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804e25ae9b5b7321467b84c32cdabb83ac650f30 | wikidoc | FA2H | FA2H
Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.
# Function
This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups.
# Clinical significance
Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia as well as fatty acid hydroxylase-associated neurodegeneration.
FA2H has been shown to modulate cell differentiation in vitro. FA2H is may be a Δ9-THC-regulated gene, as Δ9-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells. | FA2H
Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.[1]
# Function
This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups.[1]
# Clinical significance
Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia[1] as well as fatty acid hydroxylase-associated neurodegeneration.[2]
FA2H has been shown to modulate cell differentiation in vitro. FA2H is may be a Δ9-THC-regulated gene, as Δ9-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.[3] | https://www.wikidoc.org/index.php/FA2H | |
c9cc104abf73e5600be2c8aca3251931a292c08f | wikidoc | FADD | FADD
Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.
FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development.
# Structure
FADD is a 23 kDa protein, made up of 280 amino acids. It contains two main domains: a C terminal death domain (DD) and an N terminal death effector domain (DED). Each domain, although sharing very little sequence similarity, are structurally similar to one another, with each consisting of 6 α helices. The DD of FADD binds to receptors such as the Fas receptor at the plasma membrane via their DD. The interaction between the death domains are electrostatic interactions involving α helices 2 and 3 of the 6 helix domain. The DED binds to the DED of intracellular molecules such as procaspase 8. It is thought that this interaction occurs through hydrophobic interactions.
# Functions
## Extrinsic apoptosis
Upon stimulation by the Fas ligand, the Fas receptor trimerises. Many receptors, including Fas, contain a cytoplasmic DD and are therefore named death receptors. FADD binds to the DD of this trimeric structure via its death domain resulting in unmasking of FADD's DED and subsequent recruitment of procaspase 8 and 10 via an interaction between the DEDs of both FADD and the procaspases. This generates a complex known as the death inducing signalling complex (DISC). Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with other procaspases of the same type, autocatalytic cleavage occurs at an aspartate residue within their own structures, resulting in an activated protein. This activated protein can then go on to cleave and activate further caspases, initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell.
Binding of TRAIL to death receptors four and five (DR4 and DR5) can lead to apoptosis by the same mechanism.
Apoptosis can also be triggered by binding of a ligand to tumor necrosis factor receptor 1 (TNFR1); however, the mechanism by which this occurs is slightly more complex. Another DD-containing adaptor protein named TRADD, along with other proteins, binds to activated TNF1R, forming what is known as complex I. This results in activation of the NFκB pathway, which promotes cell survival. This complex is then internalised, and FADD binds to TRADD via an interaction of the DD’s of the two adapter proteins, forming what is known as complex II. FADD again recruits procaspase 8, which initiates the caspase cascade leading to apoptosis.
## Necroptosis
FADD also plays a role in regulating necroptosis, a process requiring the serine/threonine kinases, RIPK1 and RIPK3. Activated caspase 8 cleaves these kinases, inhibiting necroptosis. Since activation of caspase 8 requires FADD in order to bring the procaspase 8 molecules into close proximity to one another to facilitate their activation, FADD is required for negatively regulating necroptosis. In accordance, cells deficient in FADD induce necroptosis as they are unable to recruit and activate procaspase 8.
FADD can also bind to RIPK1 and RIPK3 directly, however the significance of this interaction is currently unclear.
## Autophagic cell death
Autophagy is a process which allows cell survival under stressed conditions but can also lead to cell death.
Using its DD, FADD interacts with ATG5, a protein involved in autophagy. This interaction has been shown to be essential for autophagic cell death, which is induced by IFN-γ.
In contrast, it has also been found to inhibit autophagic cell death and therefore promote cell survival. FADD binds to ATG5 in a complex which also contains ATG12, Caspase 8 and RIPK1. The formation of this complex is stimulated by autophagic signalling. Caspase 8 then cleaves RIPK1, leading to inhibition of this signalling, inhibiting cell death.
## Development
FADD knockout in mouse embryos is lethal, showing a role for FADD in embryonic development. This is thought to be due to abnormal development of the heart. This abnormal heart development may be due to FADD dependent regulation of the NFκB pathway.
FADD also plays a role in the development of the eyes of zebrafish.
## Cell cycle regulation
FADD is thought to have a role in regulating the cell cycle of T lymphocytes. This regulation is dependent on phosphorylation of FADD on Serine 194, which is carried out by Casein Kinase 1a (CKIα). This phosphorylated form of FADD is found mainly in the nucleus and the abundance of phosphorylated FADD increases significantly in the G2 phase of the cell cycle compared to the G1 phase where only very little can be detected. As it is found at the mitotic spindle during G2, it has been proposed to mediate the G2/M transition, however, the mechanism by which it does this it not yet known.
## Lymphocyte proliferation
FADD is essential for T cell proliferation when the T cell receptor is stimulated by antigen. In contrast, FADD has no effect on the proliferation of B cells induced by stimulation of the B cell receptor. However, it is required for B cell proliferation induced by stimulation of TLR3 and TLR4.
## Inflammation
Activation of nuclear factor kappa B (NFκB) signalling leads to transcription of various proinflammatory cytokines as well as anti-apoptotic genes. It was found that NFκB signalling was inhibited in FADD-deficient cells after stimulation of the TNF-R1 or Fas receptors. This suggests a role of FADD in activation of the NFκB pathway. Conversely, FADD also has a role in inhibition of this pathway. Normally, upon stimulation of the receptors TL4 or IL-1R1, the adaptor protein, MyD88, is recruited to the plasma membrane where is binds to IL-1 receptor associated Kinase (IRAK) via a DD-DD interaction. This activates a signalling pathway which results in translocation of NFκB to the nucleus, where it induces the transcription of the inflammatory cytokines. FADD can interfere with the interaction between MyD88 and IRAK, by binding to MyD88 via its DD and therefore this disrupts the cascade which would lead to NFκB translocation and inflammation.
## Other
FADD is required for an efficient antiviral response. Upon viral infection, FADD is needed to increase the levels of Irf7 a molecule which is needed for the production of IFN-α. IFN-α is a key molecule involved in the response against viruses.
FADD is involved in the activation of the phosphatases which dephosphorylate and deactivate Protein Kinase C (PKC). Without FADD, PKC remains active and is able to continue signalling cascades leading to processes including cytoskeletal rearrangements and cell motility.
Recent research has also shown that it may have a role in regulating glucose levels and the phosphorylated form of FADD is important for this function.
# Regulation
## Subcellular localisation
FADD can be found in both the nucleus and cytoplasm of cells. Phosphorylation of Ser194 of FADD in humans (or Ser191 in mice) is thought to regulate its subcellular localisation. A nuclear localization sequence and nuclear export signal, both located in the DED of FADD, are also required for it to enter and exit the nucleus.
Depending on its subcellular localisation, FADD can have different roles. In the cytoplasm, its main function is to induce apoptosis. However, in the nucleus, it can have the opposite effect and instead promote survival.
## c-FLIP
Cellular FLICE inhibitory protein (c-FLIP) is a regulatory protein which contains two DEDs. There are two isoforms of C-FLIP: C-FLIPS and FLIPL. It was originally thought to act as a negative regulator of apoptosis by binding to the DED of FADD and therefore preventing procaspase 8 from binding and inhibiting formation of the DISC.
However, it has been seen that both c-FLIP and procaspase 8 can be found at the same DISC. Therefore, it has been proposed that the presence of c-FLIP inhibits the close interaction of the procaspases to one another. Without this close proximity, the procaspases cannot be completely cleaved and remain in an inactive state.
## PKC
The activity of protein kinase C has a negative effect on Fas receptor mediated apoptosis. This is because it inhibits the recruitment of FADD to the receptor and so a DISC is not formed. It has been shown that by either increasing or decreasing the amount of PKC in T cells, more or less FADD is recruited to FasR respectively, when the FasR is stimulated.
## MKRN1
MKRN1 is an E3 ubiquitin ligase which negatively regulates FADD by targeting it for ubiquitin mediated degradation. In doing so, MKRN1 is able to control the level of apoptosis.
# Roles in inflammatory diseases
Increased levels of FADD were found in the leukocytes of patients with relapsing remitting multiple sclerosis, contributing to inflammation.
In rheumatoid arthritis, it is thought that stimulation of Fas receptors on macrophages, leads to formation of the FADD containing DISCs. Formation of these sequesters FADD away from MyD88 allowing MyD88 to interact with IRAK and induce the enhanced inflammation associated with this disease.
# Roles in cancer
As FADD has such an important role in apoptosis, loss of FADD can give cancer cells a proliferative advantage as apoptosis would no longer be induced when the Fas receptors are stimulated.
However, there is significant upregulation of FADD in ovarian cancer and head and neck squamous cell carcinoma. It is not yet clear what advantage this has on the cancer cells, but given FADDs roles in cell cycle regulation and cell survival, it likely that it may be related to this.
There are also elevated levels of FADD in non small cell lung cancer. FADD can be used as a prognosis marker for both of these diseases, with high levels of FADD being correlated with poor outcome.
## Therapeutic target
Taxol is a drug used in anticancer therapies due to its ability to interfere with microtubule assembly, which leads to cell cycle arrest. FADD phosphorylated at Ser194 makes cells more sensitive to cell cycle arrest induced by taxol. Taxol can also cause apoptosis of cells and this requires procaspase 10, which is activated by recruitment to FADD.
It has been shown that the activation of JNK leads to the phosphorylation of FADD. Phosphorylated FADD can induce G2/M cell cycle arrest, potentially by increasing the stability of p53. Therefore, drugs which can activate this pathway may have a therapeutic potential.
However, high levels of phosphorylated FADD have been correlated with a poor prognosis in many cancers such as that of the head and neck. This is likely to be due to its activation of the NF-κB pathway, which is antiapoptotic. Therefore, inhibition of FADD phosphorylation may be developed as a potential anti cancer strategy. For example, It has been suggested that inhibition of FADD might work as a potential targeted therapy for drug-resistant ovarian cancer.
# Interactions
FADD has been seen to interact with Fas receptor,:
- ABCA1,
- ATG5,
- C-FLIP, MKRN1,
- Casein Kinase 1a,
- DEDD,
- MBD4
- MyD88,
- NACA,
- PEA15,
- RIPK1,
- RIPK3,
- TRADD,
- TRAIL,
- procaspase 10, and
- Procaspase 8. | FADD
Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.[1]
FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development.
# Structure
FADD is a 23 kDa protein, made up of 280 amino acids. It contains two main domains: a C terminal death domain (DD) and an N terminal death effector domain (DED). Each domain, although sharing very little sequence similarity, are structurally similar to one another, with each consisting of 6 α helices.[2][3] The DD of FADD binds to receptors such as the Fas receptor at the plasma membrane via their DD.[4] The interaction between the death domains are electrostatic interactions involving α helices 2 and 3 of the 6 helix domain.[5] The DED binds to the DED of intracellular molecules such as procaspase 8.[6] It is thought that this interaction occurs through hydrophobic interactions.[3]
# Functions
## Extrinsic apoptosis
Upon stimulation by the Fas ligand, the Fas receptor trimerises. Many receptors, including Fas, contain a cytoplasmic DD and are therefore named death receptors. FADD binds to the DD of this trimeric structure via its death domain [4] resulting in unmasking of FADD's DED and subsequent recruitment of procaspase 8 and 10 via an interaction between the DEDs of both FADD and the procaspases.[7] This generates a complex known as the death inducing signalling complex (DISC).[8] Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with other procaspases of the same type, autocatalytic cleavage occurs at an aspartate residue within their own structures, resulting in an activated protein. This activated protein can then go on to cleave and activate further caspases, initiating the caspase cascade.[9] The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell.[10]
Binding of TRAIL to death receptors four and five (DR4 and DR5) can lead to apoptosis by the same mechanism.[11]
Apoptosis can also be triggered by binding of a ligand to tumor necrosis factor receptor 1 (TNFR1); however, the mechanism by which this occurs is slightly more complex. Another DD-containing adaptor protein named TRADD, along with other proteins, binds to activated TNF1R, forming what is known as complex I. This results in activation of the NFκB pathway, which promotes cell survival. This complex is then internalised, and FADD binds to TRADD via an interaction of the DD’s of the two adapter proteins, forming what is known as complex II. FADD again recruits procaspase 8, which initiates the caspase cascade leading to apoptosis.[12]
## Necroptosis
FADD also plays a role in regulating necroptosis, a process requiring the serine/threonine kinases, RIPK1 and RIPK3. Activated caspase 8 cleaves these kinases, inhibiting necroptosis. Since activation of caspase 8 requires FADD in order to bring the procaspase 8 molecules into close proximity to one another to facilitate their activation, FADD is required for negatively regulating necroptosis. In accordance, cells deficient in FADD induce necroptosis as they are unable to recruit and activate procaspase 8.
FADD can also bind to RIPK1 and RIPK3 directly, however the significance of this interaction is currently unclear.[10]
## Autophagic cell death
Autophagy is a process which allows cell survival under stressed conditions but can also lead to cell death.
Using its DD, FADD interacts with ATG5, a protein involved in autophagy. This interaction has been shown to be essential for autophagic cell death, which is induced by IFN-γ.[13]
In contrast, it has also been found to inhibit autophagic cell death and therefore promote cell survival. FADD binds to ATG5 in a complex which also contains ATG12, Caspase 8 and RIPK1. The formation of this complex is stimulated by autophagic signalling. Caspase 8 then cleaves RIPK1, leading to inhibition of this signalling, inhibiting cell death.[14]
## Development
FADD knockout in mouse embryos is lethal, showing a role for FADD in embryonic development. This is thought to be due to abnormal development of the heart.[15] This abnormal heart development may be due to FADD dependent regulation of the NFκB pathway.[16]
FADD also plays a role in the development of the eyes of zebrafish.[17]
## Cell cycle regulation
FADD is thought to have a role in regulating the cell cycle of T lymphocytes. This regulation is dependent on phosphorylation of FADD on Serine 194, which is carried out by Casein Kinase 1a (CKIα). This phosphorylated form of FADD is found mainly in the nucleus and the abundance of phosphorylated FADD increases significantly in the G2 phase of the cell cycle compared to the G1 phase where only very little can be detected. As it is found at the mitotic spindle during G2, it has been proposed to mediate the G2/M transition, however, the mechanism by which it does this it not yet known.[18]
## Lymphocyte proliferation
FADD is essential for T cell proliferation when the T cell receptor is stimulated by antigen.[19] In contrast, FADD has no effect on the proliferation of B cells induced by stimulation of the B cell receptor. However, it is required for B cell proliferation induced by stimulation of TLR3 and TLR4.[20]
## Inflammation
Activation of nuclear factor kappa B (NFκB) signalling leads to transcription of various proinflammatory cytokines as well as anti-apoptotic genes. It was found that NFκB signalling was inhibited in FADD-deficient cells after stimulation of the TNF-R1 or Fas receptors. This suggests a role of FADD in activation of the NFκB pathway. Conversely, FADD also has a role in inhibition of this pathway. Normally, upon stimulation of the receptors TL4 or IL-1R1, the adaptor protein, MyD88, is recruited to the plasma membrane where is binds to IL-1 receptor associated Kinase (IRAK) via a DD-DD interaction. This activates a signalling pathway which results in translocation of NFκB to the nucleus, where it induces the transcription of the inflammatory cytokines. FADD can interfere with the interaction between MyD88 and IRAK, by binding to MyD88 via its DD and therefore this disrupts the cascade which would lead to NFκB translocation and inflammation.[21][22]
## Other
FADD is required for an efficient antiviral response. Upon viral infection, FADD is needed to increase the levels of Irf7 a molecule which is needed for the production of IFN-α. IFN-α is a key molecule involved in the response against viruses.[23]
FADD is involved in the activation of the phosphatases which dephosphorylate and deactivate Protein Kinase C (PKC). Without FADD, PKC remains active and is able to continue signalling cascades leading to processes including cytoskeletal rearrangements and cell motility.[24]
Recent research has also shown that it may have a role in regulating glucose levels and the phosphorylated form of FADD is important for this function.[25]
# Regulation
## Subcellular localisation
FADD can be found in both the nucleus and cytoplasm of cells. Phosphorylation of Ser194 of FADD in humans (or Ser191 in mice) is thought to regulate its subcellular localisation. A nuclear localization sequence and nuclear export signal, both located in the DED of FADD, are also required for it to enter and exit the nucleus.
Depending on its subcellular localisation, FADD can have different roles. In the cytoplasm, its main function is to induce apoptosis. However, in the nucleus, it can have the opposite effect and instead promote survival.[22][26]
## c-FLIP
Cellular FLICE inhibitory protein (c-FLIP) is a regulatory protein which contains two DEDs. There are two isoforms of C-FLIP: C-FLIPS and FLIPL. It was originally thought to act as a negative regulator of apoptosis by binding to the DED of FADD and therefore preventing procaspase 8 from binding and inhibiting formation of the DISC.[27]
However, it has been seen that both c-FLIP and procaspase 8 can be found at the same DISC.[28] Therefore, it has been proposed that the presence of c-FLIP inhibits the close interaction of the procaspases to one another. Without this close proximity, the procaspases cannot be completely cleaved and remain in an inactive state.[27]
## PKC
The activity of protein kinase C has a negative effect on Fas receptor mediated apoptosis. This is because it inhibits the recruitment of FADD to the receptor and so a DISC is not formed. It has been shown that by either increasing or decreasing the amount of PKC in T cells, more or less FADD is recruited to FasR respectively, when the FasR is stimulated.[29]
## MKRN1
MKRN1 is an E3 ubiquitin ligase which negatively regulates FADD by targeting it for ubiquitin mediated degradation. In doing so, MKRN1 is able to control the level of apoptosis.[30]
# Roles in inflammatory diseases
Increased levels of FADD were found in the leukocytes of patients with relapsing remitting multiple sclerosis, contributing to inflammation.[31]
In rheumatoid arthritis, it is thought that stimulation of Fas receptors on macrophages, leads to formation of the FADD containing DISCs. Formation of these sequesters FADD away from MyD88 allowing MyD88 to interact with IRAK and induce the enhanced inflammation associated with this disease.[32]
# Roles in cancer
As FADD has such an important role in apoptosis, loss of FADD can give cancer cells a proliferative advantage as apoptosis would no longer be induced when the Fas receptors are stimulated.[22]
However, there is significant upregulation of FADD in ovarian cancer[33] and head and neck squamous cell carcinoma. It is not yet clear what advantage this has on the cancer cells, but given FADDs roles in cell cycle regulation and cell survival, it likely that it may be related to this.[34]
There are also elevated levels of FADD in non small cell lung cancer. FADD can be used as a prognosis marker for both of these diseases, with high levels of FADD being correlated with poor outcome.[35]
## Therapeutic target
Taxol is a drug used in anticancer therapies due to its ability to interfere with microtubule assembly, which leads to cell cycle arrest. FADD phosphorylated at Ser194 makes cells more sensitive to cell cycle arrest induced by taxol.[18] Taxol can also cause apoptosis of cells and this requires procaspase 10, which is activated by recruitment to FADD.[36]
It has been shown that the activation of JNK leads to the phosphorylation of FADD. Phosphorylated FADD can induce G2/M cell cycle arrest, potentially by increasing the stability of p53. Therefore, drugs which can activate this pathway may have a therapeutic potential.[37]
However, high levels of phosphorylated FADD have been correlated with a poor prognosis in many cancers such as that of the head and neck. This is likely to be due to its activation of the NF-κB pathway, which is antiapoptotic. Therefore, inhibition of FADD phosphorylation may be developed as a potential anti cancer strategy.[38] For example, It has been suggested that inhibition of FADD might work as a potential targeted therapy for drug-resistant ovarian cancer.[33]
# Interactions
FADD has been seen to interact with Fas receptor,:[4]
- ABCA1,[39]
- ATG5,[13]
- C-FLIP,[28] MKRN1,[30]
- Casein Kinase 1a,[18]
- DEDD,[40]
- MBD4[41]
- MyD88,[22]
- NACA,[42]
- PEA15,[43]
- RIPK1,[10]
- RIPK3,[10]
- TRADD,[12]
- TRAIL,[11]
- procaspase 10,[7] and
- Procaspase 8.[7] | https://www.wikidoc.org/index.php/FADD | |
7f00267aacca5154b6715f38fa788ec7cc2d5ab4 | wikidoc | FAN1 | FAN1
FANCD2/FANCI-associated nuclease 1 (KIAA1018) is an enzyme that in humans is encoded by the FAN1 gene. It is a structure dependent endonuclease and a member of the myotubularin-related class 1 cysteine-based protein tyrosine phosphatases. It is thought to play an important role in the Fanconi Anemia (FA) pathway.
# Structure
FAN1 is a protein of 1017 amino acids. Several crystal structures of the residues 373-1017 have been characterized. This portion of FAN1 contains three domains: an SAP domain (primary-DNA binding domain), a TPR domain (mediating interdomain interaction and dimerization interface) and the virus-type replication-repair nuclease module (VRR_NUC, catalytic site) (Figure 1). DNA binding promotes dimerization of FAN1 in a "head to tail" fashion.
The SAP region contains three major components: α9, α5β1, and α7. The core helix α9 stabilizes the protein as it moves through dimer configurations and mediates the interactions between α5β1 and α7 as they adjust their positions. These three configurations are the substrate scanning, substrate latching and substrate unwinding forms (figure 2).
In the FAN1 dimer, the SAP regions of both FAN1 enzymes make contact with the DNA duplex (dsDNA). This double contact facilitates DNA induced dimerization, as well as guiding the single stranded (ssDNA) into the SAP domain of the downstream enzyme (PSAP). The SAP domain of the upstream FAN1 component enzyme (ASAP) aids in guiding the DNA to PSAP.
The SAP surface facing the catalytic site is the most conserved region between FAN1 homologs. It is positively charged for favorable hydrogen bonding and electrostatic interactions with DNA. In particular, residues Y374 and Y436 form hydrogen bonds with the phosphate backbone. FAN1 can bind DNA in either direction. However, when the 5' flab is facing away from the VRR_NUC site, substrate latching and unwinding cannot occur. The unresolved portion of FAN1 contains a Zinc finger at the N terminus called a UBZ region. This is present in proteins that bind to ubiquitinated proteins, and is highly conserved across eukaryotes. This Zinc finger is crucial for recruitment to the ubiquitinated FANCD2/FANCI complex, and is found in other nucleases. The VRR_Nuc catalytic domain is located at the C terminus and contains the endonuclease functionality. FAN1 is the first known instance of a virus type replication-repair nuclease module in eukaryotes. It is normally found as a standalone domain in bacterial and viral Holliday Junction Resolvases (HJR). FAN1 does not exhibit any activity on Holliday Junction (HJ) substrates. A subdomain of SAP consisting of six α helices connected to the VRR_Nuc region is thought to inhibit HJR activity.
# Function
Interstrand DNA crosslinks (ICLs) effectively block the progression of transcription and replication machineries. Release of this block, referred to as unhooking, is thought to require incision of one strand of the duplex on either side of the ICL.
Repair of interstrand DNA crosslinks is triggered when the DNA replication fork is unable to continue. The FA proteins play an elaborate role with FAN1 to remove these ICLs. The pathway consists of 15 known proteins. Three of them form the FA AP24-MHF1/2 complex which recognizes the ICL (from stalled replication forks). This recruits the FA core complex, which consists of 8 proteins. This complex monoubiquitinates FANCD2 and FANCI, which allows it to form a heterodimer. It is this complex that recruits FAN1 as well as other nucleases such as SLX4. Ubiquinated FANCD2 interacts with the FAN1 nuclease. Upon its recruitment by FANCD2, FAN1 acts to restrain DNA replication fork progression and to prevent chromosome abnormalities from occurring when DNA replication forks stall. FAN1 is typically localized in the nucleus, but forms very distinct loci at damaged regions when ICLs are present.
The FAN1 protein possesses endonuclease and exonuclease functions to remove ICLs. At a replication fork arrested at an ICL, FAN1 nuclease action can catalyze incisions in the double-stranded region. It is thought that this process consists of unhooking the crosslink and separating the DNA strands through two incision events, yielding one strand with a crosslinked nucleotide and another strand with a gap. FAN1 preferentially acts as a 5’ flap endonuclease. This is illustrated in Figure 2, which shows the sequence of substrate scanning, latching, and unwinding. It usually cleaves about 5 nucleotides from a junction. FAN1 will also incise at splayed arms, three way junctions, and 3’ flaps (in order of decreasing preference). In high concentrations FAN1 has been shown to exhibit 3’ 5’ exonuclease activity. In blunt end substrates, FAN1 has also 5’ recessed ends. However, FAN1 does not appear to bind to single stranded DNA.
The presence of the FANCD2/FANCI complex is unaffected by knockdown of FAN1. This is because FAN1 acts downstream to the recruitment of FANCD2/FANCI. FAN1 has also been shown to increase the frequency of homologous recombination. This suggests that the gapped intermediate that forms following ICL unhooking may be repaired through HR when homologous chromosomes are present. FAN1 does not appear to be involved in other types of DNA repair, as it does not localize to DNA upon irradiation.
# Clinical significance
Mutations affecting the function of the 15 known FA genes are associated with Fanconi anemia, a recessive autosomal disorder. It is characterized by congenital abnormalities as well as anemia, bone marrow failure, and cancer predisposition in childhood. However, some patients have “unassigned” Fanconi Anemia where no mutations in the known FA genes can be found. Mutations in FAN1 can result in chronic kidney diseases and neurological conditions such as schizophrenia. However, recent research has called into question the categorization of FAN1 as an FA gene. In 2015 researchers studied four individuals with chromosomal microdeletion of 15q13.3. Analysis of blood samples revealed only mild ICL agent sensitivity and chromosomal fragility consistent with Fanconi Anemia.
A deficiency of FAN1 increases in vitro sensitivity to cisplatin and mitomycin C, two crosslinking agents FAN1 is also able to repair mitomycin C induced double strand breaks.
Germline mutations in the FAN1 gene can cause hereditary colorectal cancer due to defective DNA repair. | FAN1
FANCD2/FANCI-associated nuclease 1 (KIAA1018) is an enzyme that in humans is encoded by the FAN1 gene. It is a structure dependent endonuclease and a member of the myotubularin-related class 1 cysteine-based protein tyrosine phosphatases. It is thought to play an important role in the Fanconi Anemia (FA) pathway.[1]
# Structure
FAN1 is a protein of 1017 amino acids.[3] Several crystal structures of the residues 373-1017 have been characterized. This portion of FAN1 contains three domains: an SAP domain (primary-DNA binding domain), a TPR domain (mediating interdomain interaction and dimerization interface) and the virus-type replication-repair nuclease module (VRR_NUC, catalytic site) (Figure 1).[4] DNA binding promotes dimerization of FAN1 in a "head to tail" fashion.[2]
The SAP region contains three major components: α9, α5β1, and α7. The core helix α9 stabilizes the protein as it moves through dimer configurations and mediates the interactions between α5β1 and α7 as they adjust their positions. These three configurations are the substrate scanning, substrate latching and substrate unwinding forms (figure 2).[2]
In the FAN1 dimer, the SAP regions of both FAN1 enzymes make contact with the DNA duplex (dsDNA). This double contact facilitates DNA induced dimerization, as well as guiding the single stranded (ssDNA) into the SAP domain of the downstream enzyme (PSAP). The SAP domain of the upstream FAN1 component enzyme (ASAP) aids in guiding the DNA to PSAP.[2]
The SAP surface facing the catalytic site is the most conserved region between FAN1 homologs. It is positively charged for favorable hydrogen bonding and electrostatic interactions with DNA. In particular, residues Y374 and Y436 form hydrogen bonds with the phosphate backbone. FAN1 can bind DNA in either direction. However, when the 5' flab is facing away from the VRR_NUC site, substrate latching and unwinding cannot occur.[2] The unresolved portion of FAN1 contains a Zinc finger at the N terminus called a UBZ region. This is present in proteins that bind to ubiquitinated proteins, and is highly conserved across eukaryotes. This Zinc finger is crucial for recruitment to the ubiquitinated FANCD2/FANCI complex, and is found in other nucleases.[3] The VRR_Nuc catalytic domain is located at the C terminus and contains the endonuclease functionality.[3] FAN1 is the first known instance of a virus type replication-repair nuclease module in eukaryotes. It is normally found as a standalone domain in bacterial and viral Holliday Junction Resolvases (HJR). FAN1 does not exhibit any activity on Holliday Junction (HJ) substrates.[4] A subdomain of SAP consisting of six α helices connected to the VRR_Nuc region is thought to inhibit HJR activity.[5]
# Function
Interstrand DNA crosslinks (ICLs) effectively block the progression of transcription and replication machineries. Release of this block, referred to as unhooking, is thought to require incision of one strand of the duplex on either side of the ICL.
