# Classification
Edema can be classified into pitting edema and non piting edema. Peripheral pitting edema is the more common type, resulting from water retention. It can be caused by systemic diseases, pregnancy in some women, either directly or as a result of heart failure, or local conditions such as varicose veins, thrombophlebitis, insect bites, and dermatitis. Non-pitting edema is observed when the indentation does not persist. It is associated with such conditions as lymphedema, lipedema, and myxedema.
# Pathophysiology
Generation of interstitial fluid is regulated by the Starling equation of tissue fluid which states that it depends on the balance of osmotic pressure and of hydrostatic pressure which act in opposite directions across the semipermeable capillary walls. Consequently, anything that increases oncotic pressure outside blood vessels (for example inflammation), or reduces oncotic pressure in the blood (states of low plasma osmolality, for example cirrhosis) will cause edema. Increased hydrostatic pressure inside the blood vessel (for example in heart failure) will have the same effect. If the permeability of the capillary walls increases, more fluid will tend to escape out of the capillary, as can happen when there is inflammation.
# Causes
Causes of edema can be grouped by its extension as generalized and localized edema. Other way to classify it is by its primary mechanism: Increased capillary hydraulic pressure, hypoalbuminemia, increased capillary permeability, lymphatic obstruction or increased interstitial oncotic pressure.
## Life Threatening Causes
Life threatening causes of edema are:[1][2][3]
- Acute kidney failure
- Acute pulmonary edema
- Adult respiratory distress syndrome
- Anaphylaxis
- Anthrax
- Burns
- Eclampsia
- Ischemic heart disease
- Sepsis
## Common Causes
- Cirrhosis
- Drugs
- Heart failure
- Nephrotic syndrome and other forms of renal disease
- Pregnancy
- Premenstrual edema
- Venous insufficiency
## Causes by Organ System
## Causes in Alphabetical Order
- Aagenaes syndrome
- Acanthocheilonemiasis
- Acute altitude sickness
- Acute glomerulonephritis
- Acute infantile hemorrhagic oedema
- Acute pulmonary edema
- Acute renal failure
- Adult respiratory distress syndrome
- Aldesleukin
- Alitretinoin
- Allergic reaction
- Alpha1 blockers
- Amlodipine
- Amnion rupture sequence
- Anaphylaxis
- Andersen disease
- Androgens
- Angioimmunoblastic T-cell lymphoma
- Anthrax
- Aorta-pulmonary artery fistula
- Aortic coarctation
- Aplasia cutis congenital - intestinal lymphangiectasia
- Aromatase inhibitors
- Aspirin
- Aspirin
- Autoimmune disease (juvenile idiopathic arthritis & Crohn's disease)
- Azficel-T
- Bicalutamide
- Bone marrow failure
- Boston ivy poisoning
- Bronchogenic carcinoma
- Burns
- C1 esterase inhibitor deficiency
- Cachexia
- Calcium channel blockers
- Capillary leak syndromes
- Carbenoxolone
- Carcinoid tumours and carcinoid syndrome
- Cardiomyopathy - hearing loss, type t-RNA lysine gene mutation
- Cefaclor
- Cetrorelix
- Chagas disease
- Chlordiazepoxide
- Chronic kidney disease
- chronic venous insufficiency - post-thrombotic syndrome
- Cirrhosis
- Cisplatin
- Classical hodgkin disease
- Combined oxidative phosphorylation deficiency 5
- Congenital disorder of glycosylation type 1h
- Conivaptan
- Conjugated estrogens
- Crizotinib
- Cushing disease
- Cystic fibrosis
- Danazol
- Decreased cardiac output
- Deep vein thrombosis
- Deserpidine
- Desmopressin
- Desogestrel and ethinyl estradiol
- Dexamethasone
- Dextrocardia-bronchiectasis-sinusitis
- Diabetes mellitus
- Diazoxide
- Dihydropyridine calcium channel blockers
- Dilated cardiomyopathy
- Diltiazem
- Distichiasis
- Docetaxel
- Early hepatic cirrhosis
- Eclampsia
- Ectodermal dysplasia - arthrogryposis - diabetes mellitus
- Eosinophilic gastroenteritis
- Encephalopathy progressive - optic atrophy
- Eosinophilia-myalgia syndrome
- Eosinophilic enteropathy, pattern II
- Epidemic dropsy
- Erythroderma
- Essential mixed cryoglobulinemia
- Estramustine
- Estrogen dependent hereditary angioedema
- Estrogens
- Ethynodiol diacetate and ethinyl estradiol
- Excessive dieting
- Felbamate
- Felodipine
- Fludrocortisone
- Flurbiprofen
- Fructose-1-phosphate aldolase deficiency, hereditary
- Fungemia
- Gabapentin
- Gallium nitrate
- Gastritis, familial giant hypertrophic
- Gestrinone
- Ginseng overuse
- Glomerular disease
- Glucocorticoids
- Glufosinate
- Gold salts
- Goldberg syndrome
- Goodpasture's syndrome
- Granulomatous lymphangitis
- Heart failure
- Hemangiomatosis, familial pulmonary capillary
- Hemolytic disease of the newborn
- Hepatic failure
- Hepatic venous obstruction
- Hepatitis
- Hepatorenal tyrosinemia
- Hereditary angioedema
- Hydralazine
- Hydrocortisone
- Hydroxyprogesterone caproate
- Hypernatremia
- Hypertensive heart disease
- Hypoproteinaemia
- Hypothyroidism
- Ichthyosis congenita
- Imatinib mesylate
- Indomethacin
- Inflammation or sepsis
- Inherited hemolytic-uremic syndrome
- Insulins
- Interleukin 11
- Interleukin-2 therapy
- Intestinal capillariasis
- Irons-bhan syndrome
- Ischemic heart disease
- Isradipine
- Jacobs syndrome
- Junin virus
- Kawasaki disease
- Kwashiorkor
- Leg injury
- Lenalidomide
- Letterer-siwe disease
- Lidocaine (cream)
- Lidocaine (ointment)
- Lipoprotein glomerulopathy
- Liver disease
- Liver failure
- Lymph node dissection
- Lymphadenitis
- Lymphangiomatosis, pulmonary
- Lymphatic filariasis
- Lymphedema praecox
- Malabsorption syndrome
- Malignant ascites
- Malnutrition
- Mefenamic acid
- Membranoproliferative glomerulonephritis
- Ménétrier's disease
- Mesangiocapillary glomerulonephritis type I
- Mesangiocapillary glomerulonephritis type III
- Methysergide
- Microcephaly -- microphthalmos -- blindness
- Milroy's disease
- Minoxidil
- Mitral valve disease
- Mixed cellularity hodgkin's disease
- Monosomy 3p14 p11
- Multiple joint dislocations -- metaphyseal dysplasia
- Nabilone
- Nephritis
- Nephrosis, idiopathic form, familiar
- Nephrotic syndrome
- Neu-laxova syndrome
- Nevus of ota retinitis pigmentosa
- Nifedipine
- Nilutamide
- Nitrendipine
- Nodal enlargement due to malignancy
- Nodular sclerosing hodgkin's lymphoma
- Non-diarrheal (d-) HUS syndrome
- Nondihydropyridine calcium channel blockers
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Noonan syndrome
- Nutritional deficiency
- Obal syndrome
- Opitz-Reynolds-Fitzgerald syndrome
- Ovarian hyperstimulation syndrome
- Oxandrolone
- Oxaprozin
- Palifermin
- Pegaspargase
- Penciclovir
- Pergolide
- Phenylbutazone
- Pimavanserin
- Pinacidil
- Pioglitazone
- Plasmodium malariae
- Plasmodium ovale
- POEMS syndrome
- Polyarteritis nodosa
- Post-streptococcal glomerulonephritis
- Pramipexole
- Prednisolone
- Pre-eclampsia
- Pregabalin
- Pregnancy and premenstrual edema
- Pregnancy
- Primary biliary cirrhosis
- Progestins
- Protein deficiency
- Protein losing enteropathy
- Proximal spinal muscular atrophy
- Pulmonary lymphangiectasia, congenital
- Recurring airway infection
- Refeeding edema
- Renal disease
- Renal failure
- Reserpine
- Rheumatic fever
- Rofecoxib
- Ropinirole
- Sargramostim
- Schneckenbecken dysplasia
- Siltuximab
- Sinecatechins
- Single ventricular heart
- Sleeping sickness (east african)
- Sleeping sickness (west african)
- Sodium overload
- Sodium phenylbutyrate
- Spinal muscular atrophy, type I
- St. Anthony's fire
- Streptozocin
- Sympatholytics
- Tamoxifen
- Tang His Ryu syndrome
- Temsirolimus
- Terconazole
- Testosterone
- Thiamine deficiency
- Thiazolidinediones
- Thyroid disorders
- Tiagabine
- Tolmetin
- Trauma
- Trichinosis
- Tricuspid atresia
- Tricuspid valve diseases
- Turner syndrome
- Type IV glycogen storage disease
- Tyrosinemia
- Uhl anomaly
- Varicose veins
- Vasodilators
- Venous stenosis
- Venous thrombosis
- Vitamin E deficiency
- Von Willebrand factor
- Waldmann disease
- Water intoxication
- Whipple's disease
- X chromosome, duplication xq13 1 q21 1
- X chromosome, monosomy xp22 pter
- X chromosome, monosomy xq28
- X chromosome, trisomy 26-28
- X chromosome, trisomy xp3
- X chromosome, trisomy xpter xq13
- X chromosome, trisomy xq
- X chromosome, trisomy xq25
- Yellow nail syndrome
# Organ-Specific Edema
Edema of specific organs (cerebral edema, pulmonary edema, macular edema, pedal edema) may also occur, each with different specific causes to peripheral edema, but all based on the same principles. Ascites is effectively edema within the peritoneal cavity, as pleural effusions are effectively edema in the pleural cavity. Causes of edema which are generalized to the whole body can cause edema in multiple organs and peripherally. For example, severe heart failure can cause peripheral edema, pulmonary edema, pleural effusions and ascites.
Common and usually harmless appearances of cutaneous edema are observed with mosquito bites and skin contact with certain plants (urticaria).
Edema may be found in the eyes after corrective surgery or procedures of that nature. | https://www.wikidoc.org/index.php/Edema | |
330f3faf3a7b90dab532b66b0a7809a84b06d9f9 | wikidoc | Elbow | Elbow
The elbow-joint is a ginglymus or hinge joint. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm.
The bony prominence at the very tip of the elbow is the olecranon process of the ulna.
# Movements
Two main movements are possible at the elbow:
- The hinge-like bending and straightening of the elbow (flexion and extension) happens at the articulation ("joint") between the humerus and the ulna.
- The complex action of turning the forearm over (pronation or supination) happens at the articulation between the radius and the ulna (this movement also occurs at the wrist joint).
In the anatomical position (with the forearm supine), the radius and ulna lie parallel to each other. During pronation, the ulna remains fixed, and the radius rolls around it at both the wrist and the elbow joints. In the prone position, the radius and ulna appear crossed.
Most of the force through the elbow joint is transferred between the humerus and the ulna. Very little force is transmitted between the humerus and the radius. (By contrast, at the wrist joint, most of the force is transferred between the radius and the carpus, with the ulna taking very little part in the wrist joint).
# Muscles, arteries, and nerves
The muscles in relation with the joint are:
- in front, the Brachialis
- behind, the Triceps brachii and Anconæus
- laterally, the Supinator, and the common tendon of origin of the Extensor muscles
- medially, the common tendon of origin of the Flexor muscles, and the Flexor carpi ulnaris
The arteries supplying the joint are derived from the anastomosis between the profunda and the superior and inferior ulnar collateral branches of the brachial, with the anterior, posterior, and interosseous recurrent branches of the ulnar, and the recurrent branch of the radial. These vessels form a complete anastomotic network around the joint.
The nerves of the joint are a twig from the ulnar, as it passes between the medial condyle and the olecranon; a filament from the musculocutaneous, and two from the median.
# Portions of joint
The elbow-joint comprises three different portions. All these articular surfaces are enveloped by a common synovial membrane, and the movements of the whole joint should be studied together.
The combination of the movements of flexion and extension of the forearm with those of pronation and supination of the hand, which is ensured by the two being performed at the same joint, is essential to the accuracy of the various minute movements of the hand.
The hand is only directly articulated to the distal surface of the radius, and the ulnar notch on the lower end of the radius travels around the lower end of the ulna. The ulna is excluded from the wrist-joint by the articular disk.
Thus, rotation of the head of the radius around an axis passing through the center of the radial head of the humerus imparts circular movement to the hand through a very considerable arc.
# Ligaments
The trochlea of the humerus is received into the semilunar notch of the ulna, and the capitulum of the humerus articulates with the fovea on the head of the radius. The articular surfaces are connected together by a capsule, which is thickened medially and laterally, and, to a less extent, in front and behind. These thickened portions are usually described as distinct ligaments.
The major ligaments are the ulnar collateral ligament, radial collateral ligament, and annular ligament.
# Synovial membrane
The synovial membrane is very extensive. It extends from the margin of the articular surface of the humerus, and lines the coronoid, radial and olecranon fossæ on that bone; it is reflected over the deep surface of the capsule and forms a pouch between the radial notch, the deep surface of the annular ligament, and the circumference of the head of the radius. Projecting between the radius and ulna into the cavity is a crescentic fold of synovial membrane, suggesting the division of the joint into two; one the humeroradial, the other the humeroulnar.
Between the capsule and the synovial membrane are three masses of fat:
- the largest, over the olecranon fossa, is pressed into the fossa by the Triceps brachii during the flexion;
- the second, over the coronoid fossa,
- and the third, over the radial fossa, are pressed by the Brachialis into their respective fossæ during extension.
# Terminology: "Elbow" and "Ell"
The now obsolete length unit ell relates closely to the elbow. This becomes especially visible when considering the Germanic origins of both words, Elle (ell, defined as the length of an arm from shoulder to fingertips) and Ellbogen (elbow).
It is unknown when or why the second "l" was dropped from English usage of the word, but a more precise suggested spelling would be "ellbow" for the joint and "ellbone" for the ulna, the etymological originator of both unit and joint.
# Carrying angle
When the arm is extended, with the palm facing forward or up, the bones of the humerus and forearm are not perfectly aligned. The deviation from a straight line (generally on the order of 5-10°) occurs in the direction of the thumb, and is referred to as the carrying angle (visible in the right half of the picture, right). In females the carrying angle is greater than in males.
The carrying angle can influence how objects are held by individuals - those with a more extreme carrying angle may be more likely to supinate the forearm when holding objects in the hand to keep the elbow closer to the body.
# Diagnostic Findings
## MRI
(Images courtesy of RadsWiki)
- Normal elbow: Cor MPGR
- Normal elbow: Cor IR
- Normal elbow: Cor PD
- Normal elbow: Axl PD
- Normal elbow: Sag PD
- Normal elbow: Sag IR | Elbow
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The elbow-joint is a ginglymus or hinge joint. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm.
The bony prominence at the very tip of the elbow is the olecranon process of the ulna.
# Movements
Two main movements are possible at the elbow:
- The hinge-like bending and straightening of the elbow (flexion and extension) happens at the articulation ("joint") between the humerus and the ulna.
- The complex action of turning the forearm over (pronation or supination) happens at the articulation between the radius and the ulna (this movement also occurs at the wrist joint).
In the anatomical position (with the forearm supine), the radius and ulna lie parallel to each other. During pronation, the ulna remains fixed, and the radius rolls around it at both the wrist and the elbow joints. In the prone position, the radius and ulna appear crossed.
Most of the force through the elbow joint is transferred between the humerus and the ulna. Very little force is transmitted between the humerus and the radius. (By contrast, at the wrist joint, most of the force is transferred between the radius and the carpus, with the ulna taking very little part in the wrist joint).
# Muscles, arteries, and nerves
The muscles in relation with the joint are:
- in front, the Brachialis
- behind, the Triceps brachii and Anconæus
- laterally, the Supinator, and the common tendon of origin of the Extensor muscles
- medially, the common tendon of origin of the Flexor muscles, and the Flexor carpi ulnaris
The arteries supplying the joint are derived from the anastomosis between the profunda and the superior and inferior ulnar collateral branches of the brachial, with the anterior, posterior, and interosseous recurrent branches of the ulnar, and the recurrent branch of the radial. These vessels form a complete anastomotic network around the joint.
The nerves of the joint are a twig from the ulnar, as it passes between the medial condyle and the olecranon; a filament from the musculocutaneous, and two from the median.
# Portions of joint
The elbow-joint comprises three different portions. All these articular surfaces are enveloped by a common synovial membrane, and the movements of the whole joint should be studied together.
The combination of the movements of flexion and extension of the forearm with those of pronation and supination of the hand, which is ensured by the two being performed at the same joint, is essential to the accuracy of the various minute movements of the hand.
The hand is only directly articulated to the distal surface of the radius, and the ulnar notch on the lower end of the radius travels around the lower end of the ulna. The ulna is excluded from the wrist-joint by the articular disk.
Thus, rotation of the head of the radius around an axis passing through the center of the radial head of the humerus imparts circular movement to the hand through a very considerable arc.
# Ligaments
The trochlea of the humerus is received into the semilunar notch of the ulna, and the capitulum of the humerus articulates with the fovea on the head of the radius. The articular surfaces are connected together by a capsule, which is thickened medially and laterally, and, to a less extent, in front and behind. These thickened portions are usually described as distinct ligaments.
The major ligaments are the ulnar collateral ligament, radial collateral ligament, and annular ligament.
# Synovial membrane
The synovial membrane is very extensive. It extends from the margin of the articular surface of the humerus, and lines the coronoid, radial and olecranon fossæ on that bone; it is reflected over the deep surface of the capsule and forms a pouch between the radial notch, the deep surface of the annular ligament, and the circumference of the head of the radius. Projecting between the radius and ulna into the cavity is a crescentic fold of synovial membrane, suggesting the division of the joint into two; one the humeroradial, the other the humeroulnar.
Between the capsule and the synovial membrane are three masses of fat:
- the largest, over the olecranon fossa, is pressed into the fossa by the Triceps brachii during the flexion;
- the second, over the coronoid fossa,
- and the third, over the radial fossa, are pressed by the Brachialis into their respective fossæ during extension.
# Terminology: "Elbow" and "Ell"
The now obsolete length unit ell relates closely to the elbow. This becomes especially visible when considering the Germanic origins of both words, Elle (ell, defined as the length of an arm from shoulder to fingertips) and Ellbogen (elbow).
It is unknown when or why the second "l" was dropped from English usage of the word, but a more precise suggested spelling would be "ellbow" for the joint and "ellbone" for the ulna, the etymological originator of both unit and joint.
# Carrying angle
When the arm is extended, with the palm facing forward or up, the bones of the humerus and forearm are not perfectly aligned. The deviation from a straight line (generally on the order of 5-10°) occurs in the direction of the thumb, and is referred to as the carrying angle (visible in the right half of the picture, right). In females the carrying angle is greater than in males.[1]
The carrying angle can influence how objects are held by individuals - those with a more extreme carrying angle may be more likely to supinate the forearm when holding objects in the hand to keep the elbow closer to the body.
# Diagnostic Findings
## MRI
(Images courtesy of RadsWiki)
- Normal elbow: Cor MPGR
- Normal elbow: Cor IR
- Normal elbow: Cor PD
- Normal elbow: Axl PD
- Normal elbow: Sag PD
- Normal elbow: Sag IR | https://www.wikidoc.org/index.php/Elbow | |
5f9488081ac927219bad1e3e9b1233cecc233f86 | wikidoc | Enone | Enone
An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone (MVK) or CH2=CHCOCH3.
As an example, an enone such as a chalcone can be synthesized in a Knoevenagel condensation. In the Meyer-Schuster rearrangement the starting compound is a propargyl alcohol.
An enone is a reactant in the Nazarov cyclization reaction and in the Rauhut-Currier reaction (dimerization).
# Related compounds
Enone is not to be confused with Ketene (R2C=C=O). An enamine is a cousin of an enone, with the carbonyl replaced by an amine group. An enal is the corresponding α,β-unsaturated aldehyde | Enone
An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone (MVK) or CH2=CHCOCH3.
As an example, an enone such as a chalcone can be synthesized in a Knoevenagel condensation. In the Meyer-Schuster rearrangement the starting compound is a propargyl alcohol.
An enone is a reactant in the Nazarov cyclization reaction and in the Rauhut-Currier reaction (dimerization).
# Related compounds
Enone is not to be confused with Ketene (R2C=C=O). An enamine is a cousin of an enone, with the carbonyl replaced by an amine group. An enal is the corresponding α,β-unsaturated aldehyde
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Enone | |
3f3db26392a3c27079d2ed090afdd9c68399e3e6 | wikidoc | Eosin | Eosin
# Overview
Eosin is a fluorescent acidic / negative compound that binds to and forms salts with basic, or eosinophilic, compounds containing positive charges (such as proteins that are basic / positive due to the presence of amino acid residues such as Arginine and Lysine) and stains them dark red or pink as a result of the actions of bromine on fluorescein. In addition to staining proteins in the cytoplasm, it can be used to stain collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic.
# Etymology
The name Eosin comes from Eos, the Ancient Greek word for 'dawn' and the name of the Ancient Greek goddess of the dawn.
# Variants
There are actually two very closely related compounds commonly referred to as eosin. Most often used is Eosin Y (also known as eosin Y ws, eosin yellowish, Acid Red 87, C.I. 45380, bromoeosine, bromofluoresceic acid, D&C Red No. 22); it has a very slightly yellowish cast. The other eosin compound is eosin B (eosin bluish, Acid Red 91, C.I. 45400, Saffrosine, Eosin Scarlet, or imperial red); it has a very faint bluish cast. The two dyes are interchangeable, and the use of one or the other is a matter of preference and tradition.
Eosin Y is a tetrabromo derivative of fluorescein. Eosin B is a dibromo dinitro derivative of fluorescein.
# Use in histology
Eosin is most often used as a counterstain to hematoxylin in H&E (haematoxylin and eosin) staining. H&E staining is one of the most commonly used techniques in histology. Tissue stained with haematoxylin and eosin shows cytoplasm stained pink-orange and nuclei stained darkly, either blue or purple. Eosin also stains red blood cells intensely red.
For staining, eosin Y is typically used in concentrations of 1 to 5 percent weight by volume, dissolved in water or ethanol. For prevention of mold growth in aqueous solutions, thymol is sometimes added. A small concentration (0.5 percent) of acetic acid usually gives a deeper red stain to the tissue.
It is listed as an IARC class 3 carcinogen. | Eosin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Eosin is a fluorescent acidic / negative compound that binds to and forms salts with basic, or eosinophilic, compounds containing positive charges (such as proteins that are basic / positive due to the presence of amino acid residues such as Arginine and Lysine) and stains them dark red or pink as a result of the actions of bromine on fluorescein. In addition to staining proteins in the cytoplasm, it can be used to stain collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic.
# Etymology
The name Eosin comes from Eos, the Ancient Greek word for 'dawn' and the name of the Ancient Greek goddess of the dawn.
# Variants
There are actually two very closely related compounds commonly referred to as eosin. Most often used is Eosin Y (also known as eosin Y ws, eosin yellowish, Acid Red 87, C.I. 45380, bromoeosine, bromofluoresceic acid, D&C Red No. 22); it has a very slightly yellowish cast. The other eosin compound is eosin B (eosin bluish, Acid Red 91, C.I. 45400, Saffrosine, Eosin Scarlet, or imperial red); it has a very faint bluish cast. The two dyes are interchangeable, and the use of one or the other is a matter of preference and tradition.
Eosin Y is a tetrabromo derivative of fluorescein.[1] Eosin B is a dibromo dinitro derivative of fluorescein.[2]
# Use in histology
Eosin is most often used as a counterstain to hematoxylin in H&E (haematoxylin and eosin) staining. H&E staining is one of the most commonly used techniques in histology. Tissue stained with haematoxylin and eosin shows cytoplasm stained pink-orange and nuclei stained darkly, either blue or purple. Eosin also stains red blood cells intensely red.
For staining, eosin Y is typically used in concentrations of 1 to 5 percent weight by volume, dissolved in water or ethanol.[3] For prevention of mold growth in aqueous solutions, thymol is sometimes added.[4] A small concentration (0.5 percent) of acetic acid usually gives a deeper red stain to the tissue.
It is listed as an IARC class 3 carcinogen. | https://www.wikidoc.org/index.php/Eosin | |
42de27fd844ed62bc1315128b5389ff586c3b150 | wikidoc | Ester | Ester
# Overview
Esters are a class of chemical compounds and functional groups. Esters consist of an inorganic or organic acid in which at least one -OH (hydroxy) group is replaced by an -O-alkyl (alkoxy) group. The most common type of esters are carboxylic acid esters (R1-C(=O)-O-R2), other esters include phosphoric acid, sulfuric acid, nitric acid, and boric acid esters. Volatile esters often have a smell and are found in perfumes, essential oils, and pheromones and give many fruits their scent. Ethyl acetate and methyl acetate are important solvents, fatty acid esters form fat and lipids, and polyesters are important plastics. Cyclic esters are called lactones. The name "ester" is derived from the German Essig-Äther (literally:vinegar ether), an old name for ethyl acetate. Esters can be synthesized in a condensation reaction between an acid and an alcohol in a reaction known as esterification.
An ester is an often fragrant organic or partially organic compound formed by the reaction between an acid (including amino acids) and an alcohol (alkyl, R) or aromatic alcohol (aryl, R') (including a more basic amino acid) with the elimination of water. For examples,
acetic acid + an alcohol acetic ester + water,
CH3COOH + ROH CH3COOR + H2O,
-r
CH3COO- + H+ + R+ + OH- CH3COOR + H2O;
with one amino acid acting as a base:
formic acid + L-methionine N-formyl-L-methionine (an amino acid) + H2O,
-r
two amino acids:
Cys + Gly Cys-Gly + H2O,
forming a dipeptide. A reaction between an inorganic hydroxide (e.g. sodium hydroxide) and an organic acid (e.g. acetic acid) produces a salt of acetic acid (sodium acetate). A compound is an ester when the hydroxide donor is organic and a salt when the hydroxide donor is inorganic. Hence, a carbonate can be thought of as a salt or an ester of carbonic acid.