Repair of interstrand DNA crosslinks is triggered when the DNA replication fork is unable to continue. The FA proteins play an elaborate role with FAN1 to remove these ICLs. The pathway consists of 15 known proteins. Three of them form the FA AP24-MHF1/2 complex which recognizes the ICL (from stalled replication forks). This recruits the FA core complex, which consists of 8 proteins. This complex monoubiquitinates FANCD2 and FANCI, which allows it to form a heterodimer. It is this complex that recruits FAN1 as well as other nucleases such as SLX4.[5] Ubiquinated FANCD2 interacts with the FAN1 nuclease. Upon its recruitment by FANCD2, FAN1 acts to restrain DNA replication fork progression and to prevent chromosome abnormalities from occurring when DNA replication forks stall.[7] FAN1 is typically localized in the nucleus, but forms very distinct loci at damaged regions when ICLs are present.[8]
The FAN1 protein possesses endonuclease and exonuclease functions to remove ICLs. At a replication fork arrested at an ICL, FAN1 nuclease action can catalyze incisions in the double-stranded region.[9] It is thought that this process consists of unhooking the crosslink and separating the DNA strands through two incision events, yielding one strand with a crosslinked nucleotide and another strand with a gap.[10][11] FAN1 preferentially acts as a 5’ flap endonuclease. This is illustrated in Figure 2, which shows the sequence of substrate scanning, latching, and unwinding. It usually cleaves about 5 nucleotides from a junction. FAN1 will also incise at splayed arms, three way junctions, and 3’ flaps (in order of decreasing preference). In high concentrations FAN1 has been shown to exhibit 3’ 5’ exonuclease activity. In blunt end substrates, FAN1 has also 5’ recessed ends. However, FAN1 does not appear to bind to single stranded DNA.[3][12]
The presence of the FANCD2/FANCI complex is unaffected by knockdown of FAN1. This is because FAN1 acts downstream to the recruitment of FANCD2/FANCI.[2][3][13] FAN1 has also been shown to increase the frequency of homologous recombination.[3] This suggests that the gapped intermediate that forms following ICL unhooking may be repaired through HR when homologous chromosomes are present.[12] FAN1 does not appear to be involved in other types of DNA repair, as it does not localize to DNA upon irradiation.[8]
# Clinical significance
Mutations affecting the function of the 15 known FA genes are associated with Fanconi anemia, a recessive autosomal disorder.[13] It is characterized by congenital abnormalities as well as anemia, bone marrow failure, and cancer predisposition in childhood.[5] However, some patients have “unassigned” Fanconi Anemia where no mutations in the known FA genes can be found. Mutations in FAN1 can result in chronic kidney diseases and neurological conditions such as schizophrenia.[2][14] However, recent research has called into question the categorization of FAN1 as an FA gene. In 2015 researchers studied four individuals with chromosomal microdeletion of 15q13.3. Analysis of blood samples revealed only mild ICL agent sensitivity and chromosomal fragility consistent with Fanconi Anemia.[15]
A deficiency of FAN1 increases in vitro sensitivity to cisplatin and mitomycin C, two crosslinking agents[2][3] FAN1 is also able to repair mitomycin C induced double strand breaks.[3]
Germline mutations in the FAN1 gene can cause hereditary colorectal cancer due to defective DNA repair.[16] | https://www.wikidoc.org/index.php/FAN1 | |
f331bef8a70f9cb51c593c51f438bb7166df9637 | wikidoc | FAT1 | FAT1
Protocadherin FAT1 is a protein that in humans is encoded by the FAT1 gene.
# Function
This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. This gene is expressed at high levels in a number of fetal epithelia. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described.
The murine Fat1 knockout mouse is not embryonically lethal but pups die within 48-hours due to the abnormal fusion of foot processes of the podocytes within the kidney. These Fat1 knockout mice also showed partially penetrant but often severe midline defects including holoprosencephaly, microphthalmia-anophthalmia and in rare cases cyclopia.
It has been shown that the EVH motifs in the cytoplasmic tail of mouse Fat1 interact with Ena/VASP and ablation of Fat1 by RNAi leads to decreased cell migration of rat epithelial cells
The cytoplasmic tail of Fat1 has also been shown to bind the transcriptional repressor Atrophin in rat vascular smooth muscle cells
At the carboxyl terminus of FAT1 lies a PDZ domain (PSD95/Dlg1/ZO-1) ligand motif (-HTEV). Zebrafish Fat1 was found to bind the protein scribble and regulate Hippo signalling
Using the human SHSY5Y cell line as a model of neuronal differentiation, human FAT1 was shown to regulate Hippo kinase components with loss of FAT1 leading to nucleocytoplasmic relocation of TAZ and enhanced transcription of the Hippo target gene CTGF. The same study also showed FAT1 was able to regulate TGF-beta signaling
FAT1 has been found to bind beta-catenin and regulate Wnt-signaling in colorectal cancer.
# Structure
The human FAT1 cadherin gene was cloned in 1995 from a human T-leukemia (T-ALL) cell line and consists of 27 exons located on chromosome 4q34–35. Structurally the FAT1 protein is a single pass transmembrane protein with the extracellular portion consisting of 34 cadherin repeats, 5 EGF-like domains and a laminin-G like domain.
The FAT1 protein once translated undergoes furin mediated S1 cleavage forming a non-covalent heterodimer before achieving cell surface expression although this processing is often perturbed in cancer cells which express non-cleaved FAT1 on the cell surface.
FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by FJX1. The ectodomain of FAT1 can also be shed from the cell surface by the sheddase ADAM10, with release of this ectodomain a possible new biomarker in pancreatic cancer.
FAT1 has also been found to undergo alternative splicing in breast cancer cells undergoing epithelial-to-mesenchymal (EMT) transition with the addition of 12 amino acids in the cytoplasmic tail. Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.
# Clinical significance
## Cancer
The FAT1 cadherin has been ascribed both as putative tumour suppressor or oncogene in different contexts. Loss of heterozygosity for FAT1 has been reported in primary oral carcinomas and astrocytic tumours. There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer, melanoma, and leukaemia. | FAT1
Protocadherin FAT1 is a protein that in humans is encoded by the FAT1 gene.[1][2]
# Function
This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. This gene is expressed at high levels in a number of fetal epithelia. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described.[2]
The murine Fat1 knockout mouse is not embryonically lethal but pups die within 48-hours due to the abnormal fusion of foot processes of the podocytes within the kidney. These Fat1 knockout mice also showed partially penetrant but often severe midline defects including holoprosencephaly, microphthalmia-anophthalmia and in rare cases cyclopia.[3]
It has been shown that the EVH motifs in the cytoplasmic tail of mouse Fat1 interact with Ena/VASP and ablation of Fat1 by RNAi leads to decreased cell migration of rat epithelial cells [4]
The cytoplasmic tail of Fat1 has also been shown to bind the transcriptional repressor Atrophin in rat vascular smooth muscle cells [5]
At the carboxyl terminus of FAT1 lies a PDZ domain (PSD95/Dlg1/ZO-1) ligand motif (-HTEV). Zebrafish Fat1 was found to bind the protein scribble and regulate Hippo signalling[6]
Using the human SHSY5Y cell line as a model of neuronal differentiation, human FAT1 was shown to regulate Hippo kinase components with loss of FAT1 leading to nucleocytoplasmic relocation of TAZ and enhanced transcription of the Hippo target gene CTGF. The same study also showed FAT1 was able to regulate TGF-beta signaling [7]
FAT1 has been found to bind beta-catenin and regulate Wnt-signaling in colorectal cancer.[8]
# Structure
The human FAT1 cadherin gene was cloned in 1995 from a human T-leukemia (T-ALL) cell line and consists of 27 exons located on chromosome 4q34–35.[1] Structurally the FAT1 protein is a single pass transmembrane protein with the extracellular portion consisting of 34 cadherin repeats, 5 EGF-like domains and a laminin-G like domain.[9]
The FAT1 protein once translated undergoes furin mediated S1 cleavage forming a non-covalent heterodimer before achieving cell surface expression although this processing is often perturbed in cancer cells which express non-cleaved FAT1 on the cell surface.[10]
FAT1 cadherin is multiply phosphorylated on its ectodomain but phosphorylation is not catalysed by FJX1.[11] The ectodomain of FAT1 can also be shed from the cell surface by the sheddase ADAM10, with release of this ectodomain a possible new biomarker in pancreatic cancer.[12]
FAT1 has also been found to undergo alternative splicing in breast cancer cells undergoing epithelial-to-mesenchymal (EMT) transition with the addition of 12 amino acids in the cytoplasmic tail.[13] Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.[14]
# Clinical significance
## Cancer
The FAT1 cadherin has been ascribed both as putative tumour suppressor or oncogene in different contexts. Loss of heterozygosity for FAT1 has been reported in primary oral carcinomas[15] and astrocytic tumours.[16] There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer,[17] melanoma,[10] and leukaemia.[18] | https://www.wikidoc.org/index.php/FAT1 | |
4f4f067742752ec362de12aa6d1bcb306175c8d3 | wikidoc | FCAR | FCAR
Fc fragment of IgA receptor (FCAR) is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89). FcαRI binds the heavy-chain constant region of Immunoglubulin A (IgA) antibodies. FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils, though it is notably absent from intestinal macrophages and does not appear on mast cells. FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound. Inside-out signaling primes FcαRI in order for it to bind its ligand, while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain (FcR γ-chain).
Though FcαRI is part of the Fc receptor immunoglobulin superfamily, the protein’s primary structure is similar to receptors in the leukocyte receptor cluster (LRC), and the FCAR gene appears amidst LRC genes on chromosome 19. This contrasts with the location of other members of the Fc receptor immunoglobulin superfamily, which are encoded on chromosome 1. Additionally, though there are equivalents to FCAR in several species, there is no such homolog in mice.
# Structure
The FcαRI α-chain consists of two extracellular domains, EC1 and EC2, at a right angle to each other, a transmembrane domain, and an intracellular domain. However, this chain alone cannot perform signaling in response to IgA binding, and FcαRI must associate with a dimeric form of FcR g-chain, the ends of which contain immunoreceptor tyrosine-based activation motifs (ITAMs). The FcR γ-chain is responsible for relaying the signal to the inside of the cell.
Two FCAR alleles differing by a single nucleotide polymorphism (SNP) code for two FcαRI molecules that differ in their ability to signal for IL-6 and TNF-α production and release. The SNP results in either serine or glycine as the 248th residue of the amino acid sequence, a position in the intracellular domain of FcαRI. Compared to FcαRI with Ser248, FcαRI molecules with Gly248 are better able to signal for the release of IL-6, even independently from FcR γ-chain association.
Alternative splicing of the transcript from this gene produces ten mRNA variants encoding different isoforms.
# Inside-Out Signaling
FcαRI must first be primed by a process called inside-out signaling in order to bind with increased ability to IgA. Priming occurs when cytokines signaling the presence of an infection bind their receptors on FcαRI-expressing cells, activating the kinase PI3K. PI3K then activates p38 and PKC, which together with PP2A lead to the dephosphorylation of the Serine 263 residue (Ser263) on the intracellular domain of the FcαRI α-chain. The priming of FcαRI to be able to bind IgA does not depend on FcαRI association with the FcR γ-chain, but does depend on cytoskeleton organization.
Once primed, FcαRI can bind IgA. The FcαRI EC1 domain binds the hinge between the IgA-Fc regions Ca2 and Ca3 regions.
# Function
Signaling and the resulting cellular response caused by FcαRI binding IgA varies depending on the state of the IgA molecules. A pro-inflammatory response is signaled when IgA molecules in an immune complex bind to multiple FcαRI, resulting in the activation of Src family kinases and the phosphorylation of the FcR γ-chain ITAMs by Lyn. Syk, a tyrosine kinase, subsequently docks at the phosphorylated ITAMs and initiates PI3K and PLC-γ signaling. The ensuing signaling cascades lead to pro-inflammatory responses such as release of cytokines, phagocytosis, respiratory bursts, antibody-dependent cell-mediated cytotoxicity, production of reactive oxygen species, and antigen presentation.
Despite signaling via ITAMs, which typically initiate activation cascades, FcαRI may either act as an activating or inhibitory receptor. Inhibitory ITAM signaling (ITAMi) results in anti-inflammatory responses. When FcαRI monovalently binds monomeric, non-antigen bound IgA, the form most common in serum, the resulting signals result in inactivation of other activating receptors such as FcγR and FcεRI. The binding of the monomeric serum IgA causes Lyn to only partly phosphorylate the FcR γ-chain ITAMs. Consequently, Src homology region 2 domain-containing phosphatase-1 (SHP-1) is recruited by Syk to the FcR γ-chain. A tyrosine phosphatase, SHP-1 coordinates the anti-inflammatory response, preventing other receptors from signaling for pro-inflammatory responses by not allowing these receptors to become phosphorylated. This ITAMi signaling supports homeostasis in the absence of pathogens.
The anti-inflammatory role of monomeric IgA-FcαRI binding may have implications for treatment of allergic asthma, as shown by targeting FcαRI in transgenic mice models with anti-FcαRI Fab antibodies, which mimic the binding of monomeric IgA. This FcαRI targeting led to decreased infiltration of airway tissue by inflammatory leukocytes.
The secreted form of IgA (sIgA), a homodimer secreted across epithelial linings such as the gut epithelium, is sterically hindered in its binding to FcαRI. This is because some of sIgA’s FcαRI binding site is obscured by a section of the cleaved polymeric Ig receptor that aided sIgA’s secretion into the gut lumen. However, the precursor to sIgA, dimeric IgA (dIgA), binds to FcαRI with approximately the same affinity as monomeric IgA. Secreted IgA plays an important role in preventing immune response to commensal gut microbes, and accordingly intestinal macrophages do not express FcαRI. However, during invasion of mucosal tissue by pathogenic bacteria, neutrophils responding to the infection will bind and phagocytose dIgA-opsonized bacteria via FcαRI.
FcαRI is also an important Fc receptor for neutrophil killing of tumor cells. When FcαRI-expressing neutrophils come into contact with IgA-opsinized tumor cells, the neutrophils not only perform antibody-dependent cell-mediated cytotoxicity, but also release the cytokines TNF-α and IL-1β which cause increased neutrophil migration to the site.
# Interactions
FCAR has been shown to interact with FCGR1A. | FCAR
Fc fragment of IgA receptor (FCAR) is a human gene[1] that codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89). FcαRI binds the heavy-chain constant region of Immunoglubulin A (IgA) antibodies.[2] FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils,[3] though it is notably absent from intestinal macrophages[4] and does not appear on mast cells.[3] FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound.[3] Inside-out signaling primes FcαRI in order for it to bind its ligand,[2] while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain (FcR γ-chain).[3]
Though FcαRI is part of the Fc receptor immunoglobulin superfamily, the protein’s primary structure is similar to receptors in the leukocyte receptor cluster (LRC), and the FCAR gene appears amidst LRC genes on chromosome 19.[2][3] This contrasts with the location of other members of the Fc receptor immunoglobulin superfamily, which are encoded on chromosome 1.[2][3] Additionally, though there are equivalents to FCAR in several species, there is no such homolog in mice.[2]
# Structure
The FcαRI α-chain consists of two extracellular domains, EC1 and EC2, at a right angle to each other, a transmembrane domain, and an intracellular domain.[2] However, this chain alone cannot perform signaling in response to IgA binding, and FcαRI must associate with a dimeric form of FcR g-chain, the ends of which contain immunoreceptor tyrosine-based activation motifs (ITAMs). The FcR γ-chain is responsible for relaying the signal to the inside of the cell.[2][3]
Two FCAR alleles differing by a single nucleotide polymorphism (SNP) code for two FcαRI molecules that differ in their ability to signal for IL-6 and TNF-α production and release.[5] The SNP results in either serine or glycine as the 248th residue of the amino acid sequence, a position in the intracellular domain of FcαRI.[5] Compared to FcαRI with Ser248, FcαRI molecules with Gly248 are better able to signal for the release of IL-6, even independently from FcR γ-chain association.[5]
Alternative splicing of the transcript from this gene produces ten mRNA variants encoding different isoforms.[1]
# Inside-Out Signaling
FcαRI must first be primed by a process called inside-out signaling in order to bind with increased ability to IgA. Priming occurs when cytokines signaling the presence of an infection bind their receptors on FcαRI-expressing cells, activating the kinase PI3K. PI3K then activates p38 and PKC, which together with PP2A lead to the dephosphorylation of the Serine 263 residue (Ser263) on the intracellular domain of the FcαRI α-chain.[6] The priming of FcαRI to be able to bind IgA does not depend on FcαRI association with the FcR γ-chain,[3] but does depend on cytoskeleton organization.[6]
Once primed, FcαRI can bind IgA.[6] The FcαRI EC1 domain binds the hinge between the IgA-Fc regions Ca2 and Ca3 regions.[2]
# Function
Signaling and the resulting cellular response caused by FcαRI binding IgA varies depending on the state of the IgA molecules. A pro-inflammatory response is signaled when IgA molecules in an immune complex bind to multiple FcαRI, resulting in the activation of Src family kinases and the phosphorylation of the FcR γ-chain ITAMs by Lyn.[7] Syk, a tyrosine kinase, subsequently docks at the phosphorylated ITAMs and initiates PI3K and PLC-γ signaling.[7] The ensuing signaling cascades lead to pro-inflammatory responses such as release of cytokines, phagocytosis, respiratory bursts, antibody-dependent cell-mediated cytotoxicity, production of reactive oxygen species, and antigen presentation.[2][3]
Despite signaling via ITAMs, which typically initiate activation cascades, FcαRI may either act as an activating or inhibitory receptor.[8] Inhibitory ITAM signaling (ITAMi) results in anti-inflammatory responses. When FcαRI monovalently binds monomeric, non-antigen bound IgA, the form most common in serum,[2] the resulting signals result in inactivation of other activating receptors such as FcγR and FcεRI. The binding of the monomeric serum IgA causes Lyn to only partly phosphorylate the FcR γ-chain ITAMs. Consequently, Src homology region 2 domain-containing phosphatase-1 (SHP-1) is recruited by Syk to the FcR γ-chain.[7] A tyrosine phosphatase, SHP-1 coordinates the anti-inflammatory response, preventing other receptors from signaling for pro-inflammatory responses by not allowing these receptors to become phosphorylated.[7] This ITAMi signaling supports homeostasis in the absence of pathogens.[7]
The anti-inflammatory role of monomeric IgA-FcαRI binding may have implications for treatment of allergic asthma, as shown by targeting FcαRI in transgenic mice models with anti-FcαRI Fab antibodies, which mimic the binding of monomeric IgA.[9] This FcαRI targeting led to decreased infiltration of airway tissue by inflammatory leukocytes.[9]
The secreted form of IgA (sIgA), a homodimer secreted across epithelial linings such as the gut epithelium, is sterically hindered in its binding to FcαRI. This is because some of sIgA’s FcαRI binding site is obscured by a section of the cleaved polymeric Ig receptor that aided sIgA’s secretion into the gut lumen.[3] However, the precursor to sIgA, dimeric IgA (dIgA), binds to FcαRI with approximately the same affinity as monomeric IgA.[3] Secreted IgA plays an important role in preventing immune response to commensal gut microbes, and accordingly intestinal macrophages do not express FcαRI.[2] However, during invasion of mucosal tissue by pathogenic bacteria, neutrophils responding to the infection will bind and phagocytose dIgA-opsonized bacteria via FcαRI.[2]
FcαRI is also an important Fc receptor for neutrophil killing of tumor cells. When FcαRI-expressing neutrophils come into contact with IgA-opsinized tumor cells, the neutrophils not only perform antibody-dependent cell-mediated cytotoxicity, but also release the cytokines TNF-α and IL-1β which cause increased neutrophil migration to the site.[10]
# Interactions
FCAR has been shown to interact with FCGR1A.[11] | https://www.wikidoc.org/index.php/FCAR | |
303c65e94415b65c0c0fccff6a18607b3db197e9 | wikidoc | FEZ1 | FEZ1
Fasciculation and elongation protein zeta-1 is a protein that in humans is encoded by the FEZ1 gene.
This gene is an ortholog of the C. elegans unc-76 gene, which is necessary for normal axonal bundling and elongation within axon bundles. Expression of this gene in C. elegans unc-76 mutants can restore to the mutants partial locomotion and axonal fasciculation, suggesting that it also functions in axonal outgrowth. The N-terminal half of the gene product is highly acidic. Alternatively spliced transcript variants encoding different isoforms of this protein have been described.
This protein is present in neurons, and it is believed to block the process of infection of these cells by HIV.
# Interactions
FEZ1 has been shown to interact with Protein kinase Mζ, NBR1 and DISC1. | FEZ1
Fasciculation and elongation protein zeta-1 is a protein that in humans is encoded by the FEZ1 gene.[1][2][3]
This gene is an ortholog of the C. elegans unc-76 gene, which is necessary for normal axonal bundling and elongation within axon bundles. Expression of this gene in C. elegans unc-76 mutants can restore to the mutants partial locomotion and axonal fasciculation, suggesting that it also functions in axonal outgrowth. The N-terminal half of the gene product is highly acidic. Alternatively spliced transcript variants encoding different isoforms of this protein have been described.[3]
This protein is present in neurons, and it is believed to block the process of infection of these cells by HIV.[4]
# Interactions
FEZ1 has been shown to interact with Protein kinase Mζ,[5] NBR1[6] and DISC1.[7] | https://www.wikidoc.org/index.php/FEZ1 | |
3d99653b151d33372277dbd3d20c493e2eba69bd | wikidoc | FGD1 | FGD1
FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF) is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans. It is a member of the FYVE, RhoGEF and PH domain containing family.
FGD1 is a guanine-nucleotide exchange factor (GEF) that can activate the Rho GTPase Cdc42. It localizes preferentially to the trans-Golgi network (TGN) of mammalian cells and regulates, for example, the secretory transport of bone-specific proteins from the Golgi complex. Thus Cdc42 and FGD1 regulate secretory membrane trafficking that occurs especially during bone growth and mineralization in humans. FGD1 promotes nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic cells. The GEF activity of FGD1, which activates Cdc42, is harbored in its DH domain and causes the formation of filopodia, enabling the cells to migrate. FGD1 also activates the c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis. It also promotes the transition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3 fibroblasts.
The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities. These severe phenotypes are consistent with a lack of Cdc42 activity, as it controls membrane traffic as well as the organization of the actin cytoskeleton. Mutations in the FGD1 gene that cause the production of non-functional proteins are responsible for the severe phenotype of the X-linked disorder faciogenital dysplasia (FGDY), also called Aarskog-Scott syndrome.
# Structure
The mature human protein contains several characteristic motifs and domains that are involved in the protein's function. The 961 amino acid long protein has an approximate size of 106kDa. The N-terminal is a proline-rich stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, stretches from amino acid 7 – 330, followed by a DH domain (DBL homology domain), which harbors the GEF enzymatic activity, and lies between the residue 373 – 561, then a first PH domain between residues 590 – 689, a FYVE zinc finger domain (named after the four proteins it was found in Fab1, YOTB, Vac1, and EEA1) between residues 730 – 790, and a second PH domain between residues 821 – 921.
The DH domain is required for the activation of Cdc42, through the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1. FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.
# Function
FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to Golgi membranes. Levels of both FGD1 and Cdc42 are enriched on the Golgi complex itself and their interdependence regulates the transport of cargo proteins from the Golgi. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport. Another interaction partner of FGD1 is cortactin, which is directly bound by the proline-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex, this interaction seems to promote actin assembly.
FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.
# Tissue distribution
Human FGD1 is expressed predominantly in fetal tissues of brain and kidney, but also present in the heart and lung. It is hardly detectable in the corresponding adult tissues. FGD1 is expressed in areas of bone formation and post-natally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.
# Clinical significance
Mutations in the FGD1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also known as Aarskog-Scott syndrome, a human developmental disorder that can occur with neurologial problems.
The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1. Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).
Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression. | FGD1
FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF) is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome.[1] Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans.[2] It is a member of the FYVE, RhoGEF and PH domain containing family.
FGD1 is a guanine-nucleotide exchange factor (GEF) that can activate the Rho GTPase Cdc42. It localizes preferentially to the trans-Golgi network (TGN) of mammalian cells and regulates, for example, the secretory transport of bone-specific proteins from the Golgi complex. Thus Cdc42 and FGD1 regulate secretory membrane trafficking that occurs especially during bone growth and mineralization in humans.[3] FGD1 promotes nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic cells. The GEF activity of FGD1, which activates Cdc42, is harbored in its DH domain and causes the formation of filopodia, enabling the cells to migrate. FGD1 also activates the c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis.[4] It also promotes the transition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3 fibroblasts.[5][6]
The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities.[4] These severe phenotypes are consistent with a lack of Cdc42 activity, as it controls membrane traffic as well as the organization of the actin cytoskeleton.[7] Mutations in the FGD1 gene that cause the production of non-functional proteins are responsible for the severe phenotype of the X-linked disorder faciogenital dysplasia (FGDY), also called Aarskog-Scott syndrome.
# Structure
The mature human protein contains several characteristic motifs and domains that are involved in the protein's function. The 961 amino acid long protein has an approximate size of 106kDa. The N-terminal is a proline-rich stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, stretches from amino acid 7 – 330, followed by a DH domain (DBL homology domain), which harbors the GEF enzymatic activity, and lies between the residue 373 – 561, then a first PH domain between residues 590 – 689, a FYVE zinc finger domain (named after the four proteins it was found in Fab1, YOTB, Vac1, and EEA1) between residues 730 – 790, and a second PH domain between residues 821 – 921.[8]
The DH domain is required for the activation of Cdc42, through the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1.[3][9] FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.[10]
# Function
FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to Golgi membranes. Levels of both FGD1 and Cdc42 are enriched on the Golgi complex itself and their interdependence regulates the transport of cargo proteins from the Golgi. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport.[3] Another interaction partner of FGD1 is cortactin, which is directly bound by the proline-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex, this interaction seems to promote actin assembly.[7]
FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.[9]
# Tissue distribution
Human FGD1 is expressed predominantly in fetal tissues of brain and kidney, but also present in the heart and lung. It is hardly detectable in the corresponding adult tissues. FGD1 is expressed in areas of bone formation and post-natally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.[1][3]
# Clinical significance
Mutations in the FGD1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also known as Aarskog-Scott syndrome, a human developmental disorder that can occur with neurologial problems.[1]
The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1.[8][11][12][13] Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).[14]
Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.[9] | https://www.wikidoc.org/index.php/FGD1 | |
7fbb68b52da2ed13c0eb6f8a63e98af1038db592 | wikidoc | FGF1 | FGF1
FGF1, also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1. Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.
FGF-1 has no definitive signal sequence and thus is not secreted through classical pathways, but it does appear to form a disulfide linked dimer inside cells that associate with a complex of proteins at the cell membrane (including S100A13 and Syt1) which then help flip it through the membrane to the exterior of the cell. Once in the reducing conditions of the surrounding tissue, the dimer dissociates into monomeric FGF1 that can enter systemic circulation or be sequestered in tissues binding to heparan sulfate proteoglycans of the extracellular matrix. FGF1 can then bind to and exert its effects via specific fibroblast growth factor receptor (FGFR) proteins which themselves constitute a family of closely related molecules.
In addition to its extracellular activity, FGF1 can also function intracellularly. The protein has a nuclear localization sequence (NLS) but the route that FGF1 takes to get to the nucleus is unclear and it appears that some sort of cell surface receptor binding is necessary, followed by its internalization and translocation to the nucleus whereupon it can interact with nuclear isoforms of FGFRs. This is different from FGF2 which also can activate nuclear FGFRs but has splicing variants of the protein that never leave the cell and go directly to the nucleus.
# Function
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 protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Three alternatively spliced variants encoding different isoforms have been described.
FGF1 is multifunctional with many reported effects. For one example, in mice with diet-induced diabetes that is an experimental equivalent of type 2 diabetes in humans, a single injection of the FGF1 protein is enough to restore blood sugar levels to a healthy range for > 2 days.
# Interactions
FGF1 has been shown to interact with:
- CSNK2A2
- CSNK2B
- CSNK2A1
- FIBP
- FGFR1
- FGFR2
- FGFR3
- FGFR4
- HSPA9 and
- S100A13
- Synaptotagmin 1 (SYT1) | FGF1
FGF1, also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene.[1][2] It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1.[3] Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.
FGF-1 has no definitive signal sequence and thus is not secreted through classical pathways, but it does appear to form a disulfide linked dimer inside cells that associate with a complex of proteins at the cell membrane (including S100A13 and Syt1) which then help flip it through the membrane to the exterior of the cell.[4][5] Once in the reducing conditions of the surrounding tissue, the dimer dissociates into monomeric FGF1 that can enter systemic circulation or be sequestered in tissues binding to heparan sulfate proteoglycans of the extracellular matrix. FGF1 can then bind to and exert its effects via specific fibroblast growth factor receptor (FGFR) proteins which themselves constitute a family of closely related molecules.[6]
In addition to its extracellular activity, FGF1 can also function intracellularly. The protein has a nuclear localization sequence (NLS) but the route that FGF1 takes to get to the nucleus is unclear and it appears that some sort of cell surface receptor binding is necessary, followed by its internalization and translocation to the nucleus whereupon it can interact with nuclear isoforms of FGFRs.[6] This is different from FGF2 which also can activate nuclear FGFRs but has splicing variants of the protein that never leave the cell and go directly to the nucleus.
# Function
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 protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Three alternatively spliced variants encoding different isoforms have been described.[7]
FGF1 is multifunctional with many reported effects. For one example, in mice with diet-induced diabetes that is an experimental equivalent of type 2 diabetes in humans, a single injection of the FGF1 protein is enough to restore blood sugar levels to a healthy range for > 2 days.[8]
# Interactions
FGF1 has been shown to interact with:
- CSNK2A2[9]
- CSNK2B[9]
- CSNK2A1[9]
- FIBP[10]
- FGFR1[11][12]
- FGFR2[12][13][14]
- FGFR3[12][15]
- FGFR4[16][17]
- HSPA9[18] and
- S100A13[5][19][20]
- Synaptotagmin 1 (SYT1) [5][19] | https://www.wikidoc.org/index.php/FGF1 | |
3c5463224ff63c3759242c8799b75fea965bd8ac | wikidoc | FGF3 | FGF3
INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene.
# Function
FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 (FGFR3) to serve as a negative regulator of bone growth during ossification. Effectively, FGF-3 inhibits proliferation of chondrocytes within growth plate.
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.
# Clinical significance
The FGF3 gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. Also, haploinsufficiency in the FGF3 gene is thought to cause otodental syndrome.
# Interactions
FGF3 (gene) has been shown to interact with EBNA1BP2. | FGF3
INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene.[1]
# Function
FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 (FGFR3) to serve as a negative regulator of bone growth during ossification. Effectively, FGF-3 inhibits proliferation of chondrocytes within growth plate.
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.[1]
# Clinical significance
The FGF3 gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation.[1] Also, haploinsufficiency in the FGF3 gene is thought to cause otodental syndrome.
# Interactions
FGF3 (gene) has been shown to interact with EBNA1BP2.[2] | https://www.wikidoc.org/index.php/FGF3 | |
7ea78c9d6f22326dbf1e9796f1560e981d70ec2e | wikidoc | FGF4 | FGF4
Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.
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 gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.
# Function
During embryonic development, the 21-kD protein FGF4 functions as a signaling molecule that is involved in many important processes. Studies using Fgf4 gene knockout mice showed developmental defects in embryos both in vivo and in vitro, revealing that FGF4 facilitates the survival and growth of the inner cell mass during the postimplantation phase of development by acting as an autocrine or paracrine ligand. FGFs produced in the apical ectodermal ridge (AER) are critical for the proper forelimb and hindlimb outgrowth. FGF signaling in the AER is involved in regulating limb digit number and cell death in the interdigital mesenchyme. When FGF signaling dynamics and regulatory processes are altered, postaxial polydactyly and cutaneous syndactyly, two phenotypic abnormalities collectively known as polysyndactyly, can occur in the limbs. Polysyndactyly is observed when an excess of Fgf4 is expressed in limb buds of wild-type mice. In mutant limb buds that do not express Fgf8, the expression of Fgf4 still results in polysyndactyly, but Fgf4 is also able to rescue all skeletal defects that arise from the lack of Fgf8. Therefore, the Fgf4 gene compensates for the loss of the Fgf8 gene, revealing that FGF4 and FGF8 perform similar functions in limb skeleton patterning and limb development. Studies of zebrafish Fgf4 knockdown embryos demonstrated that when Fgf4 signaling is inhibited, randomized left-right patterning of the liver, pancreas, and heart takes place, showing that Fgf4 is a crucial gene involved in developing left-right patterning of visceral organs. Furthermore, unlike the role of FGF4 in limb development, FGF4 and FGF8 have distinct roles and function independently in the process of visceral organ left-right patterning.
Fgf signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the Fgf4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro. | FGF4
Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.[1][2]
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 gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.[2]
# Function
During embryonic development, the 21-kD protein FGF4 functions as a signaling molecule that is involved in many important processes.[3][4] Studies using Fgf4 gene knockout mice showed developmental defects in embryos both in vivo and in vitro, revealing that FGF4 facilitates the survival and growth of the inner cell mass during the postimplantation phase of development by acting as an autocrine or paracrine ligand.[3] FGFs produced in the apical ectodermal ridge (AER) are critical for the proper forelimb and hindlimb outgrowth.[5] FGF signaling in the AER is involved in regulating limb digit number and cell death in the interdigital mesenchyme.[6] When FGF signaling dynamics and regulatory processes are altered, postaxial polydactyly and cutaneous syndactyly, two phenotypic abnormalities collectively known as polysyndactyly, can occur in the limbs. Polysyndactyly is observed when an excess of Fgf4 is expressed in limb buds of wild-type mice. In mutant limb buds that do not express Fgf8, the expression of Fgf4 still results in polysyndactyly, but Fgf4 is also able to rescue all skeletal defects that arise from the lack of Fgf8. Therefore, the Fgf4 gene compensates for the loss of the Fgf8 gene, revealing that FGF4 and FGF8 perform similar functions in limb skeleton patterning and limb development.[6] Studies of zebrafish Fgf4 knockdown embryos demonstrated that when Fgf4 signaling is inhibited, randomized left-right patterning of the liver, pancreas, and heart takes place, showing that Fgf4 is a crucial gene involved in developing left-right patterning of visceral organs. Furthermore, unlike the role of FGF4 in limb development, FGF4 and FGF8 have distinct roles and function independently in the process of visceral organ left-right patterning.[7]
Fgf signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the Fgf4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro.[8] | https://www.wikidoc.org/index.php/FGF4 | |
9d79e1ed0cea05a6b9fc52e2a024f868ba2ba4d4 | wikidoc | FGF5 | FGF5
Fibroblast growth factor 5 is a protein that in humans is encoded by the FGF5 gene.
The majority of FGF family members are glycosaminoglycan binding proteins which 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. FGF proteins interact with a family of specific tyrosine kinase receptors, a process often regulated by proteoglycans or extracellular binding protein cofactors. A number of intracellular signalling cascades are known to be activated after FGF-FGFR interaction including PI3K-AKT, PLCγ, RAS-MAPK and STAT pathways.
# FGF5 and its receptor
FGF5 is a 268 amino acid, 29.1 kDa protein, which also naturally occurs as a 123 amino acid isoform splice variant (FGF5s) ,. FGF5 is produced in the outer root sheath of the hair follicle as well as perifollicular macrophages, with maximum expression occurring in the late anagen phase of the hair cycle,. The receptor for FGF5, FGFR1, is largely expressed in the dermal papilla cells of the hair follicle.,. The alternatively spliced isoform FGF5s, has been identified as an antagonist of FGF5 in a number of studies.,,
# FGF5 and hair growth
The only described function of FGF5 in adults is in the regulation of the hair cycle. FGF5 performs a critical role in the hair cycle, where it acts as the key signalling molecule in initiating the transition from the anagen (growth) phase to the catagen (regression) phase.,, Evidence of this activity was initially gathered via targeted disruption of the homolog of the FGF5 gene in mice, which resulted in a phenotype with abnormally long hair.
In numerous genetic studies of long haired phenotypes of animals it has been shown that small changes in the FGF5 gene can disrupt its expression, leading to an increase in the length of the anagen phase of the hair cycle, resulting in phenotypes with extremely long hair. This has been demonstrated in many species, including cats dogs mice, rabbits, donkeys, sheep and goats, where it is often referred to as the angora mutation. Recently, CRISPR modification of goats to artificially knock out the FGF5 gene, was shown to result in higher wool yield, without any fertility or other negative effects on the goats.
It has been hypothesised that, in an alternate type of mutation, positive selection for increased expression of the FGF5 protein was one of the contributing factors in the evolutionary loss of hair in cetaceans as they transitioned from the terrestrial to the aquatic environment.
FGF5 also affects the hair cycle in humans. Individuals with mutations in FGF5 exhibit familial trichomegaly, a condition that involves a significant increase in the portion of anagen phase hair as well as extremely long eyelashes. . FGF5 has also been identified as a potentially important factor in androgenetic alopecia. In 2017, a large genome wide association study of men with early onset androgenetic alopecia identified polymorphisms in FGF5 as having a strong association with male pattern hair loss.
Blocking FGF5 in the human scalp extends the hair cycle, resulting in less hair fall, faster hair growth rate and increased hair growth., In vitro methods using engineered cell lines and FGFR1 expressing dermal papilla cells have identified a number of naturally derived botanical isolates including Sanguisorba officnalis and single molecule members of the monoterpenoid as inhibitors (blockers) of FGF5. Clinical studies have shown that topical application of formulations containing these natural extracts and molecules are beneficial in men and women experiencing hair loss., | FGF5
Fibroblast growth factor 5 is a protein that in humans is encoded by the FGF5 gene.
The majority of FGF family members are glycosaminoglycan binding proteins which 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. FGF proteins interact with a family of specific tyrosine kinase receptors, a process often regulated by proteoglycans or extracellular binding protein cofactors. A number of intracellular signalling cascades are known to be activated after FGF-FGFR interaction including PI3K-AKT, PLCγ, RAS-MAPK and STAT pathways.[1]
# FGF5 and its receptor
FGF5 is a 268 amino acid, 29.1 kDa protein, which also naturally occurs as a 123 amino acid isoform splice variant (FGF5s) [2],.[3] FGF5 is produced in the outer root sheath of the hair follicle as well as perifollicular macrophages, with maximum expression occurring in the late anagen phase of the hair cycle,.[4][5] The receptor for FGF5, FGFR1, is largely expressed in the dermal papilla cells of the hair follicle.,.[4][5] The alternatively spliced isoform FGF5s, has been identified as an antagonist of FGF5 in a number of studies.[2],,[3][6]
# FGF5 and hair growth
The only described function of FGF5 in adults is in the regulation of the hair cycle. FGF5 performs a critical role in the hair cycle, where it acts as the key signalling molecule in initiating the transition from the anagen (growth) phase to the catagen (regression) phase.,,[7][8] Evidence of this activity was initially gathered via targeted disruption of the homolog of the FGF5 gene in mice, which resulted in a phenotype with abnormally long hair.[8]
In numerous genetic studies of long haired phenotypes of animals it has been shown that small changes in the FGF5 gene can disrupt its expression, leading to an increase in the length of the anagen phase of the hair cycle, resulting in phenotypes with extremely long hair. This has been demonstrated in many species, including cats [9][10] dogs [11][12] mice,[8] rabbits,[13] donkeys,[14] sheep and goats,[15] where it is often referred to as the angora mutation. Recently, CRISPR modification of goats to artificially knock out the FGF5 gene, was shown to result in higher wool yield, without any fertility or other negative effects on the goats.[16]
It has been hypothesised that, in an alternate type of mutation, positive selection for increased expression of the FGF5 protein was one of the contributing factors in the evolutionary loss of hair in cetaceans as they transitioned from the terrestrial to the aquatic environment.[17]
FGF5 also affects the hair cycle in humans. Individuals with mutations in FGF5 exhibit familial trichomegaly, a condition that involves a significant increase in the portion of anagen phase hair as well as extremely long eyelashes. .[7] FGF5 has also been identified as a potentially important factor in androgenetic alopecia. In 2017, a large genome wide association study of men with early onset androgenetic alopecia identified polymorphisms in FGF5 as having a strong association with male pattern hair loss.[18]
Blocking FGF5 in the human scalp extends the hair cycle, resulting in less hair fall, faster hair growth rate and increased hair growth.,[19][20] In vitro methods using engineered cell lines and FGFR1 expressing dermal papilla cells have identified a number of naturally derived botanical isolates including Sanguisorba officnalis [19] and single molecule members of the monoterpenoid [20] as inhibitors (blockers) of FGF5. Clinical studies have shown that topical application of formulations containing these natural extracts and molecules are beneficial in men and women experiencing hair loss.,[19][20] | https://www.wikidoc.org/index.php/FGF5 | |
0e63d238e1ea826a74a35676e91e988ce5e746ee | wikidoc | FGF8 | FGF8
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 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.
Fgf8 is important and necessary for setting up and maintaining the midbrain/hindbrain border (or mesencephalon/met-encephalon border) which plays the vital role of “organizer” in development, like the Spemann “organizer” of the gastrulating embryo. Fgf8 is expressed in the region where Otx2 and Gbx2 cross inhibit each other and is maintained expression by this interaction. Once expressed, the Fgf8 induces other transcription factors to form cross-regulatory loops between cells, thus the border is established. Through development, the Fgf8 goes to regulate the growth and differentiation of progenitor cells in this region to produce ultimate structure of midbrain and hindbrain. Crossely’s experiment proves that the Fgf8 is sufficient to induce the repatterning of midbrain and hindbrain structure.
In the development of forebrain, cortical patterning centers are the boundaries or poles of cortical primordium, where multiple BMP and WNT genes are expressed. Besides, at the anterior pole several FGF family including Fgf3, 8,17 and 18 overlap in expression. The similarity in cortical gene expression in Emx2 mutants and mice in which the anterior FGF8 source is augmented suggests that FGF8 controls the graded expression(low anterior, high posterior) of Emx2 in the cortical primordium. Emx2 is one of the protomap molecular determinants that prove to be closely interacted with Pax6. Emx2 and Pax6 are expressed in opposing gradients along the A/P axis of the cortical primordium and cooperate to set up area pattern. Fgf8 and Emx2 antagonize each other to create the development map. Fgf8 promotes the development of anterior part and suppresses posterior fate, while the Emx2 does the reverse. What's more, FGF8 manipulations suggest FGF8 controls the cortical graded expression of COUP-TF1. Moreover, the sharpness of both COUPTF1 and COUP-TF2 expression borders would be expected of genes involved in boundary specification.Thus, the interaction between them regulates the A/P axis of cortical primordium and directs the development map of cortical area.
# Clinical significance
This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogenesis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs reveal roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. | FGF8
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 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.[2]
Fgf8 is important and necessary for setting up and maintaining the midbrain/hindbrain border (or mesencephalon/met-encephalon border) which plays the vital role of “organizer” in development, like the Spemann “organizer” of the gastrulating embryo. Fgf8 is expressed in the region where Otx2 and Gbx2 cross inhibit each other and is maintained expression by this interaction. Once expressed, the Fgf8 induces other transcription factors to form cross-regulatory loops between cells, thus the border is established. Through development, the Fgf8 goes to regulate the growth and differentiation of progenitor cells in this region to produce ultimate structure of midbrain and hindbrain.[3] Crossely’s experiment proves that the Fgf8 is sufficient to induce the repatterning of midbrain and hindbrain structure.[4]
In the development of forebrain, cortical patterning centers are the boundaries or poles of cortical primordium, where multiple BMP and WNT genes are expressed. Besides, at the anterior pole several FGF family including Fgf3, 8,17 and 18 overlap in expression.[5] The similarity in cortical gene expression in Emx2 mutants and mice in which the anterior FGF8 source is augmented suggests that FGF8 controls the graded expression(low anterior, high posterior) of Emx2 in the cortical primordium. Emx2 is one of the protomap molecular determinants that prove to be closely interacted with Pax6. Emx2 and Pax6 are expressed in opposing gradients along the A/P axis of the cortical primordium and cooperate to set up area pattern. Fgf8 and Emx2 antagonize each other to create the development map. Fgf8 promotes the development of anterior part and suppresses posterior fate, while the Emx2 does the reverse. What's more, FGF8 manipulations suggest FGF8 controls the cortical graded expression of COUP-TF1.[6] Moreover, the sharpness of both COUPTF1 and COUP-TF2 expression borders would be expected of genes involved in boundary specification.Thus, the interaction between them regulates the A/P axis of cortical primordium and directs the development map of cortical area.
# Clinical significance
This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogenesis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs reveal roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants.[2] | https://www.wikidoc.org/index.php/FGF8 | |
c1f2b86c11364450622328896b385aed35e50ffa | wikidoc | FGF9 | FGF9
Glia-activating factor is a protein that in humans is encoded by the FGF9 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. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis. This gene is involved in the patterning of sex determination, lung development, and skeletal development.
## Sex determination
FGF9 has also been shown to play a vital role in male sex development. FGF9’s role in sex determination begins with its expression in the bi-potent gonads for both females and males. Once activated by SOX9, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a positive feedback loop upregulating SOX9, while simultaneously inactivating the female Wnt4 signaling pathway. The absence of Fgf9 causes an individual, even an individual with X and Y chromosomes, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of Sertoli cells and creation of the testis cords.
## Lung development
In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal proliferation. Inactivation of FGF9 results in diminished epithelial branching. By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.
## Skeletal development
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and FGF18 both stimulate chondrocyte proliferation. FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of VEGF and VEGFR2 and lower osteoclast recruitment. One disease associated with this gene is multiple synostoses syndrome (SYNS), a rare bone disease that has to do with the fusion of the fingers and toes. A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS. A mutation in Noggin (NOG) and the Growth Differentiation Factor 5 (GDF5) are the other two causes of SYNS. The S99N mutation results in cell signaling irregularities that interfere with chondrogenesis and osteogenesis causing the fusion of the joints during development.
# Interactions
FGF9 has been shown to interact with Fibroblast growth factor receptor 3. | FGF9
Glia-activating factor is a protein that in humans is encoded by the FGF9 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. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis.[2] This gene is involved in the patterning of sex determination, lung development, and skeletal development.
## Sex determination
FGF9 has also been shown to play a vital role in male sex development. FGF9’s role in sex determination begins with its expression in the bi-potent gonads for both females and males.[3] Once activated by SOX9, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a positive feedback loop upregulating SOX9, while simultaneously inactivating the female Wnt4 signaling pathway.[3] The absence of Fgf9 causes an individual, even an individual with X and Y chromosomes, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of Sertoli cells and creation of the testis cords.[4]
## Lung development
In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal proliferation. Inactivation of FGF9 results in diminished epithelial branching.[5] By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.[5]
## Skeletal development
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and FGF18 both stimulate chondrocyte proliferation.[6] FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of VEGF and VEGFR2 and lower osteoclast recruitment.[6] One disease associated with this gene is multiple synostoses syndrome (SYNS), a rare bone disease that has to do with the fusion of the fingers and toes.[7] A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS.[8] A mutation in Noggin (NOG) and the Growth Differentiation Factor 5 (GDF5) are the other two causes of SYNS.[8] The S99N mutation results in cell signaling irregularities that interfere with chondrogenesis and osteogenesis causing the fusion of the joints during development.[8]
# Interactions
FGF9 has been shown to interact with Fibroblast growth factor receptor 3.[9][10] | https://www.wikidoc.org/index.php/FGF9 | |
344081ef4f3cf56d72086159ceb1642ca8733218 | wikidoc | FGL1 | FGL1
Fibrinogen-like protein 1 (FGL-1) is a protein that is structurally related to fibrinogen. In humans, FLG-1 is encoded by the FGL1 gene. Four splice variants exist for this gene.
# Function
Fibrinogen-like protein 1 is a member of the fibrinogen family of proteins, which also includes fibrinogen, fibrinogen-like protein 2, and clotting factors V, VIII, and XIII. FGL-1 is homologous to the carboxy terminus of the fibrinogen beta- and gamma- subunits which contains the four conserved cysteines of that are common to all members of the fibrinogen family. However, FGL-1 lacks the platelet-binding site, cross-linking region, and thrombin-sensitive site which allow the other members of the fibrinogen family to aid in fibrin clot formation.
# Clinical significance
FGL-1 may play a role in the development of hepatocellular carcinomas. | FGL1
Fibrinogen-like protein 1 (FGL-1) is a protein that is structurally related to fibrinogen. In humans, FLG-1 is encoded by the FGL1 gene.[1][2] Four splice variants exist for this gene.
# Function
Fibrinogen-like protein 1 is a member of the fibrinogen family of proteins, which also includes fibrinogen, fibrinogen-like protein 2, and clotting factors V, VIII, and XIII. FGL-1 is homologous to the carboxy terminus of the fibrinogen beta- and gamma- subunits which contains the four conserved cysteines of that are common to all members of the fibrinogen family. However, FGL-1 lacks the platelet-binding site, cross-linking region, and thrombin-sensitive site which allow the other members of the fibrinogen family to aid in fibrin clot formation.[2]
# Clinical significance
FGL-1 may play a role in the development of hepatocellular carcinomas.[2] | https://www.wikidoc.org/index.php/FGL1 | |
36db4dfe7d04df4113810a8e7e07a0a69bdba804 | wikidoc | FGL2 | FGL2
Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene.
# Structure
FGL2 is a 439 amino acid secreted protein that is similar to the β- and γ-chains of fibrinogen. The carboxyl-terminus of the encoded protein consists of the fibrinogen-related domains (FRED). The encoded protein forms a tetrameric complex which is stabilized by interchain disulfide bonds.
# Function
This protein may play a role in physiologic functions at mucosal sites.
FGL2 is a protein that exhibits pleiotropic effects within the body and is an important immune regulator of both innate and adaptive responses. The protein exists as both a Type II transmembrane protein (with the carboxy terminus on the extracellular side of the plasma membrane) found on the surface of macrophages and endothelial cells and can be constitutively secreted by both CD4+ and CD8+ T cells.
# Variants
## Membrane bound
Membrane bound FGL2 (mFGL2) exhibits a prothrombinase activity, resulting in fibrin deposition, vascular thrombosis and tissue inflammation within an affected tissue, largely contributing to the innate arm of immunity. Through mFGL2’s actions of promoting vascular thrombosis and tissue inflammation, it has been implicated in the pathogenesis of viral-induced fulminant hepatitis in acute hepatitis B infections. Hepatocellular necrosis ensues rapidly, due to the HBV nucleocapsid protein’s ability to markedly upregulate expression of the mFGL2 prothrombinase, leading to fibrin deposition within the vasculature networks that supply blood to the liver.
## Secreted
In addition to its constitutive secretion by CD4+ and CD8+ T cells, the secreted form of FGL2 (sFGL2) can be inducibly secreted by Foxp3+ CD4+ CD25+ T regulatory cells (Tregs). Such Treg cells play a vital role in dampening the immune response after the clearance of an infection to prevent sterile inflammation. These cells also play a fundamental role in maintaining self tolerance by suppressing the activation and expansion of self-reactive lymphocytes that may instigate autoimmunity.9 Through their roles in immune homeostasis, it has been shown that depletion of the Treg cell population in murine models for disease lead to enhanced immune responses to a variety of infectious agents including hepatitis C virus (HCV).10 Additionally, patients with a chronic HCV infection were shown to have higher counts of Treg cells in peripheral blood when compared with successfully treated or healthy controls.11
Secreted FGL2 (sFGL2) plays a role as a negative regulator of the Immune response. sFGL2 inhibits the adaptive immune response. Knockout mice for FGL2 have T cells that are hyperproliferative. sFGL2 is capable of inhibiting the proliferation of T cells stimulated by alloantigens and this inhibition is alleviated by the addition of a monoclonal antibody against sFGL2’s fibrinogen-like domain (FRED).12 When the supernatants of these T cell cultures are analyzed, they showed a predominant Th2 type polarization with upregulated levels of expression of interleukin-4 (IL-4) and Interleukin-10 (IL-10).12 There are also downregulated levels of Th1-type cytokines such as interleukin-2 (IL-2) and interferon γ (IFN-γ). This shows that sFGL2 largely inhibits the Th1 type response needed to activate cytotoxic lymphocytes to clear HCV infections. Additionally, sFGL2 can inhibit the maturation of immature dendritic cells (DCs) by preventing NF-κB translocation to the nucleus and subsequent expression of the co-stimulatory molecule CD80 and major histocompatibility complex II (MHC II). Therefore, sFGL2 may contribute to the negative regulatory activity exhibited by Treg cells.
sFGL2 works to repress immune response through its FRED Domain. The immunosuppressive activity of sFGL2 has been localized to the C-terminal region containing the FRED domain. sFGL2’s FRED domain shares significant homology to the fibrinogen related domains of potent immunoregulatory molecules like cytotaxin and tenascin.12 This works to repress immune responses by binding to the inhibitory FC receptor, FCγRIIB. Furthermore, HCV’s core protein has been found to increase the levels of expression of sFGL2 and cause virus-specific CD4+ T lymphocytes to skew largely toward a Th2 lineage, allowing for the establishment of a chronic infection.13
# Clinical significance
Human Fibrinogen-like protein 2 may be useful as a biomarker for responsiveness to antiviral therapy. | FGL2
Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene.[1][2]
# Structure
FGL2 is a 439 amino acid secreted protein that is similar to the β- and γ-chains of fibrinogen. The carboxyl-terminus of the encoded protein consists of the fibrinogen-related domains (FRED). The encoded protein forms a tetrameric complex which is stabilized by interchain disulfide bonds.[1]
# Function
This protein may play a role in physiologic functions at mucosal sites.
FGL2 is a protein that exhibits pleiotropic effects within the body and is an important immune regulator of both innate and adaptive responses.[3] The protein exists as both a Type II transmembrane protein (with the carboxy terminus on the extracellular side of the plasma membrane) found on the surface of macrophages and endothelial cells and can be constitutively secreted by both CD4+ and CD8+ T cells.[3]
# Variants
## Membrane bound
Membrane bound FGL2 (mFGL2) exhibits a prothrombinase activity, resulting in fibrin deposition, vascular thrombosis and tissue inflammation within an affected tissue, largely contributing to the innate arm of immunity.[4] Through mFGL2’s actions of promoting vascular thrombosis and tissue inflammation, it has been implicated in the pathogenesis of viral-induced fulminant hepatitis in acute hepatitis B infections.[5] Hepatocellular necrosis ensues rapidly, due to the HBV nucleocapsid protein’s ability to markedly upregulate expression of the mFGL2 prothrombinase, leading to fibrin deposition within the vasculature networks that supply blood to the liver.[5]
## Secreted
In addition to its constitutive secretion by CD4+ and CD8+ T cells, the secreted form of FGL2 (sFGL2) can be inducibly secreted by Foxp3+ CD4+ CD25+ T regulatory cells (Tregs). Such Treg cells play a vital role in dampening the immune response after the clearance of an infection to prevent sterile inflammation. These cells also play a fundamental role in maintaining self tolerance by suppressing the activation and expansion of self-reactive lymphocytes that may instigate autoimmunity.[citation needed]9 Through their roles in immune homeostasis, it has been shown that depletion of the Treg cell population in murine models for disease lead to enhanced immune responses to a variety of infectious agents including hepatitis C virus (HCV).[citation needed]10 Additionally, patients with a chronic HCV infection were shown to have higher counts of Treg cells in peripheral blood when compared with successfully treated or healthy controls.[citation needed]11
Secreted FGL2 (sFGL2) plays a role as a negative regulator of the Immune response. sFGL2 inhibits the adaptive immune response. Knockout mice for FGL2 have T cells that are hyperproliferative.[6] sFGL2 is capable of inhibiting the proliferation of T cells stimulated by alloantigens and this inhibition is alleviated by the addition of a monoclonal antibody against sFGL2’s fibrinogen-like domain (FRED).[citation needed]12 When the supernatants of these T cell cultures are analyzed, they showed a predominant Th2 type polarization with upregulated levels of expression of interleukin-4 (IL-4) and Interleukin-10 (IL-10).[citation needed]12 There are also downregulated levels of Th1-type cytokines such as interleukin-2 (IL-2) and interferon γ (IFN-γ).[6] This shows that sFGL2 largely inhibits the Th1 type response needed to activate cytotoxic lymphocytes to clear HCV infections. Additionally, sFGL2 can inhibit the maturation of immature dendritic cells (DCs) by preventing NF-κB translocation to the nucleus and subsequent expression of the co-stimulatory molecule CD80 and major histocompatibility complex II (MHC II).[6] Therefore, sFGL2 may contribute to the negative regulatory activity exhibited by Treg cells.
sFGL2 works to repress immune response through its FRED Domain. The immunosuppressive activity of sFGL2 has been localized to the C-terminal region containing the FRED domain. sFGL2’s FRED domain shares significant homology to the fibrinogen related domains of potent immunoregulatory molecules like cytotaxin and tenascin.[citation needed]12 This works to repress immune responses by binding to the inhibitory FC receptor, FCγRIIB. Furthermore, HCV’s core protein has been found to increase the levels of expression of sFGL2 and cause virus-specific CD4+ T lymphocytes to skew largely toward a Th2 lineage, allowing for the establishment of a chronic infection.[citation needed]13
# Clinical significance
Human Fibrinogen-like protein 2 may be useful as a biomarker for responsiveness to antiviral therapy.[7] | https://www.wikidoc.org/index.php/FGL2 | |
7edea4d07a821f8da3e198f6acdf19ced09ca7b6 | wikidoc | FHIT | FHIT
Bis(5'-adenosyl)-triphosphatase also known as fragile histidine triad protein (FHIT) is an enzyme that in humans is encoded by the FHIT gene.
# Function
FHIT is also known as human accelerated region 10. It may, therefore, have played a key role in differentiating humans from apes.
This gene, a member of the histidine triad gene family, encodes a diadenosine
P1,P3-bis(5'-adenosyl)-triphosphate adenylohydrolase involved in purine metabolism. The gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts of this gene. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas.
Though the exact molecular function of FHIT is still partially unclear, the gene works as a tumor suppressor as it has been demonstrated in animal studies. Furthermore FHIT has been shown to synergize with VHL, another tumor suppressor, in protecting against chemically - induced lung cancer.
FHIT also acts as a tumor suppressor of HER2/neu driven breast cancer.
# Interactions
FHIT has been shown to interact with UBE2I. | FHIT
Bis(5'-adenosyl)-triphosphatase also known as fragile histidine triad protein (FHIT) is an enzyme that in humans is encoded by the FHIT gene.[1][2]
# Function
FHIT is also known as human accelerated region 10. It may, therefore, have played a key role in differentiating humans from apes.[3]
This gene, a member of the histidine triad gene family, encodes a diadenosine
P1,P3-bis(5'-adenosyl)-triphosphate adenylohydrolase involved in purine metabolism. The gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts of this gene. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas.[4]
Though the exact molecular function of FHIT is still partially unclear, the gene works as a tumor suppressor as it has been demonstrated in animal studies.[5][6][7] Furthermore FHIT has been shown to synergize with VHL, another tumor suppressor, in protecting against chemically - induced lung cancer.[8]
FHIT also acts as a tumor suppressor of HER2/neu driven breast cancer.[9]
# Interactions
FHIT has been shown to interact with UBE2I.[10] | https://www.wikidoc.org/index.php/FHIT | |
2c75140bf940cd7f8a3b7154c1eb00734109b15d | wikidoc | FHL1 | FHL1
Four and a half LIM domains protein 1 is a protein that in humans is encoded by the FHL1 gene.