# Nomenclature
An ester is named according to the two parts that make it up: the part from the alcohol and the part from the acid (in that order), for example ethyl sulfuric acid ester.
Since most esters are derived from carboxylic acids, a specific nomenclature is used for them. For esters derived from the simplest carboxylic acids, the traditional name for the acid constituent is generally retained, e.g. formate, acetate, propionate, butyrate. For esters from more complex carboxylic acids, the systematic name for the acid is used, followed by the suffix -oate. For example, methyl formate is the ester of methanol and methanoic acid (formic acid): the simplest ester. It could also be called methyl methanoate.
Esters of aromatic acids are also encountered, including benzoates such as methyl benzoate, and phthalates, with substitution allowed in the name.
The chemical formulas of esters are typically in the format of R-COO-R', in which the alkyl group (R') is mentioned first, and the carboxylate group (R) is mentioned last. For example the ester: butyl ethanoate - derived from butanol (C4H9OH) and ethanoic acid (CH3COOH) would have the formula: CH3COOC4H9. Sometimes the formula may be 'broken up' to show the structure, in this case: CH3COO3CH3.
## Oligoesters
The acetic ester, N-formyl-L-methionine, and the dipeptide examples above are each monoesters.
The term oligoester refers to any ester polymer containing a small number of component esters. As an example, chemically, fats are generally diesters of glycerol and fatty acids. Most of the mass of a fat/triester is in the 3 fatty acids.
Tetraesters can be found as part of membrane-spanning lipids in bacteria from the order Thermotogales.
Pentaesters have been used as indicators or in isotopic labelling compounds.
Hexaesters such as calixarene have been used in optodes as sensing devices for optical determination of potassium ion concentration in pH-buffer solutions.
Heptaesters have been found in Euphorbia species.
Octaesters can be inclusions of ester moieties within cavitand cavities.
The number of esters can be up to ten as in oligo-(R)-3-hydroxybutyrate.
# Physical properties
Esters participate in hydrogen bonds as hydrogen-bond acceptors, but cannot act as hydrogen-bond donors, unlike their parent alcohols. This ability to participate in hydrogen bonding makes them more water-soluble than their parent hydrocarbons. However, the limitations on their hydrogen bonding also make them more hydrophobic than either their parent alcohols or parent acids. Their lack of hydrogen-bond-donating ability means that ester molecules cannot hydrogen-bond to each other, which makes esters generally more volatile than a carboxylic acid of similar molecular weight. This property makes them very useful in organic analytical chemistry: unknown organic acids with low volatility can often be esterified into a volatile ester, which can then be analyzed using gas chromatography, gas liquid chromatography, or mass spectrometry.
Many esters have distinctive odors, which has led to their use as artificial flavorings and fragrances. For example:
# Ester synthesis
"Esterification" (condensation of an alcohol and an acid) is not the only way to synthesize an ester. Esters can be prepared in the laboratory in a number of other ways:
- by transesterifications between other esters
- by Dieckmann condensation or Claisen condensation of esters carrying acidic α-protons
- by Favorskii rearrangement of α-haloketones in presence of base
- by nucleophilic displacement of alkyl halides with carboxylic acid salts
- by Baeyer-Villiger oxidation of ketones with peroxides
- by Pinner reaction of nitriles with an alcohol
# Ester reactions
Esters react in a number of ways:
- Esters may undergo hydrolysis - the breakdown of an ester by water. This process can be catalyzed both by acids and bases. The base-catalyzed process is called saponification. The hydrolysis yields an alcohol and a carboxylic acid or its carboxylate salt.
- Esters also react if heated with primary or secondary amines, producing amides.
- Phenyl esters react to hydroxyarylketones in the Fries rearrangement.
- Di-esters such as diethyl malonate react as nucleophile with alkyl halides in the malonic ester synthesis after deprotonation.
- Specific esters are functionalized with an α-hydroxyl group in the Chan rearrangement
- Esters are converted to isocyanates through intermediate hydroxamic acids in the Lossen rearrangement.
- Esters with β-hydrogen atoms can be converted to alkenes in ester pyrolysis | Ester
Editor-In-Chief: Henry A. Hoff
# Overview
Esters are a class of chemical compounds and functional groups. Esters consist of an inorganic or organic acid in which at least one -OH (hydroxy) group is replaced by an -O-alkyl (alkoxy) group. The most common type of esters are carboxylic acid esters (R1-C(=O)-O-R2), other esters include phosphoric acid, sulfuric acid, nitric acid, and boric acid esters. Volatile esters often have a smell and are found in perfumes, essential oils, and pheromones and give many fruits their scent. Ethyl acetate and methyl acetate are important solvents, fatty acid esters form fat and lipids, and polyesters are important plastics. Cyclic esters are called lactones. The name "ester" is derived from the German Essig-Äther (literally:vinegar ether), an old name for ethyl acetate. Esters can be synthesized in a condensation reaction between an acid and an alcohol in a reaction known as esterification.
An ester is an often fragrant organic or partially organic compound formed by the reaction between an acid (including amino acids) and an alcohol (alkyl, R) or aromatic alcohol (aryl, R') (including a more basic amino acid) with the elimination of water. For examples,
acetic acid + an alcohol <=> acetic ester + water,
CH3COOH + ROH <=> CH3COOR + H2O,
or
CH3COO- + H+ + R+ + OH- <=> CH3COOR + H2O;
with one amino acid acting as a base:
formic acid + L-methionine <=> N-formyl-L-methionine (an amino acid) + H2O,
or
two amino acids:
Cys + Gly <=> Cys-Gly + H2O,
forming a dipeptide. A reaction between an inorganic hydroxide (e.g. sodium hydroxide) and an organic acid (e.g. acetic acid) produces a salt of acetic acid (sodium acetate). A compound is an ester when the hydroxide donor is organic and a salt when the hydroxide donor is inorganic. Hence, a carbonate can be thought of as a salt or an ester of carbonic acid.
# Nomenclature
An ester is named according to the two parts that make it up: the part from the alcohol and the part from the acid (in that order), for example ethyl sulfuric acid ester.
Since most esters are derived from carboxylic acids, a specific nomenclature is used for them. For esters derived from the simplest carboxylic acids, the traditional name for the acid constituent is generally retained, e.g. formate, acetate, propionate, butyrate.[1] For esters from more complex carboxylic acids, the systematic name for the acid is used, followed by the suffix -oate. For example, methyl formate is the ester of methanol and methanoic acid (formic acid): the simplest ester. It could also be called methyl methanoate.[2]
Esters of aromatic acids are also encountered, including benzoates such as methyl benzoate, and phthalates, with substitution allowed in the name.
The chemical formulas of esters are typically in the format of R-COO-R', in which the alkyl group (R') is mentioned first, and the carboxylate group (R) is mentioned last.[3] For example the ester: butyl ethanoate - derived from butanol (C4H9OH) and ethanoic acid (CH3COOH) would have the formula: CH3COOC4H9. Sometimes the formula may be 'broken up' to show the structure, in this case: CH3COO[CH2]3CH3.
## Oligoesters
The acetic ester, N-formyl-L-methionine, and the dipeptide examples above are each monoesters.
The term oligoester refers to any ester polymer containing a small number of component esters. As an example, chemically, fats are generally diesters of glycerol and fatty acids. Most of the mass of a fat/triester is in the 3 fatty acids.
Tetraesters can be found as part of membrane-spanning lipids in bacteria from the order Thermotogales.[4]
Pentaesters have been used as indicators[5] or in isotopic labelling[6] compounds.
Hexaesters such as calix[6]arene have been used in optodes as sensing devices for optical determination of potassium ion concentration in pH-buffer solutions.[7]
Heptaesters have been found in Euphorbia species.[8]
Octaesters can be inclusions of ester moieties within cavitand cavities.[9]
The number of esters can be up to ten as in oligo-(R)-3-hydroxybutyrate[10].
# Physical properties
Esters participate in hydrogen bonds as hydrogen-bond acceptors, but cannot act as hydrogen-bond donors, unlike their parent alcohols. This ability to participate in hydrogen bonding makes them more water-soluble than their parent hydrocarbons. However, the limitations on their hydrogen bonding also make them more hydrophobic than either their parent alcohols or parent acids. Their lack of hydrogen-bond-donating ability means that ester molecules cannot hydrogen-bond to each other, which makes esters generally more volatile than a carboxylic acid of similar molecular weight. This property makes them very useful in organic analytical chemistry: unknown organic acids with low volatility can often be esterified into a volatile ester, which can then be analyzed using gas chromatography, gas liquid chromatography, or mass spectrometry.
Many esters have distinctive odors, which has led to their use as artificial flavorings and fragrances. For example:
# Ester synthesis
"Esterification" (condensation of an alcohol and an acid) is not the only way to synthesize an ester. Esters can be prepared in the laboratory in a number of other ways:
- by transesterifications between other esters
- by Dieckmann condensation or Claisen condensation of esters carrying acidic α-protons
- by Favorskii rearrangement of α-haloketones in presence of base
- by nucleophilic displacement of alkyl halides with carboxylic acid salts
- by Baeyer-Villiger oxidation of ketones with peroxides
- by Pinner reaction of nitriles with an alcohol
# Ester reactions
Esters react in a number of ways:
- Esters may undergo hydrolysis - the breakdown of an ester by water. This process can be catalyzed both by acids and bases. The base-catalyzed process is called saponification. The hydrolysis yields an alcohol and a carboxylic acid or its carboxylate salt.
- Esters also react if heated with primary or secondary amines, producing amides.
- Phenyl esters react to hydroxyarylketones in the Fries rearrangement.
- Di-esters such as diethyl malonate react as nucleophile with alkyl halides in the malonic ester synthesis after deprotonation.
- Specific esters are functionalized with an α-hydroxyl group in the Chan rearrangement
- Esters are converted to isocyanates through intermediate hydroxamic acids in the Lossen rearrangement.
- Esters with β-hydrogen atoms can be converted to alkenes in ester pyrolysis
# External links
- An introduction to esters
- Molecule of the month: Ethyl acetate and other esters
- Making an Ester A simple guide to naming and making esters, as well as the chemistry behind it. | https://www.wikidoc.org/index.php/Ester | |
e0e55d808bbe0e4314eecae0c46689dc0f8a243b | wikidoc | Ether | Ether
# Overview
Ether is the general name for a class of chemical compounds which contain an ether group — an oxygen atom connected to two (substituted) alkyl or aryl groups — of general formula R – O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether" (ethoxyethane, CH3-CH2-O-CH2-CH3).
# Physical properties
Ether molecules cannot form hydrogen bonds among each other, resulting in a relatively low boiling point comparable to that of the analogous alcohols. However, the differences in the boiling points of the ethers and their isometric alcohols become smaller as the carbon chains become longer, as the hydrophobic nature of the carbon chain becomes more predominant over the presence of hydrogen bonding.
Ethers are slightly polar as the C - O - C bond angle in the functional group is about 110 degrees, and the C - O dipole does not cancel out. Ethers are more polar than alkenes but not as polar as alcohols, esters or amides of comparable structure. However, the presence of two lone pairs of electrons on the oxygen atoms makes hydrogen bonding with water molecules possible, causing the solubility of alcohols (for instance, butan-1-ol) and ethers (ethoxyethane) to be quite dissimilar.
Cyclic ethers such as tetrahydrofuran and 1,4-dioxane are totally miscible in water because of the more exposed oxygen atom for hydrogen bonding as compared to aliphatic ethers.
Ethers can act as Lewis bases. For instance, diethyl ether forms a complex with boron compounds, such as boron trifluoride diethyl etherate (BF3.OEt2). Ethers also coordinate to magnesium in Grignard reagents (RMgBr).
# Nomenclature
In the IUPAC nomenclature system, ethers are named using the general formula "alkoxyalkane", for example CH3-CH2-O-CH3 is methoxyethane. If the ether is part of a more complex molecule, it is described as an alkoxy substituent, so -OCH3 would be considered a "methoxy-" group. The simpler alkyl radical is written in front, so CH3-O-CH2CH3 would be given as methoxy(CH3)ethane(CH2CH3). The nomenclature of describing the two alkyl groups and appending "ether", e.g. "ethyl methyl ether" in the example above, is a trivial usage.
# Similar structures
Ethers are not to be confused with the following classes of compounds with the same general structure R-O-R.
- Aromatic compounds like furan where the oxygen is part of the aromatic system.
- Compounds where one of the carbon atoms next to the oxygen is connected to oxygen, nitrogen, or sulfur:
Esters R-C(=O)-O-R
Acetals R-CH(-O-R)-O-R
Aminals R-CH(-NH-R)-O-R
Anhydrides R-C(=O)-O-C(=O)-R
- Esters R-C(=O)-O-R
- Acetals R-CH(-O-R)-O-R
- Aminals R-CH(-NH-R)-O-R
- Anhydrides R-C(=O)-O-C(=O)-R
# Primary, secondary, and tertiary ethers
The terms "primary ether", "secondary ether", and "tertiary ether" are occasionally used and refer to the carbon atom next to the ether oxygen. In a primary ether this carbon is connected to only one other carbon as in diethyl ether CH3-CH2-O-CH2-CH3. An example of a secondary ether is diisopropyl ether (CH3)2CH-O-CH(CH3)2 and that of a tertiary ether is di-tert-butyl ether (CH3)3C-O-C(CH3)3.
Dimethyl ether, a primary, a secondary, and a tertiary ether.
# Polyethers
Polyethers are compounds with more than one ether group. While the term generally refers to polymers like polyethylene glycol and polypropylene glycol, low molecular compounds such as the crown ethers may sometimes be included.
# Organic reactions
## Synthesis
Ethers can be prepared in the laboratory in several different ways.
- Intermolecular Dehydration of alcohols:
- Nucleophilic displacement of alkyl halides by alkoxides
- Nucleophilic Displacement of Alkyl halides by phenoxides
- Electrophilic addition of alcohols to alkenes.
Cyclic ethers which are also known as epoxides can be prepared:
- By the oxidation of alkenes with a peroxyacid such as m-CPBA.
- By the base intramolecular nuclephilic substitution of a halohydrin.
## Reactions
Ethers in general are of very low chemical reactivity. Organic reactions are:
- Hydrolysis.
- Nucleophilic displacement.
- Peroxide formation.
# Important ethers | Ether
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ether is the general name for a class of chemical compounds which contain an ether group — an oxygen atom connected to two (substituted) alkyl or aryl groups — of general formula R – O–R'.[1] A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether" (ethoxyethane, CH3-CH2-O-CH2-CH3).
# Physical properties
Ether molecules cannot form hydrogen bonds among each other, resulting in a relatively low boiling point comparable to that of the analogous alcohols. However, the differences in the boiling points of the ethers and their isometric alcohols become smaller as the carbon chains become longer, as the hydrophobic nature of the carbon chain becomes more predominant over the presence of hydrogen bonding.
Ethers are slightly polar as the C - O - C bond angle in the functional group is about 110 degrees, and the C - O dipole does not cancel out. Ethers are more polar than alkenes but not as polar as alcohols, esters or amides of comparable structure. However, the presence of two lone pairs of electrons on the oxygen atoms makes hydrogen bonding with water molecules possible, causing the solubility of alcohols (for instance, butan-1-ol) and ethers (ethoxyethane) to be quite dissimilar.
Cyclic ethers such as tetrahydrofuran and 1,4-dioxane are totally miscible in water because of the more exposed oxygen atom for hydrogen bonding as compared to aliphatic ethers.
Ethers can act as Lewis bases. For instance, diethyl ether forms a complex with boron compounds, such as boron trifluoride diethyl etherate (BF3.OEt2). Ethers also coordinate to magnesium in Grignard reagents (RMgBr).
# Nomenclature
In the IUPAC nomenclature system, ethers are named using the general formula "alkoxyalkane", for example CH3-CH2-O-CH3 is methoxyethane. If the ether is part of a more complex molecule, it is described as an alkoxy substituent, so -OCH3 would be considered a "methoxy-" group. The simpler alkyl radical is written in front, so CH3-O-CH2CH3 would be given as methoxy(CH3)ethane(CH2CH3). The nomenclature of describing the two alkyl groups and appending "ether", e.g. "ethyl methyl ether" in the example above, is a trivial usage.
# Similar structures
Ethers are not to be confused with the following classes of compounds with the same general structure R-O-R.
- Aromatic compounds like furan where the oxygen is part of the aromatic system.
- Compounds where one of the carbon atoms next to the oxygen is connected to oxygen, nitrogen, or sulfur:
Esters R-C(=O)-O-R
Acetals R-CH(-O-R)-O-R
Aminals R-CH(-NH-R)-O-R
Anhydrides R-C(=O)-O-C(=O)-R
- Esters R-C(=O)-O-R
- Acetals R-CH(-O-R)-O-R
- Aminals R-CH(-NH-R)-O-R
- Anhydrides R-C(=O)-O-C(=O)-R
# Primary, secondary, and tertiary ethers
The terms "primary ether", "secondary ether", and "tertiary ether" are occasionally used and refer to the carbon atom next to the ether oxygen. In a primary ether this carbon is connected to only one other carbon as in diethyl ether CH3-CH2-O-CH2-CH3. An example of a secondary ether is diisopropyl ether (CH3)2CH-O-CH(CH3)2 and that of a tertiary ether is di-tert-butyl ether (CH3)3C-O-C(CH3)3.
Dimethyl ether, a primary, a secondary, and a tertiary ether.
# Polyethers
Polyethers are compounds with more than one ether group. While the term generally refers to polymers like polyethylene glycol and polypropylene glycol, low molecular compounds such as the crown ethers may sometimes be included.
# Organic reactions
## Synthesis
Ethers can be prepared in the laboratory in several different ways.
- Intermolecular Dehydration of alcohols:
- Nucleophilic displacement of alkyl halides by alkoxides
- Nucleophilic Displacement of Alkyl halides by phenoxides
- Electrophilic addition of alcohols to alkenes.
Cyclic ethers which are also known as epoxides can be prepared:
- By the oxidation of alkenes with a peroxyacid such as m-CPBA.
- By the base intramolecular nuclephilic substitution of a halohydrin.
## Reactions
Ethers in general are of very low chemical reactivity. Organic reactions are:
- Hydrolysis.
- Nucleophilic displacement.
- Peroxide formation.
# Important ethers | https://www.wikidoc.org/index.php/Ether | |
b5727c857b0c92608f53fc8e3e0cd4b64dd18518 | wikidoc | Etrog | Etrog
Etrog, ethrog or esrog are all different pronounciations of the word אֶתְרוֹג, which is the most common Hebrew name for the citron or Citrus Medica.
It is one of the four species used in a waving ritual during the Jewish holiday of Sukkot. The other species are the lulav (date palm frond), hadass (myrtle bough), and aravah (willow branch).
Leviticus 23:40 refers to the etrog as pri eitz hadar (פְּרִי עֵץ הָדָר), which literally means, "a fruit of the beautiful tree." Modern Hebrew translates hadar as "citrus" in connection with the rabbinical definition of the etrog as the fruit referred to by the Torah. However, the commentary of Nahmanides states that the word "Hadar" was the original Hebrew word for the citron solely. The name was later replaced by the word Etrog meaning love and attraction in Talmudical Aramaic, which was initially adapted in Babylonia after destruction of the First Temple. The Arabic name for the fruit itranj اترنج is also cognate with the Hebrew; the itranj is mentioned favorably in the Hadith. Similar names like "turunj" etc. are found in different languages.
The etrog is typically grown from cuttings that are two to four years old; the tree begins to bear fruit when it is around three years old. If the tree germinates from seeds, it will not fruit until about seven years. Besides, there might be some genetic changes to the tree and its fruits, whenever seed propagation is used.
The fruit is ready to harvest when it reaches six inches in length, for the best marketing, and is typically picked off the tree while it is still green. Its inner rind is much wider than the pulp. The outer surface is somewhat hard and fragrant; the pulp should be dry, and may vary from sweet to strongly acidic, depending on the variety.
According to Halakha, the etrog used in the mitzvah of the four species must be largely unblemished and of a nice form and shape. Extra special care is needed to cut around the leaves and thorns which may scratch the fruit. Also, the bearing branch should be curved in order to get the fruit growing in a straight downward position. Otherwise, the fruit will be forced to make the curve on its own body when turned downwards because of its increasing weight.
An etrog that still has a pitom at its tip (a pitom is composed of a style called in Hebrew "dad", and the stigma which is called shoshanta, and it usually falls off during the growing process) is considered especially valuable. However, those varieties that shed their pitom during growth, just like other citrus species, are also kosher. Even when the stigma break off post harvest, it could still be considered kosher as long as part of the style is remained attached.
There is a custom amongst some Hasidim to take an etrog with a gartel (an hourglass-like waist running around the middle). Talmudic sources do not comment on this.
The marketability of the etrog depends on its form, cleanliness, and the condition of the apex of the fruit. According to some opinions, it shouldn’t be taken even from the cuttings of a grafted tree.
The primary mitzvah of using the etrog is to take it along with the rest of the four species before and during the Hallel prayer. After the holiday, some people boil the peel of the etrog to make jam, fruit cake, and candied fruit. Some people also slice the etrog thinly and add it to a bottle of vodka in order to make an interesting libation. There is an Ashkenazic tradition to eat the etrog in the sacred day Tu B'Shevat, in order to maximize the variety of fruits eaten on that holiday to praise the Creator of the trees, and to establish a prayer to God to provide a nice clean non-grafted nor hybridized etrog for the next Sukkot.
# Confusion
There is some confusion in the secular world, because the specific variety originating from the Corfu Island, and nowadays the leading cultivar in Israel, is the only one to be called etrog in order to be used for the Jewish ritual. This was generally influenced by the botanical name of the variety, which is called variety etrog.
In fact, the use of the Corfu variety was disputed during centuries and so were their descendants in Israel. In any case, many varieties were traditionally used for the Feast of Tabernacles, and may even be rather recommended.
# DNA studies
A general DNA study was arranged by the world known researcher of the etrog, Pro. E.E. Goldschmidt & colleagues, who positively testified 12 known accessions of citron for purity and being genetically related. This is all about genotypeic classification which could be changed by breeding for e.g. out cross pollination etc., not about grafting which is not suspected to change any genes. (The above Greek citron was not included in that study).
A brief documentation of this study could be found at the Global Citrus Germplasm Network.
# The etrog in popular culture
The purchase of a beautiful (and expensive) etrog forms an important plot point in the film Ushpizin. | Etrog
Etrog, ethrog or esrog are all different pronounciations of the word אֶתְרוֹג, which is the most common Hebrew name for the citron or Citrus Medica.
It is one of the four species used in a waving ritual during the Jewish holiday of Sukkot. The other species are the lulav (date palm frond), hadass (myrtle bough), and aravah (willow branch).
Leviticus 23:40 refers to the etrog as pri eitz hadar (פְּרִי עֵץ הָדָר), which literally means, "a fruit of the beautiful tree." Modern Hebrew translates hadar as "citrus" in connection with the rabbinical definition of the etrog as the fruit referred to by the Torah. However, the commentary of Nahmanides states that the word "Hadar" was the original Hebrew word for the citron solely. The name was later replaced by the word Etrog meaning love and attraction in Talmudical Aramaic, which was initially adapted in Babylonia after destruction of the First Temple. The Arabic name for the fruit itranj اترنج is also cognate with the Hebrew; the itranj is mentioned favorably in the Hadith. Similar names like "turunj" etc. are found in different languages.
The etrog is typically grown from cuttings that are two to four years old; the tree begins to bear fruit when it is around three years old.[1] If the tree germinates from seeds, it will not fruit until about seven years. Besides, there might be some genetic changes to the tree and its fruits, whenever seed propagation is used.[2]
The fruit is ready to harvest when it reaches six inches in length, for the best marketing, and is typically picked off the tree while it is still green. Its inner rind is much wider than the pulp. The outer surface is somewhat hard and fragrant; the pulp should be dry, and may vary from sweet to strongly acidic, depending on the variety.
According to Halakha, the etrog used in the mitzvah of the four species must be largely unblemished and of a nice form and shape. Extra special care is needed to cut around the leaves and thorns which may scratch the fruit. Also, the bearing branch should be curved in order to get the fruit growing in a straight downward position. Otherwise, the fruit will be forced to make the curve on its own body when turned downwards because of its increasing weight.
An etrog that still has a pitom at its tip (a pitom is composed of a style called in Hebrew "dad", and the stigma which is called shoshanta, and it usually falls off during the growing process) is considered especially valuable. However, those varieties that shed their pitom during growth, just like other citrus species, are also kosher. Even when the stigma break off post harvest, it could still be considered kosher as long as part of the style is remained attached.
There is a custom amongst some Hasidim to take an etrog with a gartel (an hourglass-like waist running around the middle). Talmudic sources do not comment on this.
The marketability of the etrog depends on its form, cleanliness, and the condition of the apex of the fruit. According to some opinions, it shouldn’t be taken even from the cuttings of a grafted tree.
The primary mitzvah of using the etrog is to take it along with the rest of the four species before and during the Hallel prayer. After the holiday, some people boil the peel of the etrog to make jam, fruit cake, and candied fruit. Some people also slice the etrog thinly and add it to a bottle of vodka in order to make an interesting libation. There is an Ashkenazic tradition to eat the etrog in the sacred day Tu B'Shevat, in order to maximize the variety of fruits eaten on that holiday to praise the Creator of the trees, and to establish a prayer to God to provide a nice clean non-grafted nor hybridized etrog for the next Sukkot.
# Confusion
There is some confusion in the secular world, because the specific variety originating from the Corfu Island, and nowadays the leading cultivar in Israel,[3] is the only one to be called etrog in order to be used for the Jewish ritual. This was generally influenced by the botanical name of the variety, which is called variety etrog.
In fact, the use of the Corfu variety was disputed during centuries and so were their descendants in Israel. In any case, many varieties were traditionally used for the Feast of Tabernacles, and may even be rather recommended.
# DNA studies
A general DNA study was arranged by the world known researcher of the etrog, Pro. E.E. Goldschmidt & colleagues, who positively testified 12 known accessions of citron for purity and being genetically related. This is all about genotypeic classification which could be changed by breeding for e.g. out cross pollination etc., not about grafting which is not suspected to change any genes. (The above Greek citron was not included in that study).
A brief documentation of this study could be found at the Global Citrus Germplasm Network.