# Structure
LIM proteins, named for 'LIN11, ISL1, and MEC3,' are defined by the possession of a highly conserved double zinc finger motif called the LIM domain.
# Role in muscle disorders
FHL1 has been shown to be heavily expressed in skeletal and cardiac muscles. In 2008 this was borne out by the discovery that defects in the FHL1 gene are responsible for a number of Muscular dystrophy-like muscle disorders, ranging from severe, childhood onset diseases through to adult-onset disorders similar to Limb girdle muscular dystrophy. At present different research groups are using different terminology for these disorders, which include: | FHL1
Four and a half LIM domains protein 1 is a protein that in humans is encoded by the FHL1 gene.[1][2][3]
# Structure
LIM proteins, named for 'LIN11, ISL1, and MEC3,' are defined by the possession of a highly conserved double zinc finger motif called the LIM domain.[3]
# Role in muscle disorders
FHL1 has been shown to be heavily expressed in skeletal and cardiac muscles.[4] In 2008 this was borne out by the discovery that defects in the FHL1 gene are responsible for a number of Muscular dystrophy-like muscle disorders, ranging from severe, childhood onset diseases through to adult-onset disorders similar to Limb girdle muscular dystrophy. At present different research groups are using different terminology for these disorders, which include: | https://www.wikidoc.org/index.php/FHL1 | |
3ea2b80bb91726cf9068b2f692db1bbce6ea45be | wikidoc | FHL2 | FHL2
Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene. LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.
# Function
FHL-2 is thought to have a role in the assembly of extracellular membranes and may function as a link between presenilin-2 and an intracellular signaling pathway.
# Family
The Four-and-a-half LIM (FHL)-only protein subfamily is one of the members of the LIM-only protein family. Protein members within the group might be originated from a common ancestor and share a high degree of similarity in their amino acid sequence. These proteins are defined by the presence of the four and a half cysteine-rich LIM homeodomain with the half-domain always located in the N-terminal. The name LIM was derived from the first letter of the transcription factors LIN-11, ISL-1 and MEC-3, from which the domain was originally characterized. No direct interactions between LIM domain and DNA have been reported. Instead, extensive evidence points towards the functional role of FHL2 in supporting protein-protein interactions of LIM-containing proteins and its binding partners. Thus far, five members have been categorized into the FHL subfamily, which are FHL1, FHL2, FHL3, FHL4 and activator of CREM in testis (ACT) in human. FHL1, FHL2 and FHL3 are predominantly expressed in muscle, while FHL4 and FHL5 are expressed exclusively in testis.
# Gene
FHL2 is the best studied member within the subfamily. The protein is encoded by the fhl2 gene being mapped in the region of human chromosome 2q12-q14. Two alternative promoters, 1a and 1b, as well as 5 transcript variants of fhl2 have been reported.
# Tissue distribution
FHL2 exhibits diverse expression patterns in a cell/tissue-specific manner, which has been found in liver, kidney, lung, ovary, pancreas, prostate, stomach, colon, cortex, and in particular, the heart. However, its expression in some immune-related tissues like the spleen, thymus and blood leukocytes has not been documented. Intriguingly, the FHL2 expression and function varies significantly between different types of cancer. Such discrepancies are most likely due to the existence of the wide variety of transcription factors governing FHL2 expression.
# Regulation of expression
Different transcription factors that have been reported responsible for the regulation of fhl2 expression include the well-known tumor suppressor protein p53, serum response factor (SRF), specificity protein 1 (Sp1). the pleiotropic factor IL-1β, MEF-2, and activator protein-1 (AP-1). Apart from being regulated by different transcription factors, FHL2 is itself involved extensively in regulating the expression of other genes. FHL2 exerts its transcriptional regulatory effects by functioning as an adaptor protein interacting indirectly with the targeted genes. In fact, LIM domain is a platform for the formation of multimeric protein complexes. Therefore, FHL2 can contribute to human carcinogenesis by interacting with transcription factors of cancer-related genes and modulates the signaling pathways underlying the expression of these genes. Different types of cancer are associated with FHL2 which act either as the cancer suppressor or inducer, for example in breast cancer, gastrointestinal (GI) cancers, liver cancer and prostate cancer.
# Clinical significance
The expression and functions of FHL2 varies greatly depending on the cancer types. It appeared that phenomenon is highly related to the differential mechanistic transcriptional regulations of FHL2 in the various types of cancer. However, the participation of fhl2 mutations and the posttranslational modifications of fhl2 in carcinogenesis cannot be ignored. In fact, functional mutation of fhl2 has been identified in a patient with familial dilated cardiomyopathy (DCM) and is associated with its pathogenesis. This implied that fhl2 mutation may also profoundly affect the diverse cancer progressions. However, records describing the effects of fhl2 mutations on carcinogenesis are scarce.
Phosphorylation of FHL-2 protein has no significant effects on FHL2 functioning both in vitro and in vivo. Provided that the existence of posttranscriptional modifications on FHL2 other than phosphorylation is still unclear and FHL2 functions almost exclusively through protein-protein interactions, research works in this direction is still interested. In particular, the mechanisms underpinning the subcellular localization of FHL2 should be focused. FHL2 can traffic freely between nuclear and the different cellular compartments. It also interacts with other proteinaceous binding partners belonging to different functional classes including, but not limited to, transcription factors and signal transducers. Therefore, FHL2 translocation could be important in regulating the different molecular signaling pathways which modify carcinogenesis, for example, nuclear translocation of FHL2 is related to aggressiveness and recurrence of prostate cancer Similar evidence also has been identified in experiment using A7FIL+ cells and NIH 3T3 cell line as the disease model.
## Breast cancer
The FHL2 protein interacts with the breast cancer type 1 susceptibility gene (BRCA1) which enhances the transactivation of BRCA1. In addition, intratumoral FHL2 level was one of the factors determining the worse survival of breast cancer patients
## Gastrointestinal cancer
FHL2 is related to gastrointestinal cancers and in particular, colon cancer. Fhl2 demonstrates an oncogenic property in colon cancer which induces the differentiation of some in vitro colon cancer models. FHL2 is as well crucial to colon cancer cells invasion, migration and adhesion to extracellular matrix. The expression of FHL2 is positively regulated by transforming growth factor beta 1 (TGF-β1) stimulations which induces epithelial-mesenchymal transition (EMT) and endows cancer cells with metastatic properties. The TGF-β1-midiated alternation of FHL2 expression level might therefore trigger colon cell invasion. Besides, the subcellular localization of FHL2 can be modulated by TGF-β1 in sporadic colon cancer which resulted in the polymerization of alpha smooth muscle actin (α-SMA). This process induces the fibroblast to take up a myofibroblast phenotype and contributes to cancer invasion. FHL2 can also induce EMT and cancer cell migration by affecting the structural integrity of membrane-associated E-cadherin-β-catenin complex.
## Liver cancer
In the most common form liver cancer, the hepatocellular carcinoma (HCC), FHL2 is always downregulated in the clinical samples. Therefore, fhl2 is exhibiting a tumor-suppressive effect on HCC. Similar to p53, overexpression of FHL2 inhibit the proliferative activity of the HCC Hep3B cell line by decreasing its cyclin D1 expression and increasing P21 and P27 expression supporting the time-dependent cellular repair process. Of note, a database of FHL2-regulated genes in murine liver has recently been established by using microarray and bioinformatics analysis, which provide useful information concerning most of the pathways and new genes related to FHL2.
## Prostate cancer
The molecular communication between androgen receptor (AR) and FHL2 is linked to the disease development of prostate cancer such as aggressiveness and biochemical recurrence (i.e., rise in circulatory prostate-specific antigen (PSA) levels after surgical or radiography treatment) FHL2 expression is profoundly initiated by androgen through the mediation of serum response factor (SFR) and the RhoA / actin / megakaryocytic acute leukemia (MAL) signaling axis functioning upstream of SRF. On the other hand, FHL2 is the coactivator of AR and is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor (AhR) imposing AR activity with as yet unknown mechanisms. Calpain cleavage of cytoskeletal protein filamin which is increased in prostate cancer could induce the nuclear translocation of FHL2, and this subsequently increase AR coactivation.
# Interactions
FHL2 has been shown to interact with:
- Androgen receptor,
- BRCA1,
- CTNNB1,
- CD18,
- CD29,
- CD49c,
- CREB1,
- EIF6,
- FHL3,
- IGFBP5,
- ITGA7,
- ITGB6,
- MAPK1,
- PSEN2,
- TRAF6,
- TTN,
- ZNF638, and
- ZBTB16. | FHL2
Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene.[1] LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.[2]
# Function
FHL-2 is thought to have a role in the assembly of extracellular membranes and may function as a link between presenilin-2 and an intracellular signaling pathway.[2]
# Family
The Four-and-a-half LIM (FHL)-only protein subfamily is one of the members of the LIM-only protein family. Protein members within the group might be originated from a common ancestor and share a high degree of similarity in their amino acid sequence.[3] These proteins are defined by the presence of the four and a half cysteine-rich LIM homeodomain with the half-domain always located in the N-terminal.[4] The name LIM was derived from the first letter of the transcription factors LIN-11, ISL-1 and MEC-3, from which the domain was originally characterized.[5] No direct interactions between LIM domain and DNA have been reported. Instead, extensive evidence points towards the functional role of FHL2 in supporting protein-protein interactions of LIM-containing proteins and its binding partners.[6][7][8][9] Thus far, five members have been categorized into the FHL subfamily, which are FHL1, FHL2, FHL3, FHL4 and activator of CREM in testis (ACT) in human.[10] FHL1, FHL2 and FHL3 are predominantly expressed in muscle,[11][12] while FHL4 and FHL5 are expressed exclusively in testis.[13]
# Gene
FHL2 is the best studied member within the subfamily. The protein is encoded by the fhl2 gene being mapped in the region of human chromosome 2q12-q14.[14] Two alternative promoters, 1a and 1b, as well as 5 transcript variants of fhl2 have been reported.[15]
# Tissue distribution
FHL2 exhibits diverse expression patterns in a cell/tissue-specific manner, which has been found in liver, kidney, lung, ovary, pancreas, prostate, stomach, colon, cortex, and in particular, the heart. However, its expression in some immune-related tissues like the spleen, thymus and blood leukocytes has not been documented.[16] Intriguingly, the FHL2 expression and function varies significantly between different types of cancer.[15][17][18][19] Such discrepancies are most likely due to the existence of the wide variety of transcription factors governing FHL2 expression.
# Regulation of expression
Different transcription factors that have been reported responsible for the regulation of fhl2 expression include the well-known tumor suppressor protein p53,[15][20] serum response factor (SRF),[21][22] specificity protein 1 (Sp1).[23] the pleiotropic factor IL-1β,[24] MEF-2,[10] and activator protein-1 (AP-1).[25] Apart from being regulated by different transcription factors, FHL2 is itself involved extensively in regulating the expression of other genes. FHL2 exerts its transcriptional regulatory effects by functioning as an adaptor protein interacting indirectly with the targeted genes. In fact, LIM domain is a platform for the formation of multimeric protein complexes.[26] Therefore, FHL2 can contribute to human carcinogenesis by interacting with transcription factors of cancer-related genes and modulates the signaling pathways underlying the expression of these genes. Different types of cancer are associated with FHL2 which act either as the cancer suppressor or inducer, for example in breast cancer, gastrointestinal (GI) cancers, liver cancer and prostate cancer.
# Clinical significance
The expression and functions of FHL2 varies greatly depending on the cancer types. It appeared that phenomenon is highly related to the differential mechanistic transcriptional regulations of FHL2 in the various types of cancer. However, the participation of fhl2 mutations and the posttranslational modifications of fhl2 in carcinogenesis cannot be ignored. In fact, functional mutation of fhl2 has been identified in a patient with familial dilated cardiomyopathy (DCM) and is associated with its pathogenesis.[27] This implied that fhl2 mutation may also profoundly affect the diverse cancer progressions. However, records describing the effects of fhl2 mutations on carcinogenesis are scarce.
Phosphorylation of FHL-2 protein has no significant effects on FHL2 functioning both in vitro and in vivo.[28][29] Provided that the existence of posttranscriptional modifications on FHL2 other than phosphorylation is still unclear and FHL2 functions almost exclusively through protein-protein interactions, research works in this direction is still interested. In particular, the mechanisms underpinning the subcellular localization of FHL2 should be focused. FHL2 can traffic freely between nuclear and the different cellular compartments.[10] It also interacts with other proteinaceous binding partners belonging to different functional classes including, but not limited to, transcription factors and signal transducers.[6][12][30][31] Therefore, FHL2 translocation could be important in regulating the different molecular signaling pathways which modify carcinogenesis, for example, nuclear translocation of FHL2 is related to aggressiveness and recurrence of prostate cancer[32] Similar evidence also has been identified in experiment using A7FIL+ cells and NIH 3T3 cell line as the disease model.[16][33][34]
## Breast cancer
The FHL2 protein interacts with the breast cancer type 1 susceptibility gene (BRCA1) which enhances the transactivation of BRCA1.[35] In addition, intratumoral FHL2 level was one of the factors determining the worse survival of breast cancer patients[36]
## Gastrointestinal cancer
FHL2 is related to gastrointestinal cancers and in particular, colon cancer. Fhl2 demonstrates an oncogenic property in colon cancer which induces the differentiation of some in vitro colon cancer models.[17][37][38] FHL2 is as well crucial to colon cancer cells invasion, migration and adhesion to extracellular matrix. The expression of FHL2 is positively regulated by transforming growth factor beta 1 (TGF-β1) stimulations which induces epithelial-mesenchymal transition (EMT) and endows cancer cells with metastatic properties. The TGF-β1-midiated alternation of FHL2 expression level might therefore trigger colon cell invasion. Besides, the subcellular localization of FHL2 can be modulated by TGF-β1 in sporadic colon cancer which resulted in the polymerization of alpha smooth muscle actin (α-SMA).[39] This process induces the fibroblast to take up a myofibroblast phenotype and contributes to cancer invasion. FHL2 can also induce EMT and cancer cell migration by affecting the structural integrity of membrane-associated E-cadherin-β-catenin complex.[40]
## Liver cancer
In the most common form liver cancer, the hepatocellular carcinoma (HCC), FHL2 is always downregulated in the clinical samples.[15] Therefore, fhl2 is exhibiting a tumor-suppressive effect on HCC. Similar to p53, overexpression of FHL2 inhibit the proliferative activity of the HCC Hep3B cell line by decreasing its cyclin D1 expression and increasing P21 and P27 expression supporting the time-dependent cellular repair process.[41] Of note, a database of FHL2-regulated genes in murine liver has recently been established by using microarray and bioinformatics analysis, which provide useful information concerning most of the pathways and new genes related to FHL2.[42]
## Prostate cancer
The molecular communication between androgen receptor (AR) and FHL2 is linked to the disease development of prostate cancer such as aggressiveness and biochemical recurrence (i.e., rise in circulatory prostate-specific antigen (PSA) levels after surgical or radiography treatment)[43][44] FHL2 expression is profoundly initiated by androgen through the mediation of serum response factor (SFR) and the RhoA / actin / megakaryocytic acute leukemia (MAL) signaling axis functioning upstream of SRF.[45][46] On the other hand, FHL2 is the coactivator of AR and is able to modulate AR signaling by altering the effect of Aryl hydrocarbon receptor (AhR) imposing AR activity with as yet unknown mechanisms.[47] Calpain cleavage of cytoskeletal protein filamin which is increased in prostate cancer could induce the nuclear translocation of FHL2, and this subsequently increase AR coactivation.[48]
# Interactions
FHL2 has been shown to interact with:
- Androgen receptor,[49]
- BRCA1,[50][51]
- CTNNB1,[52]
- CD18,[53]
- CD29,[53]
- CD49c,[53]
- CREB1,[54]
- EIF6,[53]
- FHL3,[54][55]
- IGFBP5,[56]
- ITGA7,[57]
- ITGB6,[53]
- MAPK1,[58]
- PSEN2,[59]
- TRAF6,[60]
- TTN,[61]
- ZNF638,[12] and
- ZBTB16.[62] | https://www.wikidoc.org/index.php/FHL2 | |
7e66c29bea3283f9c651fe93922554917dd7c2e0 | wikidoc | FHL5 | FHL5
Four and a half LIM domains protein 5 is a protein that in humans is encoded by the FHL5 gene.
# Function
The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene.
# Interactions
FHL5 has been shown to interact with CREB1 and CAMP responsive element modulator. | FHL5
Four and a half LIM domains protein 5 is a protein that in humans is encoded by the FHL5 gene.[1]
# Function
The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene.[1]
# Interactions
FHL5 has been shown to interact with CREB1[2] and CAMP responsive element modulator.[2][3] | https://www.wikidoc.org/index.php/FHL5 | |
b518c2e94e05642fdae59701dbe4532161fa2501 | wikidoc | FIS1 | FIS1
Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.
# Structure
The protein encoded by this gene is a 16 kDa integral protein situated in the outer mitochondrial membrane (OMM). It is composed of a transmembrane domain at the C-terminal and a cytosolic domain at the N-terminal. The transmembrane domain anchors FIS1 in the OMM, though it has been observed to target different cellular compartments, such as the peroxisome, depending on its hydrophobicity, charge, and length. Meanwhile, the cytosolic domain contains a bundle of six helices, four of which contain two tandem tetratricopeptide repeat (TPR)-like motifs. These motifs form a concave surface by their combined superhelical structure and potentially bind another FIS1 protein to form a dimer, or other proteins. Moreover, the N-terminal arm can dock at, and thus obstruct, the TPR motifs, allowing the protein to exist in a dynamic equilibrium between “open” and “closed” states.
# Function
FIS1 is indirectly involved in mitochondrial fission via binding dynamin-related protein 1 (DRP1). By extension, FIS1 helps regulate the size and distribution of mitochondria in response to local demand for ATP or calcium ions. In addition, mitochondrial fission may lead to release of cytochrome C, which eventually leads to cell death.
In a separate apoptotic signalling pathway, FIS1 interacts with BCAP31 to form a complex, the ARCosome. The ARCosome promotes cell death by bridging the mitochondria and the endoplasmic reticulum (ER), allowing FIS1 to transmit a proapoptotic signal from the mitochondria to the ER and activate procaspase-8. The ARCosome then forms a platform with procaspase-8 to increase calcium load in the mitochondria, resulting in apoptosis.
Additionally, FIS1 is involved in other modes of shaping mitochondrial morphology. For example, it interacts with TBC1D15 to regulate mitochondrial morphology, particularly with regard to lysosome and endosome fusion. FIS1 also prevents mitochondria elongation, which would otherwise lead to cell cycle delay or arrest, and ultimately, senescence. Moreover, mitochondrial dysfunction results in elevated reactive oxygen species (ROS) levels, which cause DNA damage and induce transcriptional repression, as well as induce mitophagy.
# Clinical Significance
As a fission factor, FIS1 is associated with neurodegenerative diseases. Stress, such as NO, can trigger aberrant mitochondrial fission and fusion, resulting in mitophagy. For example, increased mitochondrial fragmentation and FIS1 levels were observed in Alzheimer’s disease (AD) patients. Thus, FIS1 could serve as a biomarker for early detection of AD. FIS1 is also implicated in a variety of cancers, including acute myeloid leukemia, breast cancer, and prostate cancer.
# Interactions
FIS1 has been shown to interact with:
- BCAP31,
- procaspase-8,
- TBC1D15,
- PEX11 family, and
- DNM1L. | FIS1
Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7.[1][2][3] This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission.[3][4] Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis.[3][4][5][5][6] By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.[7][8]
# Structure
The protein encoded by this gene is a 16 kDa integral protein situated in the outer mitochondrial membrane (OMM).[5] It is composed of a transmembrane domain at the C-terminal and a cytosolic domain at the N-terminal.[5][9][10] The transmembrane domain anchors FIS1 in the OMM, though it has been observed to target different cellular compartments, such as the peroxisome, depending on its hydrophobicity, charge, and length.[10][11] Meanwhile, the cytosolic domain contains a bundle of six helices, four of which contain two tandem tetratricopeptide repeat (TPR)-like motifs. These motifs form a concave surface by their combined superhelical structure and potentially bind another FIS1 protein to form a dimer, or other proteins.[5][9] Moreover, the N-terminal arm can dock at, and thus obstruct, the TPR motifs, allowing the protein to exist in a dynamic equilibrium between “open” and “closed” states.[9]
# Function
FIS1 is indirectly involved in mitochondrial fission via binding dynamin-related protein 1 (DRP1).[8][11] By extension, FIS1 helps regulate the size and distribution of mitochondria in response to local demand for ATP or calcium ions.[9] In addition, mitochondrial fission may lead to release of cytochrome C, which eventually leads to cell death.[5]
In a separate apoptotic signalling pathway, FIS1 interacts with BCAP31 to form a complex, the ARCosome. The ARCosome promotes cell death by bridging the mitochondria and the endoplasmic reticulum (ER), allowing FIS1 to transmit a proapoptotic signal from the mitochondria to the ER and activate procaspase-8. The ARCosome then forms a platform with procaspase-8 to increase calcium load in the mitochondria, resulting in apoptosis.[4][8]
Additionally, FIS1 is involved in other modes of shaping mitochondrial morphology. For example, it interacts with TBC1D15 to regulate mitochondrial morphology, particularly with regard to lysosome and endosome fusion.[10] FIS1 also prevents mitochondria elongation, which would otherwise lead to cell cycle delay or arrest, and ultimately, senescence. Moreover, mitochondrial dysfunction results in elevated reactive oxygen species (ROS) levels, which cause DNA damage and induce transcriptional repression, as well as induce mitophagy.[5][6]
# Clinical Significance
As a fission factor, FIS1 is associated with neurodegenerative diseases.[7][8] Stress, such as NO, can trigger aberrant mitochondrial fission and fusion, resulting in mitophagy.[5][7] For example, increased mitochondrial fragmentation and FIS1 levels were observed in Alzheimer’s disease (AD) patients. Thus, FIS1 could serve as a biomarker for early detection of AD.[7] FIS1 is also implicated in a variety of cancers, including acute myeloid leukemia, breast cancer, and prostate cancer.[8]
# Interactions
FIS1 has been shown to interact with:
- BCAP31,[4]
- procaspase-8,[4]
- TBC1D15,[10]
- PEX11 family,[11] and
- DNM1L.[12] | https://www.wikidoc.org/index.php/FIS1 | |
95653b06a634d8c57d691b8433ecaab7e7a0461a | wikidoc | FLI1 | FLI1
Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.
# Function
Fli-1 is a member of the ETS transcription factor family that was first identified in erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV). Fli-1 is activated through retroviral insertional mutagenesis in 90% of F-MuLV-induced erythroleukemias. The constitutive activation of fli-1 in erythroblasts leads to a dramatic shift in the Epo/Epo-R signal transduction pathway, blocking erythroid differentiation, activating the Ras pathway, and resulting in massive Epo-independent proliferation of erythroblasts. These results suggest that Fli-1 overexpression in erythroblasts alters their responsiveness to Epo and triggers abnormal proliferation by switching the signaling event(s) associated with terminal differentiation to proliferation.
# Clinical significance
In addition to Friend erythroleukemia, proviral integration at the fli-1 locus also occurs in leukemias induced by the 10A1, Graffi, and Cas-Br-E viruses. Fli-1 aberrant expression is also associated with chromosomal abnormalities in humans. In pediatric Ewing’s sarcoma a chromosomal translocation generates a fusion of the 5’ transactivation domain of EWSR1 (also known as EWS) with the 3’ Ets domain of Fli-1. The resulting fusion oncoprotein, EWS/Fli-1, acts as an aberrant transcriptional activator. with strong transforming capabilities. EWS/Fli-1 may steer clinically important genes via interaction with enhnacer-like GGAA-microsatellites. The importance of Fli-1 in the development of human leukemia, such as acute myelogenous leukemia (AML), has been demonstrated in studies of translocation involving the Tel transcription factor, which interacts with Fli-1 through protein-protein interactions. A recent study has demonstrated high levels of Fli-1 expression in several benign and malignant neoplasms using immunohistochemistry.
A possible association with Paris-Trousseau syndrome has been suggested. | FLI1
Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.[1][2][3]
# Function
Fli-1 is a member of the ETS transcription factor family that was first identified in erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV). Fli-1 is activated through retroviral insertional mutagenesis in 90% of F-MuLV-induced erythroleukemias. The constitutive activation of fli-1 in erythroblasts leads to a dramatic shift in the Epo/Epo-R signal transduction pathway, blocking erythroid differentiation, activating the Ras pathway, and resulting in massive Epo-independent proliferation of erythroblasts. These results suggest that Fli-1 overexpression in erythroblasts alters their responsiveness to Epo and triggers abnormal proliferation by switching the signaling event(s) associated with terminal differentiation to proliferation.[citation needed]
# Clinical significance
In addition to Friend erythroleukemia, proviral integration at the fli-1 locus also occurs in leukemias induced by the 10A1, Graffi, and Cas-Br-E viruses. Fli-1 aberrant expression is also associated with chromosomal abnormalities in humans. In pediatric Ewing’s sarcoma a chromosomal translocation generates a fusion of the 5’ transactivation domain of EWSR1 (also known as EWS) with the 3’ Ets domain of Fli-1. The resulting fusion oncoprotein, EWS/Fli-1, acts as an aberrant transcriptional activator.[4] with strong transforming capabilities. EWS/Fli-1 may steer clinically important genes via interaction with enhnacer-like GGAA-microsatellites.[5] The importance of Fli-1 in the development of human leukemia, such as acute myelogenous leukemia (AML), has been demonstrated in studies of translocation involving the Tel transcription factor, which interacts with Fli-1 through protein-protein interactions. A recent study has demonstrated high levels of Fli-1 expression in several benign and malignant neoplasms using immunohistochemistry.[citation needed]
A possible association with Paris-Trousseau syndrome has been suggested.[6] | https://www.wikidoc.org/index.php/FLI1 | |
eac98745c6c90a76d1c9b88649740006ab960e4a | wikidoc | FLII | FLII
Protein flightless-1 homolog is a protein that in humans is encoded by the FLII gene.
This gene encodes a protein with a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat-protein protein interaction domain. The protein is similar to a Drosophila protein involved in early embryogenesis and the structural organization of indirect flight muscle. The gene is located within the Smith-Magenis syndrome region on chromosome 17.
# Interactions
FLII has been shown to interact with LRRFIP1 and TRAF interacting protein. | FLII
Protein flightless-1 homolog is a protein that in humans is encoded by the FLII gene.[1][2]
This gene encodes a protein with a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat-protein protein interaction domain.[3] The protein is similar to a Drosophila protein involved in early embryogenesis and the structural organization of indirect flight muscle. The gene is located within the Smith-Magenis syndrome region on chromosome 17.[2]
# Interactions
FLII has been shown to interact with LRRFIP1[4][5] and TRAF interacting protein.[6] | https://www.wikidoc.org/index.php/FLII | |
c8d006a23b863ffc2369f86c448a6e8bbfaaa42d | wikidoc | FLNA | FLNA
Filamin A, alpha (FLNA) is a protein that in humans is encoded by the FLNA gene.
# Function
Actin-binding protein, or filamin, is a 280-kD protein that crosslinks actin filaments into orthogonal networks in cortical cytoplasm and participates in the anchoring of membrane proteins for the actin cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the FLNA gene, is a widely expressed filamin that regulates the reorganization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes, and secondary messengers.
# Structure
The protein structure includes an actin binding N terminal domain, 24 internal repeats and 2 hinge regions.
# Interactions
Filamin has been shown to interact with:
- BRCA2,
- CD29
- CASR,
- FBLIM1,
- FILIP1,
- FLNB,
- NPHP1,
- RALA,
- SH2B3,
- TRIO, and
- VHL.
# RNA editing
The edited residue was previously recorded as a single nucleotide polymorphism(SNP) in dbSNP.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine.Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in a region complementary to the region of the editing site. This complementary region is usually found in a neighbouring intron but can also be located in an exonic sequence. The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS).
## Site
The one editing site of FLNA pre-mRNA is located within amino acid 2341 of the final protein. The Glutamine (Q) codon is altered due to a site specific deamination of an adenosine at the editing site to an Arginine (R) codon. The editing region is predicted to form a double stranded region of 32 base pairs in length with a complementary sequence about 200 nucleotides downstream of the editing site. This ECS is found in an intronic sequence. Editing at the Q/R site is likely to involve both ADAR1 and ADAR2.Mice ADAR2 knockouts show a decrease in editing at the Q/R site.ADAR1 double knockouts have no effect on editing.
## Structure
The edited adenosine is located in the 22 immunogloulin like repeat of the protein. This region is an integrin β binding domain and a RAC1 binding domain. The amino acid change is likely to effect the electrostatic potential of the binding domains. FLNA editing site is 2 nucleotides from a splice site like the R/G site of GluR-2. Both transcripts have 7/8 identical nucleotides around their editing sites. Since it is widely thought that editing at the GLUR-2 Q/R site influences splicing, the sequence and editing site similarity could mean that editing at the FLNA site could also regulate splicing. In vitro experiments of gluR-2 have shown that presence of ADAR2 results in inhibition of splicing. Analysis of EST data for FLNA show that there is a link between editing of the last exon codon and retention of the following intron.
## Function
The change in electrostatic potential is likely to effect the binding of FLNA to the many proteins it interacts with. | FLNA
Filamin A, alpha (FLNA) is a protein that in humans is encoded by the FLNA gene.[1][2]
# Function
Actin-binding protein, or filamin, is a 280-kD protein that crosslinks actin filaments into orthogonal networks in cortical cytoplasm and participates in the anchoring of membrane proteins for the actin cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the FLNA gene, is a widely expressed filamin that regulates the reorganization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes, and secondary messengers.[supplied by OMIM][3]
# Structure
The protein structure includes an actin binding N terminal domain, 24 internal repeats and 2 hinge regions.[4][5]
# Interactions
Filamin has been shown to interact with:
- BRCA2,[6]
- CD29[7][8]
- CASR,[9][10]
- FBLIM1,[11]
- FILIP1,[12]
- FLNB,[13]
- NPHP1,[14]
- RALA,[15]
- SH2B3,[16]
- TRIO,[17] and
- VHL.[18][19]
# RNA editing
The edited residue was previously recorded as a single nucleotide polymorphism(SNP) in dbSNP.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine.Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in a region complementary to the region of the editing site. This complementary region is usually found in a neighbouring intron but can also be located in an exonic sequence. The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS).
## Site
The one editing site of FLNA pre-mRNA is located within amino acid 2341 of the final protein. The Glutamine (Q) codon is altered due to a site specific deamination of an adenosine at the editing site to an Arginine (R) codon. The editing region is predicted to form a double stranded region of 32 base pairs in length with a complementary sequence about 200 nucleotides downstream of the editing site. This ECS is found in an intronic sequence.[20] Editing at the Q/R site is likely to involve both ADAR1 and ADAR2.Mice ADAR2 knockouts show a decrease in editing at the Q/R site.ADAR1 double knockouts have no effect on editing.[21]
## Structure
The edited adenosine is located in the 22 immunogloulin like repeat of the protein. This region is an integrin β binding domain[22] and a RAC1 binding domain.[15] The amino acid change is likely to effect the electrostatic potential of the binding domains.[20] FLNA editing site is 2 nucleotides from a splice site like the R/G site of GluR-2. Both transcripts have 7/8 identical nucleotides around their editing sites. Since it is widely thought that editing at the GLUR-2 Q/R site influences splicing, the sequence and editing site similarity could mean that editing at the FLNA site could also regulate splicing. In vitro experiments of gluR-2 have shown that presence of ADAR2 results in inhibition of splicing.[23] Analysis of EST data for FLNA show that there is a link between editing of the last exon codon and retention of the following intron.[20]
## Function
The change in electrostatic potential is likely to effect the binding of FLNA to the many proteins it interacts with.[24] | https://www.wikidoc.org/index.php/FLNA | |
fb814d727122f6d1e91bc1533736ff8c3f5c2c1e | wikidoc | FLNB | FLNB
Filamin B, beta (FLNB), also known as Filamin B, beta (actin binding protein 278), is a cytoplasmic protein which in humans is encoded by the FLNB gene.
FLNB regulates intracellular communication and signalling by cross-linking the protein actin to allow direct communication between the cell membrane and cytoskeletal network, to control and guide proper skeletal development.
Mutations in the FLNB gene are involved in several lethal bone dysplasias, including boomerang dysplasia and atelosteogenesis type I.
# Interactions
FLNB has been shown to interact with GP1BA, Filamin, FBLIM1, PSEN1, CD29 and PSEN2. | FLNB
Filamin B, beta (FLNB), also known as Filamin B, beta (actin binding protein 278), is a cytoplasmic protein which in humans is encoded by the FLNB gene.
FLNB regulates intracellular communication and signalling by cross-linking the protein actin to allow direct communication between the cell membrane and cytoskeletal network, to control and guide proper skeletal development.[1]
Mutations in the FLNB gene are involved in several lethal bone dysplasias, including boomerang dysplasia and atelosteogenesis type I.[2][3][4]
# Interactions
FLNB has been shown to interact with GP1BA,[5] Filamin,[6] FBLIM1,[7] PSEN1,[8] CD29[9] and PSEN2.[8] | https://www.wikidoc.org/index.php/FLNB | |
049821672806e8d3fcb126e937cacb2280b0c3ee | wikidoc | FMR1 | FMR1
FMR1 (fragile X mental retardation 1) is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.
# Function
## Synaptic plasticity
FMRP has a diverse array of functions throughout different areas of the neuron; however these functions have not been fully characterized. FMRP has been suggested to play roles in nucleocytoplasmic shuttling of mRNA, dendritic mRNA localization, and synaptic protein synthesis. Studies of Fragile X syndrome have significantly aided in the understanding of the functionality of FMRP through the observed effects of FMRP loss on neurons. A mouse model of fragile X mental retardation implicated the involvement of FMRP in synaptic plasticity. Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors. It is the production of proteins in response to stimulation which is hypothesized to allow for the permanent physical changes and altered synaptic connections that are linked with the processes of learning and memory.
Group 1 metabotropic glutamate receptor (mGluR) signaling has been implicated in playing an important role in FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in the up-regulation of protein synthesis through a second messenger system. A role for mGluR in synaptic plasticity is further evidenced by the observation of dendritic spine elongation following mGluR stimulation. Furthermore, mGluR activation results in the synthesis of FMRP near synapses. The produced FMRP associates with polyribosomal complexes after mGluR stimulation, proposing the involvement of fragile X mental retardation protein in the process of translation. This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections. The loss of FMRP results in an abnormal dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in an increase in spine synapse number.
## Role in translation
The proposed mechanism of FMRP's effect upon synaptic plasticity are through its role as a negative regulator of translation. FMRP is an RNA-binding protein which associates with polyribosomes. The RNA-binding abilities of FMRP are dependent upon its KH domains and RGG boxes. The KH domain is a conserved motif which characterizes many RNA-binding proteins. Mutagenesis of this domain resulted in impaired FMRP binding to RNA.
FMRP has been shown to inhibit translation of mRNA. Mutation of the FMRP protein resulted in the inability to repress translation as opposed to the wild-type counterpart which was able to do so. As previously mentioned, mGluR stimulation is associated with increased FMRP protein levels. In addition, mGluR stimulation results in increased levels of FMRP target mRNAs. A study found basal levels of proteins encoded by these target mRNAs to be significantly elevated and improperly regulated in FMRP deficient mice.
FMRP translation repression acts by inhibiting the initiation of translation. FMRP directly binds CYFIP1, which in turn binds the translation initiation factor eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation. When applied to the observed phenotype in fragile X Syndrome, the excess protein levels and reduction of translational control can be explained by the loss of translational repression by FMRP in fragile X syndrome. FMRP acts to control translation of a large group of target mRNAs; however the extent of FMRPs translational control is unknown. The protein has been shown to repress the translation of target mRNAs at synapses, including those encoding the cytoskeletal proteins Arc/Arg3.1 and MAP1B, and the CaM kinase II. In addition, FMRP binds PSD-95 and GluR1/2 mRNAs. Importantly, these FMRP-binding mRNAs play significant roles in neuronal plasticity.
FMRP translational control has been shown to be regulated by mGluR signaling. mGluR stimulation may result in the transportation of mRNA complexes to synapses for local protein synthesis. FMRP granules have been shown to localize with MAP1B mRNA and ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites. FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules. Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, ubiquitination, and proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.
# Gene expression
The FMR1 gene is located on the X chromosome and contains a repeated CGG trinucleotide. In most people, the CGG segment is repeated approximately 5-44 times. Higher numbers of repeats of the CGG segment are associated with impaired cognitive and reproductive function. If a person has 45-54 repeats this is considered the “gray zone” or borderline risk, 55-200 repeats is called premutation, and more than 200 repeats is considered a full mutation of the FMR1 gene according to the American College of Medical Genetics and Genomics. The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing. This is an example of a Trinucleotide repeat disorder. Trinucleotide repeat expansion is likely a consequence of strand slippage either during DNA repair or DNA replication.
FMR1 is a chromatin-binding protein that functions in the DNA damage response. FMR1 occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.
The FMR1 gene can be found on the long (q) arm of the X chromosome at position 27.3, from base pair 146,699,054 to base pair 146,738,156
# Related conditions
## Fragile X syndrome
Almost all cases of fragile X syndrome are caused by expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times. As a result, this part of the FMR1 gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMR1, severe learning deficits or mental retardation can develop, along with physical abnormalities seen in fragile X syndrome.
Fewer than 1% of all cases of fragile X syndrome are caused by mutations that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the amino acids in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome.
A CGG sequence in the FMR1 gene that is repeated between 55 and 200 times is described as a premutation. Although most individuals with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience mental health problems such as anxiety or depression.
## Fragile X-associated tremor/ataxia syndrome
Premutations are associated with an increased risk of fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by ataxia (loss of coordination), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy) and mental and behavioral changes. The disorder usually develops late in life.
## Premature ovarian aging
The FMR1 gene plays a very important role in ovarian function, independent from cognitive/neurological effects. Minor expansions of CGG repeats that do not cause fragile X syndrome are associated with an increased risk for premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function.
## Polycystic ovarian syndrome
A very specific sub-genotype of FMR1 has been found to be associated with polycystic ovarian syndrome (PCOS). The gene expression, called heterozygous-normal/low may cause PCOS-like excessive follicle-activity and hyperactive ovarian function when women are younger.
# Interactions
FMR1 has been shown to interact with:
- CYFIP1,
- CYFIP2,
- FXR1, and
- FXR2,
- NUFIP1, and
- NUFIP2. | FMR1
FMR1 (fragile X mental retardation 1) is a human gene[1] that codes for a protein called fragile X mental retardation protein, or FMRP.[2] This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits.[3] The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.[4]
# Function
## Synaptic plasticity
FMRP has a diverse array of functions throughout different areas of the neuron; however these functions have not been fully characterized. FMRP has been suggested to play roles in nucleocytoplasmic shuttling of mRNA, dendritic mRNA localization, and synaptic protein synthesis.[5] Studies of Fragile X syndrome have significantly aided in the understanding of the functionality of FMRP through the observed effects of FMRP loss on neurons. A mouse model of fragile X mental retardation implicated the involvement of FMRP in synaptic plasticity.[6] Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors. It is the production of proteins in response to stimulation which is hypothesized to allow for the permanent physical changes and altered synaptic connections that are linked with the processes of learning and memory.
Group 1 metabotropic glutamate receptor (mGluR) signaling has been implicated in playing an important role in FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in the up-regulation of protein synthesis through a second messenger system.[7] A role for mGluR in synaptic plasticity is further evidenced by the observation of dendritic spine elongation following mGluR stimulation.[8] Furthermore, mGluR activation results in the synthesis of FMRP near synapses. The produced FMRP associates with polyribosomal complexes after mGluR stimulation, proposing the involvement of fragile X mental retardation protein in the process of translation. This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections.[9] The loss of FMRP results in an abnormal dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in an increase in spine synapse number.[10]
## Role in translation
The proposed mechanism of FMRP's effect upon synaptic plasticity are through its role as a negative regulator of translation. FMRP is an RNA-binding protein which associates with polyribosomes.[9][11] The RNA-binding abilities of FMRP are dependent upon its KH domains and RGG boxes. The KH domain is a conserved motif which characterizes many RNA-binding proteins. Mutagenesis of this domain resulted in impaired FMRP binding to RNA.[12]
FMRP has been shown to inhibit translation of mRNA. Mutation of the FMRP protein resulted in the inability to repress translation as opposed to the wild-type counterpart which was able to do so.[13] As previously mentioned, mGluR stimulation is associated with increased FMRP protein levels. In addition, mGluR stimulation results in increased levels of FMRP target mRNAs. A study found basal levels of proteins encoded by these target mRNAs to be significantly elevated and improperly regulated in FMRP deficient mice.[14]
FMRP translation repression acts by inhibiting the initiation of translation. FMRP directly binds CYFIP1, which in turn binds the translation initiation factor eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation.[15] When applied to the observed phenotype in fragile X Syndrome, the excess protein levels and reduction of translational control can be explained by the loss of translational repression by FMRP in fragile X syndrome.[15][16] FMRP acts to control translation of a large group of target mRNAs; however the extent of FMRPs translational control is unknown. The protein has been shown to repress the translation of target mRNAs at synapses, including those encoding the cytoskeletal proteins Arc/Arg3.1 and MAP1B, and the CaM kinase II.[17] In addition, FMRP binds PSD-95 and GluR1/2 mRNAs. Importantly, these FMRP-binding mRNAs play significant roles in neuronal plasticity.
FMRP translational control has been shown to be regulated by mGluR signaling. mGluR stimulation may result in the transportation of mRNA complexes to synapses for local protein synthesis. FMRP granules have been shown to localize with MAP1B mRNA and ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites.[5] FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules.[18] Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, ubiquitination, and proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.[14]
# Gene expression
The FMR1 gene is located on the X chromosome and contains a repeated CGG trinucleotide. In most people, the CGG segment is repeated approximately 5-44 times. Higher numbers of repeats of the CGG segment are associated with impaired cognitive and reproductive function. If a person has 45-54 repeats this is considered the “gray zone” or borderline risk, 55-200 repeats is called premutation, and more than 200 repeats is considered a full mutation of the FMR1 gene according to the American College of Medical Genetics and Genomics.[19] The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.[20] This is an example of a Trinucleotide repeat disorder. Trinucleotide repeat expansion is likely a consequence of strand slippage either during DNA repair or DNA replication.[21]
FMR1 is a chromatin-binding protein that functions in the DNA damage response.[22][23] FMR1 occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.[22]
The FMR1 gene can be found on the long (q) arm of the X chromosome at position 27.3, from base pair 146,699,054 to base pair 146,738,156
# Related conditions
## Fragile X syndrome
Almost all cases of fragile X syndrome are caused by expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times. As a result, this part of the FMR1 gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMR1, severe learning deficits or mental retardation can develop, along with physical abnormalities seen in fragile X syndrome.
Fewer than 1% of all cases of fragile X syndrome are caused by mutations that delete part or all of the FMR1 gene, or change a base pair, leading to a change in one of the amino acids in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome.
A CGG sequence in the FMR1 gene that is repeated between 55 and 200 times is described as a premutation. Although most individuals with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience mental health problems such as anxiety or depression.
## Fragile X-associated tremor/ataxia syndrome
Premutations are associated with an increased risk of fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by ataxia (loss of coordination), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy) and mental and behavioral changes. The disorder usually develops late in life.
## Premature ovarian aging
The FMR1 gene plays a very important role in ovarian function, independent from cognitive/neurological effects. Minor expansions of CGG repeats that do not cause fragile X syndrome are associated with an increased risk for premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function.[24][25][26]
## Polycystic ovarian syndrome
A very specific sub-genotype of FMR1 has been found to be associated with polycystic ovarian syndrome (PCOS). The gene expression, called heterozygous-normal/low may cause PCOS-like excessive follicle-activity and hyperactive ovarian function when women are younger.
# Interactions
FMR1 has been shown to interact with:
- CYFIP1,[27]
- CYFIP2,[27][28]
- FXR1,[29][30] and
- FXR2,[29][30][31]
- NUFIP1,[28][32] and
- NUFIP2.[28] | https://www.wikidoc.org/index.php/FMR1 | |
02cfeb73bf81c7aa3ca8769118cd00bb244c0e61 | wikidoc | FNTA | FNTA
Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha is an enzyme that in humans is encoded by the FNTA gene.
Prenyltransferases attach either a farnesyl group or a geranylgeranyl group in thioether linkage to the cysteine residue of protein's with a C-terminal CAAX box. CAAX geranylgeranyltransferase and CAAX farnesyltransferase are heterodimers that share the same alpha subunit but have different beta subunits. This gene encodes the alpha subunit of these transferases. Alternative splicing results in multiple transcript variants encoding different isoforms.
# Interactions
FNTA has been shown to interact with TGF beta receptor 1. | FNTA
Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha is an enzyme that in humans is encoded by the FNTA gene.[1][2]
Prenyltransferases attach either a farnesyl group or a geranylgeranyl group in thioether linkage to the cysteine residue of protein's with a C-terminal CAAX box. CAAX geranylgeranyltransferase and CAAX farnesyltransferase are heterodimers that share the same alpha subunit but have different beta subunits. This gene encodes the alpha subunit of these transferases. Alternative splicing results in multiple transcript variants encoding different isoforms.[2]
# Interactions
FNTA has been shown to interact with TGF beta receptor 1.[3] | https://www.wikidoc.org/index.php/FNTA | |
326469f4621ad0c4d128bc96a8b37915c2dfd895 | wikidoc | RBM9 | RBM9
RNA binding motif protein 9 (RBM9), also known as Rbfox2, is a protein which in humans is encoded by the RBM9 gene.
# Function
Rbfox2 is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative splicing in the nervous system and other cell types. Rbfox2 and the related protein Rbfox1 bind to conserved (U)GCAUG RNA motifs in the introns adjacent to many alternatively spliced exons and promotes inclusion or exclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene.
Rbfox2, as determined by CLIP-seq, binds near alternatively spliced exons and regulates the inclusion or exclusion of exons during alternative splicing by binding in introns either downstream (inclusion) or upstream (exon skipping) of exons. Its presence is important for stem cell survival and knockdowns of Rbfox2 activate markers for apoptosis. | RBM9
RNA binding motif protein 9 (RBM9), also known as Rbfox2, is a protein which in humans is encoded by the RBM9 gene.[1]
# Function
Rbfox2 is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative splicing in the nervous system and other cell types. Rbfox2 and the related protein Rbfox1 bind to conserved (U)GCAUG RNA motifs in the introns adjacent to many alternatively spliced exons and promotes inclusion or exclusion of the alternative exon in mature transcripts.[2][3] The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene.[1]
Rbfox2, as determined by CLIP-seq, binds near alternatively spliced exons and regulates the inclusion or exclusion of exons during alternative splicing by binding in introns either downstream (inclusion) or upstream (exon skipping) of exons. Its presence is important for stem cell survival and knockdowns of Rbfox2 activate markers for apoptosis.[4] | https://www.wikidoc.org/index.php/FOX-2 | |
eec2117ac826c276d4112b228cc69cf2ccb572d0 | wikidoc | FUT8 | FUT8
Alpha-(1,6)-fucosyltransferase is an enzyme that in humans is encoded by the FUT8 gene.
This enzyme belongs to the family of fucosyltransferases. The product of this gene catalyzes the transfer of fucose from GDP-fucose to N-linked type complex glycopeptides. This enzyme is distinct from other fucosyltransferases which catalyze alpha1-2, alpha1-3, and alpha1-4 fucose addition. The expression of this gene may contribute to the malignancy of cancer cells and to their invasive and metastatic capabilities. Alternatively spliced variants encoding different isoforms have been identified.
Kyowa Hakko Kirin's "Potelligent" platform uses a CHO cell line in which FUT8 has been knocked out to make afucosylated monoclonal antibodies. | FUT8
Alpha-(1,6)-fucosyltransferase is an enzyme that in humans is encoded by the FUT8 gene.[1][2]
This enzyme belongs to the family of fucosyltransferases. The product of this gene catalyzes the transfer of fucose from GDP-fucose to N-linked type complex glycopeptides. This enzyme is distinct from other fucosyltransferases which catalyze alpha1-2, alpha1-3, and alpha1-4 fucose addition. The expression of this gene may contribute to the malignancy of cancer cells and to their invasive and metastatic capabilities. Alternatively spliced variants encoding different isoforms have been identified.[2]
Kyowa Hakko Kirin's "Potelligent" platform uses a CHO cell line in which FUT8 has been knocked out to make afucosylated monoclonal antibodies.[3] | https://www.wikidoc.org/index.php/FUT8 | |
24bda6a52e42a0144b4f2dbdc98705a8f7a0eaa0 | wikidoc | FXR1 | FXR1
Fragile X mental retardation syndrome-related protein 1 is a protein that in humans is encoded by the FXR1 gene.
The protein encoded by this gene is an RNA binding protein that interacts with the functionally similar proteins FMR1 and FXR2. These proteins shuttle between the nucleus and cytoplasm and associate with polyribosomes, predominantly with the 60S ribosomal subunit. Three transcript variants encoding different isoforms have been found for this gene.
# Interactions
FXR1 has been shown to interact with FXR2, FMR1 and CYFIP2. | FXR1
Fragile X mental retardation syndrome-related protein 1 is a protein that in humans is encoded by the FXR1 gene.[1][2][3]
The protein encoded by this gene is an RNA binding protein that interacts with the functionally similar proteins FMR1 and FXR2. These proteins shuttle between the nucleus and cytoplasm and associate with polyribosomes, predominantly with the 60S ribosomal subunit. Three transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
FXR1 has been shown to interact with FXR2,[4][5] FMR1 [4][5] and CYFIP2.[6] | https://www.wikidoc.org/index.php/FXR1 | |
7ce47931744c748c72e47fb24508f4e6d35bfaa7 | wikidoc | FZD3 | FZD3
Frizzled-3 is a protein that in humans is encoded by the FZD3 gene.
# Function
This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. It may play a role in mammalian hair follicle development.
The function of this gene is largely derived from mouse studies. Fzd3 in the mouse functions through planar cell polarity signaling instead of the canonical Wnt/beta-catenin pathway. Fzd3 controls axon growth and guidance in the mouse nervous system, and migration of neural crest cells. | FZD3
Frizzled-3 is a protein that in humans is encoded by the FZD3 gene.[1][2][3]
# Function
This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. It may play a role in mammalian hair follicle development.[3]
The function of this gene is largely derived from mouse studies. Fzd3 in the mouse functions through planar cell polarity signaling instead of the canonical Wnt/beta-catenin pathway. Fzd3 controls axon growth and guidance in the mouse nervous system, and migration of neural crest cells.[4][5] | https://www.wikidoc.org/index.php/FZD3 | |
9b912ea41b439b3326d46831bb5f0685ff29b91e | wikidoc | FZD6 | FZD6
Frizzled-6 is a protein that in humans is encoded by the FZD6 gene.
Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for WNT signaling proteins. The FZD6 protein contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and 7 transmembrane domains. However, unlike many other FZD family members, FDZ6 does not contain a C-terminal PDZ domain-binding motif. The FZD6 protein is believed to be the receptor for the WNT4 ligand.
# Interactions
FZD6 has been shown to interact with Secreted frizzled-related protein 1. | FZD6
Frizzled-6 is a protein that in humans is encoded by the FZD6 gene.[1][2][3]
Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for WNT signaling proteins. The FZD6 protein contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and 7 transmembrane domains. However, unlike many other FZD family members, FDZ6 does not contain a C-terminal PDZ domain-binding motif.[3] The FZD6 protein is believed to be the receptor for the WNT4 ligand.[4]
# Interactions
FZD6 has been shown to interact with Secreted frizzled-related protein 1.[5] | https://www.wikidoc.org/index.php/FZD6 | |
1b274e670297871f7c6ea147907b3d2ee1995064 | wikidoc | Face | Face
# Overview
The face is the front part of the head and includes the hair, forehead, eyebrow, eyes, nose, ears, cheeks, mouth, lips, philtrum, teeth, skin, and chin. The face is used for expression, appearance, and identity amongst others.
# The face as a means of recognition
The face is the feature which best distinguishes a person, often at first glance. It is unique to each person.
Caricatures often exaggerate facial features to make a face easily recognized in association with a pronounced portion of the face of the individual in question. Exaggeration of memorable features helps people to recognize others when presented in a caricature form.
Cosmetic surgery is often used to alter the appearance of the facial features. | Face
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The face is the front part of the head and includes the hair, forehead, eyebrow, eyes, nose, ears, cheeks, mouth, lips, philtrum, teeth, skin, and chin.[1] The face is used for expression, appearance, and identity amongst others. [2]
# The face as a means of recognition
The face is the feature which best distinguishes a person, often at first glance. It is unique to each person.
Caricatures often exaggerate facial features to make a face easily recognized in association with a pronounced portion of the face of the individual in question. Exaggeration of memorable features helps people to recognize others when presented in a caricature form. [3]
Cosmetic surgery is often used to alter the appearance of the facial features. [4] | https://www.wikidoc.org/index.php/Face | |
6313e6565a460ed7e3a1efefc6970cccd6edc983 | wikidoc | Fear | Fear
Fear is an emotional response to tangible and realistic dangers. Fear should be distinguished from anxiety, an emotion that often arises out of proportion to the actual threat or danger involved, and can be subjectively experienced without any specific attention to the threatening object.
Most fear is usually connected to pain (i.e., some fear heights because if they fall, when they land, they will be in great pain). Behavioral theorists, like Watson and Ekman, have both suggested that fear is one of several very basic emotions (e.g., joy and anger). Fear is a survival mechanism, and usually occurs in response to a specific negative stimulus.
# Etymology
The English term "fear" originally comes from the Latin term Feanis meaning "calamity, disaster". The Old English term fǣr meant not the emotion engendered by a calamity or disaster but rather the event itself. The first recorded usage of the term "fear" with the sense of the “emotion of fear” is found in a medieval work written in Middle English and composed around 1290. The most probable explanation for the change in the meaning of the word fear is the existence in Old English of the related verb fǣran, which meant “to terrify, take by surprise.”
# Varieties
Serious fear is a response to some formidable impending peril, while trifling fear arises from confrontation with inconsequential danger.
Fear can be described by different terms in accordance with its relative degrees. Personal fear varies extremely in degree from mild caution to extreme phobia and paranoia. Fear is related to a number of emotional states including worry, anxiety, terror, fright, paranoia, horror, panic (social and personal), persecution complex and dread.
Fears may be a factor within a larger social network, wherein personal fears are synergetically compounded as mass hysteria.
- Paranoia is a term used to describe a psychosis of fear, described as a heightened perception of being persecuted, false or otherwise. This degree of fear often indicates that one has changed their normal behavior in radical ways, and may have become extremely compulsive. Sometimes, the result of extreme paranoia is a phobia.
- Distrust in the context of interpersonal fear, is sometimes explained as the inward feeling of caution, usually focused towards a person, representing an unwillingness to trust in someone else. Distrust is not a lack of faith or belief in someone, but a feeling of warning towards someone or something questionable or unknown. For example, one may "distrust" a stranger who acts in a way that is perceived as "odd." Likewise one may "distrust" the safety of a rusty old bridge across a 100 ft drop.
- Terror refers to a pronounced state of fear - which usually occurs before the state of horror - when someone becomes overwhelmed with a sense of immediate danger. Also, it can be caused by perceiving the (possibly extreme) phobia. As a consequence, terror overwhelms the person to the point of making irrational choices and non-typical behavior.
Fear can also affect the subconscious and unconscious mind, most notably through nightmares.
Fear can also be imagined, and the sideffects can also be imagined.
# Causes
- Although fear is an innate response, objects of fear can be learned. This has been studied in psychology as fear conditioning, beginning with Watson's Little Albert experiment in 1920. In this study, an 11-month-old boy was conditioned to fear a white rat in the laboratory. In the real world, fear may also be acquired by a traumatic accident. For example, if a child falls into a well and struggles to get out, he or she may develop a fear of wells, enclosed spaces (claustrophobia) or of water (hydrophobia).
- Researchers have found that certain fears (e.g. animals, heights) are much more common than others (e.g. flowers, clouds). They are also much easier to induce in the laboratory. This phenomenon has been called preparedness. Physiologically, the fear response is linked to activity in the amygdala of the limbic system.
- The experience of fear may also be influenced by social norms and values. In the early 20th century, many people feared polio, a disease which cripples the body part it affects, leaving the body part immobilized for the rest of one's life.
- Drug side effect: Hydrocodone bitartrate and acetaminophen
# Characteristics
## Behavioral
In fear, one may go through various emotional stages. A good example of this is the cornered rat, which will try to run away until it is finally cornered by its predator, at which point it will become belligerent and fight back with heavy aggression until it either escapes or is destroyed.
The same goes for most animals. Humans can become very intimidated by fear; causing them to go along with another's wishes without caring about their own input. They can also become equally violent, and can even become deadly; it is an instinctive reaction caused by rising adrenaline levels rather than a consciously thought-out decision. This is why in many cases the full penalty cannot be made in cases of the court of law.
The facial expression of fear includes the following components:
- One's eyes widen (out of anticipation for what will happen next)
- The pupils dilate (to take in more light)
- The upper lip rises
- The brows draw together
- Lips stretch horizontally.
## Physiological
The physiological effects of fear can be better understood from the perspective of the sympathetic nervous responses (fight-or-flight), as compared to parasympathetic response, which is a more relaxed state.
- muscles used for physical movement are tightened and primed with oxygen in preparation for a physical fight or flight response.
- perspiration occurs due to blood being shunted from body's viscera to the peripheral parts of the body. Blood that is shunted from the viscera to the rest of the body will transfer, along with oxygen and nutrients, heat, prompting perspiration to cool the body.
- when the stimulus is shocking or abrupt, a common reaction is to cover or otherwise protect vulnerable parts of the anatomy, particularly the face and head.
- when a fear stimulus occurs unexpectedly, the victim of the fear response could possibly jump or give a small start.
- the person's heart rate and heartbeat may increase.
Fear is the flip side of anger in the inbuilt human 'fight or flight' response.
Many people feel the effects of fear on a day to day basis in the workplace through the stress of a modern working environment. This fear has a direct correlation to one's working efficiency and has been crystallised into a chart through an ongoing linear study in Bristol. The fear-o-meter shows the range of emotions caused by the latent fear that a significant workload and impending deadline can create. Whilst one's ability to work effectively diminishes as the level of fear increases, productivity on the other hand increases exponentially as the impending deadline approaches. For example, a student might fail to start an essay until the level of fear reaches 5 or above, choosing to either go out or perform menial tasks until the fear has increased to the required level.
- Satisfaction
- Ennui
- Despondency
- Anxiety
- Fear / Vexed
- Despair / Anger
- Apathy / Rage
- Terror / Apoplectic
# Moral and legal issues
Fear may be a consideration in determining the wrongness of acts, in some views.