# The etrog in popular culture
The purchase of a beautiful (and expensive) etrog forms an important plot point in the film Ushpizin. | https://www.wikidoc.org/index.php/Etrog | |
68f5d329cc6a6d8bafcfeeceb34adc9fa924928d | wikidoc | Ezrin | Ezrin
Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the EZR gene.
# Structure
The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contain a ERM domain.
# Function
The cytoplasmic peripheral protein encoded by this gene can be phosphorylated by protein-tyrosine kinase in microvilli and is a member of the ERM protein family. This protein serves as a linker between plasma membrane and actin cytoskeleton. It plays a key role in cell surface structure adhesion, migration, and organization.
The N-terminal domain (also called FERM domain) binds sodium-hydrogen exchanger regulatory factor (NHERF) protein (involving long-range allostery). This binding can happen only when ezrin is in its active state. The activation of ezrin occurs in synergism of the two factors: 1) binding of the N-terminal domain to phosphatidylinositol(4,5)bis-phosphate (PIP2) and 2) phosphorylation of threonine T567 in the C-terminal domain. Binding to actin filaments (via C-terminal) and to membrane proteins (via N-terminal) stabilizes the protein's conformation in its active mode. The membrane proteins like CD44 and ICAM-2 are indirect binding partners of ezrin, while EBP50 (ERM binding protein 50) can associate with ezrin directly.
# Interactions
VIL2 has been shown to interact with:
- CD43,
- FASLG,
- ICAM-1,
- ICAM2,
- ICAM3,
- Merlin,
- MSN,
- PIK3R1,
- PALLD
- S100P,
- SDC2,
- SLC9A3R1,
- SLC9A3R2, and
- VCAM-1. | Ezrin
Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the EZR gene.[1]
# Structure
The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contain a ERM domain.
# Function
The cytoplasmic peripheral protein encoded by this gene can be phosphorylated by protein-tyrosine kinase in microvilli and is a member of the ERM protein family. This protein serves as a linker between plasma membrane and actin cytoskeleton. It plays a key role in cell surface structure adhesion, migration, and organization.[2]
The N-terminal domain (also called FERM domain) binds sodium-hydrogen exchanger regulatory factor (NHERF) protein (involving long-range allostery).[3] This binding can happen only when ezrin is in its active state. The activation of ezrin occurs in synergism of the two factors: 1) binding of the N-terminal domain to phosphatidylinositol(4,5)bis-phosphate (PIP2) and 2) phosphorylation of threonine T567 in the C-terminal domain.[4][5] Binding to actin filaments (via C-terminal) and to membrane proteins (via N-terminal) stabilizes the protein's conformation in its active mode. The membrane proteins like CD44 and ICAM-2 are indirect binding partners of ezrin, while EBP50 (ERM binding protein 50) can associate with ezrin directly.[6]
# Interactions
VIL2 has been shown to interact with:
- CD43,[7]
- FASLG,[8][9]
- ICAM-1,[10]
- ICAM2,[10]
- ICAM3,[10][11]
- Merlin,[12]
- MSN,[8][13][14]
- PIK3R1,[15]
- PALLD[16]
- S100P,[17]
- SDC2,[18]
- SLC9A3R1,[19][20]
- SLC9A3R2,[21][22] and
- VCAM-1.[23] | https://www.wikidoc.org/index.php/Ezrin | |
1cdad83fa2d5dcd7620523023725a1e62bf80d71 | wikidoc | FABP1 | FABP1
FABP1 is a human gene coding for the protein product FABP1 (Fatty Acid-Binding Protein 1). It is also frequently known as liver-type fatty acid-binding protein (LFABP).
FABP1 is primarily expressed in the liver where it is involved in the binding, transport and metabolism of long-chain fatty acids (LCFAs), endocannabinoids, phytocannabinoids (and less so for synthetic cannabinoid receptor (CBR) agonists and antagonists) and other hydrophobic molecules. Altered expression of the protein has been linked to metabolic conditions including obesity.
# Discovery
The fatty acid-binding proteins (FABPs) were initially discovered in 1972 with experiments using 14C labelled oleate to identify the presence of a soluble fatty acid carrier in the enterocyte responsible for intestinal absorption of (LCFAs). Since then, ten members of the FABP family have been identified on the human genome. Nine are well established (FABP1-9) with a recently discovered tenth (FABP12). Each FABP corresponds to particular organs/tissue around the body where they play a role in fatty-acid uptake, transport and metabolism.
# Gene location
The human FABP1 gene is located on the short (p) arm of chromosome 2 from base pair 88,122,982 to base pair 88,128,131.
# Protein structure
FABP1 has been found to have a unique structure compared to other members of the FABP family, allowing it to bind multiple ligands simultaneously. It also has a larger solvent-accessible core compared to other FABPs allowing more diverse substrate binding. The “portal hypothesis” has been proposed to explain the binding process of FABPs. It has been suggested that fatty acids enter the solvent-accessible area of the protein through a dynamic region consisting of α-helix II and turns between βC-βD and βE-βF loops. The fatty acid is then bound in the protein cavity for transport.
# Function
The FABPs are a family of small, highly conserved cytoplasmic proteins involved in the binding of LCFAs. FABP1 is expressed abundantly in the human liver where it accounts for 7-11% of the total cytosolic protein, and can also be found in the intestine, kidney, pancreas stomach and lung. FABP1 is unique in the wider range of other hydrophobic ligands it can bind including bilirubin, monoglycerides, bile acids and fatty acyl CoA. It has been proposed that FABP1 plays a significant role in preventing cytotoxicity by binding heme, fatty acids and other molecules that are potentially toxic when unbound.
# Mutations
On exon 3 of the human FABP1 gene an Ala to Thr substitution has been identified leading to a T94A missense mutation. Carriers of this particular single nucleotide polymorphism (SNP) exhibit higher baseline plasma-free fatty acid levels, lower BMI and a smaller waist circumference. The T94A mutant has also been associated with metabolic syndrome conditions, cardiovascular disease and T2DM.
# Protein expression
## Suppression
Studies with mice to determine the effect of suppressing the FABP1 gene have been performed. When provided with high-fat or high-cholesterol based diets those with suppressed FABP1 expression demonstrated a significant impact on metabolic regulation and weight gain.
## Increased levels in obesity
A study in Chinese young adults indicates a strong relationship between serum FABP1 levels and lipid profile, body measurements and homeostatic parameters. Increased BMI and insulin resistance in subjects demonstrated higher serum FABP1 with a particular correlation in subjects with central adiposity. This elevation is suggested to occur as a compensatory up-regulation of the protein in an attempt to counter the high metabolic stress associated with obesity. Alternately obesity may in fact lead the human body to develop resistance to the actions of FABP1 leading to the compensatory up-regulation.
## Disease marker
Evaluation of increased levels of urinary and serum FABP1 have also shown to be effective markers in the detection of intestinal ischaemia, progressive end-stage renal failure and ischaemic damage caused by renal transplantation or cardiac bypass surgery. | FABP1
FABP1 is a human gene coding for the protein product FABP1 (Fatty Acid-Binding Protein 1). It is also frequently known as liver-type fatty acid-binding protein (LFABP).
FABP1 is primarily expressed in the liver where it is involved in the binding, transport and metabolism of long-chain fatty acids (LCFAs), endocannabinoids, phytocannabinoids (and less so for synthetic cannabinoid receptor (CBR) agonists and antagonists) and other hydrophobic molecules.[1][2][3][4] Altered expression of the protein has been linked to metabolic conditions including obesity.[5]
# Discovery
The fatty acid-binding proteins (FABPs) were initially discovered in 1972 with experiments using 14C labelled oleate to identify the presence of a soluble fatty acid carrier in the enterocyte responsible for intestinal absorption of (LCFAs).[6] Since then, ten members of the FABP family have been identified on the human genome. Nine are well established (FABP1-9) with a recently discovered tenth (FABP12).[3] Each FABP corresponds to particular organs/tissue around the body where they play a role in fatty-acid uptake, transport and metabolism.[6]
# Gene location
The human FABP1 gene is located on the short (p) arm of chromosome 2 from base pair 88,122,982 to base pair 88,128,131.[7]
# Protein structure
FABP1 has been found to have a unique structure compared to other members of the FABP family, allowing it to bind multiple ligands simultaneously.[8] It also has a larger solvent-accessible core compared to other FABPs allowing more diverse substrate binding.[3] The “portal hypothesis” has been proposed to explain the binding process of FABPs.[3] It has been suggested that fatty acids enter the solvent-accessible area of the protein through a dynamic region consisting of α-helix II and turns between βC-βD and βE-βF loops.[9] The fatty acid is then bound in the protein cavity for transport.[9]
# Function
The FABPs are a family of small, highly conserved cytoplasmic proteins involved in the binding of LCFAs. FABP1 is expressed abundantly in the human liver where it accounts for 7-11% of the total cytosolic protein, and can also be found in the intestine, kidney, pancreas stomach and lung.[3][10] FABP1 is unique in the wider range of other hydrophobic ligands it can bind including bilirubin, monoglycerides, bile acids and fatty acyl CoA.[11][12][13][14] It has been proposed that FABP1 plays a significant role in preventing cytotoxicity by binding heme, fatty acids and other molecules that are potentially toxic when unbound.[8]
# Mutations
On exon 3 of the human FABP1 gene an Ala to Thr substitution has been identified leading to a T94A missense mutation.[15] Carriers of this particular single nucleotide polymorphism (SNP) exhibit higher baseline plasma-free fatty acid levels, lower BMI and a smaller waist circumference.[15] The T94A mutant has also been associated with metabolic syndrome conditions, cardiovascular disease and T2DM.[15]
# Protein expression
## Suppression
Studies with mice to determine the effect of suppressing the FABP1 gene have been performed. When provided with high-fat or high-cholesterol based diets those with suppressed FABP1 expression demonstrated a significant impact on metabolic regulation and weight gain.[16][17][18][19]
## Increased levels in obesity
A study in Chinese young adults indicates a strong relationship between serum FABP1 levels and lipid profile, body measurements and homeostatic parameters.[5] Increased BMI and insulin resistance in subjects demonstrated higher serum FABP1 with a particular correlation in subjects with central adiposity.[5] This elevation is suggested to occur as a compensatory up-regulation of the protein in an attempt to counter the high metabolic stress associated with obesity. Alternately obesity may in fact lead the human body to develop resistance to the actions of FABP1 leading to the compensatory up-regulation.[5]
## Disease marker
Evaluation of increased levels of urinary and serum FABP1 have also shown to be effective markers in the detection of intestinal ischaemia, progressive end-stage renal failure and ischaemic damage caused by renal transplantation or cardiac bypass surgery.[20][21][22] | https://www.wikidoc.org/index.php/FABP1 | |
cd4fdebd5b365cda93f495f88d6e4bc541100a3d | wikidoc | FABP2 | FABP2
Fatty acid-binding protein 2 (FABP2) also known as Intestinal-type fatty acid-binding protein (I-FABP) is a protein that in humans is encoded by the FABP2 gene.
# Function
The intracellular fatty acid-binding proteins (FABPs) belong to a multigene family with nearly twenty identified members. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of long-chain fatty acids. They may also be responsible in the modulation of cell growth and proliferation. Intestinal fatty acid-binding protein 2 gene contains four exons and is an abundant cytosolic protein in small intestine epithelial cells.
# Clinical significance
This gene has a polymorphism at codon 54 that identified an alanine-encoding allele and a threonine-encoding allele. Thr-54 protein is associated with increased fat oxidation and insulin resistance. | FABP2
Fatty acid-binding protein 2 (FABP2) also known as Intestinal-type fatty acid-binding protein (I-FABP) is a protein that in humans is encoded by the FABP2 gene.[1]
# Function
The intracellular fatty acid-binding proteins (FABPs) belong to a multigene family with nearly twenty identified members. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of long-chain fatty acids. They may also be responsible in the modulation of cell growth and proliferation. Intestinal fatty acid-binding protein 2 gene contains four exons and is an abundant cytosolic protein in small intestine epithelial cells.[1]
# Clinical significance
This gene has a polymorphism at codon 54 that identified an alanine-encoding allele and a threonine-encoding allele. Thr-54 protein is associated with increased fat oxidation and insulin resistance.[1] | https://www.wikidoc.org/index.php/FABP2 | |
fdec2585160401b05ef9f1092c95aa9b04e52de1 | wikidoc | FABP5 | FABP5
Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene.
# Function
This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis tissue. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism.
The phytocannabinoids (THC and CBD) inhibit endocannabinoid anandamide (AEA) uptake by targeting FABP5, and competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.
# Interactions
FABP5 has been shown to interact with S100A7. | FABP5
Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene.[1][2]
# Function
This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis tissue. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism.[2]
The phytocannabinoids (THC and CBD) inhibit endocannabinoid anandamide (AEA) uptake by targeting FABP5, and competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.[3] Results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.[4]
# Interactions
FABP5 has been shown to interact with S100A7.[5][6] | https://www.wikidoc.org/index.php/FABP5 | |
9641de3fedc7dc679505d7cd7d26bf8cda1f78c5 | wikidoc | FABP7 | FABP7
Fatty acid binding protein 7, brain (FABP7; also brain lipid binding protein, BLBP), is a human gene.
# Function
The protein encoded by this gene is a brain fatty acid binding protein. Fatty acid binding proteins (FABPs) are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. FABPs are thought to play roles in fatty acid uptake, transport, and metabolism.
FABP7 is expressed, during development, in radial glia by the activation of Notch receptors. Reelin was shown to induce FABP7 expression in neural progenitor cells via Notch-1 activation.
According to one study, FABP7 binds DHA with the highest affinity among all of the FABPs.
# Role in pathology
FABP7 maps onto human chromosome 6q22.31, a schizophrenia linkage region corroborated by a meta-analysis.
As of 2008, two studies have been conducted into FABP7 as a possible risk gene for schizophrenia, with one, that tested for only one SNP, showing negative and another, with seven SNPs, a positive result. The effect of the gene in the latter study was stronger in males. This study also linked FABP7 variation to weak prepulse inhibition in mice; deficit in PPI is an endophenotypic trait observed in schizophrenia patients and their relatives. | FABP7
Fatty acid binding protein 7, brain (FABP7; also brain lipid binding protein, BLBP), is a human gene.[1]
# Function
The protein encoded by this gene is a brain fatty acid binding protein. Fatty acid binding proteins (FABPs) are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. FABPs are thought to play roles in fatty acid uptake, transport, and metabolism.[1]
FABP7 is expressed, during development, in radial glia by the activation of Notch receptors.[2] Reelin was shown to induce FABP7 expression in neural progenitor cells via Notch-1 activation.[3]
According to one study, FABP7 binds DHA with the highest affinity among all of the FABPs.[4]
# Role in pathology
FABP7 maps onto human chromosome 6q22.31, a schizophrenia linkage region corroborated by a meta-analysis.[5]
As of 2008, two studies have been conducted into FABP7 as a possible risk gene for schizophrenia,[6] with one, that tested for only one SNP, showing negative[7] and another, with seven SNPs,[8] a positive result. The effect of the gene in the latter study was stronger in males. This study also linked FABP7 variation to weak prepulse inhibition in mice; deficit in PPI is an endophenotypic trait observed in schizophrenia patients and their relatives. | https://www.wikidoc.org/index.php/FABP7 | |
fb24c073dc6816b9772b24d29e0420c065618127 | wikidoc | FADS1 | FADS1
Fatty acid desaturase 1 is an enzyme that in humans is encoded by the FADS1 gene.
# Function
The protein encoded by the FADS1 gene is a member of the fatty acid desaturase (FADS) gene family and desaturates omega-3 and omega-6 polyunsaturated fatty acids at the delta-5 position, catalyzing the final step in the formation of eicosapentaenoic acid (EPA) and Arachidonic acid. Desaturase enzymes (such as those encoded by FADS1) regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization.
# Clinical significance
Single nucleotide polymorphisms (SNPs) of FADS1 and FADS2 may affect long-chain polyunsaturated fatty acids (LC-PUFA) metabolism and have a potential role in the development of atopic diseases. | FADS1
Fatty acid desaturase 1 is an enzyme that in humans is encoded by the FADS1 gene.[1]
# Function
The protein encoded by the FADS1 gene is a member of the fatty acid desaturase (FADS) gene family and desaturates omega-3 and omega-6 polyunsaturated fatty acids at the delta-5 position, catalyzing the final step in the formation of eicosapentaenoic acid (EPA) and Arachidonic acid.[2] Desaturase enzymes (such as those encoded by FADS1) regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization.[1]
# Clinical significance
Single nucleotide polymorphisms (SNPs) of FADS1 and FADS2 may affect long-chain polyunsaturated fatty acids (LC-PUFA) metabolism and have a potential role in the development of atopic diseases.[3] | https://www.wikidoc.org/index.php/FADS1 | |
66b810962ebc80c8101f64b32e69fdcdb0f5c42d | wikidoc | FADS2 | FADS2
This article is about the gene, for main associated enzyme see D6D.
Fatty acid desaturase 2 (FADS2) is encoded by the FADS2 gene, the associated enzyme is sometimes known as FADS2 as well. Its main associated enzyme is Delta 6 desaturase (D6D) however the human enzyme been shown to also catalyze some delta-8 and delta-4 desaturases in spite of naming conventions.
# Function
Fatty acid desaturase 2 is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes cause desaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization.
# Clinical significance
It was reported the FADS2 interacts with breastfeeding such that breast-fed children with the "C" version of the gene appear about 7 intelligence quotient (IQ) points higher than those with the less common "G" version (less than this when adjusted for maternal IQ).
An attempt to replicate this study in 5934 8 year old children failed: No relationship of the common C allele to negative effects of formula feeding was apparent, and contra to the original report, the rare GG homozygote children performed worse when formula fed than other children on formula milk. A study of over 700 families recently found no evidence for either main or moderating effects of the original SNP (rs174575), nor of two additional FADS2 polymorphisms (rs1535 and rs174583), nor any effect of maternal FADS2 status on offspring IQ. | FADS2
This article is about the gene, for main associated enzyme see D6D.
Fatty acid desaturase 2 (FADS2) is encoded by the FADS2 gene, the associated enzyme is sometimes known as FADS2 as well.[1][2] Its main associated enzyme is Delta 6 desaturase (D6D) however the human enzyme been shown to also catalyze some delta-8 and delta-4 desaturases in spite of naming conventions.[3]
# Function
Fatty acid desaturase 2 is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes cause desaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members FADS1 and FADS2 at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization.[1]
# Clinical significance
It was reported the FADS2 interacts with breastfeeding such that breast-fed children with the "C" version of the gene appear about 7 intelligence quotient (IQ) points higher than those with the less common "G" version (less than this when adjusted for maternal IQ).[4][5]
An attempt to replicate this study in 5934 8 year old children failed: No relationship of the common C allele to negative effects of formula feeding was apparent, and contra to the original report, the rare GG homozygote children performed worse when formula fed than other children on formula milk.[6] A study of over 700 families recently found no evidence for either main or moderating effects of the original SNP (rs174575), nor of two additional FADS2 polymorphisms (rs1535 and rs174583), nor any effect of maternal FADS2 status on offspring IQ.[7] | https://www.wikidoc.org/index.php/FADS2 | |
f36dd808d981e40bc95d3c8fc891b16bf56565d2 | wikidoc | FAHD1 | FAHD1
Fumarylacetoacetate hydrolase domain-containing protein 1, also known as FLJ36880 protein, is an enzyme that in humans is encoded by the FAHD1 gene on chromosome 16.
# Structure
The FAHD1 gene encodes for a 24-kDa protein that is localized to the mitochondrion and belongs to the fumarylacetoacetate hydrolase family of proteins. The structure of FAHD1 has been resolved using X-ray crystallography at 2.2-Å resolution. The overall structure is similar to the C-terminal domain of the bifunctional enzyme HpcE from Escherichia coli C, fumarylacetoacetate hydrolase from Mus musculus and to YcgM (Apc5008) from E. coli 1262. A number of conserved amino acids including Asp-102 and Arg-106 of FAHD1 appear to be important for its catalytic activity.
# Function
The FAHD1 protein has been shown to function as an oxaloacetate decarboxylase in eukaryotes. The FAHD1 protein probably also functions as an acylpyruvase, having been shown to catalyze the hydrolysis of acetylpyruvate and fumarylpyruvate in in vitro experiments. Mg(2+) was required for maximal enzyme activity. | FAHD1
Fumarylacetoacetate hydrolase domain-containing protein 1, also known as FLJ36880 protein, is an enzyme that in humans is encoded by the FAHD1 gene on chromosome 16.[1]
# Structure
The FAHD1 gene encodes for a 24-kDa protein that is localized to the mitochondrion and belongs to the fumarylacetoacetate hydrolase family of proteins.[2] The structure of FAHD1 has been resolved using X-ray crystallography at 2.2-Å resolution. The overall structure is similar to the C-terminal domain of the bifunctional enzyme HpcE from Escherichia coli C, fumarylacetoacetate hydrolase from Mus musculus and to YcgM (Apc5008) from E. coli 1262.[2] A number of conserved amino acids including Asp-102 and Arg-106 of FAHD1 appear to be important for its catalytic activity.[3]
# Function
The FAHD1 protein has been shown to function as an oxaloacetate decarboxylase in eukaryotes.[4] The FAHD1 protein probably also functions as an acylpyruvase, having been shown to catalyze the hydrolysis of acetylpyruvate and fumarylpyruvate in in vitro experiments.[2] Mg(2+) was required for maximal enzyme activity.[3] | https://www.wikidoc.org/index.php/FAHD1 | |
5971a0296622533fca60e47312106938e25dabbe | wikidoc | FANCA | FANCA
Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.
Mutations involving the FANCA gene are associated with many somatic and congenital defects, primarily involving phenotypic variations of Fanconi anaemia, aplastic anaemia, and forms of cancer such as squamous cell carcinoma and acute myeloid leukaemia.
# Function
The Fanconi anaemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. The previously defined group FANCH is the same as FANCA. The members of the Fanconi anaemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. The FANCA gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms.
## Gene and protein
In humans, the gene FANCA is 79 kilobases (kb) in length, and is located on chromosome 16 (16q24.3). The FANCA protein is composed of 1455 amino acids. Within cells, the major purpose of FANCA belongs to its putative involvement in a multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. In complex with FANCF, FANCG and FANCL, FANCA interacts with HES1. This interaction has been proposed as essential for the stability and nuclear localization of FA core complex proteins. The complex with FANCC and FANCG may also include EIF2AK2 and HSP70. In cells, FANCA involvement in this ‘FA core complex’ is required for the activation of the FANCD2 protein to a monoubiquitinated isoform (FANCD2-Ub) in response to DNA damage, catalysing activation of the FA/BRCA DNA damage-response pathway, leading to repair.
FANCA binds to both single-stranded (ssDNA) and double-stranded (dsDNA) DNAs; however, when tested in an electrophoretic mobility shift assay, its affinity for ssDNA is significantly higher than for dsDNA. FANCA also binds to RNA with a higher affinity than its DNA counterpart. FANCA requires a certain number of nucleotides for optimal binding, with the minimum for FANCA recognition being approximately 30 for both DNA and RNA. Yuan et al. (2012) found through affinity testing FANCA with a variety of DNA structures that a 5'-flap or 5'-tail on DNA facilitates its interaction with FANCA, while the complementing C-terminal fragment of Q772X, C772-1455, retains the differentiated nucleic acid-binding activity (i.e. preferencing RNA before ssDNA and dsDNA), indicating that the nucleic acid-binding domain of FANCA is located primarily at the C terminus, a location where many disease-causing mutations are found.
FANCA is ubiquitously expressed at low levels in all cells with subcellular localisation in primarily nucleus but also cytoplasm corresponding with its putative caretaker role in DNA damage-response pathways, and FA complex formation. The distribution of proteins in different tissues is not well understood currently. Immunochemical study of mouse tissue indicates that FANCA is present at a higher level in lymphoid tissues, the testis and the ovary, and though the significance of this is unclear, it suggests that the presence of FA proteins might be related to cellular proliferation. For example, in human immortalized lymphoblasts and leukaemia cells, FA proteins are readily detectable by immunoprecipitation.
# Clinical significance
Mutations in this gene are the most common cause of Fanconi's anaemia. Fanconi anaemia is an inherited autosomal recessive disorder, the main features of which are aplastic anaemia in childhood, multiple congenital abnormalities, susceptibility to leukemia and other cancers, and cellular hypersensitivity to interstrand DNA cross-linking agents. Generally cells from Fanconi anaemia patients show a markedly higher frequency of spontaneous chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin-C (MMC) when compared to normal cells. The primary diagnostic test for Fanconi anaemia is based on the increased chromosomal breakage seen in afflicted cells after exposure to these agents – the DEB/MMC stress test. Other features of the Fanconi anaemia cell phenotype also include abnormal cell cycle kinetics (prolonged G2 phase), hypersensitivity to oxygen, increased apoptosis and accelerated telomere shortening.
FANCA mutations are by far the most common cause of Fanconi anaemia, accounting for between 60-70% of all cases. FANCA was cloned in 1996 and it is one of the largest FA genes. Hundreds of different mutations have been recorded with 30% point mutations, 30% 1-5 base pair microdeletions or microinsertions, and 40% large deletions, removing up to 31 exons from the gene. These large deletions have a high correlation with specific breakpoints and arise as a result of Alu mediated recombination. A highly relevant observation is that different mutations produce Fanconi anaemia phenotypes of varying severity.
Patients homozygous for null-mutations in this gene have an earlier onset of anaemia than those with mutations that produce an altered or incorrect protein. However, as most patients are compound heterozygotes, diagnostic screening for mutations is difficult. Certain founder mutations can also occur in some populations, such as the deletion exon 12-31 mutation, which accounts for 60% of mutations in Afrikaners.
## Involvement in FA/BRCA pathway
In cells from Fanconi anaemia patients, FA core complex induction of FANCD2 ubiquitination is not observed, assumably a result from impaired complex formation due to the lack of a working FANCA protein. Ultimately, regardless of specific mutation, it is disruption of this FA/BRCA pathway that results in the adverse cellular and clinical phenotypes common to all FANCA-impaired Fanconi anaemia sufferers. Interactions between BRCA1 and many FANC proteins have been investigated. Amongst known FANC proteins, most evidence points for a direct interaction primarily between FANCA protein and BRCA1. Evidence from yeast two-hybrid analysis, coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts shows that the site of interaction is between the terminal amino group of FANCA and the central part of BRCA1, located within amino acids 740–1083.
However, as FANCA and BRCA1 undergo a constitutive interaction, this may not depend solely on detection of actual DNA damage. Instead BRCA1 protein may be more crucial in the detection of double stranded DNA breaks, or an intermediate in interstrand crosslink (ICL) repair, and rather serve to bring some of the many DNA repair proteins it interacts with to the site. One such protein would be FANCA, which in turn may serve as a docking site or anchor point at the site of ICL damage for the FA core complex. Other FANC proteins, such as FANCC, FANCE and FANCG are then assembled in this nuclear complex in the presence of FANCA as required for the action of FANCD2. This mechanic is also supported by the protein-protein interactions between BRG1 and both BRCA1 and FANCA, that serve to modulate cell-cycle kinetics alongside this. Alternatively, BRCA1 might localize FANCA to the site of DNA damage and then release it to initiate complex formation. The complex would allow ubiquitination of FANCD2, a later functioning protein in the FA path, promoting ICL and DNA repair.
FANCA’s emerging putative and clearly integral function within activation the FA core complex also provides an explanation for its particularly high correlation with mutations causing Fanconi anaemia. Whilst many FANC protein mutations account for only 1% of the total observed cases, they are also stabilized by FANCA within the complex. For example, FANCA stabilises FANCG within the core complex, and hence mutations in FANCG are compensated for as the complex can still catalyse FANCD2-ubiquitination further downstream. FANCA upregulation also increases expression of FANCG in cells, and the fact this transduction is not mutual – FANCG upregulation does not cause increased expression of FANCA – suggests that FANCA is not only the primary stabilizing protein in the core complex, but may act as a natural regulator in patients who would otherwise suffer from mutations in FANC genes other than FANCA or FANCD2.
## Participation in haematopoiesis
FANCA is hypothesised to play a crucial role in adult (definitive) haematopoiesis during embryonic development, and is thought to be expressed in all haematopoietic sites that contribute to the formation of haematopoietic stem cells and progenitor cells (HSPCs). Most patients with a mutation develop haematological abnormalities within the first decade of life, and continue to decline until developing its most prevalent adverse effect, pancytopenia, potentially leading to death. In particular many patients develop megaloblastic anaemia around the age of 7, with this macrocytosis being the first haematological marker. Defective in vitro haematopoiesis has been recorded for over two decades resulting from mutated FANCA proteins, in particular developmental defects such as impaired granulomonocytopoiesis due to FANCA mutation.
Studies using clonogenic myeloid progenitors (CFU-GM) have also shown that the frequency of CFU-GM in normal bone marrow increased and their proliferative capacity decreased exponentially with age, with a particularly marked proliferative impairment in Fanconi anaemia afflicted children compared to age-matched healthy controls. As haematopoietic progenitor cell function begins at birth and continues throughout life, it is easily inferred that prolonged incapacitation of FANCA protein production results in total haematopoietic failure in patients.
### Potential impact on erythroid development
The three distinct stages of mammalian erythroid development are primitive, foetal and adult definitive. Adult, or definitive erythrocytes are the most common blood cell type and characteristically most similar across mammalian species. Primitive and foetal erythrocytes however, have markedly different characteristics. These include: they are larger in size (primitive even more so than foetal), circulate during early stages of development with a shorter lifespan, and, in particular, primitive cells are nucleated.
As the reasons for these disparities are not well understood, FANCA may be a gene responsible for instigating these morphological differences when considering its variations in erythrocyte expression. In primitive and foetal erythrocyte precursors, FANCA expression is low, and almost zero during reticulocyte formation. The marginal overall increase in the foetal stage is dwarfed by its sudden increase in expression solely during adult definitive proerythroblast formation. Here, the mean expression increases by 400% compared to foetal and primitive erythrocytes, and covers a huge margin of deviation. As FANCA is heavily implicated in controlling cellular proliferation, and often results in patients developing megaloblastic anaemia around age 7, a haematological disorder marked physically by proliferation-impaired, oversized erythrocytes, it is possible that the size and proliferative discrepancies between primitive, foetal and adult erythroid lineages may be explained by FANCA expression. As FANCA is also linked to cell-cycling and its progression from G2 phase, the stage impaired in megaloblastic anaemia, its expression in definitive proerythroblast development may be an upstream determinant of erythroid size.
## Implications in cancer
FANCA mutations have also been implicated in increased risks of cancer and malignancies. For example, patients with homozygous null-mutations in FANCA have a markedly increased susceptibility to acute myeloid leukaemia. Furthermore, as FANC mutations in general affect DNA repair throughout the body and are predisposed to affect dynamic cell division particularly in bone marrow, it is unsurprising that patients are more likely to develop myelodysplastic syndromes (MDS) and acute myeloid leukaemia.
# Mouse knockout
Knockout mice have been generated for FANCA. However, both single and double knockout murine models are healthy, viable, and do not readily show the phenotypic abnormalities typical of human Fanconi anaemia sufferers, such as haematological failure and increased susceptibility to cancers. Other markers such as infertility however still do arise. This can be seen as evidence for a lack of functional redundancy in the FANCA gene-encoded proteins. Murine models instead require induction of typical anaemic phenotypes by elevated dosing with MMC that does not affect wild-type animals, before they can be used experimentally as preclinical models for bone marrow failure and potential stem cell transplant or gene therapies.
Both female and male mice homozygous for a FANCA mutation show hypogonadism and impaired fertility. Homozygous mutant females exhibit premature reproductive senescence and an increased frequency of ovarian cysts.
In spermatocytes, the FANCA protein is ordinarily present at a high level during the pachytene stage of meiosis. This is the stage when chromosomes are fully synapsed, and Holliday junctions are formed and then resolved into recombinants. FANCA mutant males exhibit an increased frequency of mispaired meiotic chromosomes, implying a role for FANCA in meiotic recombination. Also apoptosis is increased in the mutant germ cells. The Fanconi anemia DNA repair pathway appears to play a key role in meiotic recombination and the maintenance of reproductive germ cells.
Loss of FANCA provokes neural progenitor apoptosis during forebrain development, likely related to defective DNA repair. This effect persists in adulthood leading to depletion of the neural stem cell pool with aging. The Fanconi anemia phenotype can be interpreted as a premature aging of stem cells, DNA damages being the driving force of aging. (Also see DNA damage theory of aging.)
# Interactions
FANCA has been shown to interact with:
- BRCA1,
- CHUK,
- ERCC4,
- FANCE,
- FANCF,
- FANCG,
- FANCC,
- IKK2,
- SMARCA4
- SNX5
- SPTAN1 and
- HES1 | FANCA
Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene.[1] It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.[2]
Mutations involving the FANCA gene are associated with many somatic and congenital defects, primarily involving phenotypic variations of Fanconi anaemia, aplastic anaemia, and forms of cancer such as squamous cell carcinoma and acute myeloid leukaemia.[3]
# Function
The Fanconi anaemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. The previously defined group FANCH is the same as FANCA. The members of the Fanconi anaemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. The FANCA gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms.[1]
## Gene and protein
In humans, the gene FANCA is 79 kilobases (kb) in length, and is located on chromosome 16 (16q24.3). The FANCA protein is composed of 1455 amino acids.[4] Within cells, the major purpose of FANCA belongs to its putative involvement in a multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. In complex with FANCF, FANCG and FANCL, FANCA interacts with HES1. This interaction has been proposed as essential for the stability and nuclear localization of FA core complex proteins. The complex with FANCC and FANCG may also include EIF2AK2 and HSP70.[5] In cells, FANCA involvement in this ‘FA core complex’ is required for the activation of the FANCD2 protein to a monoubiquitinated isoform (FANCD2-Ub) in response to DNA damage, catalysing activation of the FA/BRCA DNA damage-response pathway,[6] leading to repair.[7]
FANCA binds to both single-stranded (ssDNA) and double-stranded (dsDNA) DNAs; however, when tested in an electrophoretic mobility shift assay, its affinity for ssDNA is significantly higher than for dsDNA. FANCA also binds to RNA with a higher affinity than its DNA counterpart.[8] FANCA requires a certain number of nucleotides for optimal binding, with the minimum for FANCA recognition being approximately 30 for both DNA and RNA. Yuan et al. (2012) found through affinity testing FANCA with a variety of DNA structures that a 5'-flap or 5'-tail on DNA facilitates its interaction with FANCA, while the complementing C-terminal fragment of Q772X, C772-1455, retains the differentiated nucleic acid-binding activity (i.e. preferencing RNA before ssDNA and dsDNA), indicating that the nucleic acid-binding domain of FANCA is located primarily at the C terminus, a location where many disease-causing mutations are found.[8]
FANCA is ubiquitously expressed at low levels in all cells[9] with subcellular localisation in primarily nucleus but also cytoplasm[10] corresponding with its putative caretaker role in DNA damage-response pathways, and FA complex formation. The distribution of proteins in different tissues is not well understood currently. Immunochemical study of mouse tissue indicates that FANCA is present at a higher level in lymphoid tissues, the testis and the ovary,[9] and though the significance of this is unclear, it suggests that the presence of FA proteins might be related to cellular proliferation. For example, in human immortalized lymphoblasts and leukaemia cells, FA proteins are readily detectable by immunoprecipitation.[11]
# Clinical significance
Mutations in this gene are the most common cause of Fanconi's anaemia.[1][2][3] Fanconi anaemia is an inherited autosomal recessive disorder, the main features of which are aplastic anaemia in childhood, multiple congenital abnormalities, susceptibility to leukemia and other cancers, and cellular hypersensitivity to interstrand DNA cross-linking agents.[3] Generally cells from Fanconi anaemia patients show a markedly higher frequency of spontaneous chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin-C (MMC) when compared to normal cells. The primary diagnostic test for Fanconi anaemia is based on the increased chromosomal breakage seen in afflicted cells after exposure to these agents – the DEB/MMC stress test. Other features of the Fanconi anaemia cell phenotype also include abnormal cell cycle kinetics (prolonged G2 phase), hypersensitivity to oxygen, increased apoptosis and accelerated telomere shortening.[2][12]
FANCA mutations are by far the most common cause of Fanconi anaemia, accounting for between 60-70% of all cases. FANCA was cloned in 1996[13] and it is one of the largest FA genes. Hundreds of different mutations have been recorded[14][15] with 30% point mutations, 30% 1-5 base pair microdeletions or microinsertions, and 40% large deletions, removing up to 31 exons from the gene.[16] These large deletions have a high correlation with specific breakpoints and arise as a result of Alu mediated recombination. A highly relevant observation is that different mutations produce Fanconi anaemia phenotypes of varying severity.
Patients homozygous for null-mutations in this gene have an earlier onset of anaemia than those with mutations that produce an altered or incorrect protein.[17] However, as most patients are compound heterozygotes, diagnostic screening for mutations is difficult. Certain founder mutations can also occur in some populations, such as the deletion exon 12-31 mutation, which accounts for 60% of mutations in Afrikaners.[18]
## Involvement in FA/BRCA pathway
In cells from Fanconi anaemia patients, FA core complex induction of FANCD2 ubiquitination is not observed, assumably a result from impaired complex formation due to the lack of a working FANCA protein.[19][20] Ultimately, regardless of specific mutation, it is disruption of this FA/BRCA pathway that results in the adverse cellular and clinical phenotypes common to all FANCA-impaired Fanconi anaemia sufferers.[2] Interactions between BRCA1 and many FANC proteins have been investigated. Amongst known FANC proteins, most evidence points for a direct interaction primarily between FANCA protein and BRCA1. Evidence from yeast two-hybrid analysis,[21] coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts shows that the site of interaction is between the terminal amino group of FANCA and the central part of BRCA1, located within amino acids 740–1083.[12][22]
However, as FANCA and BRCA1 undergo a constitutive interaction, this may not depend solely on detection of actual DNA damage. Instead BRCA1 protein may be more crucial in the detection of double stranded DNA breaks, or an intermediate in interstrand crosslink (ICL) repair, and rather serve to bring some of the many DNA repair proteins it interacts with to the site. One such protein would be FANCA, which in turn may serve as a docking site or anchor point at the site of ICL damage for the FA core complex.[22] Other FANC proteins, such as FANCC, FANCE and FANCG are then assembled in this nuclear complex in the presence of FANCA as required for the action of FANCD2. This mechanic is also supported by the protein-protein interactions between BRG1 and both BRCA1 and FANCA, that serve to modulate cell-cycle kinetics alongside this.[23] Alternatively, BRCA1 might localize FANCA to the site of DNA damage and then release it to initiate complex formation.[6][22] The complex would allow ubiquitination of FANCD2, a later functioning protein in the FA path, promoting ICL and DNA repair.
FANCA’s emerging putative and clearly integral function within activation the FA core complex also provides an explanation for its particularly high correlation with mutations causing Fanconi anaemia. Whilst many FANC protein mutations account for only 1% of the total observed cases,[2] they are also stabilized by FANCA within the complex. For example, FANCA stabilises FANCG within the core complex, and hence mutations in FANCG are compensated for as the complex can still catalyse FANCD2-ubiquitination further downstream. FANCA upregulation also increases expression of FANCG in cells, and the fact this transduction is not mutual – FANCG upregulation does not cause increased expression of FANCA – suggests that FANCA is not only the primary stabilizing protein in the core complex, but may act as a natural regulator in patients who would otherwise suffer from mutations in FANC genes other than FANCA or FANCD2.[24][25]
## Participation in haematopoiesis
FANCA is hypothesised to play a crucial role in adult (definitive) haematopoiesis during embryonic development, and is thought to be expressed in all haematopoietic sites that contribute to the formation of haematopoietic stem cells and progenitor cells (HSPCs). Most patients with a mutation develop haematological abnormalities within the first decade of life,[3] and continue to decline until developing its most prevalent adverse effect, pancytopenia, potentially leading to death.[2] In particular many patients develop megaloblastic anaemia around the age of 7, with this macrocytosis being the first haematological marker.[3] Defective in vitro haematopoiesis has been recorded for over two decades resulting from mutated FANCA proteins, in particular developmental defects such as impaired granulomonocytopoiesis due to FANCA mutation.[26]
Studies using clonogenic myeloid progenitors (CFU-GM) have also shown that the frequency of CFU-GM in normal bone marrow increased and their proliferative capacity decreased exponentially with age, with a particularly marked proliferative impairment in Fanconi anaemia afflicted children compared to age-matched healthy controls.[27][28] As haematopoietic progenitor cell function begins at birth and continues throughout life, it is easily inferred that prolonged incapacitation of FANCA protein production results in total haematopoietic failure in patients.
### Potential impact on erythroid development
The three distinct stages of mammalian erythroid development are primitive, foetal and adult definitive. Adult, or definitive erythrocytes are the most common blood cell type and characteristically most similar across mammalian species.[29] Primitive and foetal erythrocytes however, have markedly different characteristics. These include: they are larger in size (primitive even more so than foetal), circulate during early stages of development with a shorter lifespan, and, in particular, primitive cells are nucleated.[30]
As the reasons for these disparities are not well understood, FANCA may be a gene responsible for instigating these morphological differences when considering its variations in erythrocyte expression.[31] In primitive and foetal erythrocyte precursors, FANCA expression is low, and almost zero during reticulocyte formation. The marginal overall increase in the foetal stage is dwarfed by its sudden increase in expression solely during adult definitive proerythroblast formation. Here, the mean expression increases by 400% compared to foetal and primitive erythrocytes, and covers a huge margin of deviation.[31] As FANCA is heavily implicated in controlling cellular proliferation, and often results in patients developing megaloblastic anaemia around age 7,[2] a haematological disorder marked physically by proliferation-impaired, oversized erythrocytes, it is possible that the size and proliferative discrepancies between primitive, foetal and adult erythroid lineages may be explained by FANCA expression. As FANCA is also linked to cell-cycling and its progression from G2 phase, the stage impaired in megaloblastic anaemia, its expression in definitive proerythroblast development may be an upstream determinant of erythroid size.
## Implications in cancer
FANCA mutations have also been implicated in increased risks of cancer and malignancies.[3] For example, patients with homozygous null-mutations in FANCA have a markedly increased susceptibility to acute myeloid leukaemia.[17] Furthermore, as FANC mutations in general affect DNA repair throughout the body and are predisposed to affect dynamic cell division particularly in bone marrow, it is unsurprising that patients are more likely to develop myelodysplastic syndromes (MDS) and acute myeloid leukaemia.[2]
# Mouse knockout
Knockout mice have been generated for FANCA.[9] However, both single and double knockout murine models are healthy, viable, and do not readily show the phenotypic abnormalities typical of human Fanconi anaemia sufferers, such as haematological failure and increased susceptibility to cancers. Other markers such as infertility however still do arise.[3][32] This can be seen as evidence for a lack of functional redundancy in the FANCA gene-encoded proteins.[33] Murine models instead require induction of typical anaemic phenotypes by elevated dosing with MMC that does not affect wild-type animals, before they can be used experimentally as preclinical models for bone marrow failure and potential stem cell transplant or gene therapies.[2][33]
Both female and male mice homozygous for a FANCA mutation show hypogonadism and impaired fertility.[34] Homozygous mutant females exhibit premature reproductive senescence and an increased frequency of ovarian cysts.
In spermatocytes, the FANCA protein is ordinarily present at a high level during the pachytene stage of meiosis.[35] This is the stage when chromosomes are fully synapsed, and Holliday junctions are formed and then resolved into recombinants. FANCA mutant males exhibit an increased frequency of mispaired meiotic chromosomes, implying a role for FANCA in meiotic recombination. Also apoptosis is increased in the mutant germ cells. The Fanconi anemia DNA repair pathway appears to play a key role in meiotic recombination and the maintenance of reproductive germ cells.[35]
Loss of FANCA provokes neural progenitor apoptosis during forebrain development, likely related to defective DNA repair.[36] This effect persists in adulthood leading to depletion of the neural stem cell pool with aging. The Fanconi anemia phenotype can be interpreted as a premature aging of stem cells, DNA damages being the driving force of aging.[36] (Also see DNA damage theory of aging.)
# Interactions
FANCA has been shown to interact with:
- BRCA1,[22]
- CHUK,[12][37]
- ERCC4,[38]
- FANCE,[19][20][39][40]
- FANCF,[39][41][42]
- FANCG,[19][21][25][37][39][40][43][44][45][46][47][48][49][50][51][52][53][54]
- FANCC,[25][37][39][40][41][43][44][55]
- IKK2,[37]
- SMARCA4[12][23]
- SNX5[56]
- SPTAN1[22][55][57] and
- HES1[58] | https://www.wikidoc.org/index.php/FANCA | |
d319b8c08bbf87d635638e78cc712dd398e76d4e | wikidoc | FANCB | FANCB
Fanconi anemia group B protein is a protein that in humans is encoded by the FANCB gene.
# Function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group B. Alternative splicing results in two transcript variants encoding the same protein.
# Gene
FANCB is the only gene known to cause X-linked Fanconi Anemia. In female carriers of FANCB mutations (one wild-type FANCB allele and one mutant FANCB allele) there is strong selection through X-inactivation for expression of only the wild-type allele. In contrast, males have only one FANCB allele. Only male patients with Fanconi anemia have ever been linked to FANCB mutations, and they make up about 4% of cases.
# Protein
The FANCB gene product is FANCB protein. FANCB is a component of a "core complex" of nine Fanconi Anemia proteins: FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FAAP100 and FAAP20. The core complex localises to DNA damage sites during DNA replication where it catalyzes transfer of ubiquitin to FANCD2 and FANCI. In particular, this reaction is necessary for the repair of DNA interstrand crosslinks, such as those formed by chemotherapy drugs cisplatin, mitomycin c and melphalan.
Within the Fanconi anemia core complex, FANCB has an obligate interaction with FAAP100 and FANCL, to form a catalytic E3 RING ligase enzyme. FANCB creates a dimer interface within this subcomplex that is required for simultaneous ubiquitination of FANCD2 and FANCI. Electron microscopy imaging of the FANCB-FANCL-FAAP100 complex revealed a symmetry that is centred on FANCB, and biochemical investigation confirmed that the entire complex is a dimer containing two of each subunit. Further imaging reveals the overall architecture of the Fanconi Anemia core complex centres on FANCB protein.
# Meiosis
FANCB mutant mice are infertile and exhibit primordial germ cell defects during embryogenesis. The germ cells and testicular size are severely compromised in FANCB mutant mice. FANCB protein is essential for spermatogenesis and likely has a role in the activation of the Fanconi anemia DNA repair pathway during meiosis. | FANCB
Fanconi anemia group B protein is a protein that in humans is encoded by the FANCB gene.[1][2][3]
# Function
The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group B. Alternative splicing results in two transcript variants encoding the same protein.[3]
# Gene
FANCB is the only gene known to cause X-linked Fanconi Anemia. In female carriers of FANCB mutations (one wild-type FANCB allele and one mutant FANCB allele) there is strong selection through X-inactivation for expression of only the wild-type allele.[4] In contrast, males have only one FANCB allele. Only male patients with Fanconi anemia have ever been linked to FANCB mutations, and they make up about 4% of cases.[5]
# Protein
The FANCB gene product is FANCB protein. FANCB is a component of a "core complex" of nine Fanconi Anemia proteins: FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FAAP100 and FAAP20. The core complex localises to DNA damage sites during DNA replication where it catalyzes transfer of ubiquitin to FANCD2 and FANCI.[6] In particular, this reaction is necessary for the repair of DNA interstrand crosslinks, such as those formed by chemotherapy drugs cisplatin, mitomycin c and melphalan.[7]
Within the Fanconi anemia core complex, FANCB has an obligate interaction with FAAP100 and FANCL, to form a catalytic E3 RING ligase enzyme. FANCB creates a dimer interface within this subcomplex that is required for simultaneous ubiquitination of FANCD2 and FANCI.[8] Electron microscopy imaging of the FANCB-FANCL-FAAP100 complex revealed a symmetry that is centred on FANCB, and biochemical investigation confirmed that the entire complex is a dimer containing two of each subunit[9]. Further imaging reveals the overall architecture of the Fanconi Anemia core complex centres on FANCB protein.[9]
# Meiosis
FANCB mutant mice are infertile and exhibit primordial germ cell defects during embryogenesis. The germ cells and testicular size are severely compromised in FANCB mutant mice.[10] FANCB protein is essential for spermatogenesis and likely has a role in the activation of the Fanconi anemia DNA repair pathway during meiosis.[10] | https://www.wikidoc.org/index.php/FANCB | |
5a10dc59b927a82ff6e60de36306487374b6b80f | wikidoc | FANCE | FANCE
Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the FANCE gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA cross-linking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation groufcrp E.
A nuclear complex containing FANCE protein (as well as FANCC, FANCF and FANCG) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform. In normal, non-mutant cells, FANCD2 is mono-ubiquinated in response to DNA damage. FANCE together with FANCC acts as the substrate adapter for this reaction Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. Activated FANCD2 protein may function prior to the initiation of meiotic recombination, perhaps to prepare chromosomes for synapses, or to regulate subsequent recombination events.
# Gene Expression
FANCE is stated to have been expressed in 151 organs with the highest level in female gonads.
# Chromosomal Location
The location of the gene is in 6p21.31, where p is the short arm of chromosome 6 at position 21.31
The location at molecular level is in base pairs 35,452,339 to 35,467,106 on chromosome 6 (Homo sapiens Annotation Release 109, GRCh38.p12)
# Protein Characteristics
The main complex of FA contains a nuclear multi-subunit complex of notably 8 FA proteins. This adds a single ubiquiting chain to the FANCD2 following DNA damage or duplicative pressure.
For the collection of FANCC, FANCE is important in the nucleus and gathering of the core complex. Some characteristics of FANCE is that it can set itself with ubiquitinated FANCD2, BRCA2 and constructed nuclear foci. Also, as it is the only member showing direct union with FANCD2 and gives the needed links between FA core complex and FANCD2.
The structure of FANCE has an epitope on its surface that is found to be important for its binding with FANCD2. The existence of recurrent helical motif was not clear when analysis of amino acids were done.
## Protein Structure
It consists of 13 α-helices, 1 310-helix and no β-strand. Long shaped, non-globular shape and 70 Å n size. Width of 30 Å and thickness 20 Å. The protein folds continuously in right-handed manner from N- to C- terminal. Identifying it is easy because of its helices at the end of C-end.
# Function
It restores DNA cross-links and is needed for nuclear accumulation of FANCC, delivering a critical bridge between FA complex and FANCD2.
# Applications
- FANCE has its application in Western Blot and IHC-P (Immunohistochemistry) where the predicted molecular weight was 58 kDa in Western blot and antigen recovery with citrate buffer pH6 was done before the onset of IHC-P .
- FANCE is also used in Gene Mapping, here homozygosity mapping, where it is fused with 3 DNA cells that will help in calculating the sensitivity to composites of Mitomycin C, a DNA cross-linking agent (Sigma). It also then examines the use of micro satellite markers D6S422 and D6S1610, for linking. From this, a chromosomal region on chromosome 6p is located for FANCE.
- Immunoblotting showed that FANCE-L348M and FANCE-E263K mutants showed a division in the nuclear membrane of FA-E EUFA409 LCL indicating that irrespective of FANCE having putative nuclear localization signals, it limits primarily to the nucleus.
# Interactions
FANCE has been shown to interact with:
- FANCA,
- FANCD2,
- FANCF
- FANCG, and
- FANCC. | FANCE
Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the FANCE gene.[1][2][3] The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA cross-linking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation groufcrp E.[3]
A nuclear complex containing FANCE protein (as well as FANCC, FANCF and FANCG) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.[4] In normal, non-mutant cells, FANCD2 is mono-ubiquinated in response to DNA damage. FANCE together with FANCC acts as the substrate adapter for this reaction [5] Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. Activated FANCD2 protein may function prior to the initiation of meiotic recombination, perhaps to prepare chromosomes for synapses, or to regulate subsequent recombination events.[4]
# Gene Expression
FANCE is stated to have been expressed in 151 organs with the highest level in female gonads.[6]
# Chromosomal Location
The location of the gene is in 6p21.31, where p is the short arm of chromosome 6 at position 21.31[7]
The location at molecular level is in base pairs 35,452,339 to 35,467,106 on chromosome 6 (Homo sapiens Annotation Release 109, GRCh38.p12) [7]
# Protein Characteristics
The main complex of FA contains a nuclear multi-subunit complex of notably 8 FA proteins[8]. This adds a single ubiquiting chain to the FANCD2 following DNA damage or duplicative pressure[9].