Actions done under stress of fear, unless of course it be so intense as to have dethroned reason, are accounted the legitimate progeny of the human will, or are, as the theologians say, simply voluntary, and therefore imputable. The reason is obvious; such acts lack neither adequate advertence nor sufficient consent, even though the latter be elicited only to avoid a greater evil or one conceived to be greater. Inasmuch, however, as they are accompanied by a more or less vehement repugnance, they are said to be in a limited and partial sense involuntary.
Since fear diminishes freedom of action, contracts entered into through fear may be judged invalid; similarly fear sometimes excuses from the application of the law in a particular case; it also excuses from the penalty attached to an act contrary to the law. The cause of fear is found in oneself or in a natural cause (intrinsic fear) or it is found in another person (extrinsic fear). Fear may be grave, such for instance as would influence a steadfast man, or it may be slight, such as would affect a person of weak will. In order that fear may be considered grave, certain conditions are requisite: the fear must be grave in itself, and not merely in the estimation of the person fearing; it must be based on a reasonable foundation; the threats must be possible of execution; the execution of the threats must be inevitable. Fear, again, is either just or unjust, according to the justness or otherwise of the reasons which lead to the use of fear as a compelling force. Reverential fear is that which may exist between superiors and their subjects. Grave fear diminishes willpower but cannot be said to totally take it away, except in some very exceptional cases. Slight fear (metus levis) is not considered even to diminish the will power, hence the legal expression "Foolish fear is not a just excuse."
# Death from fear
Research conducted at the University of California, San Diego and published in the British Medical Journal, suggests that deaths attributed to heart mortality increase under psychological stress, particularly terror. Otherwise healthy people have been known to be "scared to death," that is, to suddenly die under extreme fear or emotional trauma. People of all ages have died from fright brought on by everything from earthquakes to amusement-park rides.
While the mechanism is not fully understood, it is believed that sudden death can occur from cardiac arrhythmia brought on by a terrifying event. While the otherwise instinctual flight-or-fight response, which prepares the body for impending danger, is countered by the parasympathetic nervous system when the danger has passed, in certain cases an excessive response can damage the heart enough to kill. | Fear
Template:Emotion
Fear is an emotional response to tangible and realistic dangers. Fear should be distinguished from anxiety, an emotion that often arises out of proportion to the actual threat or danger involved, and can be subjectively experienced without any specific attention to the threatening object. [1][2]
Most fear is usually connected to pain (i.e., some fear heights because if they fall, when they land, they will be in great pain). Behavioral theorists, like Watson and Ekman, have both suggested that fear is one of several very basic emotions (e.g., joy and anger). Fear is a survival mechanism, and usually occurs in response to a specific negative stimulus.
# Etymology
The English term "fear" originally comes from the Latin term Feanis meaning "calamity, disaster". The Old English term fǣr meant not the emotion engendered by a calamity or disaster but rather the event itself. The first recorded usage of the term "fear" with the sense of the “emotion of fear” is found in a medieval work written in Middle English and composed around 1290. The most probable explanation for the change in the meaning of the word fear is the existence in Old English of the related verb fǣran, which meant “to terrify, take by surprise.” [3]
# Varieties
Serious fear is a response to some formidable impending peril, while trifling fear arises from confrontation with inconsequential danger.
Fear can be described by different terms in accordance with its relative degrees. Personal fear varies extremely in degree from mild caution to extreme phobia and paranoia. Fear is related to a number of emotional states including worry, anxiety, terror, fright, paranoia, horror, panic (social and personal), persecution complex and dread.
Fears may be a factor within a larger social network, wherein personal fears are synergetically compounded as mass hysteria.
- Paranoia is a term used to describe a psychosis of fear, described as a heightened perception of being persecuted, false or otherwise. This degree of fear often indicates that one has changed their normal behavior in radical ways, and may have become extremely compulsive. Sometimes, the result of extreme paranoia is a phobia.
- Distrust in the context of interpersonal fear, is sometimes explained as the inward feeling of caution, usually focused towards a person, representing an unwillingness to trust in someone else. Distrust is not a lack of faith or belief in someone, but a feeling of warning towards someone or something questionable or unknown. For example, one may "distrust" a stranger who acts in a way that is perceived as "odd." Likewise one may "distrust" the safety of a rusty old bridge across a 100 ft drop.
- Terror refers to a pronounced state of fear - which usually occurs before the state of horror - when someone becomes overwhelmed with a sense of immediate danger. Also, it can be caused by perceiving the (possibly extreme) phobia. As a consequence, terror overwhelms the person to the point of making irrational choices and non-typical behavior.
Fear can also affect the subconscious and unconscious mind, most notably through nightmares.
Fear can also be imagined, and the sideffects can also be imagined.
# Causes
- Although fear is an innate response, objects of fear can be learned. This has been studied in psychology as fear conditioning, beginning with Watson's Little Albert experiment in 1920. In this study, an 11-month-old boy was conditioned to fear a white rat in the laboratory. In the real world, fear may also be acquired by a traumatic accident. For example, if a child falls into a well and struggles to get out, he or she may develop a fear of wells, enclosed spaces (claustrophobia) or of water (hydrophobia).
- Researchers have found that certain fears (e.g. animals, heights) are much more common than others (e.g. flowers, clouds). They are also much easier to induce in the laboratory. This phenomenon has been called preparedness. Physiologically, the fear response is linked to activity in the amygdala of the limbic system.
- The experience of fear may also be influenced by social norms and values. In the early 20th century, many people feared polio, a disease which cripples the body part it affects, leaving the body part immobilized for the rest of one's life.
- Drug side effect: Hydrocodone bitartrate and acetaminophen
# Characteristics
## Behavioral
In fear, one may go through various emotional stages. A good example of this is the cornered rat, which will try to run away until it is finally cornered by its predator, at which point it will become belligerent and fight back with heavy aggression until it either escapes or is destroyed.
The same goes for most animals. Humans can become very intimidated by fear; causing them to go along with another's wishes without caring about their own input. They can also become equally violent, and can even become deadly; it is an instinctive reaction caused by rising adrenaline levels rather than a consciously thought-out decision. This is why in many cases the full penalty cannot be made in cases of the court of law.
The facial expression of fear includes the following components:
- One's eyes widen (out of anticipation for what will happen next)
- The pupils dilate (to take in more light)
- The upper lip rises
- The brows draw together
- Lips stretch horizontally.
## Physiological
The physiological effects of fear can be better understood from the perspective of the sympathetic nervous responses (fight-or-flight), as compared to parasympathetic response, which is a more relaxed state.
- muscles used for physical movement are tightened and primed with oxygen in preparation for a physical fight or flight response.
- perspiration occurs due to blood being shunted from body's viscera to the peripheral parts of the body. Blood that is shunted from the viscera to the rest of the body will transfer, along with oxygen and nutrients, heat, prompting perspiration to cool the body.
- when the stimulus is shocking or abrupt, a common reaction is to cover or otherwise protect vulnerable parts of the anatomy, particularly the face and head.
- when a fear stimulus occurs unexpectedly, the victim of the fear response could possibly jump or give a small start.
- the person's heart rate and heartbeat may increase.
Fear is the flip side of anger in the inbuilt human 'fight or flight' response.
Many people feel the effects of fear on a day to day basis in the workplace through the stress of a modern working environment. This fear has a direct correlation to one's working efficiency and has been crystallised into a chart through an ongoing linear study in Bristol. The fear-o-meter shows the range of emotions caused by the latent fear that a significant workload and impending deadline can create. Whilst one's ability to work effectively diminishes as the level of fear increases, productivity on the other hand increases exponentially as the impending deadline approaches. For example, a student might fail to start an essay until the level of fear reaches 5 or above, choosing to either go out or perform menial tasks until the fear has increased to the required level.
- Satisfaction
- Ennui
- Despondency
- Anxiety
- Fear / Vexed
- Despair / Anger
- Apathy / Rage
- Terror / Apoplectic
# Moral and legal issues
Fear may be a consideration in determining the wrongness of acts, in some views.
Actions done under stress of fear, unless of course it be so intense as to have dethroned reason, are accounted the legitimate progeny of the human will, or are, as the theologians say, simply voluntary, and therefore imputable. The reason is obvious; such acts lack neither adequate advertence nor sufficient consent, even though the latter be elicited only to avoid a greater evil or one conceived to be greater. Inasmuch, however, as they are accompanied by a more or less vehement repugnance, they are said to be in a limited and partial sense involuntary.
Since fear diminishes freedom of action, contracts entered into through fear may be judged invalid; similarly fear sometimes excuses from the application of the law in a particular case; it also excuses from the penalty attached to an act contrary to the law. The cause of fear is found in oneself or in a natural cause (intrinsic fear) or it is found in another person (extrinsic fear). Fear may be grave, such for instance as would influence a steadfast man, or it may be slight, such as would affect a person of weak will. In order that fear may be considered grave, certain conditions are requisite: the fear must be grave in itself, and not merely in the estimation of the person fearing; it must be based on a reasonable foundation; the threats must be possible of execution; the execution of the threats must be inevitable. Fear, again, is either just or unjust, according to the justness or otherwise of the reasons which lead to the use of fear as a compelling force. Reverential fear is that which may exist between superiors and their subjects. Grave fear diminishes willpower but cannot be said to totally take it away, except in some very exceptional cases. Slight fear (metus levis) is not considered even to diminish the will power, hence the legal expression "Foolish fear is not a just excuse."
# Death from fear
Research conducted at the University of California, San Diego and published in the British Medical Journal, suggests that deaths attributed to heart mortality increase under psychological stress, particularly terror.[4] Otherwise healthy people have been known to be "scared to death," that is, to suddenly die under extreme fear or emotional trauma. People of all ages have died from fright brought on by everything from earthquakes to amusement-park rides.[5][6]
While the mechanism is not fully understood, it is believed that sudden death can occur from cardiac arrhythmia brought on by a terrifying event. While the otherwise instinctual flight-or-fight response, which prepares the body for impending danger, is countered by the parasympathetic nervous system when the danger has passed, in certain cases an excessive response can damage the heart enough to kill.[5] | https://www.wikidoc.org/index.php/Fear | |
b0f9eea987a45b9fc60513b08210a596045a2497 | wikidoc | Fern | Fern
A fern is any one of a group of about 20,000 species of plants classified in the phylum or division Pteridophyta, also known as Filicophyta. The group is also referred to as Polypodiophyta, or Polypodiopsida when treated as a subdivision of tracheophyta (vascular plants). The study of ferns and other pteridophytes is called pteridology, and one who studies ferns and other pteridophytes is called a pteridologist. The term "pteridophyte" has traditionally been used to describe all seedless vascular plants, making it synonymous with "ferns and fern allies". This can be confusing since members of the fern phylum Pteridophyta are also sometimes referred to as pteridophytes.
# Life cycle
Ferns are vascular plants differing from the more primitive lycophytes by having true leaves (megaphylls), and they differ from seed plants (gymnosperms and angiosperms) in their mode of reproduction - lacking flowers and seeds. Like all other vascular plants, they have a life cycle referred to as alternation of generations, characterized by a diploid sporophytic and a haploid gametophytic phase. Unlike the gymnosperms and angiosperms, the ferns' gametophyte is a free-living organism. The life cycle of a typical fern is as follows:
- A sporophyte (diploid) phase produces haploid spores by meiosis;
- A spore grows by mitosis into a gametophyte, which typically consists of a photosynthetic prothallus
- The gametophyte produces gametes (often both sperm and eggs on the same prothallus) by mitosis
- A mobile, flagellate sperm fertilizes an egg that remains attached to the prothallus
- The fertilized egg is now a diploid zygote and grows by mitosis into a sporophyte (the typical "fern" plant).
# Fern ecology
The stereotypic image of ferns growing in moist shady woodland nooks is far from being a complete picture of the habitats where ferns can be found growing. Fern species live in a wide variety of habitats, from remote mountain elevations, to dry desert rock faces, to bodies of water or in open fields. Ferns in general may be thought of as largely being specialists in marginal habitats, often succeeding in places where various environmental factors limit the success of flowering plants. Some ferns are among the world's most serious weed species, including the bracken fern growing in the British highlands, or the mosquito fern (Azolla) growing in tropical lakes, both species form large aggressively spreading colonies. There are four particular types of habitats that ferns are found in: moist, shady forests; crevices in rock faces, especially when sheltered from the full sun; acid wetlands including bogs and swamps; and tropical trees, where many species are epiphytes.
Many ferns depend on associations with mycorrhizal fungi. Many ferns only grow within specific pH ranges; for instance, the climbing fern (Lygodium) of eastern North America will only grow in moist, intensely acid soils, while the bulblet bladder fern (Cystopteris bulbifera), with an overlapping range, is only ever found on limestone.
# Fern structure
Like the sporophytes of seed plants, those of ferns consist of:
- Stems: Most often an underground creeping rhizome, but sometimes an above-ground creeping stolon (e.g., Polypodiaceae), or an above-ground erect semi-woody trunk (e.g., Cyatheaceae) reaching up to 20 m in a few species (e.g., Cyathea brownii on Norfolk Island and Cyathea medullaris in New Zealand).
- Leaf: The green, photosynthetic part of the plant. In ferns, it is often referred to as a frond, but this is because of the historical division between people who study ferns and people who study seed plants, rather than because of differences in structure. New leaves typically expand by the unrolling of a tight spiral called a crozier or fiddlehead. This uncurling of the leaf is termed circinate vernation. Leaves are divided into three types:
Trophophyll: A leaf that does not produce spores, instead only producing sugars by photosynthesis. Analogous to the typical green leaves of seed plants.
Sporophyll: A leaf that produces spores. These leaves are analogous to the scales of pine cones or to stamens and pistil in gymnosperms and angiosperms, respectively. Unlike the seed plants, however, the sporophylls of ferns are typically not very specialized, looking similar to trophophylls and producing sugars by photosynthesis as the trophophylls do.
Brophophyll: A leaf that produces abnormally large amounts of spores. There leaves are also larger than the other leaves but bare a resemblance to trophopylls.
- Trophophyll: A leaf that does not produce spores, instead only producing sugars by photosynthesis. Analogous to the typical green leaves of seed plants.
- Sporophyll: A leaf that produces spores. These leaves are analogous to the scales of pine cones or to stamens and pistil in gymnosperms and angiosperms, respectively. Unlike the seed plants, however, the sporophylls of ferns are typically not very specialized, looking similar to trophophylls and producing sugars by photosynthesis as the trophophylls do.
- Brophophyll: A leaf that produces abnormally large amounts of spores. There leaves are also larger than the other leaves but bare a resemblance to trophopylls.
- Roots: The underground non-photosynthetic structures that take up water and nutrients from soil. They are always fibrous and are structurally very similar to the roots of seed plants.
The gametophytes of ferns, however, are very different from those of seed plants. They typically consist of:
- Prothallus: A green, photosynthetic structure that is one cell thick, usually heart or kidney shaped, 3-10 mm long and 2-8 mm broad. The prothallus produces gametes by means of:
Antheridia: Small spherical structures that produce flagellate sperm.
Archegonia: A flask-shaped structure that produces a single egg at the bottom, reached by the sperm by swimming down the neck.
- Antheridia: Small spherical structures that produce flagellate sperm.
- Archegonia: A flask-shaped structure that produces a single egg at the bottom, reached by the sperm by swimming down the neck.
- Rhizoids: root-like structures (not true roots) that consist of single greatly-elongated cells, water and mineral salts are absorbed over the whole structure. Rhizoids anchor the prothallus to the soil.
One interesting difference between sporophytes and gametophytes might be summed up by the saying that "Nothing eats ferns, but everything eats gametophytes." This is an over-simplification, but it is true that gametophytes are often difficult to find in the field because they are far more likely to be food than are the sporophytes.
# Evolution and classification
Ferns first appear in the fossil record in the early-Carboniferous period. By the Triassic, the first evidence of ferns related to several modern families appeared. The "great fern radiation" occurred in the late-Cretaceous, when many modern families of ferns first appeared.
Ferns have traditionally been grouped in the Class Filices, but modern classifications assign them their own division in the plant kingdom, called Pteridophyta.
Traditionally, three discrete groups of plants have been considered ferns: two groups of eusporangiate ferns--families Ophioglossaceae (adders-tongues, moonworts, and grape-ferns) and Marattiaceae--and the leptosporangiate ferns. The Marattiaceae are a primitive group of tropical ferns with a large, fleshy rhizome, and are now thought to be a sibling taxon to the main group of ferns, the leptosporangiate ferns. Several other groups of plants were considered "fern allies": the clubmosses, spikemosses, and quillworts in the Lycopodiophyta, the whisk ferns in Psilotaceae, and the horsetails in the Equisetaceae. More recent genetic studies have shown that the Lycopodiophyta are only distantly related to any other vascular plants, having radiated evolutionarily at the base of the vascular plant clade, while both the whisk ferns and horsetails are as much "true" ferns as are the Ophioglossoids and Marattiaceae. In fact, the whisk ferns and Ophioglossoids are demonstrably a clade, and the horsetails and Marattiaceae are arguably another clade. Molecular data - which remain poorly constrained for many parts of the plants' phylogeny - have been supplemented by recent morphological observations supporting the inclusion of Equisetaceae within the ferns, notably relating to the construction of their sperm, and peculiarities of their roots (Smith et al 2006, and references therein).
One possible means of treating this situation is to consider only the leptosporangiate ferns as "true" ferns, while considering the other three groups as "fern allies". In practice, numerous classification schemes have been proposed for ferns and fern allies, and there has been little consensus among them. A new classification by Smith et al. (2006) is based on recent molecular systematic studies, in addition to morphological data. This classification divides ferns into four classes:
- Psilotopsida
- Equisetopsida
- Marattiopsida
- Polypodiopsida
The last group includes most plants familiarly known as ferns. Modern research supports older ideas based on morphology that the Osmundaceae diverged early in the evolutionary history of the leptosporangiate ferns; in certain ways this family is intermediate between the eusporangiate ferns and the leptosporangiate ferns.
The complete classification scheme proposed by Smith et al. (2006; alternative names in brackets):
- Class Psilotopsida
Order Ophioglossales
Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
Order Psilotales
Family Psilotaceae (incl. Tmesipteridaceae)
- Order Ophioglossales
Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
- Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
- Order Psilotales
Family Psilotaceae (incl. Tmesipteridaceae)
- Family Psilotaceae (incl. Tmesipteridaceae)
- Class Equisetopsida
Order Equisetales
Family Equisetaceae
- Order Equisetales
Family Equisetaceae
- Family Equisetaceae
- Class Marattiopsida
Order Marattiales
Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Order Marattiales
Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Class Pteridopsida
Order Osmundales
Family Osmundaceae
Order Hymenophyllales
Family Hymenophyllaceae (incl. Trichomanaceae)
Order Gleicheniales
Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
Family Dipteridaceae (incl. Cheiropleuriaceae)
Family Matoniaceae
Order Schizaeales
Family Lygodiaceae
Family Anemiaceae (incl. Mohriaceae)
Family Schizaeaceae
Order Salviniales
Family Marsileaceae (incl. Pilulariaceae)
Family Salviniaceae (incl. Azollaceae)
Order Cyatheales
Family Thyrsopteridaceae
Family Loxomataceae
Family Culcitaceae
Family Plagiogyriaceae
Family Cibotiaceae
Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
Family Dicksoniaceae (incl. Lophosoriaceae)
Family Metaxyaceae
Order Polypodiales
Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
Family Saccolomataceae
Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
Family Aspleniaceae
Family Thelypteridaceae
Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
Family Blechnaceae (incl. Stenochlaenaceae)
Family Onocleaceae
Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
Family Oleandraceae
Family Davalliaceae
Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
- Order Osmundales
Family Osmundaceae
- Family Osmundaceae
- Order Hymenophyllales
Family Hymenophyllaceae (incl. Trichomanaceae)
- Family Hymenophyllaceae (incl. Trichomanaceae)
- Order Gleicheniales
Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
Family Dipteridaceae (incl. Cheiropleuriaceae)
Family Matoniaceae
- Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
- Family Dipteridaceae (incl. Cheiropleuriaceae)
- Family Matoniaceae
- Order Schizaeales
Family Lygodiaceae
Family Anemiaceae (incl. Mohriaceae)
Family Schizaeaceae
- Family Lygodiaceae
- Family Anemiaceae (incl. Mohriaceae)
- Family Schizaeaceae
- Order Salviniales
Family Marsileaceae (incl. Pilulariaceae)
Family Salviniaceae (incl. Azollaceae)
- Family Marsileaceae (incl. Pilulariaceae)
- Family Salviniaceae (incl. Azollaceae)
- Order Cyatheales
Family Thyrsopteridaceae
Family Loxomataceae
Family Culcitaceae
Family Plagiogyriaceae
Family Cibotiaceae
Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
Family Dicksoniaceae (incl. Lophosoriaceae)
Family Metaxyaceae
- Family Thyrsopteridaceae
- Family Loxomataceae
- Family Culcitaceae
- Family Plagiogyriaceae
- Family Cibotiaceae
- Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
- Family Dicksoniaceae (incl. Lophosoriaceae)
- Family Metaxyaceae
- Order Polypodiales
Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
Family Saccolomataceae
Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
Family Aspleniaceae
Family Thelypteridaceae
Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
Family Blechnaceae (incl. Stenochlaenaceae)
Family Onocleaceae
Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
Family Oleandraceae
Family Davalliaceae
Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
- Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
- Family Saccolomataceae
- Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
- Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
- Family Aspleniaceae
- Family Thelypteridaceae
- Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
- Family Blechnaceae (incl. Stenochlaenaceae)
- Family Onocleaceae
- Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
- Family Oleandraceae
- Family Davalliaceae
- Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
# Economic uses
Ferns are not as important economically as seed plants but have considerable importance. Some ferns are used for food, including the fiddleheads of bracken, Pteridium aquilinum, ostrich fern, Matteuccia struthiopteris, and cinnamon fern, Osmunda cinnamomea]. Diplazium esculentum is also used by some tropical peoples as food.
Ferns of the genus Azolla are very small, floating plants that do not look like ferns. Called mosquito fern, they are used as a biological fertilizer in the rice paddies of southeast Asia, taking advantage of their ability to fix nitrogen from the air into compounds that can then be used by other plants.
A great many ferns are grown in horticulture as landscape plants, for cut foliage and as houseplants, especially the Boston fern (Nephrolepis exaltata). The Bird's Nest Fern, Asplenium nidus, is also popular, and the staghorn ferns, genus Platycerium, have a considerable following.
Several ferns are noxious weeds or invasive species, including Japanese climbing fern (Lygodium japonicum), mosquito fern and sensitive fern (Onoclea sensibilis). Giant water fern (Salvinia molesta) is one of the world's worst aquatic weeds. The important fossil fuel coal consists of the remains of primitive plants, including ferns.
Ferns have been studied and found to be useful in the removal of heavy metals, especially arsenic, from the soil
Other ferns with some economic significance include:
- Dryopteris filix-mas (male fern), used as a vermifuge, and formerly in the US Pharmacopeia; also, this fern accidentally sprouting in a bottle resulted in Nathaniel Bagshaw Ward's 1829 invention of the terrarium or Wardian case
- Rumohra adiantoides (floral fern), extensively used in the florist trade
- Osmunda regalis (royal fern) and Osmunda cinnamomea (cinnamon fern), the root fiber being used horticulturally; the fiddleheads of O. cinnamomea are also used as a cooked vegetable
- Matteuccia struthiopteris (ostrich fern), the fiddleheads used as a cooked vegetable in North America
- Pteridium aquilinum (bracken), the fiddleheads used as a cooked vegetable in Japan and are believed to be responsible for the high rate of stomach cancer in Japan. It is also one of the world's most important agricultural weeds, especially in the British highlands, and often poisons cattle and horses.
- Diplazium esculentum (vegetable fern), a source of food for some native societies
- Pteris vittata (brake fern), used to absorb arsenic from the soil
- Polypodium glycyrrhiza (licorice fern), roots chewed for their pleasant flavor
- Tree ferns, used as building material in some tropical areas
- Cyathea cooperi (Australian tree fern), an important invasive species in Hawaii
- Ceratopteris richardii, a model plant for teaching and research, often called C-fern
# Cultural connotations
In Slavic folklore, ferns are believed to bloom once a year, during the Ivan Kupala night. Although it's exceedingly difficult to find, anyone who takes a look of a fern flower will be happy and rich for the rest of his life. Similarly in Finland, the tradition holds that one who finds the seed of a fern in bloom on Midsummer night, will by the possession of it be able to travel under a glamour of invisibility and shall be guided to the locations where eternally blazing Will o' the wisps mark the spot of hidden treasure caches.
Ferns were popular as a decorative motif in Victorian England, the designs frequently appeared on crockery, glassware, cast iron objects, and textiles. The fashion for growing ferns indoors led to the development of the Wardian case, a glazed cabinet that would exclude air pollutants and maintain the necessary humidity.
The dried form of ferns was also used in other arts, being used a stencil or directly inked for use in a design. The botanical work, The Ferns of Great Britain and Ireland, is a notable example of this type of nature printing. The process, patented by the artist and publisher Henry Bradbury, impressed a specimen on to a soft lead plate. The first publication to demonstrate this was Alois Auer's The Discovery of the Nature Printing-Process.
# Medicinal Value
Ferns are sometimes used in medicine to treat cuts and clean them out. Ferns are also good bandages if you are stuck out in the wild.
# Misunderstood names
Several non-fern plants are called "ferns" and are sometimes confused with true ferns. These include:
- "Asparagus fern" - This may apply to one of several species of the monocot genus Asparagus, which are flowering plants.
- "Sweetfern" - A flowering shrub of the genus Comptonia.
- "Air fern" - A group of animals called hydrozoan that are distantly related to jellyfish and corals. They are harvested, dried, dyed green, and then sold as a "plant" that can "live on air". While it may look like a fern, it is merely the skeleton of this colonial animal.
In addition, the book Where the Red Fern Grows has elicited many questions about the mythical "red fern" named in the book. There is no such known plant, although there has been speculation that the oblique grape-fern, Sceptridium dissectum, could be referred to here, because it is known to appear on disturbed sites and its fronds may redden over the winter.
# Gallery
- Fern leaf, probably Blechnum nudum
Fern leaf, probably Blechnum nudum
- A tree fern unrolling a new frond
- Tree fern, probably Dicksonia antarctica
Tree fern, probably Dicksonia antarctica
- Tree ferns, probably Dicksonia antarctica
Tree ferns, probably Dicksonia antarctica
- "Filicinae" from Ernst Haeckel's Kunstformen der Natur, 1904
"Filicinae" from Ernst Haeckel's Kunstformen der Natur, 1904
- Unidentified tree fern in Oaxaca
Unidentified tree fern in Oaxaca
- Tree Fern Spores San Diego, CA
Tree Fern Spores San Diego, CA
- Leaf of fern
Leaf of fern
- Unidentified fern with spores showing in Rotorua, NZ.
Unidentified fern with spores showing in Rotorua, NZ.
- Ferns in one of many natural Coast Redwood undergrowth settings Santa Cruz, CA.
Ferns in one of many natural Coast Redwood undergrowth settings Santa Cruz, CA.
- Nature prints in The Ferns of Great Britain and Ireland used fronds to produce the plates
Nature prints in The Ferns of Great Britain and Ireland used fronds to produce the plates | Fern
A fern is any one of a group of about 20,000 species of plants classified in the phylum or division Pteridophyta, also known as Filicophyta. The group is also referred to as Polypodiophyta, or Polypodiopsida when treated as a subdivision of tracheophyta (vascular plants). The study of ferns and other pteridophytes is called pteridology, and one who studies ferns and other pteridophytes is called a pteridologist. The term "pteridophyte" has traditionally been used to describe all seedless vascular plants, making it synonymous with "ferns and fern allies". This can be confusing since members of the fern phylum Pteridophyta are also sometimes referred to as pteridophytes.
# Life cycle
Ferns are vascular plants differing from the more primitive lycophytes by having true leaves (megaphylls), and they differ from seed plants (gymnosperms and angiosperms) in their mode of reproduction - lacking flowers and seeds. Like all other vascular plants, they have a life cycle referred to as alternation of generations, characterized by a diploid sporophytic and a haploid gametophytic phase. Unlike the gymnosperms and angiosperms, the ferns' gametophyte is a free-living organism. The life cycle of a typical fern is as follows:
- A sporophyte (diploid) phase produces haploid spores by meiosis;
- A spore grows by mitosis into a gametophyte, which typically consists of a photosynthetic prothallus
- The gametophyte produces gametes (often both sperm and eggs on the same prothallus) by mitosis
- A mobile, flagellate sperm fertilizes an egg that remains attached to the prothallus
- The fertilized egg is now a diploid zygote and grows by mitosis into a sporophyte (the typical "fern" plant).
# Fern ecology
The stereotypic image of ferns growing in moist shady woodland nooks is far from being a complete picture of the habitats where ferns can be found growing. Fern species live in a wide variety of habitats, from remote mountain elevations, to dry desert rock faces, to bodies of water or in open fields. Ferns in general may be thought of as largely being specialists in marginal habitats, often succeeding in places where various environmental factors limit the success of flowering plants. Some ferns are among the world's most serious weed species, including the bracken fern growing in the British highlands, or the mosquito fern (Azolla) growing in tropical lakes, both species form large aggressively spreading colonies. There are four particular types of habitats that ferns are found in: moist, shady forests; crevices in rock faces, especially when sheltered from the full sun; acid wetlands including bogs and swamps; and tropical trees, where many species are epiphytes.