For the collection of FANCC, FANCE is important in the nucleus and gathering of the core complex. Some characteristics of FANCE is that it can set itself with ubiquitinated FANCD2, BRCA2 and constructed nuclear foci. Also, as it is the only member showing direct union with FANCD2 and gives the needed links between FA core complex and FANCD2.[10]
The structure of FANCE has an epitope on its surface that is found to be important for its binding with FANCD2. The existence of recurrent helical motif was not clear when analysis of amino acids were done.
## Protein Structure
It consists of 13 α-helices, 1 310-helix and no β-strand. Long shaped, non-globular shape and 70 Å n size. Width of 30 Å and thickness 20 Å. The protein folds continuously in right-handed manner from N- to C- terminal. Identifying it is easy because of its helices at the end of C-end[10].
# Function
It restores DNA cross-links and is needed for nuclear accumulation of FANCC, delivering a critical bridge between FA complex and FANCD2.[11]
# Applications
- FANCE has its application in Western Blot and IHC-P (Immunohistochemistry) where the predicted molecular weight was 58 kDa in Western blot and antigen recovery with citrate buffer pH6 was done before the onset of IHC-P [11].
- FANCE is also used in Gene Mapping, here homozygosity mapping, where it is fused with 3 DNA cells that will help in calculating the sensitivity to composites of Mitomycin C, a DNA cross-linking agent (Sigma). It also then examines the use of micro satellite markers D6S422 and D6S1610[12], for linking. From this, a chromosomal region on chromosome 6p is located for FANCE[13].
- Immunoblotting showed that FANCE-L348M and FANCE-E263K mutants showed a division in the nuclear membrane of FA-E EUFA409 LCL indicating that irrespective of FANCE having putative nuclear localization signals,[14] it limits primarily to the nucleus[15].
# Interactions
FANCE has been shown to interact with:
- FANCA,[16][17][18][19]
- FANCD2,[18][20][21]
- FANCF[18][22]
- FANCG,[16][17][18] and
- FANCC.[16][17][18][20][22] | https://www.wikidoc.org/index.php/FANCE | |
2176f5d573321a560f314bb19dd15eec08010a07 | wikidoc | FANCF | FANCF
Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.
# Interactions
FANCF has been shown to interact with Fanconi anemia, complementation group C, FANCG, FANCA and FANCE.
# Function
FANCF is an adaptor protein that plays a key role in the proper assembly of the FA core complex. The FA core complex is composed of eight proteins (FANCA, -B, -C, -E, -F, -G, -L and -M). FANCF stabilizes the interaction between the FANCC/FANCE subcomplex and the FANCA/FANCG subcomplex and locks the whole FA core complex in a conformation that is essential to perform its function in DNA repair.
The FA core complex is a nuclear core complex that is essential for the monoubiquitination of FANCD2 and this modified form of FANCD2 colocalizes with BRCA1, RAD51 and PCNA in foci that also contain other DNA repair proteins. All these proteins function together to facilitate DNA interstrand cross-link repair. They also function in other DNA damage response repair processes including recovering and stabilizing stalled replication forks. FoxF1 protein also interacts with the FA protein core and induces its binding to chromatin to promote DNA repair.
# Cancer
DNA damage appears to be the primary underlying cause of cancer, and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to cancer.
Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are most often much more frequent than mutational defects in DNA repair genes in cancers. (Also see Frequencies of epimutations in DNA repair genes.)
Methylation of the promoter region of the FANCF gene causes reduced expression of FANCF protein.
The frequencies of FANCF promoter methylation in several different cancers is indicated in the table.
In invasive breast cancers, microRNA-210 (miR-210) was increased, along with decreased expression of FANCF, where FANCF was one of the likely targets of miR-210.
Although mutations in FANCF are ordinarily not observed in human tumors, an FANCF-deficient mouse model was prone to ovarian cancers.
FANCF appears to be one of about 26 DNA repair genes that are epigenetically repressed in various cancers (see Cancer epigenetics).
# Infertility
The gonads of FANCF mutant mice function abnormally, having compromised follicle development and spermatogenesis as has been observed in other Fanconi anemia mouse models and in Fanconi anemia patients. Histological examination of the testes from FANCF-deficient mice showed that the seminiferous tubules were devoid of germ cells. At 14 weeks of age, FANCF-deficient female mice were almost or completely devoid of primordial follicles. It was concluded that FANCF-deficient mice display a rapid depletion of primordial follicles at a young age resulting in advanced ovarian aging. | FANCF
Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.[1][2]
# Interactions
FANCF has been shown to interact with Fanconi anemia, complementation group C,[3][4] FANCG,[3][4][5][6] FANCA[3][4][7] and FANCE.[3][8]
# Function
FANCF is an adaptor protein that plays a key role in the proper assembly of the FA core complex.[3] The FA core complex is composed of eight proteins (FANCA, -B, -C, -E, -F, -G, -L and -M).[9][10] FANCF stabilizes the interaction between the FANCC/FANCE subcomplex and the FANCA/FANCG subcomplex and locks the whole FA core complex in a conformation that is essential to perform its function in DNA repair.[3]
The FA core complex is a nuclear core complex that is essential for the monoubiquitination of FANCD2 and this modified form of FANCD2 colocalizes with BRCA1, RAD51 and PCNA in foci that also contain other DNA repair proteins.[3] All these proteins function together to facilitate DNA interstrand cross-link repair. They also function in other DNA damage response repair processes including recovering and stabilizing stalled replication forks.[10] FoxF1 protein also interacts with the FA protein core and induces its binding to chromatin to promote DNA repair.[10]
# Cancer
DNA damage appears to be the primary underlying cause of cancer,[11][12] and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer.[13][14] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[15][16] Such mutations and epigenetic alterations may give rise to cancer.
Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are most often much more frequent than mutational defects in DNA repair genes in cancers.[17] (Also see Frequencies of epimutations in DNA repair genes.)
Methylation of the promoter region of the FANCF gene causes reduced expression of FANCF protein.[18]
The frequencies of FANCF promoter methylation in several different cancers is indicated in the table.
In invasive breast cancers, microRNA-210 (miR-210) was increased, along with decreased expression of FANCF, where FANCF was one of the likely targets of miR-210.[25]
Although mutations in FANCF are ordinarily not observed in human tumors, an FANCF-deficient mouse model was prone to ovarian cancers.[26]
FANCF appears to be one of about 26 DNA repair genes that are epigenetically repressed in various cancers (see Cancer epigenetics).
# Infertility
The gonads of FANCF mutant mice function abnormally, having compromised follicle development and spermatogenesis as has been observed in other Fanconi anemia mouse models and in Fanconi anemia patients.[26] Histological examination of the testes from FANCF-deficient mice showed that the seminiferous tubules were devoid of germ cells. At 14 weeks of age, FANCF-deficient female mice were almost or completely devoid of primordial follicles. It was concluded that FANCF-deficient mice display a rapid depletion of primordial follicles at a young age resulting in advanced ovarian aging.[26] | https://www.wikidoc.org/index.php/FANCF | |
1ee579510fd7fe6620f34dd9ead3d15209811d37 | wikidoc | FANCG | FANCG
Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.
# Function
FANCG, involved in Fanconi anemia, confers resistance to both hygromycin B and mitomycin C. FANCG contains a 5-prime GC-rich untranslated region characteristic of housekeeping genes. The putative 622-amino acid protein has a leucine-zipper motif at its N-terminus. Fanconi anemia is an autosomal recessive disorder with diverse clinical symptoms, including developmental anomalies, bone marrow failure, and early occurrence of malignancies. A minimum of 8 FA genes have been identified. The FANCG gene is responsible for complementation group G.
The clinical phenotype of all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins interact through a multiprotein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1), but the exact biochemical roles of these proteins is currently unclear.
A nuclear complex containing FANCG (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCL and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform. In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage).
# Meiosis
Activated FANCD2 protein may function prior to the initiation of meiotic recombination, perhaps to prepare chromosomes for synapsis, or to regulate subsequent recombination events.
Male and female FANCG mutant mice have defective gametogenesis, hypogonadism and impaired fertility, consistent with the phenotype of FA patients. In the non-mutant mouse, FANCG protein is expressed in spermatogonia, preleptotene spermatocytes and spermatocytes in the leptotene, zygotene and early pachytene stages of meiosis.
# Aging
Loss of FANCG causes neural progenitor apoptosis during forebrain development, likely related to defective DNA repair. (Sii-Felice et al., 2008). This effect persists in adulthood leading to depletion of the neural stem cell pool with aging. The FA phenotype can be interpreted as a premature aging of stem cells, DNA damages being the driving force of aging. (Also see DNA damage theory of aging).
# Interactions
FANCG has been shown to interact with FANCF,
FANCA, FANCE and BRCA2. | FANCG
Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.[1][2][3]
# Function
FANCG, involved in Fanconi anemia, confers resistance to both hygromycin B and mitomycin C. FANCG contains a 5-prime GC-rich untranslated region characteristic of housekeeping genes. The putative 622-amino acid protein has a leucine-zipper motif at its N-terminus. Fanconi anemia is an autosomal recessive disorder with diverse clinical symptoms, including developmental anomalies, bone marrow failure, and early occurrence of malignancies. A minimum of 8 FA genes have been identified. The FANCG gene is responsible for complementation group G.[3]
The clinical phenotype of all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins interact through a multiprotein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1), but the exact biochemical roles of these proteins is currently unclear.
A nuclear complex containing FANCG (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCL and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.[4] In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage).
# Meiosis
Activated FANCD2 protein may function prior to the initiation of meiotic recombination, perhaps to prepare chromosomes for synapsis, or to regulate subsequent recombination events.[11]
Male and female FANCG mutant mice have defective gametogenesis, hypogonadism and impaired fertility, consistent with the phenotype of FA patients.[12][13] In the non-mutant mouse, FANCG protein is expressed in spermatogonia, preleptotene spermatocytes and spermatocytes in the leptotene, zygotene and early pachytene stages of meiosis.[14]
# Aging
Loss of FANCG causes neural progenitor apoptosis during forebrain development, likely related to defective DNA repair.[15] (Sii-Felice et al., 2008). This effect persists in adulthood leading to depletion of the neural stem cell pool with aging. The FA phenotype can be interpreted as a premature aging of stem cells, DNA damages being the driving force of aging.[15] (Also see DNA damage theory of aging).
# Interactions
FANCG has been shown to interact with FANCF,[16][17][18][19]
FANCA,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] FANCE[19][33][36] and BRCA2.[37] | https://www.wikidoc.org/index.php/FANCG | |
8281f7eb89f3640f5805e95fcc9f84ed2e719919 | wikidoc | FANCL | FANCL
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.
# Function
The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins interact through a multi-protein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1).
The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with FANCB. The ELF domain of FANCL is also required to mediate a non-covalent interaction
between FANCL and ubiquitin. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.
A nuclear complex containing FANCL (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform. In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage). | FANCL
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.[1]
# Function
The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects.[9] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.[10] The FA proteins interact through a multi-protein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1).
The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with FANCB.[11] The ELF domain of FANCL is also required to mediate a non-covalent interaction
between FANCL and ubiquitin. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.[12]
A nuclear complex containing FANCL (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.[2] In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage). | https://www.wikidoc.org/index.php/FANCL | |
d5af1561c13aacb23f9027475f65074e8688aeed | wikidoc | FANCM | FANCM
Fanconi anemia, complementation group M, also known as FANCM is a human gene.
# Function
The protein encoded by this gene, FANCM displays DNA binding against fork structures and an ATPase activity associated with DNA branch migration. It is believed that FANCM in conjunction with other Fanconi anemia- proteins repair DNA at stalled replication forks, and stalled transcription structures called R-loops.
The structure of the C-terminus of FANCM (amino acids 1799-2048), bound to a partner protein FAAP24, reveals how the protein complex recognises branched DNA. A structure of amino acids 675-790 of FANCM reveal how the protein binds duplex DNA through a remodeling of the MHF1:MHF2 histone-like protein complex.
# Disease linkage
Homozygous mutations in the FANCM gene are associated with Fanconi anemia, although several individuals with FANCM deficiency do not appear to have the disorder. A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers. FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours
# Meiosis
Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and Homologous recombination). The pathway leading to a NCO is referred to as synthesis dependent strand annealing (SDSA).
In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants. The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana. A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination. These two pathways likely act by unwinding different joint molecule substrates (e.g. nascent versus extended D-loops; see Figure).
Only about 4% of DSBs in A. thaliana are repaired by CO recombination; the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al. suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.
In the fission yeast Schizosaccharomyces pombe, FANCM helicase also directs NCO recombination during meiosis. | FANCM
Fanconi anemia, complementation group M, also known as FANCM is a human gene.[1][2]
# Function
The protein encoded by this gene, FANCM displays DNA binding against fork structures[3] and an ATPase activity associated with DNA branch migration. It is believed that FANCM in conjunction with other Fanconi anemia- proteins repair DNA at stalled replication forks, and stalled transcription structures called R-loops.[4][5]
The structure of the C-terminus of FANCM (amino acids 1799-2048), bound to a partner protein FAAP24, reveals how the protein complex recognises branched DNA.[3] A structure of amino acids 675-790 of FANCM reveal how the protein binds duplex DNA through a remodeling of the MHF1:MHF2 histone-like protein complex.
# Disease linkage
Homozygous mutations in the FANCM gene are associated with Fanconi anemia, although several individuals with FANCM deficiency do not appear to have the disorder.[7][8] A founder mutation in the Scandinavian population is also associated with a higher than average frequency of triple negative breast cancer in heterozygous carriers.[9] FANCM carriers also have elevated levels of Ovarian cancer and other solid tumours[10]
# Meiosis
Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and Homologous recombination). The pathway leading to a NCO is referred to as synthesis dependent strand annealing (SDSA).
In the plant Arabidopsis thaliana FANCM helicase antagonizes the formation of CO recombinants during meiosis, thus favoring NCO recombinants.[11] The FANCM helicase is required for genome stability in humans and yeast, and is a major factor limiting meiotic CO formation in A. thaliana.[12] A pathway involving another helicase, RECQ4A/B, also acts independently of FANCM to reduce CO recombination.[11] These two pathways likely act by unwinding different joint molecule substrates (e.g. nascent versus extended D-loops; see Figure).
Only about 4% of DSBs in A. thaliana are repaired by CO recombination;[12] the remaining 96% are likely repaired mainly by NCO recombination. Sequela-Arnaud et al.[11] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.
In the fission yeast Schizosaccharomyces pombe, FANCM helicase also directs NCO recombination during meiosis.[13] | https://www.wikidoc.org/index.php/FANCM | |
7c14377bc0b44f814ad0f2d45787b8132b615a02 | wikidoc | FARP2 | FARP2
FERM, RhoGEF and pleckstrin domain-containing protein 2 is a protein that in humans is encoded by the FARP2 gene.
# Model organisms
Model organisms have been used in the study of FARP2 function. A conditional knockout mouse line, called Farp2tm1a(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 four tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals had a thickened cerebral cortex and displayed abnormal hair shedding.
# Interactions
FARP2 has been shown to interact with PDZK1. | FARP2
FERM, RhoGEF and pleckstrin domain-containing protein 2 is a protein that in humans is encoded by the FARP2 gene.[1][2][3]
# Model organisms
Model organisms have been used in the study of FARP2 function. A conditional knockout mouse line, called Farp2tm1a(KOMP)Wtsi[8][9] 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.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.[6] Homozygous mutant animals had a thickened cerebral cortex and displayed abnormal hair shedding.[6]
# Interactions
FARP2 has been shown to interact with PDZK1.[14] | https://www.wikidoc.org/index.php/FARP2 | |
c4936ba0230457d53e8b62dc9eb9ef18437ad43a | wikidoc | FARS2 | FARS2
Phenylalanyl-tRNA synthetase, mitochondrial (FARS2) is an enzyme that in humans is encoded by the FARS2 gene. This protein encoded by FARS2 localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 14, also known as Alpers encephalopathy, as well as spastic paraplegia 77 and infantile-onset epilepsy and cytochrome c oxidase deficiency.
# Structure
FARS2 is located on the p arm of chromosome 6 in position 25.1 and has 15 exons. This gene encodes a member of the class-II aminoacyl-tRNA synthetase family. FARS2 is a phenylalanine-tRNA synthetase (PheRS) localized to the mitochondrion which consists of a single polypeptide chain, unlike the (alpha-beta)2 structure of the prokaryotic and eukaryotic cytoplasmic forms of PheRS. Structure analysis and catalytic properties indicate mitochondrial PheRSs may constitute a class of PheRS distinct from the enzymes found in prokaryotes and in the eukaryotic cytoplasm.
# Function
Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. FARS2 charges tRNA(Phe) with phenylalanine and catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe). This makes it important for mitochondrial translation and for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins. Alternative splicing results in multiple transcript variants.
## Catalytic activity
ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + L-phenylalanyl-tRNA(Phe)
# Clinical significance
Mutations in FARS2 have been associated to combined oxidative phosphorylation deficiency 14, spastic paraplegia 77, and infantile-onset epilepsy and cytochrome c oxidase deficiency. Both combined oxidative phosphorylation deficiency 14 and spastic paraplegia 77 are autosomal recessive in nature and have been linked to several pathogenic variants including Y144C, I329T, D391V, and D142Y. Combined oxidative phosphorylation deficiency 14 is characterized by neonatal onset of global developmental delay, refractory seizures, lactic acidosis, and deficiencies of multiple mitochondrial respiratory enzymes. Spastic paraplegia, meanwhile, is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs, with patients often exhibiting difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. One case of infantile-onset epilepsy and cytochrome c oxidase deficiency resulting from a FARS2 Asp325Tyr missense mutation has also been reported. Early-onset epilepsy, neurological deficits, and complex IV deficiency are the main characteristics of the disease stemming from this mutation.
# Interactions
FARS2 has been shown to have 193 binary protein-protein interactions including 12 co-complex interactions. FARS2 appears to interact with RCBTB2, KRTAP10-9, CALCOCO2, KRT40, MID2, APPL1, IKZF3, KRT13, TADA2A, STX11, TRIM27, KRTAP10-5, KRTAP10-7, TFCP2, MKRN3, KRT31, HMBOX1, AGTRAP, ADAMTSL4, NOTCH2NL, CMTM5, TRIM54, FSD2, CYSRT1, HIGD1C, homez, SPRY1, ZNF500, KRT34, YIF1A, BAG4, TPM2, SYP, KRTAP10-8, KRTAP1-1, AP1B1, TRAF2, GRB10, MESD, TRIP6, CCDC152, BEX5, FHL5, MORN3, DGAT2L6, ZNF438, KCTD17, ZNF655, BANP, SPERT, NFKBID, ZNF526, PCSK5, DVL3, AJUBA, PPP1R16B, MDFI, DPH2, CDCA4, KRTAP3-3, BACH2, KCNF1, MAN1C1, RIMBP3, ZRANB1, ISY1, FKBP7, and E7. | FARS2
Phenylalanyl-tRNA synthetase, mitochondrial (FARS2) is an enzyme that in humans is encoded by the FARS2 gene.[1] This protein encoded by FARS2 localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 14, also known as Alpers encephalopathy, as well as spastic paraplegia 77 and infantile-onset epilepsy and cytochrome c oxidase deficiency.[2][3]
# Structure
FARS2 is located on the p arm of chromosome 6 in position 25.1 and has 15 exons.[2] This gene encodes a member of the class-II aminoacyl-tRNA synthetase family.[4][5] FARS2 is a phenylalanine-tRNA synthetase (PheRS) localized to the mitochondrion which consists of a single polypeptide chain, unlike the (alpha-beta)2 structure of the prokaryotic and eukaryotic cytoplasmic forms of PheRS. Structure analysis and catalytic properties indicate mitochondrial PheRSs may constitute a class of PheRS distinct from the enzymes found in prokaryotes and in the eukaryotic cytoplasm.[2]
# Function
Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids.[2] FARS2 charges tRNA(Phe) with phenylalanine and catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe). This makes it important for mitochondrial translation and for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.[4][5][6][7] Alternative splicing results in multiple transcript variants.[2]
## Catalytic activity
ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + L-phenylalanyl-tRNA(Phe)[4][5][6][7]
# Clinical significance
Mutations in FARS2 have been associated to combined oxidative phosphorylation deficiency 14, spastic paraplegia 77, and infantile-onset epilepsy and cytochrome c oxidase deficiency. Both combined oxidative phosphorylation deficiency 14 and spastic paraplegia 77 are autosomal recessive in nature and have been linked to several pathogenic variants including Y144C,[8] I329T, D391V,[7] and D142Y.[9] Combined oxidative phosphorylation deficiency 14 is characterized by neonatal onset of global developmental delay, refractory seizures, lactic acidosis, and deficiencies of multiple mitochondrial respiratory enzymes. Spastic paraplegia, meanwhile, is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs, with patients often exhibiting difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking.[4][5] One case of infantile-onset epilepsy and cytochrome c oxidase deficiency resulting from a FARS2 Asp325Tyr missense mutation has also been reported. Early-onset epilepsy, neurological deficits, and complex IV deficiency are the main characteristics of the disease stemming from this mutation.[3]
# Interactions
FARS2 has been shown to have 193 binary protein-protein interactions including 12 co-complex interactions. FARS2 appears to interact with RCBTB2, KRTAP10-9, CALCOCO2, KRT40, MID2, APPL1, IKZF3, KRT13, TADA2A, STX11, TRIM27, KRTAP10-5, KRTAP10-7, TFCP2, MKRN3, KRT31, HMBOX1, AGTRAP, ADAMTSL4, NOTCH2NL, CMTM5, TRIM54, FSD2, CYSRT1, HIGD1C, homez, SPRY1, ZNF500, KRT34, YIF1A, BAG4, TPM2, SYP, KRTAP10-8, KRTAP1-1, AP1B1, TRAF2, GRB10, MESD, TRIP6, CCDC152, BEX5, FHL5, MORN3, DGAT2L6, ZNF438, KCTD17, ZNF655, BANP, SPERT, NFKBID, ZNF526, PCSK5, DVL3, AJUBA, PPP1R16B, MDFI, DPH2, CDCA4, KRTAP3-3, BACH2, KCNF1, MAN1C1, RIMBP3, ZRANB1, ISY1, FKBP7, and E7.[10] | https://www.wikidoc.org/index.php/FARS2 | |
ea7c49c841bbabd95b9257c72d837a912aae17ed | wikidoc | FATE1 | FATE1
Fetal and Adult Testis-Expressed 1, encoded by the FATE1 gene in humans, is a protein identified as a cancer-testis antigen (CTA) in hepatocellular carcinomas and gastric and colon cancers. It is testis-specific in the fetus (aged 6 – 11 weeks). In adults, it is expressed predominantly in the testis and adrenal glands, with some expression in the lungs, heart, kidneys and throughout the brain.
FATE1 is member of the Miff protein family, with its C-terminal domain, consisting of a transmembrane domain with a coiled-coil domain, showing high similarity to the mitochondrial fission factor (MFF) protein which is involved in mitochondrial and peroxisomal fission.
# Gene location
FATE1 gene in humans is located on the long arm of the X chromosome at region 28, from base pair 150,884,502 to base pair 150,891,617.
# Mechanism
It has been hypothesized that FATE1 uses its C-terminal transmembrane domain to attach to endoplasmic reticulum (ER) membrane and with its C-terminal coiled-coil domain it interacts with mitochondria.
FATE1 is localized in mitochondria-associated ER membranes (MAM) and modulates ER-mitochondria distance to regulate Ca2+- and drug dependent apoptosis in cancer cells.
FATE1 expression leads to reduction of Ca2+ uptake by mitochondria and therefore decrease in fragmentation of mitochondria, associated with mitochondrial Ca2+ uptake, consequently providing protection against cell death.
# Relation to cancer
FATE1 is detectable in all cell lines derived from tumors, but is low or undetectable in telomere immortalized, non-tumorigenic fibroblasts and lung epithelial cells. FATE1 is suggested to be essential for survival of tumor cells as depletion of FATE1 results in viability reduction in melanoma, breast, prostate and sarcoma settings.
Upregulation of FATE1 by a transcription factor steroidogenic factor-1 (SF-1), involved in adrenal and gonadal development as well as in adrenocortical carcinoma, increases ER-mitochondria distance and is utilized by cancer cell to functionally uncouple ER and mitochondria.
Silencing FATE1 gene sensitizes non-small-cell lung cancer cell lines to paclitaxel, a chemotherapeutic drug against many different types of cancers.
Elevated level of FATE1 is found to be associated with higher mortality rate in colorectal cancers, but in non-small-cell lung cancers, elevation of FATE1 alone did not decrease chance of survival, but decreased if RNF183 expression is also increased. | FATE1
Fetal and Adult Testis-Expressed 1, encoded by the FATE1 gene in humans, is a protein identified as a cancer-testis antigen (CTA) in hepatocellular carcinomas and gastric and colon cancers.[1][2][3] It is testis-specific in the fetus (aged 6 – 11 weeks). In adults, it is expressed predominantly in the testis and adrenal glands, with some expression in the lungs, heart, kidneys and throughout the brain.[4][5][citation needed]
FATE1 is member of the Miff protein family, with its C-terminal domain, consisting of a transmembrane domain with a coiled-coil domain, showing high similarity to the mitochondrial fission factor (MFF) protein which is involved in mitochondrial and peroxisomal fission.[3]
# Gene location
FATE1 gene in humans is located on the long arm of the X chromosome at region 28, from base pair 150,884,502 to base pair 150,891,617.[1][6]
# Mechanism
It has been hypothesized that FATE1 uses its C-terminal transmembrane domain to attach to endoplasmic reticulum (ER) membrane and with its C-terminal coiled-coil domain it interacts with mitochondria.[3]
FATE1 is localized in mitochondria-associated ER membranes (MAM) and modulates ER-mitochondria distance to regulate Ca2+- and drug dependent apoptosis in cancer cells.[3]
FATE1 expression leads to reduction of Ca2+ uptake by mitochondria and therefore decrease in fragmentation of mitochondria, associated with mitochondrial Ca2+ uptake, consequently providing protection against cell death.[7]
# Relation to cancer
FATE1 is detectable in all cell lines derived from tumors, but is low or undetectable in telomere immortalized, non-tumorigenic fibroblasts and lung epithelial cells. FATE1 is suggested to be essential for survival of tumor cells as depletion of FATE1 results in viability reduction in melanoma, breast, prostate and sarcoma settings.[8]
Upregulation of FATE1 by a transcription factor steroidogenic factor-1 (SF-1), involved in adrenal and gonadal development as well as in adrenocortical carcinoma, increases ER-mitochondria distance and is utilized by cancer cell to functionally uncouple ER and mitochondria.[3]
Silencing FATE1 gene sensitizes non-small-cell lung cancer cell lines to paclitaxel, a chemotherapeutic drug against many different types of cancers.[9]
Elevated level of FATE1 is found to be associated with higher mortality rate in colorectal cancers, but in non-small-cell lung cancers, elevation of FATE1 alone did not decrease chance of survival, but decreased if RNF183 expression is also increased.[8] | https://www.wikidoc.org/index.php/FATE1 | |
802e602681f67d9eecdbdcfd66c0dddee0643f9c | wikidoc | FBLN1 | FBLN1
FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein.