Many ferns depend on associations with mycorrhizal fungi. Many ferns only grow within specific pH ranges; for instance, the climbing fern (Lygodium) of eastern North America will only grow in moist, intensely acid soils, while the bulblet bladder fern (Cystopteris bulbifera), with an overlapping range, is only ever found on limestone.
# Fern structure
Like the sporophytes of seed plants, those of ferns consist of:
- Stems: Most often an underground creeping rhizome, but sometimes an above-ground creeping stolon (e.g., Polypodiaceae), or an above-ground erect semi-woody trunk (e.g., Cyatheaceae) reaching up to 20 m in a few species (e.g., Cyathea brownii on Norfolk Island and Cyathea medullaris in New Zealand).
- Leaf: The green, photosynthetic part of the plant. In ferns, it is often referred to as a frond, but this is because of the historical division between people who study ferns and people who study seed plants, rather than because of differences in structure. New leaves typically expand by the unrolling of a tight spiral called a crozier or fiddlehead. This uncurling of the leaf is termed circinate vernation. Leaves are divided into three types:
Trophophyll: A leaf that does not produce spores, instead only producing sugars by photosynthesis. Analogous to the typical green leaves of seed plants.
Sporophyll: A leaf that produces spores. These leaves are analogous to the scales of pine cones or to stamens and pistil in gymnosperms and angiosperms, respectively. Unlike the seed plants, however, the sporophylls of ferns are typically not very specialized, looking similar to trophophylls and producing sugars by photosynthesis as the trophophylls do.
Brophophyll: A leaf that produces abnormally large amounts of spores. There leaves are also larger than the other leaves but bare a resemblance to trophopylls.
- Trophophyll: A leaf that does not produce spores, instead only producing sugars by photosynthesis. Analogous to the typical green leaves of seed plants.
- Sporophyll: A leaf that produces spores. These leaves are analogous to the scales of pine cones or to stamens and pistil in gymnosperms and angiosperms, respectively. Unlike the seed plants, however, the sporophylls of ferns are typically not very specialized, looking similar to trophophylls and producing sugars by photosynthesis as the trophophylls do.
- Brophophyll: A leaf that produces abnormally large amounts of spores. There leaves are also larger than the other leaves but bare a resemblance to trophopylls.
- Roots: The underground non-photosynthetic structures that take up water and nutrients from soil. They are always fibrous and are structurally very similar to the roots of seed plants.
The gametophytes of ferns, however, are very different from those of seed plants. They typically consist of:
- Prothallus: A green, photosynthetic structure that is one cell thick, usually heart or kidney shaped, 3-10 mm long and 2-8 mm broad. The prothallus produces gametes by means of:
Antheridia: Small spherical structures that produce flagellate sperm.
Archegonia: A flask-shaped structure that produces a single egg at the bottom, reached by the sperm by swimming down the neck.
- Antheridia: Small spherical structures that produce flagellate sperm.
- Archegonia: A flask-shaped structure that produces a single egg at the bottom, reached by the sperm by swimming down the neck.
- Rhizoids: root-like structures (not true roots) that consist of single greatly-elongated cells, water and mineral salts are absorbed over the whole structure. Rhizoids anchor the prothallus to the soil.
One interesting difference between sporophytes and gametophytes might be summed up by the saying that "Nothing eats ferns, but everything eats gametophytes." This is an over-simplification, but it is true that gametophytes are often difficult to find in the field because they are far more likely to be food than are the sporophytes.
# Evolution and classification
Template:Cleanup-laundry
Ferns first appear in the fossil record in the early-Carboniferous period. By the Triassic, the first evidence of ferns related to several modern families appeared. The "great fern radiation" occurred in the late-Cretaceous, when many modern families of ferns first appeared.
Ferns have traditionally been grouped in the Class Filices, but modern classifications assign them their own division in the plant kingdom, called Pteridophyta.
Traditionally, three discrete groups of plants have been considered ferns: two groups of eusporangiate ferns--families Ophioglossaceae (adders-tongues, moonworts, and grape-ferns) and Marattiaceae--and the leptosporangiate ferns. The Marattiaceae are a primitive group of tropical ferns with a large, fleshy rhizome, and are now thought to be a sibling taxon to the main group of ferns, the leptosporangiate ferns. Several other groups of plants were considered "fern allies": the clubmosses, spikemosses, and quillworts in the Lycopodiophyta, the whisk ferns in Psilotaceae, and the horsetails in the Equisetaceae. More recent genetic studies have shown that the Lycopodiophyta are only distantly related to any other vascular plants, having radiated evolutionarily at the base of the vascular plant clade, while both the whisk ferns and horsetails are as much "true" ferns as are the Ophioglossoids and Marattiaceae. In fact, the whisk ferns and Ophioglossoids are demonstrably a clade, and the horsetails and Marattiaceae are arguably another clade. Molecular data - which remain poorly constrained for many parts of the plants' phylogeny - have been supplemented by recent morphological observations supporting the inclusion of Equisetaceae within the ferns, notably relating to the construction of their sperm, and peculiarities of their roots (Smith et al 2006, and references therein).
One possible means of treating this situation is to consider only the leptosporangiate ferns as "true" ferns, while considering the other three groups as "fern allies". In practice, numerous classification schemes have been proposed for ferns and fern allies, and there has been little consensus among them. A new classification by Smith et al. (2006) is based on recent molecular systematic studies, in addition to morphological data. This classification divides ferns into four classes:
- Psilotopsida
- Equisetopsida
- Marattiopsida
- Polypodiopsida
The last group includes most plants familiarly known as ferns. Modern research supports older ideas based on morphology that the Osmundaceae diverged early in the evolutionary history of the leptosporangiate ferns; in certain ways this family is intermediate between the eusporangiate ferns and the leptosporangiate ferns.
The complete classification scheme proposed by Smith et al. (2006; alternative names in brackets):
- Class Psilotopsida
Order Ophioglossales
Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
Order Psilotales
Family Psilotaceae (incl. Tmesipteridaceae)
- Order Ophioglossales
Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
- Family Ophioglossaceae (incl. Botrychiaceae, Helminthostachyaceae)
- Order Psilotales
Family Psilotaceae (incl. Tmesipteridaceae)
- Family Psilotaceae (incl. Tmesipteridaceae)
- Class Equisetopsida [=Sphenopsida]
Order Equisetales
Family Equisetaceae
- Order Equisetales
Family Equisetaceae
- Family Equisetaceae
- Class Marattiopsida
Order Marattiales
Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Order Marattiales
Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Family Marattiaceae (incl. Angiopteridaceae, Christenseniaceae, Danaeaceae, Kaulfussiaceae)
- Class Pteridopsida [=Filicopsida, Polypodiopsida]
Order Osmundales
Family Osmundaceae
Order Hymenophyllales
Family Hymenophyllaceae (incl. Trichomanaceae)
Order Gleicheniales
Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
Family Dipteridaceae (incl. Cheiropleuriaceae)
Family Matoniaceae
Order Schizaeales
Family Lygodiaceae
Family Anemiaceae (incl. Mohriaceae)
Family Schizaeaceae
Order Salviniales
Family Marsileaceae (incl. Pilulariaceae)
Family Salviniaceae (incl. Azollaceae)
Order Cyatheales
Family Thyrsopteridaceae
Family Loxomataceae
Family Culcitaceae
Family Plagiogyriaceae
Family Cibotiaceae
Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
Family Dicksoniaceae (incl. Lophosoriaceae)
Family Metaxyaceae
Order Polypodiales
Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
Family Saccolomataceae
Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
Family Aspleniaceae
Family Thelypteridaceae
Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
Family Blechnaceae (incl. Stenochlaenaceae)
Family Onocleaceae
Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
Family Oleandraceae
Family Davalliaceae
Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
- Order Osmundales
Family Osmundaceae
- Family Osmundaceae
- Order Hymenophyllales
Family Hymenophyllaceae (incl. Trichomanaceae)
- Family Hymenophyllaceae (incl. Trichomanaceae)
- Order Gleicheniales
Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
Family Dipteridaceae (incl. Cheiropleuriaceae)
Family Matoniaceae
- Family Gleicheniaceae (incl. Dicranopteridaceae, Stromatopteridaceae)
- Family Dipteridaceae (incl. Cheiropleuriaceae)
- Family Matoniaceae
- Order Schizaeales
Family Lygodiaceae
Family Anemiaceae (incl. Mohriaceae)
Family Schizaeaceae
- Family Lygodiaceae
- Family Anemiaceae (incl. Mohriaceae)
- Family Schizaeaceae
- Order Salviniales
Family Marsileaceae (incl. Pilulariaceae)
Family Salviniaceae (incl. Azollaceae)
- Family Marsileaceae (incl. Pilulariaceae)
- Family Salviniaceae (incl. Azollaceae)
- Order Cyatheales
Family Thyrsopteridaceae
Family Loxomataceae
Family Culcitaceae
Family Plagiogyriaceae
Family Cibotiaceae
Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
Family Dicksoniaceae (incl. Lophosoriaceae)
Family Metaxyaceae
- Family Thyrsopteridaceae
- Family Loxomataceae
- Family Culcitaceae
- Family Plagiogyriaceae
- Family Cibotiaceae
- Family Cyatheaceae (incl. Alsophilaceae, Hymenophyllopsidaceae)
- Family Dicksoniaceae (incl. Lophosoriaceae)
- Family Metaxyaceae
- Order Polypodiales
Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
Family Saccolomataceae
Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
Family Aspleniaceae
Family Thelypteridaceae
Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
Family Blechnaceae (incl. Stenochlaenaceae)
Family Onocleaceae
Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
Family Oleandraceae
Family Davalliaceae
Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
- Family Lindsaeaceae (incl. Cystodiaceae, Lonchitidaceae)
- Family Saccolomataceae
- Family Dennstaedtiaceae (incl. Hypolepidaceae, Monachosoraceae, Pteridiaceae)
- Family Pteridaceae (incl. Acrostichaceae, Actiniopteridaceae, Adiantaceae, Anopteraceae, Antrophyaceae, Ceratopteridaceae, Cheilanthaceae, Cryptogrammaceae, Hemionitidaceae, Negripteridaceae, Parkeriaceae, Platyzomataceae, Sinopteridaceae, Taenitidaceae, Vittariaceae)
- Family Aspleniaceae
- Family Thelypteridaceae
- Family Woodsiaceae (incl. Athyriaceae, Cystopteridaceae)
- Family Blechnaceae (incl. Stenochlaenaceae)
- Family Onocleaceae
- Family Dryopteridaceae (incl. Aspidiaceae, Bolbitidaceae, Elaphoglossaceae, Hypodematiaceae, Peranemataceae)
- Family Oleandraceae
- Family Davalliaceae
- Family Polypodiaceae (incl. Drynariaceae, Grammitidaceae, Gymnogrammitidaceae, Loxogrammaceae, Platyceriaceae, Pleurisoriopsidaceae)
# Economic uses
Ferns are not as important economically as seed plants but have considerable importance. Some ferns are used for food, including the fiddleheads of bracken, Pteridium aquilinum, ostrich fern, Matteuccia struthiopteris, and cinnamon fern, Osmunda cinnamomea]. Diplazium esculentum is also used by some tropical peoples as food.
Ferns of the genus Azolla are very small, floating plants that do not look like ferns. Called mosquito fern, they are used as a biological fertilizer in the rice paddies of southeast Asia, taking advantage of their ability to fix nitrogen from the air into compounds that can then be used by other plants.
A great many ferns are grown in horticulture as landscape plants, for cut foliage and as houseplants, especially the Boston fern (Nephrolepis exaltata). The Bird's Nest Fern, Asplenium nidus, is also popular, and the staghorn ferns, genus Platycerium, have a considerable following.
Several ferns are noxious weeds or invasive species, including Japanese climbing fern (Lygodium japonicum), mosquito fern and sensitive fern (Onoclea sensibilis). Giant water fern (Salvinia molesta) is one of the world's worst aquatic weeds. The important fossil fuel coal consists of the remains of primitive plants, including ferns.
Ferns have been studied and found to be useful in the removal of heavy metals, especially arsenic, from the soil[3]
Other ferns with some economic significance include:
- Dryopteris filix-mas (male fern), used as a vermifuge, and formerly in the US Pharmacopeia; also, this fern accidentally sprouting in a bottle resulted in Nathaniel Bagshaw Ward's 1829 invention of the terrarium or Wardian case
- Rumohra adiantoides (floral fern), extensively used in the florist trade
- Osmunda regalis (royal fern) and Osmunda cinnamomea (cinnamon fern), the root fiber being used horticulturally; the fiddleheads of O. cinnamomea are also used as a cooked vegetable
- Matteuccia struthiopteris (ostrich fern), the fiddleheads used as a cooked vegetable in North America
- Pteridium aquilinum (bracken), the fiddleheads used as a cooked vegetable in Japan and are believed to be responsible for the high rate of stomach cancer in Japan. It is also one of the world's most important agricultural weeds, especially in the British highlands, and often poisons cattle and horses.
- Diplazium esculentum (vegetable fern), a source of food for some native societies
- Pteris vittata (brake fern), used to absorb arsenic from the soil
- Polypodium glycyrrhiza (licorice fern), roots chewed for their pleasant flavor
- Tree ferns, used as building material in some tropical areas
- Cyathea cooperi (Australian tree fern), an important invasive species in Hawaii
- Ceratopteris richardii, a model plant for teaching and research, often called C-fern
# Cultural connotations
In Slavic folklore, ferns are believed to bloom once a year, during the Ivan Kupala night. Although it's exceedingly difficult to find, anyone who takes a look of a fern flower will be happy and rich for the rest of his life. Similarly in Finland, the tradition holds that one who finds the seed of a fern in bloom on Midsummer night, will by the possession of it be able to travel under a glamour of invisibility and shall be guided to the locations where eternally blazing Will o' the wisps mark the spot of hidden treasure caches[citation needed].
Ferns were popular as a decorative motif in Victorian England, the designs frequently appeared on crockery, glassware, cast iron objects, and textiles. The fashion for growing ferns indoors led to the development of the Wardian case, a glazed cabinet that would exclude air pollutants and maintain the necessary humidity.
The dried form of ferns was also used in other arts, being used a stencil or directly inked for use in a design. The botanical work, The Ferns of Great Britain and Ireland, is a notable example of this type of nature printing. The process, patented by the artist and publisher Henry Bradbury, impressed a specimen on to a soft lead plate. The first publication to demonstrate this was Alois Auer's The Discovery of the Nature Printing-Process.
# Medicinal Value
Ferns are sometimes used in medicine to treat cuts and clean them out. Ferns are also good bandages if you are stuck out in the wild.[citation needed]
# Misunderstood names
Several non-fern plants are called "ferns" and are sometimes confused with true ferns. These include:
- "Asparagus fern" - This may apply to one of several species of the monocot genus Asparagus, which are flowering plants.
- "Sweetfern" - A flowering shrub of the genus Comptonia.
- "Air fern" - A group of animals called hydrozoan that are distantly related to jellyfish and corals. They are harvested, dried, dyed green, and then sold as a "plant" that can "live on air". While it may look like a fern, it is merely the skeleton of this colonial animal.
In addition, the book Where the Red Fern Grows has elicited many questions about the mythical "red fern" named in the book. There is no such known plant, although there has been speculation that the oblique grape-fern, Sceptridium dissectum, could be referred to here, because it is known to appear on disturbed sites and its fronds may redden over the winter.
# Gallery
- Fern leaf, probably Blechnum nudum
Fern leaf, probably Blechnum nudum
- A tree fern unrolling a new frond
- Tree fern, probably Dicksonia antarctica
Tree fern, probably Dicksonia antarctica
- Tree ferns, probably Dicksonia antarctica
Tree ferns, probably Dicksonia antarctica
- "Filicinae" from Ernst Haeckel's Kunstformen der Natur, 1904
"Filicinae" from Ernst Haeckel's Kunstformen der Natur, 1904
- Unidentified tree fern in Oaxaca
Unidentified tree fern in Oaxaca
- Tree Fern Spores San Diego, CA
Tree Fern Spores San Diego, CA
- Leaf of fern
Leaf of fern
- Unidentified fern with spores showing in Rotorua, NZ.
Unidentified fern with spores showing in Rotorua, NZ.
- Ferns in one of many natural Coast Redwood undergrowth settings Santa Cruz, CA.
Ferns in one of many natural Coast Redwood undergrowth settings Santa Cruz, CA.
- Nature prints in The Ferns of Great Britain and Ireland used fronds to produce the plates
Nature prints in The Ferns of Great Britain and Ireland used fronds to produce the plates | https://www.wikidoc.org/index.php/Fern | |
cb47b87258e322b01333fc4545884152453157cf | wikidoc | FiO2 | FiO2
FiO2, in the field of medicine, is the fraction of inspired oxygen in a gas mixture.
The FiO2 is expressed as a number from 0 (0%) to 1 (100%).
The FiO2 of normal room air is 0.21 (21%).
A patient's FiO2 may be varied through the use of different Venturi masks, in combination with varying oxygen flow rates. In addition, most mechanical ventilators have controls for adjusting FiO2. An increased FiO2 is necessary in managing adequate oxygenation in patients who are critically ill due to causes such as major surgery, acute lung injury, sepsis, pneumonia, congestive heart failure, or other cardiopulmonary disease.
Another common misconception is that the FiO2 changes with elevation. It remains at 0.21 at all altitudes within the atmosphere. What changes is the barometric pressure of air. At altitude, therefore, the partial pressure of oxygen delivered by that 21% of oxygen is lower. The partial pressure is the driving force to oxygenate the blood and therefore a lower partial pressure makes it that much harder to get O2 delivered to the tissues that require it, resulting in hypoxia. | FiO2
FiO2, in the field of medicine, is the fraction of inspired oxygen in a gas mixture.
The FiO2 is expressed as a number from 0 (0%) to 1 (100%).
The FiO2 of normal room air is 0.21 (21%).
A patient's FiO2 may be varied through the use of different Venturi masks, in combination with varying oxygen flow rates. In addition, most mechanical ventilators have controls for adjusting FiO2. An increased FiO2 is necessary in managing adequate oxygenation in patients who are critically ill due to causes such as major surgery, acute lung injury, sepsis, pneumonia, congestive heart failure, or other cardiopulmonary disease.
Another common misconception is that the FiO2 changes with elevation. It remains at 0.21 at all altitudes within the atmosphere. What changes is the barometric pressure of air. At altitude, therefore, the partial pressure of oxygen delivered by that 21% of oxygen is lower. The partial pressure is the driving force to oxygenate the blood and therefore a lower partial pressure makes it that much harder to get O2 delivered to the tissues that require it, resulting in hypoxia.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/FiO2 | |
f3cea63a08bb911410fe832503c5a362b0f63bdb | wikidoc | Fig4 | Fig4
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced Gene.
# Function
Sac3 protein belongs to a family of human phosphoinositide phosphatases that contain a Sac1-homology domain. The Sac1 phosphatase domain encompasses approximately 400 amino acids and consists of seven conserved motifs, which harbor the signature CX5R(T/S) catalytic sequence also found in other lipid and protein tyrosine phosphatases. The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1. There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L,INPP5F and FIG4), harbor a single Sac1 domain. In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis. The human Sac3 cDNA that predicts a 907 aminoacid protein and gene localization to chromosome 6 has been reported in 1996.
Sac3 is characterized as a widespread 97-kDa protein that displays in vitro phosphatase activity towards a range of 5’-phosphorylated phosphoinositides. Sac3 forms a hetero-oligomer with ArPIKfyve (gene symbol, VAC14) and this binary complex associates with the phosphoinositide kinase PIKFYVE in a ternary PAS complex (from the first letters of PIKfyve-ArPIKfyve-Sac3), which is required to maintain proper endosomal membrane dynamics. This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increased PtdIns(3,5)P2 production. Sac3 is active in the triple complex and responsible for turning over PtdIns(3,5)P2 to PtdIns3P. The PAS complex function is critical for life, because the knockout of each of the 3 genes encoding the PIKfyve, ArPIKfyve or Sac3 protein causes early embryonic, perinatal, or early juvenile lethality in mice.
Ectopically expressed Sac3 protein has a very short half-life of only ~18 min due to fast degradation in the proteasome. Co-expression of ArPIKfyve markedly prolongs Sac3 half-life, whereas siRNA-mediated ArPIKfyve knockdown profoundly reduces Sac3 levels. The Sac3 cellular levels are critically dependent on Sac3 physical interaction with ArPIKfyve. The C-terminal part of Sac3 is essential for this interaction. Insulin treatment of 3T3L1 adipocytes inhibits the Sac3 phosphatase activity as measured in vitro. Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin. In contrast, ectopic expression of Sac3, but not that of a phosphatase-deficient point-mutant, decreases GLUT4 plasma membrane abundance in response to insulin. Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness.
# Medical significance
Mutations in the FIG4 gene cause the rare autosomal recessive Charcot-Marie-Tooth peripheral neuropathy type 4J (CMT4J). FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS). Most CMT4J patients (15 out of the reported 16) are compound heterozygotes, i.e., the one FIG4 allele is null whereas the other encodes a mutant protein with threonine for isoleucine substitution at position 41. The Sac3I41T point mutation abrogates the protective action of ArPIKfyve on Sac3 half-life yet the association between the two is largely preserved. Consequently, the Sac3I41T protein level in patient fibroblasts is very low due to mutant degradation in the proteasome. Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease. In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system. How the initial molecular defect, affecting all cells of the body, results in selective peripheral neuropathy is unknown.
# Mouse models
Spontaneous FIG4 knockout leads to mutant mice with smaller size, selectively reduced PtdIns(3,5)P2 levels in isolated fibroblasts, diluted pigmentation, central and peripheral neurodegeneration, hydrocephalus, abnormal tremor and gait, and eventually juvenile lethality, hence the name pale tremor mouse (plt). Neuronal autophagy has been suggested as an important consequence of the knockout, however, its primary relevance is disputed. The plt mice show distinct morphological defects in motor and central neurons on the one hand, and sensory neurons - on the other. Transgenic mice with one spontaneously null allele and another encoding several copies of mouse Sac3I41T mutant (i.e., the genotypic equivalent of human CMT4J), are dose-dependently rescued from the lethality, neurodegeneration, and brain apoptosis observed in the plt mice. However, the hydrocephalus and diluted pigmentation seen in plt mice are not corrected.
# Evolutionary biology
Genes encoding orthologs of human Sac3 are found in all eukaryotes. The most studied is the S. cerevisae gene, discovered in a screen for yeast pheromone (Factor)-Induced Genes, hence the name Fig, with the number 4 reflecting the serendipity of isolation. Yeast Fig4p is a specific PtdIns(3,5)P2 5’-phosphatase, which physically interacts with Vac14p (the ortholog of human ArPIKfyve), and the PtdIns(3,5)P2-producing enzyme Fab1p (the ortholog of PIKfyve). The yeast Fab1p-Vac14p-Fig4p complex also involves Vac7p and potentially Atg18p. Deletion of Fig4p in budding yeast has relatively little effect on growth, basal PtdIns(3,5)P2 levels and the vacuolar size in comparison with the deletions of Vac14p or Fab1p. In brief, in evolution Sac3/Fig4 retained the Sac1 domain, phosphoinositide phosphatase activity, and the protein interactions from yeast. In mice, the protein is essential in early postnatal development. In humans, its I41T point mutation in combination with a null allele causes a neurodegenerative disorder. | Fig4
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene.[1] Fig4 is an abbreviation for Factor-Induced Gene.[2]
# Function
Sac3 protein belongs to a family of human phosphoinositide phosphatases that contain a Sac1-homology domain. The Sac1 phosphatase domain encompasses approximately 400 amino acids and consists of seven conserved motifs, which harbor the signature CX5R(T/S) catalytic sequence also found in other lipid and protein tyrosine phosphatases.[3] The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1.[4] There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L,INPP5F and FIG4), harbor a single Sac1 domain.[5] In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis.[6][7][8] The human Sac3 cDNA that predicts a 907 aminoacid protein and gene localization to chromosome 6 has been reported in 1996.[9]
Sac3 is characterized as a widespread 97-kDa protein that displays in vitro phosphatase activity towards a range of 5’-phosphorylated phosphoinositides.[10][11] Sac3 forms a hetero-oligomer with ArPIKfyve (gene symbol, VAC14) and this binary complex associates with the phosphoinositide kinase PIKFYVE in a ternary PAS complex (from the first letters of PIKfyve-ArPIKfyve-Sac3), which is required to maintain proper endosomal membrane dynamics.[12][13] This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increased PtdIns(3,5)P2 production. Sac3 is active in the triple complex and responsible for turning over PtdIns(3,5)P2 to PtdIns3P.[12][13] The PAS complex function is critical for life, because the knockout of each of the 3 genes encoding the PIKfyve, ArPIKfyve or Sac3 protein causes early embryonic,[14] perinatal,[15] or early juvenile lethality[16] in mice.
Ectopically expressed Sac3 protein has a very short half-life of only ~18 min due to fast degradation in the proteasome. Co-expression of ArPIKfyve markedly prolongs Sac3 half-life, whereas siRNA-mediated ArPIKfyve knockdown profoundly reduces Sac3 levels. The Sac3 cellular levels are critically dependent on Sac3 physical interaction with ArPIKfyve.[12][17] The C-terminal part of Sac3 is essential for this interaction.[13] Insulin treatment of 3T3L1 adipocytes inhibits the Sac3 phosphatase activity as measured in vitro. Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin. In contrast, ectopic expression of Sac3, but not that of a phosphatase-deficient point-mutant, decreases GLUT4 plasma membrane abundance in response to insulin.[18] Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness.
# Medical significance
Mutations in the FIG4 gene cause the rare autosomal recessive Charcot-Marie-Tooth peripheral neuropathy type 4J (CMT4J).[16] FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS).[19] Most CMT4J patients (15 out of the reported 16) are compound heterozygotes, i.e., the one FIG4 allele is null whereas the other encodes a mutant protein with threonine for isoleucine substitution at position 41.[20] The Sac3I41T point mutation abrogates the protective action of ArPIKfyve on Sac3 half-life yet the association between the two is largely preserved.[17] Consequently, the Sac3I41T protein level in patient fibroblasts is very low due to mutant degradation in the proteasome.[21] Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease. In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system.[22] How the initial molecular defect, affecting all cells of the body, results in selective peripheral neuropathy is unknown.
# Mouse models
Spontaneous FIG4 knockout leads to mutant mice with smaller size, selectively reduced PtdIns(3,5)P2 levels in isolated fibroblasts, diluted pigmentation, central and peripheral neurodegeneration, hydrocephalus, abnormal tremor and gait, and eventually juvenile lethality, hence the name pale tremor mouse (plt).[16][21] Neuronal autophagy has been suggested as an important consequence of the knockout,[23] however, its primary relevance is disputed.[24] The plt mice show distinct morphological defects in motor and central neurons on the one hand, and sensory neurons - on the other.[24] Transgenic mice with one spontaneously null allele and another encoding several copies of mouse Sac3I41T mutant (i.e., the genotypic equivalent of human CMT4J), are dose-dependently rescued from the lethality, neurodegeneration, and brain apoptosis observed in the plt mice. However, the hydrocephalus and diluted pigmentation seen in plt mice are not corrected.[21]
# Evolutionary biology
Genes encoding orthologs of human Sac3 are found in all eukaryotes. The most studied is the S. cerevisae gene, discovered in a screen for yeast pheromone (Factor)-Induced Genes, hence the name Fig, with the number 4 reflecting the serendipity of isolation.[25] Yeast Fig4p is a specific PtdIns(3,5)P2 5’-phosphatase, which physically interacts with Vac14p (the ortholog of human ArPIKfyve),[26] and the PtdIns(3,5)P2-producing enzyme Fab1p (the ortholog of PIKfyve).[27] The yeast Fab1p-Vac14p-Fig4p complex also involves Vac7p and potentially Atg18p.[28] Deletion of Fig4p in budding yeast has relatively little effect on growth, basal PtdIns(3,5)P2 levels and the vacuolar size in comparison with the deletions of Vac14p or Fab1p.[29] In brief, in evolution Sac3/Fig4 retained the Sac1 domain, phosphoinositide phosphatase activity, and the protein interactions from yeast. In mice, the protein is essential in early postnatal development. In humans, its I41T point mutation in combination with a null allele causes a neurodegenerative disorder. | https://www.wikidoc.org/index.php/Fig4 | |
5aba21a42bf25695fd48810dcdb7a44586952805 | wikidoc | Flax | Flax
Flax (also known as Common Flax or Linseed) is a member of the genus Linum in the family Linaceae. The New Zealand flax is unrelated. Flax is native to the region extending from the eastern Mediterranean to India and was probably first domesticated in the Fertile Crescent. It was extensively cultivated in ancient Egypt.
It is an erect annual plant growing to 1.2 m tall, with slender stems. The leaves are glaucous green, slender lanceolate, 20-40 mm long and 3 mm broad. The flowers are pure pale blue, 15-25 mm diameter, with five petals. The fruit is a round, dry capsule 5-9 mm diameter, containing several glossy brown seeds shaped like an apple pip, 4-7 mm long.
In addition to the plant itself, flax may refer to the unspun fibres of the flax plant.
# Uses
Flax is grown both for its seed and for its fibres. Various parts of the plant have been used to make fabric, dye, paper, medicines, fishing nets and soap. It is also grown as an ornamental plant in gardens, as flax is one of the few plant species capable of producing truly blue flowers (most "blue" flowers are really shades of purple), although not all flax varieties produce blue flowers.
## Flax seed
The seeds produce a vegetable oil known as linseed oil or flaxseed oil. It is one of the oldest commercial oils and solvent-processed flax seed oil has been used for centuries as a drying oil in painting and varnishing.