# Function
Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin-containing fibers and basement membranes. Fibulin-1 binds to a number of extracellular matrix constituents including fibronectin, nidogen-1, and the proteoglycan, versican. Fibulin-1 is also a blood protein capable of binding to fibrinogen.
# Structure
Fibulin-1 has modular domain structure and includes a series of nine epidermal growth factor-like modules followed by a fibulin-type module, a module found in all members of the fibulin gene family.
The human fibulin-1 gene, FBLN1, encodes four splice variants designated fibulin-1A, B, C and D, which differ in their carboxy terminal regions. In mouse, chicken and the nematode, C. elegans, only two fibulin-1 variants are produced, fibulin-1C and fibulin-1D.
# Interactions
FBLN1 has been shown to interact with:
- NOV/CCN3,
- amyloid precursor protein,
- entactin,
- fibrinogen, and
- fibronectin. | FBLN1
FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein.[1][2][3]
# Function
Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin-containing fibers and basement membranes. Fibulin-1 binds to a number of extracellular matrix constituents including fibronectin,[3] nidogen-1, and the proteoglycan, versican.[3][4] Fibulin-1 is also a blood protein capable of binding to fibrinogen.[5]
# Structure
Fibulin-1 has modular domain structure and includes a series of nine epidermal growth factor-like modules followed by a fibulin-type module, a module found in all members of the fibulin gene family.[2]
The human fibulin-1 gene, FBLN1, encodes four splice variants designated fibulin-1A, B, C and D, which differ in their carboxy terminal regions. In mouse, chicken and the nematode, C. elegans, only two fibulin-1 variants are produced, fibulin-1C and fibulin-1D.[1]
# Interactions
FBLN1 has been shown to interact with:
- NOV/CCN3,[6]
- amyloid precursor protein,[7]
- entactin,[8][9][10]
- fibrinogen,[5] and
- fibronectin.[11] | https://www.wikidoc.org/index.php/FBLN1 | |
212af4956673ffe1e4c6cd1d5b48fdf0b8b633f9 | wikidoc | FBLN2 | FBLN2
Fibulin-2 is a protein that in humans is encoded by the FBLN2 gene.
This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified.
# Interactions
FBLN2 has been shown to interact with Laminin, alpha 1, Laminin, alpha 5 and Perlecan. | FBLN2
Fibulin-2 is a protein that in humans is encoded by the FBLN2 gene.[1][2]
This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified.[2]
# Interactions
FBLN2 has been shown to interact with Laminin, alpha 1,[3][4] Laminin, alpha 5[3] and Perlecan.[5][6] | https://www.wikidoc.org/index.php/FBLN2 | |
f48e2cb3b90300068263a4aa4aacbd5935b42770 | wikidoc | FBLN5 | FBLN5
Fibulin-5 (also known as DANCE (developmental arteries and neural crest epidermal growth factor (EGF)-like)) is a protein that in humans is encoded by the FBLN5 gene.
# Function
The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling.
# Interactions
FBLN5 has been shown to interact with LOXL1 and apolipoprotein(a).
# Clinical relevance
FBLN5 mutations have been described in patients with age-related macular degeneration, as well as being involved in Charcot-Marie-Tooth neuropathies. | FBLN5
Fibulin-5 (also known as DANCE (developmental arteries and neural crest epidermal growth factor (EGF)-like)) is a protein that in humans is encoded by the FBLN5 gene.[1][2]
# Function
The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling.[2]
# Interactions
FBLN5 has been shown to interact with LOXL1 [3] and apolipoprotein(a).[4]
# Clinical relevance
FBLN5 mutations have been described in patients with age-related macular degeneration, as well as being involved in Charcot-Marie-Tooth neuropathies.[5] | https://www.wikidoc.org/index.php/FBLN5 | |
da3592669634892085417d87d1457dd0c24af322 | wikidoc | FBXL3 | FBXL3
FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3).
FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.
The FBXL3 protein participates in the negative feedback loop responsible for generating molecular circadian rhythms in mammals by binding to the CRY1 and CRY2 proteins to facilitate their polyubiquitination by the SCF complex and their subsequent degradation by the proteasome.
# Discovery
The Fbxl3 gene function was independently identified in 2007 by three groups lead by Michele Pagano, Joseph S. Takahashi, Dr. Patrick Nolan and Michael Hastings, respectively. Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene. Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice. The phenotypes identified in mice were mechanistically explained by Pagano who discovered that the FBXL3 protein is necessary for the reactivation of the CLOCK and BMAL1 protein heterodimer by inducing the degradation of CRY proteins.
## Overtime
Mice with the homozygous mutation of Ovtm, free run with an intrinsic period of 26 hours. Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins PER1 and PER2 are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of Per1 and Per2 transcription and translation.
## After-hours
The After-hours mutation is a substitution of cysteine to serine at position 358. Similar to Overtime, the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the Afh mutation have a free running period of about 27 hours. The Afh mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein.
## Fbxl21
The closest homologue to Fbxl3 is Fbxl21 as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, Fbxl21 has been proposed to antagonize the action of Fbxl3 through ubiquitination and stabilization of CRY proteins instead of leading it to degradation. FBXL21 is expressed predominantly in the suprachiasmatic nucleus, which is the region in the brain that functions as the master pacemaker in mammals.
# Characteristics
The human FBXL3 gene is located on the long arm of chromosome 13 at position 22.3. The protein is composed of 428 amino acids and has a mass of 48,707 Daltons. The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition. It has eight post-translational modification sites involving ubiquitination and four sites involving phosphorylation. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1.
# Function
The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the proteasome. FBXL3 binds to CRY2 by occupying its flavin adenine dinucleotide (FAD) cofactor pocket with a C-terminal tail and buries the PER-binding interface on the CRY2 protein.
The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the Bmal1 gene. Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression. FBXL3 decreases the repression of Bmal1 transcription by inactivating the REV-ERBα and HDAC3 repressor complex.
The FBXL3 protein has also been found to cooperatively degrade c-MYC when bound to CRY2. The c-MYC protein is a transcription factor important in regulating cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein.
# Interactions
FBXL3 has been shown to interact with:
- SKP1A
- CRY1
- CRY2
- REV-ERBα
- HDAC3
- c-MYC | FBXL3
FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3).[1][2]
FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.[3]
The FBXL3 protein participates in the negative feedback loop responsible for generating molecular circadian rhythms in mammals by binding to the CRY1 and CRY2 proteins to facilitate their polyubiquitination by the SCF complex and their subsequent degradation by the proteasome.[4][5][6]
# Discovery
The Fbxl3 gene function was independently identified in 2007 by three groups lead by Michele Pagano, Joseph S. Takahashi, Dr. Patrick Nolan and Michael Hastings, respectively. Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene.[5] Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice.[6] The phenotypes identified in mice were mechanistically explained by Pagano who discovered that the FBXL3 protein is necessary for the reactivation of the CLOCK and BMAL1 protein heterodimer by inducing the degradation of CRY proteins.[4]
## Overtime
Mice with the homozygous mutation of Ovtm, free run with an intrinsic period of 26 hours. Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins PER1 and PER2 are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of Per1 and Per2 transcription and translation.[5]
## After-hours
The After-hours mutation is a substitution of cysteine to serine at position 358. Similar to Overtime, the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the Afh mutation have a free running period of about 27 hours. The Afh mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein.[4][6]
## Fbxl21
The closest homologue to Fbxl3 is Fbxl21 as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, Fbxl21 has been proposed to antagonize the action of Fbxl3 through ubiquitination and stabilization of CRY proteins instead of leading it to degradation.[7] FBXL21 is expressed predominantly in the suprachiasmatic nucleus, which is the region in the brain that functions as the master pacemaker in mammals.[8]
# Characteristics
The human FBXL3 gene is located on the long arm of chromosome 13 at position 22.3.[7][9] The protein is composed of 428 amino acids and has a mass of 48,707 Daltons.[10] The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition. It has eight post-translational modification sites involving ubiquitination and four sites involving phosphorylation. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1.[9][11]
# Function
The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the proteasome.[4] FBXL3 binds to CRY2 by occupying its flavin adenine dinucleotide (FAD) cofactor pocket with a C-terminal tail and buries the PER-binding interface on the CRY2 protein.[12]
The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the Bmal1 gene. Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression.[13] FBXL3 decreases the repression of Bmal1 transcription by inactivating the REV-ERBα and HDAC3 repressor complex.[14]
The FBXL3 protein has also been found to cooperatively degrade c-MYC when bound to CRY2. The c-MYC protein is a transcription factor important in regulating cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein.[15]
# Interactions
FBXL3 has been shown to interact with:
- SKP1A[9]
- CRY1 [13]
- CRY2 [15][16]
- REV-ERBα [14]
- HDAC3 [14]
- c-MYC [15] | https://www.wikidoc.org/index.php/FBXL3 | |
a61d693a5cc4190991a32ca025a9d33c467dc10d | wikidoc | FBXL5 | FBXL5
F-box/LRR-repeat protein 5 is a protein that in humans is encoded by the FBXL5 gene.
This gene encodes a member of 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 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 Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants.
FBXL5 is an iron sensor. It promotes IRP2 ubiquitination and then its degradation. | FBXL5
F-box/LRR-repeat protein 5 is a protein that in humans is encoded by the FBXL5 gene.[1][2]
This gene encodes a member of 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 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 Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants.[2]
FBXL5 is an iron sensor. It promotes IRP2 ubiquitination and then its degradation. | https://www.wikidoc.org/index.php/FBXL5 | |
46023e47e036479356012465a62eecb5a0a9b0f6 | wikidoc | FBXO5 | FBXO5
F-box only protein 5 is a protein that in humans is encoded by the FBXO5 gene.
# Function
This gene encodes a member of 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. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.
# Disease
Gene and protein expression of FBXO5/Emi1 are increased in many human cancers and increased expression has been shown to cause chromosome instability and cancer.
# Interactions
FBXO5 has been shown to interact with:
- CDC20,
- FZR1, and
- SKP1A. | FBXO5
F-box only protein 5 is a protein that in humans is encoded by the FBXO5 gene.[1][2][3]
# Function
This gene encodes a member of 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. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.[3]
# Disease
Gene and protein expression of FBXO5/Emi1 are increased in many human cancers and increased expression has been shown to cause chromosome instability and cancer.[4]
# Interactions
FBXO5 has been shown to interact with:
- CDC20,[5]
- FZR1,[5] and
- SKP1A.[6] | https://www.wikidoc.org/index.php/FBXO5 | |
cc48133e721db3680d6b140eb836414517876a2b | wikidoc | FBXW7 | FBXW7
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.
# Function
This gene encodes a member of 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 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 was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Other well established pro-proliferative targets of FBXW7 are c-Myc and Notch1. Mono-allelic mutations in this gene are detected in sporadic cancers . These findings implicate the gene's potential role in the pathogenesis of human cancers. Despite being commonly acknowledged as a haploinsufficient tumor suppressor, mutations are not found in some cancers, such as acute myeloid leukemia and multiple myeloma. One possibility is that FBXW7 substrate stabilization is detrimental in these neoplasms. For example, the FBXW7 substrate C/EBPα suppresses AML and multiple myelomas require constitutive NF-κB signaling; therefore, disruption of FBXW7-mediated ubiquitylation of IκBd in these tumors results in cell death.
Three transcript variants encoding three different isoforms have been found for this gene.
# Interactions
FBXW7 has been shown to interact with:
- MYB,
- PPARGC1A,
- Parkin (ligase), and
- SKP1A. | FBXW7
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.[1][2][3]
# Function
This gene encodes a member of 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 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 was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Other well established pro-proliferative targets of FBXW7 are c-Myc and Notch1. Mono-allelic mutations in this gene are detected in sporadic cancers [e.g., cholangiocarcinoma (35%), T-ALL (31%), endometrial carcinoma (16%), colorectal carcinoma (16%), bladder cancer (10%), gastric carcinoma (6%), lung squamous cell carcinoma (5%), etc.]. These findings implicate the gene's potential role in the pathogenesis of human cancers. Despite being commonly acknowledged as a haploinsufficient tumor suppressor, mutations are not found in some cancers, such as acute myeloid leukemia and multiple myeloma. One possibility is that FBXW7 substrate stabilization is detrimental in these neoplasms. For example, the FBXW7 substrate C/EBPα suppresses AML[4] and multiple myelomas require constitutive NF-κB signaling; therefore, disruption of FBXW7-mediated ubiquitylation of IκBd in these tumors results in cell death.[5][6]
Three transcript variants encoding three different isoforms have been found for this gene.[3]
# Interactions
FBXW7 has been shown to interact with:
- MYB,[7]
- PPARGC1A,[8]
- Parkin (ligase),[9] and
- SKP1A.[9][10] | https://www.wikidoc.org/index.php/FBXW7 | |
fe063c1bfba22ac92c2a623619ac2b38732aadcb | wikidoc | FCER1 | FCER1
The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in the allergy disorder and parasites immunity. FcεRI is a tetrameric receptor complex that binds Fc portion of the ε heavy chain of IgE. It consists of one alpha (FcεRIα - antibody binding site), one beta (FcεRIβ - which amplifies the downstream signal), and two gamma chains (FcεRIγ - the site where the downstream signal initiates) connected by two disulfide bridges. It is constitutively expressed on mast cells and basophils and is inducible in eosinophils.
# Tissue distribution
FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells, and basophils. As a result of its cellular distribution, this receptor plays a major role in controlling allergic responses. FcεRI is also expressed on antigen-presenting cells, and controls the production of important immune mediators (cytokines, interleukins, leukotrienes, and prostaglandins) that promote inflammation. The most known mediator is histamine, which results in the five symptoms of inflammation: heat, swelling, pain, redness and loss of function.
# Mechanism of action
Crosslinking of the FcεRI via IgE-antigen complexes leads to degranulation of mast cells or basophils and release of inflammatory mediators. Under laboratory conditions, degranulation of isolated basophils can also be induced with antibodies to the FcεRIα, which crosslink the receptor. Such crosslinking and potentially pathogenic autoantibodies to the FcεRIα have been isolated from human cord blood, which suggest that they occur naturally and are present already at birth. However, their epitope on FcεRIα was masked by IgE, and the affinity of the corresponding autoantibodies found in healthy adults appeared lowered. | FCER1
The high-affinity IgE receptor, also known as FcεRI, or Fc epsilon RI, is the high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in the allergy disorder and parasites immunity. FcεRI is a tetrameric receptor complex that binds Fc portion of the ε heavy chain of IgE.[1] It consists of one alpha (FcεRIα - antibody binding site), one beta (FcεRIβ - which amplifies the downstream signal), and two gamma chains (FcεRIγ - the site where the downstream signal initiates) connected by two disulfide bridges. It is constitutively expressed on mast cells and basophils[2] and is inducible in eosinophils.
# Tissue distribution
FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells, and basophils.[3][4] As a result of its cellular distribution, this receptor plays a major role in controlling allergic responses. FcεRI is also expressed on antigen-presenting cells, and controls the production of important immune mediators (cytokines, interleukins, leukotrienes, and prostaglandins) that promote inflammation.[5] The most known mediator is histamine, which results in the five symptoms of inflammation: heat, swelling, pain, redness and loss of function.
# Mechanism of action
Crosslinking of the FcεRI via IgE-antigen complexes leads to degranulation of mast cells or basophils and release of inflammatory mediators.[6] Under laboratory conditions, degranulation of isolated basophils can also be induced with antibodies to the FcεRIα, which crosslink the receptor. Such crosslinking and potentially pathogenic autoantibodies to the FcεRIα have been isolated from human cord blood, which suggest that they occur naturally and are present already at birth. However, their epitope on FcεRIα was masked by IgE, and the affinity of the corresponding autoantibodies found in healthy adults appeared lowered.[7] | https://www.wikidoc.org/index.php/FCER1 | |
50cbfa5ed2c8cd2fef0eff9d2e3e735932836cf7 | wikidoc | FGF10 | FGF10
Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.
# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. Fibroblast growth factor 10 is a paracrine signaling molecule seen first in the limb bud and organogenesis development. FGF10 starts the developing of limbs and its involved in the branching of morphogenesis in multiple organs such as the lungs, skin, ear and salivary glands. During the limb development Tbx4/Tbx5 stimulate the production of FGF10 in the lateral plate mesoderm where it will create an epithelial-mesenchymal FGF signal with FGF8. This positive feedback loop will increase the amount of mesenchyme resulting in a bulge. Afterwards, FGF10 will induce the formation of apical ectodermal ridge (AER) where the foot and hands will be formed. Lung development uses the same epithelial-mesenchymal signaling from FGF10 in the foregut mesenchyme with FGFR2 in the foregut epithelium. FGF10 signaling is required for epithelial branching. Therefore, all branching morphogen organs such as the lungs, skin, ear and salivary glands required the constant expression of FGF10. This protein exhibits mitogenic activity for keratinizing epidermal cells, but essentially no activity for fibroblasts, which is similar to the biological activity of FGF7.
# Clinical significance
Nonsense mutations may also occur with the absence of FGF10 such as LADD and ALSG syndrome. Nevertheless complications may arise from FGF10 signaling such as pancreatic and breast cancer. Although this gene is also implicated to be a primary factor in the process of wound healing.
# Animal studies
FGF10 knockout mice die right after birth. The mice showed no developing organs such as lungs, salivary glands, kidney or definitive limbs once autopsied. Studies of the mouse homolog suggested that this gene is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of limb bud formation. | FGF10
Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.[1][2]
# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. Fibroblast growth factor 10 is a paracrine signaling molecule seen first in the limb bud and organogenesis development. FGF10 starts the developing of limbs and its involved in the branching of morphogenesis in multiple organs such as the lungs, skin, ear and salivary glands. During the limb development Tbx4/Tbx5 stimulate the production of FGF10 in the lateral plate mesoderm where it will create an epithelial-mesenchymal FGF signal with FGF8. This positive feedback loop will increase the amount of mesenchyme resulting in a bulge. Afterwards, FGF10 will induce the formation of apical ectodermal ridge (AER) where the foot and hands will be formed. Lung development uses the same epithelial-mesenchymal signaling from FGF10 in the foregut mesenchyme with FGFR2 in the foregut epithelium. FGF10 signaling is required for epithelial branching. Therefore, all branching morphogen organs such as the lungs, skin, ear and salivary glands required the constant expression of FGF10. This protein exhibits mitogenic activity for keratinizing epidermal cells, but essentially no activity for fibroblasts, which is similar to the biological activity of FGF7.[2]
# Clinical significance
Nonsense mutations may also occur with the absence of FGF10 such as LADD and ALSG syndrome. Nevertheless complications may arise from FGF10 signaling such as pancreatic and breast cancer. Although this gene is also implicated to be a primary factor in the process of wound healing.[2]
# Animal studies
FGF10 knockout mice die right after birth. The mice showed no developing organs such as lungs, salivary glands, kidney or definitive limbs once autopsied. Studies of the mouse homolog suggested that this gene is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of limb bud formation.[3] | https://www.wikidoc.org/index.php/FGF10 | |
dab0d46d590cda1516877d2738e31bc59721ee9a | wikidoc | FGF16 | FGF16
Fibroblast growth factor 16 is a protein which in humans is encoded by the FGF16 gene.
# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. The rat homolog is predominantly expressed in embryonic brown adipose tissue and has significant mitogenic activity, which suggests a role in proliferation of embryonic brown adipose tissue.
Mutations in this gene have been found associated to cases of X-linked recessive metacarpal 4/5 fusion. | FGF16
Fibroblast growth factor 16 is a protein which in humans is encoded by the FGF16 gene.[1][2]
# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. The rat homolog is predominantly expressed in embryonic brown adipose tissue and has significant mitogenic activity, which suggests a role in proliferation of embryonic brown adipose tissue.[3]
Mutations in this gene have been found associated to cases of X-linked recessive metacarpal 4/5 fusion.[4] | https://www.wikidoc.org/index.php/FGF16 | |
934c0951e5d676987641a86a362569e985f73fab | wikidoc | FGF19 | FGF19
Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders.
# Functions
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This growth factor is a high affinity, heparin dependent ligand for FGFR4. Expression of this gene was detected only in fetal but not adult brain tissue. Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development.
The orthologous protein in mouse is FGF15, which shares about 50% amino acid identity and has similar functions. Together they are often referred to as FGF15/19.
FGF19 has important roles as a hormone produced in the ileum in response to bile acid absorption. Bile acids bind to the farnesoid X receptor (FXR), stimulating FGF19 transcription. Several FXR / bile acid response elements have been identified in the FGF19 gene. Human FGF19 transcripts have been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including chenodeoxycholic acid, glycochenodeoxycholic acid and obeticholic acid in explants of ileal mucosa.
FGF19 regulates new bile acid synthesis, acting through the FGFR4/Klotho-β receptor complexes in the liver to inhibit CYP7A1.
FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models.
When FGF19 was inhibited by specific anti-FGF19 antibodies in monkeys, severe diarrhea was the result. There was also evidence of liver toxicity. Increases in bile acid synthesis, serum and fecal total bile acids, and specific bile acid transporters were found.
# Clinical significance
Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19. Surgical resection of the ileum (as often occurs in Crohn's disease) will reduce bile acid absorption and remove the stimulus for FGF19 production.
In primary bile acid diarrhea, absorption of bile acids is usually normal, but defective FGF19 production can produce excessive bile acid synthesis, as shown by increased levels of 7α-hydroxy-4-cholesten-3-one, and excessive bile acid fecal loss, indicated by reduced SeHCAT retention. This was confirmed in a prospective study of patients with chronic diarrhea, where the predictive value for FGF19 in diagnosis of primary bile acid diarrhea and response to bile acid sequestrants was demonstrated.
FGF19 is also found in the liver of patients with cholestasis. It can be synthesised in the gall-bladder and secreted into bile. FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.
Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19. FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass bariatric surgery. | FGF19
Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.[1] It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders.[2][3]
# Functions
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This growth factor is a high affinity, heparin dependent ligand for FGFR4.[4] Expression of this gene was detected only in fetal but not adult brain tissue.[5] Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development.[1][6][7]
The orthologous protein in mouse is FGF15, which shares about 50% amino acid identity and has similar functions. Together they are often referred to as FGF15/19.[2][3]
FGF19 has important roles as a hormone produced in the ileum in response to bile acid absorption.[3] Bile acids bind to the farnesoid X receptor (FXR), stimulating FGF19 transcription. Several FXR / bile acid response elements have been identified in the FGF19 gene.[8] Human FGF19 transcripts have been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including chenodeoxycholic acid, glycochenodeoxycholic acid and obeticholic acid in explants of ileal mucosa.[9]
FGF19 regulates new bile acid synthesis, acting through the FGFR4/Klotho-β receptor complexes in the liver to inhibit CYP7A1.[10][11][12][13]
FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models.[14][15][16]
When FGF19 was inhibited by specific anti-FGF19 antibodies in monkeys, severe diarrhea was the result. There was also evidence of liver toxicity. Increases in bile acid synthesis, serum and fecal total bile acids, and specific bile acid transporters were found.[17]
# Clinical significance
Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19.[18] Surgical resection of the ileum (as often occurs in Crohn's disease) will reduce bile acid absorption and remove the stimulus for FGF19 production.
In primary bile acid diarrhea, absorption of bile acids is usually normal, but defective FGF19 production can produce excessive bile acid synthesis, as shown by increased levels of 7α-hydroxy-4-cholesten-3-one, and excessive bile acid fecal loss, indicated by reduced SeHCAT retention.[18][19] This was confirmed in a prospective study of patients with chronic diarrhea, where the predictive value for FGF19 in diagnosis of primary bile acid diarrhea and response to bile acid sequestrants was demonstrated.[20]
FGF19 is also found in the liver of patients with cholestasis.[21] It can be synthesised in the gall-bladder and secreted into bile.[22] FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.[23]
Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19.[24][25] FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass bariatric surgery.[26] | https://www.wikidoc.org/index.php/FGF19 | |
6d8012e656b8864f7884cac7aaabe08203fb5380 | wikidoc | FGF21 | FGF21
Fibroblast growth factor 21 is a protein that in mammals is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho.
FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGFs act through a family of four FGF receptors. Binding is complicated and requires both interaction of the FGF molecule with an FGF receptor and binding to heparin through an heparin binding domain. Endocrine FGFs lack a heparin binding domain and thus can be released into the circulation.
FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that regulates simple sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlates with reduced dopamine neurotransmission within the nucleus accumbens.
A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.
# Regulation
FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism. HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.
While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice. In liver FGF21 expression is regulated by PPARα and levels rise substantially with both fasting and consumption of ketogenic diets.
Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.
# Function
FGF21 stimulates glucose uptake in adipocytes but not in other cell types. This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents. Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.
Beta Klotho (KLB) functions as a cofactor essential for FGF21 activity.
In cows plasma FGF21 was nearly undetectable in late pregnancy (LP), peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation (EL). Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT.
# Clinical significance
Serum FGF-21 levels were significantly increased in patients with type 2 diabetes mellitus (T2DM) which may indicate a role in the pathogenesis of T2DM. Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state.
A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.
# Animal studies
Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.
FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism.
In mice FGF21 is strongly induced in liver by prolonged fasting via PPAR-alpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response. FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state. FGF21 is induced in both rodents and humans consuming a low protein diet. FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acid methionine or with reduced levels of branched-chain amino acids.
Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC-1α-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1α and histone 3.
Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking. Chronically, the rise in FGF21 expression in the liver may protect against liver damage. | FGF21
Fibroblast growth factor 21 is a protein that in mammals is encoded by the FGF21 gene.[1][1][2] The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho.[3]
FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.[2] FGFs act through a family of four FGF receptors. Binding is complicated and requires both interaction of the FGF molecule with an FGF receptor and binding to heparin through an heparin binding domain. Endocrine FGFs lack a heparin binding domain and thus can be released into the circulation.
FGF21 is a hepatokine – i.e., a hormone secreted by the liver – that regulates simple sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the paraventricular nucleus of the hypothalamus and correlates with reduced dopamine neurotransmission within the nucleus accumbens.[4][5][6]
A single-nucleotide polymorphism of the FGF21 gene – the FGF21 rs838133 variant – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.[7][8][9]
# Regulation
FGF21 is specifically induced by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a sirtuin 1 (SIRT1)-dependent mechanism.[10] HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.[11]
While FGF21 is expressed in numerous tissues, including liver, brown adipose tissue, white adipose tissue (WAT) and pancreas, circulating levels of FGF21 are derived specifically from the liver in mice.[12] In liver FGF21 expression is regulated by PPARα and levels rise substantially with both fasting and consumption of ketogenic diets.
Liver X receptor (LXR) represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.[13]
# Function
FGF21 stimulates glucose uptake in adipocytes but not in other cell types.[14] This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents.[14] Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.[15]
Beta Klotho (KLB) functions as a cofactor essential for FGF21 activity.[16]
In cows plasma FGF21 was nearly undetectable in late pregnancy (LP), peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation (EL). Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT.[17]
# Clinical significance
Serum FGF-21 levels were significantly increased in patients with type 2 diabetes mellitus (T2DM) which may indicate a role in the pathogenesis of T2DM.[18] Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease[19] and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state.[20]
A single-nucleotide polymorphism (SNP) of the FGF21 gene – the FGF21 rs838133 variant – has been identified as a genetic mechanism responsible for the sweet tooth behavioral phenotype, a trait associated with cravings for sweets and high sugar consumption, in both humans and mice.[7][8][9]
# Animal studies
Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.[21]
FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism.[22]
In mice FGF21 is strongly induced in liver by prolonged fasting via PPAR-alpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response. FGF21 expression is also induced in white adipose tissue by PPAR-gamma, which may indicate it also regulates metabolism in the fed state.[23] FGF21 is induced in both rodents and humans consuming a low protein diet.[24][25] FGF21 expression is also induced by diets with reduced levels of the essential dietary amino acid methionine[26][27] or with reduced levels of branched-chain amino acids.[28]
Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC-1α-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1α and histone 3.[29]
Acutely, the rise in FGF21 in response to alcohol consumption inhibits further drinking. Chronically, the rise in FGF21 expression in the liver may protect against liver damage.[3] | https://www.wikidoc.org/index.php/FGF21 | |
7645d1873d1864bd186a8182de79a0ea0ffc2163 | wikidoc | FHAD1 | FHAD1
Forkhead-associated domain containing protein 1 (FHAD1) is a protein encoded by the FHAD1 gene.
As the name suggests, it has a forkhead-associated domain and an extensive coiled coil structure. It is predicted to have a function related to DNA transcription. It is localized to the nucleus and has a nuclear localization signal.
# Gene
## Locus and Size
In humans, the FHAD1 gene is located on chromosome 1 (1p36.21) and the genomic sequence is on the plus strand starting from 15236559 bp and ending at 15400283 bp. There are 3 main genes around FHAD1, out of which 2 encode proteins with known functions. Two genes, EFHD2 and Chymotrypsin-C (CTRC) lie downstream of FHAD1 on the plus strand. TMEM51 lies upstream of FHAD1.
FHAD1 is 163,682 bases long and contains 43 exons.
## Common Aliases
FHAD1 has 4 aliases, Forkhead associated phosphopeptide binding domain 1, Forkhead-associated (FHA) phosphopeptide binding domain 1, FHA Domain-Containing Protein 1, and KIAA1937.
# mRNA
The mRNA transcript of FHAD1 5138 bp long. The gene has 30 isoforms based on NCBI gene data.
# Protein
The FHAD 1 protein is 1412 aa long, weighs 16.2 kDa and has an isoelectric point of 6.52. It has 3 isoforms, namely 1, 3 and 4, but only isoform 1 is supported by experimental evidence. It consists of 1 glutamic acid rich region and 1 proline rich region.
## Domains and Motifs
### Forehead-associated domain
The FHA domain extends from 18 - 84 aa in the protein. It can recognize and bind to phosphorylation sites, specifically pSer, pThr and pTyr. The exact mechanism and function of this domain still being studied, but it is found in proteins performing many different functions, mainly DNA repair and transduction.
### Smc region
FHAD1 contains one Smc (Structural maintenance of chromosomes) region from 275 - 1401 aa. This region encodes Smc proteins that are involved in cell cycle control, cell division and chromosome separation.
### TMPIT-like protein, pfam07851
This region extends from 394 - 494 aa in FHAD1. The proteins encoded by the TMPIT proteins are predicted to be transmembrane proteins. However, there is lack of literature to support this.
### DUF342
This domain extends from 694 - 777 aa in FHAD1. It encodes a protein from a family of bacterial proteins with no known function.
## Structure
FHAD1 contains the forkhead-associated domain that consists of beta sheets. Based on structure prediction softwares, the rest of the protein consists of alpha helices and random coils. Overall, FHAD1 has a coiled coil structure as shown in the figure.
## Post-translational modifications
FHAD1 is predicted to undergo multiple different types of post-translational modifications based on prediction softwares.
- Glycosylation: There were 101 possible glycosylation sites on FHAD1 and consisted mainly of amino acids involved in O-linked glycosyaltion.
- Phosphorylation: The protein was predicted to have a large number of phosphorylation sites, at least more than 100.
- Glycation: Multiple lysine residues of FHAD1 were predicted for glycation of their ε amino groups.
- SUMOylation: 4 SUMOylation consensus sequences and 3 interaction sites were predicted on FHAD1.
- O-GlcNAc sites: 6 sites for O-GlcNAc glycosylation were predicted on FHAD1. Research has shown that this specific type of glycosylation is most abundant in nucleocytoplasmic proteins.
## Subcellular localization
FHAD1 has been predicted to be a nuclear protein with 94.1% reliability. It also contains possible nuclear localization signal sequences between 1100 - 1107 aa. Two pat4 and one pat7 sequences were predicted. Pat4 and pat7 are consensus sequences consisting of clusters of lysine or arginine residues.
# Expression
In humans, FHAD1 is expressed in testis, fallopian tube and uterine tissues in females, nasopharynx and bronchi of lungs based on studies found on the Human Protein Atlas. NCBI's EST Profile also showed that FHAD1 is highly expressed in the testis, with some expression in the trachea and esophagus. In mice, the gene was also expressed in the testis, along with the pituitary gland, lung and brain.
# Regulation of expression
FHAD1 has a promoter that extends from 15246234 – 15247380 bp and is 1147 bp long. It includes an initial part of the 5' UTR of FHAD1. Some transcription factors predicted to bind to this promoter are:
- MAX binding protein - This protein is likely a transcriptional repressor from the E-box binding factors family
- TR4/TR2 - These proteins are part of a family of nuclear receptors and bind to DR1 (direct repeat) elements of promoters. They act as anchors to recruit other corepressorsFile:5' UTR stem loop structure .png5' UTR stem loops
- Kaiso - This transcriptional regulator is encoded by the ZBTB33 gene and is involved in response to DNA damage by interacting with p53
- LYL1-E12 - This transcriptional factor is a dimer of two proteins, LYL1 and E12, where E12 is an E-box binding protein. LYL1 is also involved in some leukemias and is a possible oncogenic factor.
- Nur 77 - This protein is also known as NGFIB (Nerve growth factor IB) and belongs to a family of nuclear receptors. It is involved in apoptosis and cell growth pathways.
In the 5' UTR and 3' UTR of FHAD1, multiple stem loops are predicted to form .
# Function
FHAD1 can be involved in transcriptional regulation through interaction with other transcriptional regulators.
## Protein interactions
FHAD1 was found to be a binding partner for GTF2IRD1 (GTF2I repeat domain containing protein 1) via a yeast 2 hybrid screen. GTF2I is a gene that encodes the general transcription factor II-1. This specific study showed that GTF2IRD1 is a nuclear protein that is involved transcriptional regulation through chromatin modification. The fact that it exists in the nucleus and was found in neuronal cells correlates with the localization and functional data for FHAD1. Additionally, FHAD1 and GTF2IRD1 interacted through RD2 (repeat domain 2) of GTF2IRD1. RD2 has shown some level of DNA binding activity.
FHAD1 was found to interact (colocalization) with14-3-3 protein epsilon via cosedimentation. This protein binds to a number of binding partners, mostly by recognizing phosphothreonine or phosphoserine motifs.
## Clinical Significance
FHAD1 showed differential expression in patients diagnosed with endometriosis and obesity.
# Homology and Evolution
FHAD1 has no known paralogs. It has orthologs in the organisms in the following classes: Mammalia, Reptilia, Aves, Sarcopterygii, Actinopterygii, Gastropoda and Lingulata. There was significant conservation in the FHA domain in all the organisms in the table below.
The rate of evolution of FHAD1 was compared with that of fibrinogen and cytochrome c and it showed that FHAD1 is a rapidly evolving gene. | FHAD1
Forkhead-associated domain containing protein 1 (FHAD1) is a protein encoded by the FHAD1 gene.
As the name suggests, it has a forkhead-associated domain and an extensive coiled coil structure. It is predicted to have a function related to DNA transcription. It is localized to the nucleus and has a nuclear localization signal.
# Gene
## Locus and Size
In humans, the FHAD1 gene is located on chromosome 1 (1p36.21) and the genomic sequence is on the plus strand starting from 15236559 bp and ending at 15400283 bp.[1] There are 3 main genes around FHAD1, out of which 2 encode proteins with known functions. Two genes, EFHD2 and Chymotrypsin-C (CTRC) lie downstream of FHAD1 on the plus strand.[1] TMEM51 lies upstream of FHAD1.[1]
FHAD1 is 163,682 bases long and contains 43 exons.
## Common Aliases
FHAD1 has 4 aliases, Forkhead associated phosphopeptide binding domain 1, Forkhead-associated (FHA) phosphopeptide binding domain 1, FHA Domain-Containing Protein 1, and KIAA1937.[2]
# mRNA
The mRNA transcript of FHAD1 5138 bp long. The gene has 30 isoforms based on NCBI gene data.
# Protein
The FHAD 1 protein is 1412 aa long, weighs 16.2 kDa and has an isoelectric point of 6.52.[3] It has 3 isoforms, namely 1, 3 and 4, but only isoform 1 is supported by experimental evidence. It consists of 1 glutamic acid rich region and 1 proline rich region.
## Domains and Motifs
### Forehead-associated domain
The FHA domain extends from 18 - 84 aa in the protein. It can recognize and bind to phosphorylation sites, specifically pSer, pThr and pTyr. The exact mechanism and function of this domain still being studied, but it is found in proteins performing many different functions, mainly DNA repair and transduction.[4]
### Smc region
FHAD1 contains one Smc (Structural maintenance of chromosomes) region from 275 - 1401 aa. This region encodes Smc proteins that are involved in cell cycle control, cell division and chromosome separation.[5]
### TMPIT-like protein, pfam07851
This region extends from 394 - 494 aa in FHAD1. The proteins encoded by the TMPIT proteins are predicted to be transmembrane proteins.[6] However, there is lack of literature to support this.
### DUF342
This domain extends from 694 - 777 aa in FHAD1. It encodes a protein from a family of bacterial proteins with no known function.[7]
## Structure
FHAD1 contains the forkhead-associated domain that consists of beta sheets. Based on structure prediction softwares, the rest of the protein consists of alpha helices and random coils. Overall, FHAD1 has a coiled coil structure as shown in the figure.
## Post-translational modifications
FHAD1 is predicted to undergo multiple different types of post-translational modifications based on prediction softwares.
- Glycosylation: There were 101 possible glycosylation sites on FHAD1 and consisted mainly of amino acids involved in O-linked glycosyaltion.
- Phosphorylation: The protein was predicted to have a large number of phosphorylation sites, at least more than 100.
- Glycation: Multiple lysine residues of FHAD1 were predicted for glycation of their ε amino groups.
- SUMOylation: 4 SUMOylation consensus sequences and 3 interaction sites were predicted on FHAD1.
- O-GlcNAc sites: 6 sites for O-GlcNAc glycosylation were predicted on FHAD1. Research has shown that this specific type of glycosylation is most abundant in nucleocytoplasmic proteins.[8]
## Subcellular localization
FHAD1 has been predicted to be a nuclear protein with 94.1% reliability. It also contains possible nuclear localization signal sequences between 1100 - 1107 aa. Two pat4 and one pat7 sequences were predicted. Pat4 and pat7 are consensus sequences consisting of clusters of lysine or arginine residues.
# Expression
In humans, FHAD1 is expressed in testis, fallopian tube and uterine tissues in females, nasopharynx and bronchi of lungs based on studies found on the Human Protein Atlas.[9] NCBI's EST Profile also showed that FHAD1 is highly expressed in the testis, with some expression in the trachea and esophagus. In mice, the gene was also expressed in the testis, along with the pituitary gland, lung and brain.
# Regulation of expression
FHAD1 has a promoter that extends from 15246234 – 15247380 bp and is 1147 bp long. It includes an initial part of the 5' UTR of FHAD1. Some transcription factors predicted to bind to this promoter are:
- MAX binding protein - This protein is likely a transcriptional repressor from the E-box binding factors family[10]
- TR4/TR2 - These proteins are part of a family of nuclear receptors and bind to DR1 (direct repeat) elements of promoters. They act as anchors to recruit other corepressors[11]File:5' UTR stem loop structure .png5' UTR stem loops
- Kaiso - This transcriptional regulator is encoded by the ZBTB33 gene and is involved in response to DNA damage by interacting with p53[12]
- LYL1-E12 - This transcriptional factor is a dimer of two proteins, LYL1 and E12, where E12 is an E-box binding protein. LYL1 is also involved in some leukemias and is a possible oncogenic factor[13].
- Nur 77 - This protein is also known as NGFIB (Nerve growth factor IB) and belongs to a family of nuclear receptors. It is involved in apoptosis and cell growth pathways.[14]
In the 5' UTR and 3' UTR of FHAD1, multiple stem loops are predicted to form .
# Function
FHAD1 can be involved in transcriptional regulation through interaction with other transcriptional regulators.
## Protein interactions
FHAD1 was found to be a binding partner for GTF2IRD1 (GTF2I repeat domain containing protein 1) via a yeast 2 hybrid screen[15]. GTF2I is a gene that encodes the general transcription factor II-1. This specific study showed that GTF2IRD1 is a nuclear protein that is involved transcriptional regulation through chromatin modification. The fact that it exists in the nucleus and was found in neuronal cells correlates with the localization and functional data for FHAD1. Additionally, FHAD1 and GTF2IRD1 interacted through RD2 (repeat domain 2) of GTF2IRD1. RD2 has shown some level of DNA binding activity.
FHAD1 was found to interact (colocalization) with14-3-3 protein epsilon via cosedimentation. This protein binds to a number of binding partners, mostly by recognizing phosphothreonine or phosphoserine motifs[16].
## Clinical Significance
FHAD1 showed differential expression in patients diagnosed with endometriosis and obesity[17].
# Homology and Evolution
FHAD1 has no known paralogs. It has orthologs in the organisms in the following classes: Mammalia, Reptilia, Aves, Sarcopterygii, Actinopterygii, Gastropoda and Lingulata. There was significant conservation in the FHA domain in all the organisms in the table below.
The rate of evolution of FHAD1 was compared with that of fibrinogen and cytochrome c and it showed that FHAD1 is a rapidly evolving gene.
- | https://www.wikidoc.org/index.php/FHAD1 | |
9ad490555c4ff0b6ecf2c8a5b44db7ec0e680e6e | wikidoc | FIGLA | FIGLA
Folliculogenesis-specific basic helix-loop-helix, also known as factor in the germline alpha (FIGalpha) or transcription factor FIGa, is a protein that in humans is encoded by the FIGLA gene. The FIGLA gene is a germ cell-specific transcription factor preferentially expressed in oocytes that can be found on human chromosome 2p13.3.
# Function
This gene encodes a protein that functions in postnatal oocyte-specific gene expression. The protein is a basic helix-loop-helix transcription factor that regulates multiple oocyte-specific genes, including genes involved in folliculogenesis, oocyte differentiation, and those that encode the zona pellucida. FIGLA is related to the zona pellucida genes ZP1, ZP2, and ZP3.
# Clinical significance
Mutation in the FIGLA gene are associated with premature ovarian failure. Premature ovarian failure is a genetic disorder that leads to hypergonadotropic ovarian failure and infertility. It is believed that premature ovarian failure in humans is caused by FIGLA haploninsuffciency, which disrupts the formation of the primordial follicles. This was observed in FIGLA mice knockouts which had diminished follicular endowment and accelerated oocyte loss throughout their reproductive life span. Women with mutations in their FIGLA were shown to have a form of premature ovarian failure. As well as the failure to form primordial follicles, knockout mice also lacked zona pellucida genes Zp1, Zp2, and ZP3 expression. | FIGLA
Folliculogenesis-specific basic helix-loop-helix, also known as factor in the germline alpha (FIGalpha) or transcription factor FIGa, is a protein that in humans is encoded by the FIGLA gene.[1][2] The FIGLA gene is a germ cell-specific transcription factor preferentially expressed in oocytes that can be found on human chromosome 2p13.3.
# Function
This gene encodes a protein that functions in postnatal oocyte-specific gene expression. The protein is a basic helix-loop-helix transcription factor that regulates multiple oocyte-specific genes, including genes involved in folliculogenesis, oocyte differentiation, and those that encode the zona pellucida.[1] FIGLA is related to the zona pellucida genes ZP1, ZP2, and ZP3.
# Clinical significance
Mutation in the FIGLA gene are associated with premature ovarian failure.[3] Premature ovarian failure is a genetic disorder that leads to hypergonadotropic ovarian failure and infertility. It is believed that premature ovarian failure in humans is caused by FIGLA haploninsuffciency, which disrupts the formation of the primordial follicles.[3][4] This was observed in FIGLA mice knockouts which had diminished follicular endowment and accelerated oocyte loss throughout their reproductive life span.[3][4] Women with mutations in their FIGLA were shown to have a form of premature ovarian failure.[3][4] As well as the failure to form primordial follicles, knockout mice also lacked zona pellucida genes Zp1, Zp2, and ZP3 expression.[4] | https://www.wikidoc.org/index.php/FIGLA | |
95a610a9cf9e073e3e55fab2b0b6eaf11c22844c | wikidoc | FITM2 | FITM2
Fat storage-inducing transmembrane protein 2 is a protein that in humans is encoded by the FITM2 gene. It plays a role in fat storage. Its location is 20q13.12 and it contains 2 exons. It is also a member of the FIT protein family that has been conserved throughout evolution. Conserved from Saccharomyces cerevisiae to humans is the capability to take fat and store it as cytoplasmic triglyceride droplets. While FIT proteins facilitate the segregation of triglycerides (TGs) into cytosolic lipid droplets, they are not involved in triglyceride biosynthesis. In mammals, both FIT2 and FIT1 from the same family are present, embedded in the wall of the endoplasmic reticulum (ER) where they regulate lipid droplet formation in the cytosol. In S. cerevisiae, it also plays a role in the metabolism of phospholipids. These TGs are in the cytoplasm, encapsulated by a phospholipid monolayer in configurations or organelles that have been given many different names including lipid particles, oil bodies, adiposomes, eicosasomes, and most prevalent in scientific research – lipid droplets.
# FIT protein family
FITM2 one of two genes in its family. The other being FITM1 also known as FIT1 in which it shares 35% identity with. However, FITM1 and FITM2 have a similarity score of 50% at the amino acid level. Of the two protein coding genes, FITM2 is the ancient orthologue of this family of FIT proteins with orthologues also found in S.cerevisiae. FITM1 is also found in humans but is conserved from fish. FITM1 is not seen in adipose tissue or adipocytes but it is however, displayed mostly in muscles both skeletal and cardiac in nature. FITM2 is seen most frequently and in increased expression in adipose tissue. It is controlled by receptor γ (peroxisome proliferator activated) directly. This receptor γ is the principal transcription factor for the differentiation of adipocytes.
# Lipid droplets (LDs)
Cytosolic lipid droplets are organelles that are composed of a core that is hydrophobic in nature containing neutral lipids (like triglycerides) as well as cholesteryl esters that have a phospholipid monolayer in addition to a distinctive set of expressed proteins that surrounds them. The most generally accepted view on the creation of lipid droplets is that the neutral lipids build up between the ER leaflets due to de novo synthesizing enzymes for both triglyceride phospholipids and cholesteryl esters. This leads to the budding lipid droplets growing into the cytoplasm space. There are two different groups of lipid droplets that are known: the first is characterized by its phospholipid leaflet in continuity with the membrane of the ER and the second is classified as definitively cytosolic without a connection to the ER.
# Structure
A generally acknowledged model of the creation of a lipid droplet includes the construction of a center or lens of TGs that are produced new. This TG center is flanked by the leaflets of the membrane in the ER that sprouts off with the leaflet in the cytoplasm of the ER that surrounds the core of the lipid (neutral). It is then able to obtain interchangeable proteins that are associated with lipid droplets in the cytosol.
Studies done have suggested that FITM2 works downstream of diglyceride acyltransferase (DGAT) enzymes and binds to TGs, which is crucial for a cell’s FITM2 facilitated lipid droplet formation after being purified. When looking at the most recent view of lipid droplet formation as described above where a TG lens is established between ER leaflets, FITM2’s capacity to bind TG may aid in the increase of TG’s solubility in the ER. This can then instigate the gathering of amounts of TG necessary to mediate the progression of lipid droplet formation. Consequently, FITM2 has been referred to as a “gatekeeper” because it is situated downstream of TG biosynthesis and controls the number of lipid droplets formed.
In mammals, FITM2 protein is made up of 262 amino acids (while FIT1 part of the same family is 292 amino acids long) and has six transmembrane domains in which the N and C termini are both geared to face the cytosol. When FITM2 has a mutation in its fourth transmembrane domain that happens to be a gain-of-function one, is found overexpressed in cells, it has unfailingly caused the buildup of TG rich lipid droplets. This mutation has been described as having a significant effect on increasing both the amount and size and lipid droplets. A comparative sequence analysis of FITM2 showed a tract of residues that were deemed as extensively conserved located in this transmembrane 4 that was later named the “FIT signature sequence”.
# Function
In the cells of mammals, the construction of lipid droplets is a process that is strictly controlled, using hormone induced signals, proteins related to droplets, and lipases as well. Four observations support the role of FIT proteins in the buildup and mediation of lipid droplets. First, they have been conserved throughout evolution and solely found in the ER which is the primary site for the biosynthesis of TGs. Second, when FIT proteins are overexpressed in either the liver of a mouse of even in cells that have been cultured in vivo, there has been observable buildup of lipid droplets that are rich in triglycerides as an outcome. Third, FIT proteins are not DGATs. DGATs facilitate the biosynthesis of the TGs. FIT proteins strictly aid in the conversion of the TGs (made by DGATs) into lipid droplets. Therefore, knowing the function of these FIT proteins helps us to make sense of why they are placed downstream of the DGATs. Lastly, a shRNA-facilitated reduction in FITM2 in adipocytes (3T3-L1) or even a knockdown of it in the embryos of zebrafish resulted in great declines in lipid droplet build-up.
FITM2 has been identified as being overexpressed throughout the time 3T3-L1 (from the adipocyte cell line) is being differentiated which shows resemblance to the peroxisome proliferator-activated receptor gamma (PPAR γ) at a specific period when lipid droplets have been identified to build-up which results in the adipocyte phenotype that is seen in the 3T3-L1 cells. The overexpression of FITM2 was also displayed when the 3T3-L1 cells were combined with rosiglitazone (a PPAR γ agonist). This serves as evidence for the idea FITM2 is functionally regulated by PPAR γ.
The specificity of the tissue dispersal of FITM1 and FITM2 and the fact that FITM2 binds TG more intensely than FITM1 (which forms a weak bond) presents separate functions for these FIT family proteins in regards to the metabolism of lipids. Lipid droplet development induced by FITM2 may function in TG storage for long-term purposes in adipose whereas FITM1 may function to make the smaller lipid droplets that are seen in skeletal muscle where there is a fast replacement of LDs.
# Clinical Uses
When physiological circumstances are regular, lipid droplets are depended on to keep energy balanced at not only at the cellular level, but for the sake of the whole organism’s sustainability. However, excessive acquirement of lipid droplets can result in obesity, and increased risk for obtaining disease including type 2 diabetes, atherosclerosis, and heart disease. The documentation of the FIT proteins should help in evolving substances to revert FIT expression or activity back to a normal regulatory state as treatment for these diseases.
In addition, a recent study was performed on a family with a new homozygous mutation in FITM2, resulting in a truncated protein. The individuals in the family that are affected by this mutation exhibit Siddiqi syndrome. Siddiqi syndrome is identified by gradual development of hearing loss, late motor development, decreased BMI, ichthyosis-like changes to the skin, and minor fiber neuropathy. In this family, the collection of symptoms presented for this syndrome is new. However, they also overlap with several recognized monogenic conditions that are neurological in nature including Troyer syndrome, Mohr-Tranebjaerg syndrome, and Megdel syndrome. | FITM2
Fat storage-inducing transmembrane protein 2 is a protein that in humans is encoded by the FITM2 gene. It plays a role in fat storage. Its location is 20q13.12 and it contains 2 exons.[1] It is also a member of the FIT protein family that has been conserved throughout evolution. Conserved from Saccharomyces cerevisiae to humans is the capability to take fat and store it as cytoplasmic triglyceride droplets.[2] While FIT proteins facilitate the segregation of triglycerides (TGs) into cytosolic lipid droplets, they are not involved in triglyceride biosynthesis.[3] In mammals, both FIT2 and FIT1 from the same family are present, embedded in the wall of the endoplasmic reticulum (ER) where they regulate lipid droplet formation in the cytosol. In S. cerevisiae, it also plays a role in the metabolism of phospholipids.[4] These TGs are in the cytoplasm, encapsulated by a phospholipid monolayer in configurations or organelles that have been given many different names including lipid particles, oil bodies, adiposomes, eicosasomes, and most prevalent in scientific research – lipid droplets.[2]
# FIT protein family
FITM2 one of two genes in its family. The other being FITM1 also known as FIT1 in which it shares 35% identity with.[4] However, FITM1 and FITM2 have a similarity score of 50% at the amino acid level. Of the two protein coding genes, FITM2 is the ancient orthologue of this family of FIT proteins with orthologues also found in S.cerevisiae.[3] FITM1 is also found in humans but is conserved from fish. FITM1 is not seen in adipose tissue or adipocytes but it is however, displayed mostly in muscles both skeletal and cardiac in nature.[3] FITM2 is seen most frequently and in increased expression in adipose tissue. It is controlled by receptor γ (peroxisome proliferator activated) directly. This receptor γ is the principal transcription factor for the differentiation of adipocytes.[4]
# Lipid droplets (LDs)
Cytosolic lipid droplets are organelles that are composed of a core that is hydrophobic in nature containing neutral lipids (like triglycerides) as well as cholesteryl esters that have a phospholipid monolayer in addition to a distinctive set of expressed proteins that surrounds them.[4] The most generally accepted view on the creation of lipid droplets is that the neutral lipids build up between the ER leaflets due to de novo synthesizing enzymes for both triglyceride phospholipids and cholesteryl esters. This leads to the budding lipid droplets growing into the cytoplasm space.[4] There are two different groups of lipid droplets that are known: the first is characterized by its phospholipid leaflet in continuity with the membrane of the ER and the second is classified as definitively cytosolic without a connection to the ER.[4]
# Structure
A generally acknowledged model of the creation of a lipid droplet includes the construction of a center or lens of TGs that are produced new. This TG center is flanked by the leaflets of the membrane in the ER that sprouts off with the leaflet in the cytoplasm of the ER that surrounds the core of the lipid (neutral). It is then able to obtain interchangeable proteins that are associated with lipid droplets in the cytosol.[2]
Studies done have suggested that FITM2 works downstream of diglyceride acyltransferase (DGAT) enzymes and binds to TGs, which is crucial for a cell’s FITM2 facilitated lipid droplet formation after being purified.[5] When looking at the most recent view of lipid droplet formation as described above where a TG lens is established between ER leaflets, FITM2’s capacity to bind TG may aid in the increase of TG’s solubility in the ER. This can then instigate the gathering of amounts of TG necessary to mediate the progression of lipid droplet formation. Consequently, FITM2 has been referred to as a “gatekeeper” because it is situated downstream of TG biosynthesis and controls the number of lipid droplets formed.[5]
In mammals, FITM2 protein is made up of 262 amino acids (while FIT1 part of the same family is 292 amino acids long) and has six transmembrane domains in which the N and C termini are both geared to face the cytosol.[3] When FITM2 has a mutation in its fourth transmembrane domain that happens to be a gain-of-function one, is found overexpressed in cells, it has unfailingly caused the buildup of TG rich lipid droplets. This mutation has been described as having a significant effect on increasing both the amount and size and lipid droplets.[4] A comparative sequence analysis of FITM2 showed a tract of residues that were deemed as extensively conserved located in this transmembrane 4 that was later named the “FIT signature sequence”.[6]
# Function
In the cells of mammals, the construction of lipid droplets is a process that is strictly controlled, using hormone induced signals, proteins related to droplets, and lipases as well. Four observations support the role of FIT proteins in the buildup and mediation of lipid droplets.[2] First, they have been conserved throughout evolution and solely found in the ER which is the primary site for the biosynthesis of TGs.[2] Second, when FIT proteins are overexpressed in either the liver of a mouse of even in cells that have been cultured in vivo, there has been observable buildup of lipid droplets that are rich in triglycerides as an outcome.[2] Third, FIT proteins are not DGATs. DGATs facilitate the biosynthesis of the TGs. FIT proteins strictly aid in the conversion of the TGs (made by DGATs) into lipid droplets. Therefore, knowing the function of these FIT proteins helps us to make sense of why they are placed downstream of the DGATs.[2] Lastly, a shRNA-facilitated reduction in FITM2 in adipocytes (3T3-L1) or even a knockdown of it in the embryos of zebrafish resulted in great declines in lipid droplet build-up.[2]
FITM2 has been identified as being overexpressed throughout the time 3T3-L1 (from the adipocyte cell line) is being differentiated which shows resemblance to the peroxisome proliferator-activated receptor gamma (PPAR γ) at a specific period when lipid droplets have been identified to build-up which results in the adipocyte phenotype that is seen in the 3T3-L1 cells.[2] The overexpression of FITM2 was also displayed when the 3T3-L1 cells were combined with rosiglitazone (a PPAR γ agonist). This serves as evidence for the idea FITM2 is functionally regulated by PPAR γ.[2]
The specificity of the tissue dispersal of FITM1 and FITM2 and the fact that FITM2 binds TG more intensely than FITM1 (which forms a weak bond) presents separate functions for these FIT family proteins in regards to the metabolism of lipids.[3] Lipid droplet development induced by FITM2 may function in TG storage for long-term purposes in adipose whereas FITM1 may function to make the smaller lipid droplets that are seen in skeletal muscle where there is a fast replacement of LDs.[3]
# Clinical Uses
When physiological circumstances are regular, lipid droplets are depended on to keep energy balanced at not only at the cellular level, but for the sake of the whole organism’s sustainability. However, excessive acquirement of lipid droplets can result in obesity, and increased risk for obtaining disease including type 2 diabetes, atherosclerosis, and heart disease.[2] The documentation of the FIT proteins should help in evolving substances to revert FIT expression or activity back to a normal regulatory state as treatment for these diseases.
In addition, a recent study was performed on a family with a new homozygous mutation in FITM2, resulting in a truncated protein. The individuals in the family that are affected by this mutation exhibit Siddiqi syndrome. Siddiqi syndrome is identified by gradual development of hearing loss, late motor development, decreased BMI, ichthyosis-like changes to the skin, and minor fiber neuropathy.[7] In this family, the collection of symptoms presented for this syndrome is new. However, they also overlap with several recognized monogenic conditions that are neurological in nature including Troyer syndrome, Mohr-Tranebjaerg syndrome, and Megdel syndrome.[7] | https://www.wikidoc.org/index.php/FITM2 | |
823465152525382d402ec092c17e55d3d7646935 | wikidoc | FKBP3 | FKBP3
FK506-binding protein 3 is a protein that in humans is encoded by the FKBP3 gene.
# Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin. It has a higher affinity for rapamycin than for FK506 and thus may be an important target molecule for immunosuppression by rapamycin.
# Interactions
FKBP3 has been shown to interact with YY1, HDAC1, Histone deacetylase 2, DNA, and Mdm2. | FKBP3
FK506-binding protein 3 is a protein that in humans is encoded by the FKBP3 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin. It has a higher affinity for rapamycin than for FK506 and thus may be an important target molecule for immunosuppression by rapamycin.[3]
# Interactions
FKBP3 has been shown to interact with YY1,[4] HDAC1,[4] Histone deacetylase 2[4], DNA,[5] and Mdm2.[6] | https://www.wikidoc.org/index.php/FKBP3 | |
862d8d96d9dcba050c24be91b0db115da0b10b5c | wikidoc | FKBP5 | FKBP5
FK506 binding protein 5, also known as FKBP5, is a protein which in humans is encoded by the FKBP5 gene.
# Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature corticoid receptor hetero-complexes (i.e. progesterone-, glucocorticoid-, mineralocorticoid-receptor complexes) along with the 90 kDa heat shock protein and P23 protein.
# Clinical significance
The FKBP5 gene has been found to have multiple polyadenylation sites and is statistically associated with a higher rate of depressive disorders.
# Interactions
FKBP5 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1. | FKBP5
FK506 binding protein 5, also known as FKBP5, is a protein which in humans is encoded by the FKBP5 gene.[1]
# Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature corticoid receptor hetero-complexes (i.e. progesterone-, glucocorticoid-, mineralocorticoid-receptor complexes) along with the 90 kDa heat shock protein and P23 protein.
# Clinical significance
The FKBP5 gene has been found to have multiple polyadenylation sites[1] and is statistically associated with a higher rate of depressive disorders.[2]
# Interactions
FKBP5 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[3] | https://www.wikidoc.org/index.php/FKBP5 | |
6b8149a57122d349c2f3c6b22b83cf6c53ea656d | wikidoc | FKBP6 | FKBP6
FK506 binding protein 6, also known as FKBP6, is a human gene. The encoded protein shows structural homology to FKBP immunophilins, which bind to the immunosuppressants FK506 and rapamycin.
FKBP6 is essential for homologous chromosome pairing in meiosis during spermatogenesis. Targeted inactivation of FKBP6 in mice results in infertile males, but apparently normal females. Rats with spermatogenic failure at meiosis were found to have a deletion in the exon 8 portion of the FKBP6 gene. Mutations in this gene have been associated with male infertility in humans.
FKBP6 is deleted in Williams syndrome, however this hemizygous loss of FKBP6 is not associated with infertility.
FKBP6 contains 3 α-helices and 11 β-sheet strands, and as a FK506-family protein, has been shown to be a potent immunosuppressant which can assist in the prevention of allograft rejections. | FKBP6
FK506 binding protein 6, also known as FKBP6, is a human gene. The encoded protein shows structural homology to FKBP immunophilins, which bind to the immunosuppressants FK506 and rapamycin.
FKBP6 is essential for homologous chromosome pairing in meiosis during spermatogenesis. Targeted inactivation of FKBP6 in mice results in infertile males, but apparently normal females. Rats with spermatogenic failure at meiosis were found to have a deletion in the exon 8 portion of the FKBP6 gene.[2] Mutations in this gene have been associated with male infertility in humans.[3]
FKBP6 is deleted in Williams syndrome, however this hemizygous loss of FKBP6 is not associated with infertility.[4]
FKBP6 contains 3 α-helices and 11 β-sheet strands,[1] and as a FK506-family protein, has been shown to be a potent immunosuppressant which can assist in the prevention of allograft rejections.[5] | https://www.wikidoc.org/index.php/FKBP6 | |
02097e86185437703c3ad8bfee8706cec05bcb5c | wikidoc | FKBPL | FKBPL
FK506-binding protein like, also known as FKBPL, is a protein that in humans is encoded by the FKBPL gene.
# Function
FKBPL has similarity to the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. The encoded protein is thought to have a potential role in the induced radioresistance. Also it appears to have some involvement in the control of the cell cycle.
FKBPL is involved in cellular response to stress. It was first isolated in 1999 and was initially named DIR1. It was later reclassified because of its homology to the FKBP family of proteins and was renamed FKBP-like (FKBPL). A separate study that found it to be involved in the stabilisation of newly synthesised p21 termed it Wisp39.
It is known to interact with Hsp90, glucocorticoid receptor and dynamitin and may play a role in signalling, like other FKBPs.
FKBPL has also been shown to influence estrogen receptor signalling and can have a determinant effect on response to the breast cancer drug tamoxifen. | FKBPL
FK506-binding protein like, also known as FKBPL, is a protein that in humans is encoded by the FKBPL gene.[1]
# Function
FKBPL has similarity to the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. The encoded protein is thought to have a potential role in the induced radioresistance. Also it appears to have some involvement in the control of the cell cycle.[2]
FKBPL is involved in cellular response to stress. It was first isolated in 1999 and was initially named DIR1.[3] It was later reclassified because of its homology to the FKBP family of proteins and was renamed FKBP-like (FKBPL). A separate study that found it to be involved in the stabilisation of newly synthesised p21 termed it Wisp39.[4]
It is known to interact with Hsp90, glucocorticoid receptor and dynamitin and may play a role in signalling, like other FKBPs.[5]
FKBPL has also been shown to influence estrogen receptor signalling and can have a determinant effect on response to the breast cancer drug tamoxifen.[6] | https://www.wikidoc.org/index.php/FKBPL | |
9f6cd9f9037d8fce8690e12a169e724925092b01 | wikidoc | FLOT2 | FLOT2
Flotillin-2 is a protein that in humans is encoded by the FLOT2 gene.
Flotillin 2 (flot-2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathways. Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may influence tumour progression.
Caveolae are small domains on the inner cell membrane involved in vesicular trafficking and signal transduction. This gene encodes a caveolae-associated, integral membrane protein, which is thought to function in neuronal signaling. | FLOT2
Flotillin-2 is a protein that in humans is encoded by the FLOT2 gene.[1][2]
Flotillin 2 (flot-2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathways. Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may influence tumour progression.[3]
Caveolae are small domains on the inner cell membrane involved in vesicular trafficking and signal transduction. This gene encodes a caveolae-associated, integral membrane protein, which is thought to function in neuronal signaling.[2] | https://www.wikidoc.org/index.php/FLOT2 | |
70cee9c7612c8384c2f5bdd26d3ff25518761614 | wikidoc | FMNL1 | FMNL1
Formin-like protein 1 is a protein that in humans is encoded by the FMNL1 gene.
This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined.
# Interactions
FMNL1 has been shown to interact with Profilin 1, PFN2 and RAC1. | FMNL1
Formin-like protein 1 is a protein that in humans is encoded by the FMNL1 gene.[1][2]
This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined.[2]
# Interactions
FMNL1 has been shown to interact with Profilin 1,[3] PFN2[3] and RAC1.[3] | https://www.wikidoc.org/index.php/FMNL1 | |
f8f7483f926cde690184a59b25159b2d40419d93 | wikidoc | FMNL2 | FMNL2
Formin-like protein 2 is a protein that in humans is encoded by the FMNL2 gene.
# Expression
Alternatively spliced transcript variants of the FMNL2 gene encoding different isoforms have been described. The full length FMNL2 (FRL3) protein (1092 amino acids-NCBI Reference Sequence: NP_443137.2) is regulated through autoinhibition, and may become activated through Rho proteins. The FMNL2 gene is expressed in multiple human tissues.
# Function
Formin-like protein 2 is a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity.
# Clinical significance
FMNL2 expression is considerably higher in colorectal cancer tumors compared to normal tissue. | FMNL2
Formin-like protein 2 is a protein that in humans is encoded by the FMNL2 gene.[1][2]
# Expression
Alternatively spliced transcript variants of the FMNL2 gene encoding different isoforms have been described.[1] The full length FMNL2 (FRL3) protein (1092 amino acids-NCBI Reference Sequence: NP_443137.2[3]) is regulated through autoinhibition, and may become activated through Rho proteins.[4] The FMNL2 gene is expressed in multiple human tissues.[5]
# Function
Formin-like protein 2 is a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity.[1]
# Clinical significance
FMNL2 expression is considerably higher in colorectal cancer tumors compared to normal tissue.[6] | https://www.wikidoc.org/index.php/FMNL2 | |
14efe23fd56a2a0007e44d543c5864205d7eba7f | wikidoc | FNAEG | FNAEG
The Fichier National Automatisé des Empreintes Génétiques (Automated National File of Genetic Prints) is the French national DNA database, used by both the national police force and local gendarmerie.
# Origins of FNAEG
In 1996 Alain Marsaud, the former chief of the French central antiterrorist service, proposed the creation of a central DNA database. The following year, a bill was filed relating to the implementation of a national database for identification of child sex offenders. In June 1998, the Guigou law on the prevention of sexually-related crimes, passed by the Plural Left Jospin government, created a national DNA database. The implementation, originally planned for 1999, was finally completed in 2001, with the database itself located at Écully in the Rhône, managed by a subdirectorate of the technical and scientific departments of the French police force.
In the aftermath of the September 11 attacks on the USA in 2001, the French government increased the scope of the database to include DNA related to other serious criminal offences, such as voluntary manslaughter, criminal violence and terrorism.
A further 'law for interior safety' introduced by Nicolas Sarkozy on March 18, 2003 expanded the scope still further to cover almost all violent crimes to people or property and other serious crimes such as drug trafficking etc., but not traffic offenses or crimes committed abroad.
# Relative size
As at October 1 2003, FNAEG was understood to contain the DNA records of approximately 8,000 convicted criminals and another 3,200 suspects. In 2006, this number was believed to now be in excess of 330,000 entries.
# Privacy concerns
With the expansion of the database in 2003, it also became an offense for suspects to fail to provide a DNA sample, with punishment ranging from a prison sentence of between six months and two years, and a fine of between 7,500 and 30,000 euros.
At the end of 2006, the media raised the case of individuals refusing to provide DNA samples. Many of them were civil disobedience activists opposed to Genetically modified organism (GMO) (See fr:Faucheurs volontaires). Although this was only around 200 cases, they denounced what they regarded as the threat to personal freedom. | FNAEG
The Fichier National Automatisé des Empreintes Génétiques (Automated National File of Genetic Prints) is the French national DNA database, used by both the national police force and local gendarmerie.
# Origins of FNAEG
In 1996 Alain Marsaud, the former chief of the French central antiterrorist service, proposed the creation of a central DNA database. The following year, a bill was filed relating to the implementation of a national database for identification of child sex offenders. In June 1998, the Guigou law on the prevention of sexually-related crimes, passed by the Plural Left Jospin government, created a national DNA database. The implementation, originally planned for 1999, was finally completed in 2001, with the database itself located at Écully in the Rhône, managed by a subdirectorate of the technical and scientific departments of the French police force.
In the aftermath of the September 11 attacks on the USA in 2001, the French government increased the scope of the database to include DNA related to other serious criminal offences, such as voluntary manslaughter, criminal violence and terrorism.
A further 'law for interior safety' introduced by Nicolas Sarkozy on March 18, 2003 expanded the scope still further to cover almost all violent crimes to people or property and other serious crimes such as drug trafficking etc., but not traffic offenses or crimes committed abroad.
# Relative size
As at October 1 2003, FNAEG was understood to contain the DNA records of approximately 8,000 convicted criminals and another 3,200 suspects. In 2006, this number was believed to now be in excess of 330,000 entries[1].
# Privacy concerns
With the expansion of the database in 2003, it also became an offense for suspects to fail to provide a DNA sample, with punishment ranging from a prison sentence of between six months and two years, and a fine of between 7,500 and 30,000 euros.
At the end of 2006, the media raised the case of individuals refusing to provide DNA samples. Many of them were civil disobedience activists opposed to Genetically modified organism (GMO) (See fr:Faucheurs volontaires). Although this was only around 200 cases, they denounced what they regarded as the threat to personal freedom. | https://www.wikidoc.org/index.php/FNAEG | |
1a52cf16ce1d00777d189ecbf4c7bd6f4295b2f3 | wikidoc | FNDC5 | FNDC5
Fibronectin type III domain-containing protein 5, the precursor of irisin, is a protein that is encoded by the FNDC5 gene. Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.
Fibronectin domain-containing protein 5 is a membrane protein comprising a short cytoplasmic domain, a transmembrane segment, and an ectodomain consisting of a ~100 kDa fibronectin type III (FNIII) domain.
# History
FNDC5 was discovered during a genome search for fibronectin type III domains and independently in a search for peroxisomal proteins.
The ectodomain was proposed to be cleaved to give a soluble peptide hormone named irisin. Separately it was proposed that irisin is secreted from muscle in response to exercise, and may mediate some beneficial effects of exercise in humans and the potential for generating weight loss and blocking diabetes has been suggested. Others questioned these findings.
# Biosynthesis and secretion
The FNDC5 gene encodes a prohormone, a single-pass type I membrane protein (human, 212 amino acids; mouse and rat, 209 amino acids) that is upregulated by muscular exercise and undergoes post-translational processing to generate irisin. The sequence of the protein includes a signal peptide, a single fibronectin type III domain, and a C-terminal hydrophobic domain that is anchored in the cell membrane.
The production of irisin is similar to the shedding and release of other hormones and hormone-like polypeptides, such as epidermal growth factor and TGF alpha, from transmembrane precursors. After the N-terminal signal peptide is removed, the peptide is proteolytically cleaved from the C-terminal moiety, glycosylated and released as a hormone of 112 amino acids (in human, amino acids 32-143 of the full-length protein; in mouse and rat, amino acids 29-140) that comprises most of the FNIII repeat region.
The sequence of irisin, the cleaved and secreted portion of FNDC5, is highly conserved in mammals; the human and murine sequences are identical. However, the start codon of human FNDC5 is mutated to ATA, which causes it to be expressed at only 1% the level of other animals with the normal ATG start. A mass spectrometry study reported irisin levels ~3 ng/ml in human plasma, a level on par with other key human hormones, such as insulin.. There is no comparable study of irisin levels in other animals, where the ATG vs ATA start codon would predict a 100x higher concentration.
A difference in the nucleotide sequence of human FNDC5 from that of mouse Fndc5 creates a different initiation codon, potentially generating a protein that begins at methionine-76 (Met-76). A protein initiated at Met-76 would be missing the signal peptide and would be trapped in the cytoplasm. Via mass spectrometry, irisin has been found to circulate in humans in levels similar to other key hormones, such as insulin..
# Function
Exercise causes increased expression in muscle of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), which is involved in adaptation to exercise. In mice, this causes production of the FNDC5 protein which is cleaved to give a new product irisin. Due to its production through a mechanism initiated by muscular contraction, irisin has been classified as a myokine.
Based on the findings that FNDC5 induces thermogenin expression in fat cells, overexpression of FNDC5 in the liver of mice prevents diet-induced weight gain, and FNDC5 mRNA levels are elevated in human muscle samples after exercise, it has been proposed that irisin promotes the conversion of white fat to brown fat in humans which would make it a health promoting hormone. However this proposal has been challenged because FNDC5 is upregulated only in highly active elderly humans.
A 2016 in vitro study of white and brown fat cell tissue found dose-related upregulation of a protein called UCP1 that contributes to the browning of white fat and found other markers that would indicate that the white cells were browning and that fat cells were more metabolically active. Many of the stem cells became a type of cell that matures into bone. The tissue treated with irisin produced about 40 percent fewer mature fat cells.
In mice, irisin released from skeletal muscle during exercise acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia. | FNDC5
Fibronectin type III domain-containing protein 5, the precursor of irisin, is a protein that is encoded by the FNDC5 gene.[1] Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.[2]
Fibronectin domain-containing protein 5 is a membrane protein comprising a short cytoplasmic domain, a transmembrane segment, and an ectodomain consisting of a ~100 kDa fibronectin type III (FNIII) domain.
# History
FNDC5 was discovered during a genome search for fibronectin type III domains[3] and independently in a search for peroxisomal proteins.[1][4]
The ectodomain was proposed to be cleaved to give a soluble peptide hormone named irisin. Separately it was proposed that irisin is secreted from muscle in response to exercise, and may mediate some beneficial effects of exercise in humans and the potential for generating weight loss and blocking diabetes has been suggested.[2][5][6][7][8][9][10][11] Others questioned these findings.[1][12][13][14]
# Biosynthesis and secretion
The FNDC5 gene encodes a prohormone, a single-pass type I membrane protein (human, 212 amino acids; mouse and rat, 209 amino acids) that is upregulated by muscular exercise and undergoes post-translational processing to generate irisin. The sequence of the protein includes a signal peptide, a single fibronectin type III domain, and a C-terminal hydrophobic domain that is anchored in the cell membrane.
The production of irisin is similar to the shedding and release of other hormones and hormone-like polypeptides, such as epidermal growth factor and TGF alpha, from transmembrane precursors. After the N-terminal signal peptide is removed, the peptide is proteolytically cleaved from the C-terminal moiety, glycosylated and released as a hormone of 112 amino acids (in human, amino acids 32-143 of the full-length protein; in mouse and rat, amino acids 29-140) that comprises most of the FNIII repeat region.
The sequence of irisin, the cleaved and secreted portion of FNDC5, is highly conserved in mammals; the human and murine sequences are identical.[2] However, the start codon of human FNDC5 is mutated to ATA, which causes it to be expressed at only 1% the level of other animals with the normal ATG start. A mass spectrometry study reported irisin levels ~3 ng/ml in human plasma, a level on par with other key human hormones, such as insulin.[15]. There is no comparable study of irisin levels in other animals, where the ATG vs ATA start codon would predict a 100x higher concentration.
A difference in the nucleotide sequence of human FNDC5 from that of mouse Fndc5 creates a different initiation codon, potentially generating a protein that begins at methionine-76 (Met-76). A protein initiated at Met-76 would be missing the signal peptide and would be trapped in the cytoplasm. Via mass spectrometry, irisin has been found to circulate in humans in levels similar to other key hormones, such as insulin.[15].
# Function
Exercise causes increased expression in muscle of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), which is involved in adaptation to exercise. In mice, this causes production of the FNDC5 protein which is cleaved to give a new product irisin.[2][7] Due to its production through a mechanism initiated by muscular contraction, irisin has been classified as a myokine.[16]
Based on the findings that FNDC5 induces thermogenin expression in fat cells, overexpression of FNDC5 in the liver of mice prevents diet-induced weight gain, and FNDC5 mRNA levels are elevated in human muscle samples after exercise, it has been proposed that irisin promotes the conversion of white fat to brown fat in humans which would make it a health promoting hormone.[5][6] However this proposal has been challenged[17] because FNDC5 is upregulated only in highly active elderly humans.[12]
A 2016 in vitro study of white and brown fat cell tissue found dose-related upregulation of a protein called UCP1 that contributes to the browning of white fat and found other markers that would indicate that the white cells were browning and that fat cells were more metabolically active. Many of the stem cells became a type of cell that matures into bone. The tissue treated with irisin produced about 40 percent fewer mature fat cells.[18]
In mice, irisin released from skeletal muscle during exercise acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia.[19][20][unreliable medical source] | https://www.wikidoc.org/index.php/FNDC5 |
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