Flax seeds come in two basic varieties; brown and yellow (also referred to as golden). Although brown flax can be consumed and has been for thousands of years, it is better known as an ingredient in paints, fibre and cattle feed. Brown and yellow flax have similar nutritional values and equal amounts of short-chain omega-3 fatty acids. The exception is a type of yellow flax called solin,also known as Linola, which is very low in omega-3 and has a completely different oil profile.
A North Dakota State University research project led to the creation of a new variety of the yellow flax seed called "Omega." This new variety was created primarily as a food source; it has a nutty-buttery flavour, with a level of the beneficial omega-3 fatty acids comparable to brown flax.
One tablespoon of ground flax seeds and three tablespoons of water may serve as a replacement for one egg in baking by binding the other ingredients together. Ground flax seeds can also be mixed in with oatmeal, yogurt, water (similar to Metamucil), or any other food item where a nutty flavour is appropriate. Flaxseed oil is most commonly consumed with salads or in capsules. Flax seed owes its nutritional benefits to lignans and omega-3 essential fatty acids. Omega-3s, often in short supply in populations with low-fish diets, promote heart health by reducing cholesterol, blood pressure and plaque formation in arteries. In addition, flaxseed oil is often recommended as a galactagogue. Eating too many Flax seeds can also cause diarrhea.
Lignans benefit the heart and possess anti-cancer properties: A series of research studies by Lilian U. Thompson and her colleagues at the Department of Nutritional Science of the University of Toronto have reported that flaxseed can have a beneficial effect in reducing tumour growth in mice, particularly the kind of tumour found in human post-menopausal breast cancer. The effects are thought to be due to the lignans in flaxseed, and are additive with those of tamoxifen. Initial studies suggest that flaxseed taken in the diet have similar beneficial effects in human cancer patients. Reports that flaxseed is beneficial in other cancers, e.g., prostate cancer, are less numerous but also positive.
Flax may also lessen the severity of diabetes by stabilizing blood-sugar levels.
Flax seed sprouts are edible, with a slightly spicy flavour.
Flaxseed is also known as linseed. Flaxseeds are known as San, Alsi in Hindi, Gujarati, and Punjabi, Ali Vidai in Tamil. In Marathi, it is also known as Jawas and Alashi. In Bengali, it is known as Tishi, In Oriya it is called Pesi. In Kannada, it's called Agasi. The Telugu people call it Avise ginzalu. Finally, in Kerala, the Malayalis call it Cheruchana vithu.
## Flax fibers
Flax fibers are amongst the oldest fibre crops in the world. The use of flax for the production of linen goes back 5000 years. Pictures on tombs and temple walls at Thebes depict flowering flax plants. The use of flax fibre in the manufacturing of cloth in northern Europe dates back to Neolithic times. In North America, flax was introduced by the Puritans. Currently most flax produced in the USA and Canada are seed flax types for the production of linseed oil or flaxseeds for human nutrition.
Flax fibre is extracted from the bast or skin of the stem of flax plant. Flax fibre is soft, lustrous and flexible. It is stronger than cotton fibre but less elastic. The best grades are used for linen fabrics such as damasks, lace and sheeting. Coarser grades are used for the manufacturing of twine and rope. Flax fibre is also a raw material for the high-quality paper industry for the use of printed banknotes and rolling paper for cigarettes.
## Flax mills
Flax mills for spinning flaxen yarn were invented by John Kendrew and Thomas Porthouse of Darlington in 1787 .
# Cultivation
The major fibre flax-producing countries are Canada, USA and China, though there is also significant production in India and throughout Europe.
The soils most suitable for flax, besides the alluvial kind, are deep friable loams, and containing a large proportion of organic matter. Heavy clays are unsuitable, as are soils of a gravelly or dry sandy nature. Farming flax requires few fertilizers or pesticides. Within six weeks of sowing, the plant will reach 10-15 cm in height, and will grow several centimetres per day under its optimal growth conditions, reaching 70-80 cm within fifteen days.
Flax is harvested for fibre production after approximately 100 days, a month after the plant flowers and two weeks after the seed capsules form. The base of the plant will begin to turn yellow; if the plant is still green the seed will not be useful, and the fiber will be underdeveloped. The fiber degrades once the plant is brown. The mature plant is pulled up with the roots (not cut), so as to maximize the fiber length. After this the flax is allowed to dry, the seeds are removed, and is then retted. Dependant upon climatic conditions, characteristics of the sown flax and fields, the flax remains in the ground between 2 weeks and 2 months for retting. As a result of alternating rain and the sun, an enzymatic action degrades the pectins which bind fibres to the straw. The farmers turn over the straw during retting to evenly rett the stalks. When the straw is retted and sufficiently dry, it is rolled up. It will then be stored by farmers before scutching to extract fibres.
Flax grown for seed is allowed to mature until the seed capsules are yellow and just starting to split; it is then harvested by combine harvester and dried to extract the seed.
## Threshing flax
Threshing is the process of removing the seeds from the rest of the plant.
The process is divided into two parts: the first part is intended for the farmer, or flax-grower, to bring the flax into a fit state for general or common purposes. This is performed by three machines: one for threshing out the seed, one for breaking and separating the wood from the fibre, and one for further separating the broken wood and matter from the fibre. In some cases the farmers thrash out the seed in their own mill and therefore, in such cases, the first machine will be unnecessary.
The second part of the process is intended for the manufacturer to bring the flax into a state for the very finest purposes, such as lace, cambric, damask, and very fine linen. This second part is performed by the refining machine only.
The threshing process would be conducted as follows:
- Take the flax in small bundles, as it comes from the field or stack, and holding it in the left hand, put the seed end between the threshing machine and the bed or block against which the machine is to strike; then take the handle of the machine in the right hand, and move the machine backward and forward, to strike on the flax, until the seed is all threshed out.
- Take the flax in small handfuls in the left hand, spread it flat between the third and little finger, with the seed end downwards, and the root-end above, as near the hand as possible.
- Put the handful between the beater of the breaking machine, and beat it gently till the three or four inches, which have been under the operation of the machine, appear to be soft.
- Remove the flax a little higher in the hand, so as to let the soft part of the flax rest upon the little finger, and continue to beat it till all is soft, and the wood is separated from the fibre, keeping the left hand close to the block and the flax as flat upon the block as possible.
- The other end of the flax is then to be turned, and the end which has been beaten is to be wrapped round the little finger, the root end flat, and beaten in the machine till the wood is separated, exactly in the same way as the other end was beaten.
## Diseases
# Preparation for spinning
Before the flax fibers can be spun into linen, they must be separated from the rest of the stalk. The first step in this process is called "retting". Retting is the process of rotting away the inner stalk, leaving the outer fibres intact. At this point there is still straw, or coarse fibers, remaining. To remove these the flax is "broken", the straw is broken up into small, short bits, while the actual fiber is left unharmed, then "scutched", where the straw is scraped away from the fiber, and then pulled through "hackles", which act like combs and comb the straw out of the fiber.
## Retting flax
There are several methods of retting flax. It can be retted in a pond, stream, field or a container. When the retting is complete the bundles of flax feel soft and slimy, and quite a few fibres are standing out from the stalks. When wrapped around a finger the inner woody part springs away from the fibres.
Pond retting is the fastest. It consists of placing the flax in a pool of water which will not evaporate. It generally takes place in a shallow pool which will warm up dramatically in the sun; the process may take from only a couple days to a couple weeks. Pond retted flax is traditionally considered lower quality, possibly because the product can become dirty, and easily over-retts, damaging the fiber. This form of retting also produces quite an odor.
Stream retting is similar to pool retting, but the flax is submerged in bundles in a stream or river. This generally takes longer than pond retting, normally a two or three weeks, but the end product is less likely to be dirty, does not stink as much, and because the water is cooler it is less likely to be over-retted.
Both Pond and Stream retting were traditionally used less because they pollute the waters used for that process.
Field retting is laying the flax out in a large field, and allowing dew to collect on it. This process normally takes a month or more, but is generally considered to provide the highest quality flax fibers, and produces the least pollution.
Retting can also be done in a plastic trash can, or any type of water tight container of wood, concrete, earthenware or plastic. Metal containers will not work, as an acid is produced when retting, and it would corrode the metal. If the water temperature is kept at 80 °F, the retting process under these conditions takes 4 or 5 days, and if the water is any colder it takes longer. Scum will collect at the top, and an odour is given off, like in pond retting.
## Dressing the flax
Dressing the flax is the term given to removing the straw from the fibers. It consists of three steps, breaking, scutching, and hackling. The breaking breaks up the straw, then some of the straw is scraped from the fibers in the scutching process, then the fiber is pulled through hackles to remove the last bits of straw.
The dressing is done as follows:
# Flax as a symbolic image
- Common flax is the national flower of Belarus.
- Flax is the emblem of the Northern Ireland Assembly.
- The flax plant, in a coronet, appeared on the reverse of the British one pound coin to represent Northern Ireland on coins minted in 1986 and 1991.
# Flax in popular culture
- In English, blond hair is traditionally referred to as "fair" or "flaxen". | Flax
Flax (also known as Common Flax or Linseed) is a member of the genus Linum in the family Linaceae. The New Zealand flax is unrelated. Flax is native to the region extending from the eastern Mediterranean to India and was probably first domesticated in the Fertile Crescent.[1] It was extensively cultivated in ancient Egypt.
It is an erect annual plant growing to 1.2 m tall, with slender stems. The leaves are glaucous green, slender lanceolate, 20-40 mm long and 3 mm broad. The flowers are pure pale blue, 15-25 mm diameter, with five petals. The fruit is a round, dry capsule 5-9 mm diameter, containing several glossy brown seeds shaped like an apple pip, 4-7 mm long.
In addition to the plant itself, flax may refer to the unspun fibres of the flax plant.
# Uses
Flax is grown both for its seed and for its fibres. Various parts of the plant have been used to make fabric, dye, paper, medicines, fishing nets and soap. It is also grown as an ornamental plant in gardens, as flax is one of the few plant species capable of producing truly blue flowers (most "blue" flowers are really shades of purple), although not all flax varieties produce blue flowers.
## Flax seed
The seeds produce a vegetable oil known as linseed oil or flaxseed oil. It is one of the oldest commercial oils and solvent-processed flax seed oil has been used for centuries as a drying oil in painting and varnishing.
Flax seeds come in two basic varieties; brown and yellow (also referred to as golden). Although brown flax can be consumed and has been for thousands of years, it is better known as an ingredient in paints, fibre and cattle feed. Brown and yellow flax have similar nutritional values and equal amounts of short-chain omega-3 fatty acids. The exception is a type of yellow flax called solin,also known as Linola, which is very low in omega-3 and has a completely different oil profile.
Template:Nutritionalvalue
A North Dakota State University research project led to the creation of a new variety of the yellow flax seed called "Omega."[2] This new variety was created primarily as a food source; it has a nutty-buttery flavour, with a level of the beneficial omega-3 fatty acids comparable to brown flax.
One tablespoon of ground flax seeds and three tablespoons of water may serve as a replacement for one egg in baking by binding the other ingredients together. Ground flax seeds can also be mixed in with oatmeal, yogurt, water (similar to Metamucil), or any other food item where a nutty flavour is appropriate. Flaxseed oil is most commonly consumed with salads or in capsules. Flax seed owes its nutritional benefits to lignans and omega-3 essential fatty acids. Omega-3s, often in short supply in populations with low-fish diets, promote heart health by reducing cholesterol, blood pressure and plaque formation in arteries. In addition, flaxseed oil is often recommended as a galactagogue. Eating too many Flax seeds can also cause diarrhea.[3]
Lignans benefit the heart and possess anti-cancer properties: A series of research studies by Lilian U. Thompson and her colleagues at the Department of Nutritional Science of the University of Toronto have reported that flaxseed can have a beneficial effect in reducing tumour growth in mice, particularly the kind of tumour found in human post-menopausal breast cancer. The effects are thought to be due to the lignans in flaxseed, and are additive with those of tamoxifen. Initial studies suggest that flaxseed taken in the diet have similar beneficial effects in human cancer patients. Reports that flaxseed is beneficial in other cancers, e.g., prostate cancer, are less numerous but also positive.
Flax may also lessen the severity of diabetes by stabilizing blood-sugar levels.[4]
Flax seed sprouts are edible, with a slightly spicy flavour.
Flaxseed is also known as linseed. Flaxseeds are known as San, Alsi in Hindi, Gujarati, and Punjabi, Ali Vidai in Tamil. In Marathi, it is also known as Jawas and Alashi. In Bengali, it is known as Tishi, In Oriya it is called Pesi. In Kannada, it's called Agasi. The Telugu people call it Avise ginzalu. Finally, in Kerala, the Malayalis call it Cheruchana vithu.[citation needed]
## Flax fibers
Flax fibers are amongst the oldest fibre crops in the world. The use of flax for the production of linen goes back 5000 years. Pictures on tombs and temple walls at Thebes depict flowering flax plants. The use of flax fibre in the manufacturing of cloth in northern Europe dates back to Neolithic times. In North America, flax was introduced by the Puritans. Currently most flax produced in the USA and Canada are seed flax types for the production of linseed oil or flaxseeds for human nutrition.
Flax fibre is extracted from the bast or skin of the stem of flax plant. Flax fibre is soft, lustrous and flexible. It is stronger than cotton fibre but less elastic. The best grades are used for linen fabrics such as damasks, lace and sheeting. Coarser grades are used for the manufacturing of twine and rope. Flax fibre is also a raw material for the high-quality paper industry for the use of printed banknotes and rolling paper for cigarettes.
## Flax mills
Flax mills for spinning flaxen yarn were invented by John Kendrew and Thomas Porthouse of Darlington in 1787 .[5]
# Cultivation
The major fibre flax-producing countries are Canada, USA and China, though there is also significant production in India and throughout Europe.
The soils most suitable for flax, besides the alluvial kind, are deep friable loams, and containing a large proportion of organic matter. Heavy clays are unsuitable, as are soils of a gravelly or dry sandy nature. Farming flax requires few fertilizers or pesticides. Within six weeks of sowing, the plant will reach 10-15 cm in height, and will grow several centimetres per day under its optimal growth conditions, reaching 70-80 cm within fifteen days.
Flax is harvested for fibre production after approximately 100 days, a month after the plant flowers and two weeks after the seed capsules form. The base of the plant will begin to turn yellow; if the plant is still green the seed will not be useful, and the fiber will be underdeveloped. The fiber degrades once the plant is brown. The mature plant is pulled up with the roots (not cut), so as to maximize the fiber length. After this the flax is allowed to dry, the seeds are removed, and is then retted. Dependant upon climatic conditions, characteristics of the sown flax and fields, the flax remains in the ground between 2 weeks and 2 months for retting. As a result of alternating rain and the sun, an enzymatic action degrades the pectins which bind fibres to the straw. The farmers turn over the straw during retting to evenly rett the stalks. When the straw is retted and sufficiently dry, it is rolled up. It will then be stored by farmers before scutching to extract fibres.
Flax grown for seed is allowed to mature until the seed capsules are yellow and just starting to split; it is then harvested by combine harvester and dried to extract the seed.
## Threshing flax
Threshing is the process of removing the seeds from the rest of the plant.
The process is divided into two parts: the first part is intended for the farmer, or flax-grower, to bring the flax into a fit state for general or common purposes. This is performed by three machines: one for threshing out the seed, one for breaking and separating the wood from the fibre, and one for further separating the broken wood and matter from the fibre. In some cases the farmers thrash out the seed in their own mill and therefore, in such cases, the first machine will be unnecessary.
The second part of the process is intended for the manufacturer to bring the flax into a state for the very finest purposes, such as lace, cambric, damask, and very fine linen. This second part is performed by the refining machine only.
The threshing process would be conducted as follows:
- Take the flax in small bundles, as it comes from the field or stack, and holding it in the left hand, put the seed end between the threshing machine and the bed or block against which the machine is to strike; then take the handle of the machine in the right hand, and move the machine backward and forward, to strike on the flax, until the seed is all threshed out.
- Take the flax in small handfuls in the left hand, spread it flat between the third and little finger, with the seed end downwards, and the root-end above, as near the hand as possible.
- Put the handful between the beater of the breaking machine, and beat it gently till the three or four inches, which have been under the operation of the machine, appear to be soft.
- Remove the flax a little higher in the hand, so as to let the soft part of the flax rest upon the little finger, and continue to beat it till all is soft, and the wood is separated from the fibre, keeping the left hand close to the block and the flax as flat upon the block as possible.[citation needed]
- The other end of the flax is then to be turned, and the end which has been beaten is to be wrapped round the little finger, the root end flat, and beaten in the machine till the wood is separated, exactly in the same way as the other end was beaten.
## Diseases
# Preparation for spinning
Before the flax fibers can be spun into linen, they must be separated from the rest of the stalk. The first step in this process is called "retting". Retting is the process of rotting away the inner stalk, leaving the outer fibres intact. At this point there is still straw, or coarse fibers, remaining. To remove these the flax is "broken", the straw is broken up into small, short bits, while the actual fiber is left unharmed, then "scutched", where the straw is scraped away from the fiber, and then pulled through "hackles", which act like combs and comb the straw out of the fiber.
## Retting flax
There are several methods of retting flax. It can be retted in a pond, stream, field or a container. When the retting is complete the bundles of flax feel soft and slimy, and quite a few fibres are standing out from the stalks. When wrapped around a finger the inner woody part springs away from the fibres.
Pond retting is the fastest. It consists of placing the flax in a pool of water which will not evaporate. It generally takes place in a shallow pool which will warm up dramatically in the sun; the process may take from only a couple days to a couple weeks. Pond retted flax is traditionally considered lower quality, possibly because the product can become dirty, and easily over-retts, damaging the fiber. This form of retting also produces quite an odor.
Stream retting is similar to pool retting, but the flax is submerged in bundles in a stream or river. This generally takes longer than pond retting, normally a two or three weeks, but the end product is less likely to be dirty, does not stink as much, and because the water is cooler it is less likely to be over-retted.
Both Pond and Stream retting were traditionally used less because they pollute the waters used for that process.
Field retting is laying the flax out in a large field, and allowing dew to collect on it. This process normally takes a month or more, but is generally considered to provide the highest quality flax fibers, and produces the least pollution.
Retting can also be done in a plastic trash can, or any type of water tight container of wood, concrete, earthenware or plastic. Metal containers will not work, as an acid is produced when retting, and it would corrode the metal. If the water temperature is kept at 80 °F, the retting process under these conditions takes 4 or 5 days, and if the water is any colder it takes longer. Scum will collect at the top, and an odour is given off, like in pond retting.
## Dressing the flax
Dressing the flax is the term given to removing the straw from the fibers. It consists of three steps, breaking, scutching, and hackling. The breaking breaks up the straw, then some of the straw is scraped from the fibers in the scutching process, then the fiber is pulled through hackles to remove the last bits of straw.
The dressing is done as follows:
# Flax as a symbolic image
- Common flax is the national flower of Belarus.
- Flax is the emblem of the Northern Ireland Assembly.
- The flax plant, in a coronet, appeared on the reverse of the British one pound coin to represent Northern Ireland on coins minted in 1986 and 1991.
# Flax in popular culture
- In English, blond hair is traditionally referred to as "fair" or "flaxen". | https://www.wikidoc.org/index.php/Flax | |
9fde835269396afad4e2c7c96537acebe20411f6 | wikidoc | Flea | Flea
# Overview
Flea is the common name for any of the small wingless insects of the order Siphonaptera (some authorities use the name Aphaniptera because it is older, but names above family rank need not follow the ICZN rules of priority, so most taxonomists use the more familiar name). Fleas are external parasites, living by hematophagy off the blood of mammals and birds. Genetic and morphological evidence indicates that they are descendants of the Scorpionfly family Boreidae, which are also flightless; accordingly it is possible that they will eventually be reclassified as a suborder within the Mecoptera. In the past, however, it was most commonly supposed that fleas had evolved from the flies (Diptera), based on similarities of the larvae. In any case, all these groups seem to represent a clade of closely related insect lineages, for which the names Mecopteroidea and Antliophora have been proposed.
Some well known flea species include:
- Cat flea (Ctenocephalides felis),
- Dog flea (Ctenocephalides canis),
- Human flea (Pulex irritans),
- Northern rat flea (Nosopsyllus fasciatus),
- Oriental rat flea (Xenopsylla cheopis).
# Morphology and behavior
Fleas are small (1/16 to 1/8-inch (1.5 to 3.3 mm) long), agile, usually dark coloured (e.g. the reddish-brown of the cat flea), wingless insects with tube-like mouthparts adapted to feeding on the blood of their hosts. Their bodies are laterally compressed, (i.e., flattened side to side) permitting easy movement through the hairs (or feathers etc.) on the host's body. Their legs are long, the hind pair well adapted for jumping (vertically up to seven inches (18 cm); horizontally thirteen inches (33 cm)) - around 200 times their own body length, making the flea the best jumper out of all animals (in comparison to body size). The flea body is hard, polished, and covered with many hairs and short spines directed backward, allowing the flea a smooth passage through the hairs of its host. Its tough body is able to withstand great pressure, likely an adaptation to survive scratching etc. Even hard squeezing between the fingers is normally insufficient to kill the flea; it may be necessary to crush them between the fingernails or roll them between the fingers.
Fleas lay tiny white oval shaped eggs. Their larvae are small and pale with bristles covering their worm-like body. They are without eyes, and have mouthparts adapted to chewing. While the adult flea's diet consists solely of blood, their larvae feed on various organic matter including the feces of mature fleas. In the pupae phase the larvae are enclosed in a silken, debris covered cocoon.
# Life cycle and habitat
Fleas are holometabolous insects, going through the four life cycle stages of embryo, larva, pupa and imago (adult). The flea life cycle begins when the female lays after feeding. Adult fleas must feed on blood before they can become capable of reproduction. Eggs are laid in batches of up to 20 or so, usually on the host itself, which easily roll onto the ground. As such, areas where the host rests and sleeps become one of the primary habitats of eggs and developing fleas. The eggs take around two days to two weeks to hatch.
Flea larvae emerge from the eggs to feed on any available organic material such as dead insects, feces and vegetable matter. They are blind and avoid sunlight, keeping to dark places like sand, cracks and crevices, and bedding. Given an adequate supply of food, larvae should pupate within 1-2 weeks. After going through three larval stages they spin a silken cocoon. After another week or two the adult flea is fully developed and ready to emerge from the cocoon. They may however remain resting during this period until they receive a signal that a host is near - vibrations (including sound), heat and carbon dioxide are all stimuli indicating the probable presence of a host. Fleas are known to overwinter in the larval or pupal stages.
Once the flea reaches adulthood its primary goal is to find blood - adult fleas must feed on blood in order to reproduce. Adult fleas only have around a week to find food once they emerge, though they can survive two months to a year between meals. A flea population is unevenly distributed, with 50 percent eggs, 35 percent larvae, 10 percent pupae and 5 percent adults. Their total life cycle can take as little as two weeks, but may be lengthened to many months if conditions are favourable. Female fleas can lay 500 or more eggs over their life, allowing for phenomenal growth rates.
# Evolution and classification
Fleas are apparently related to scorpionflies, winged insects with good eyesight. The flightless snow flea with its rudimentary wings seems to be close to the common ancestor of the 2000 or so currently known varieties of flea, which split off in many directions around 160 million years ago. Their evolution continued to produce adaptations for their specialized parasitic niche, such that they now have no wings and their eyes are covered over. The large number of flea species may be attributed to the wide variety of host species they feed on, which provides so many specific ecological niches to adapt to.
Flea systematics is not entirely fixed. While compared to many other insect groups fleas have been studied and classified fairly thoroughly, details still remain to be learned about the evolutionary relationships among the different flea lineages.
Infraorder Pulicomorpha
- Superfamily Pulicoidea
Family Tungidae – sticktight and chigoe fleas ("chiggers" of Latin America)
Family Pulicidae – common fleas
- Family Tungidae – sticktight and chigoe fleas ("chiggers" of Latin America)
- Family Pulicidae – common fleas
- Superfamily Malacopsylloidea
Family Malacopsyllidae
Family Rhopalopsyllidae – hosts: marsupials
- Family Malacopsyllidae
- Family Rhopalopsyllidae – hosts: marsupials
- Superfamily Vermipsylloidea
Family Vermipsyllidae – hosts: carnivores
- Family Vermipsyllidae – hosts: carnivores
- Superfamily Coptopsylloidea
Family Coptopsyllidae
- Family Coptopsyllidae
- Superfamily Ancistropsylloidea
Family Ancistropsyllidae
- Family Ancistropsyllidae
Infraorder Pygiopsyllomorpha
- Superfamily Pygiopsylloidea
Family Lycopsyllidae
Family Pygiopsyllidae
Family Stivaliidae
- Family Lycopsyllidae
- Family Pygiopsyllidae
- Family Stivaliidae
Infraorder Hystrichopsyllomorpha
- Superfamily Hystrichopsylloidea
Family Hystrichopsyllidae – hosts: rats and mice. Includes Ctenopsyllidae, Amphipsyllidae
Family Chimaeropsyllidae
- Family Hystrichopsyllidae – hosts: rats and mice. Includes Ctenopsyllidae, Amphipsyllidae
- Family Chimaeropsyllidae
- Superfamily Macropsylloidea
Family Macropsyllidae
- Family Macropsyllidae
- Superfamily Stephanocircidoidea
Family Stephanocircidae - hosts: rodents
- Family Stephanocircidae - hosts: rodents
Infraorder Ceratophyllomorpha
- Superfamily Ceratophylloidea
Family Ceratophyllidae - hosts: rodents and birds. Includes Dolichopsyllidae
Family Leptopsyllidae – hosts: mice and rats
Family Ischnopsyllidae – hosts: bats
Family Xiphiopsyllidae
- Family Ceratophyllidae - hosts: rodents and birds. Includes Dolichopsyllidae
- Family Leptopsyllidae – hosts: mice and rats
- Family Ischnopsyllidae – hosts: bats
- Family Xiphiopsyllidae
# Relationship with host
Fleas attack a wide variety of warm-blooded vertebrates including dogs, cats, humans, chickens, rabbits, squirrels, rats and mice. Fleas are a nuisance to their hosts, causing an itching sensation which in turn may result in the host attempting to remove the pest by biting, pecking, scratching etc the vicinity of the parasite. Fleas are not simply a source of annoyance, however. Some people and animals suffer allergic reactions to flea saliva resulting in rashes. Flea bites generally result in the formation of a slightly-raised swollen itching spot with a single puncture point at the center. The bites often appear in clusters or lines, and can remain itchy and inflamed for up to several weeks afterwards. Fleas can also lead to hair loss as a result of frequent scratching and biting by the animal, and can cause anemia in extreme cases.
Besides the problems posed by the creature itself, fleas can also act as a vector for disease. For example, fleas transmitted the bubonic plague between rodents and humans by carrying Yersinia pestis bacteria. Murine typhus (endemic typhus) fever, and in some cases Hymenolepiasis (tapeworm) can also be transmitted by fleas.
# Flea treatments
## For humans
The itching associated with flea bites can be treated with anti-itch creams, usually antihistaminics or hydrocortisone. Calamine lotion has been shown to lack any effect on itching.
## For pets
The fleas, their larvae, or their eggs can be controlled with insecticides. Lufenuron and fipronil are popular veterinary preparation that attacks the larval flea's ability to produce chitin. Flea medicines need to be used with care as many, especially the acetylcholinesterase inhibitors, also affect mammals. Popular brands include Bayer Advantage, Advantix, and Frontline.
## For the home
Combating a flea infestation in the home takes patience as for every flea found on an animal there are many more developing in the home. A spot-on insecticide, such as Advantage, Frontline or Revolution will kill the fleas on the pet and in turn the pet itself will be a roving fleatrap and mop up newly hatched fleas. The environment ought to be treated with a fogger containing an insect growth regulator, such as pyriproxyfen or methoprene to kill eggs and pupae, which are quite resistant against insecticides. Frequent vacuuming is also helpful.
Even though organophosphate-based insecticides are still sold as flea collars, flea powders and flea shampoos those are not recommended. Many strains of insects have become resistant against that class of compounds, and they display an unacceptably high level of toxicity against mammals.
# Other
The Moche people of ancient Peru worshipped nature. They placed emphasis on animals and even depicted fleas in their art. | Flea
# Overview
Flea is the common name for any of the small wingless insects of the order Siphonaptera (some authorities use the name Aphaniptera because it is older, but names above family rank need not follow the ICZN rules of priority, so most taxonomists use the more familiar name). Fleas are external parasites, living by hematophagy off the blood of mammals and birds. Genetic and morphological evidence indicates that they are descendants of the Scorpionfly family Boreidae, which are also flightless; accordingly it is possible that they will eventually be reclassified as a suborder within the Mecoptera. In the past, however, it was most commonly supposed that fleas had evolved from the flies (Diptera), based on similarities of the larvae. In any case, all these groups seem to represent a clade of closely related insect lineages, for which the names Mecopteroidea and Antliophora have been proposed.
Some well known flea species include:
- Cat flea (Ctenocephalides felis),
- Dog flea (Ctenocephalides canis),
- Human flea (Pulex irritans),
- Northern rat flea (Nosopsyllus fasciatus),
- Oriental rat flea (Xenopsylla cheopis).
# Morphology and behavior
Fleas are small (1/16 to 1/8-inch (1.5 to 3.3 mm) long), agile, usually dark coloured (e.g. the reddish-brown of the cat flea), wingless insects with tube-like mouthparts adapted to feeding on the blood of their hosts. Their bodies are laterally compressed, (i.e., flattened side to side) permitting easy movement through the hairs (or feathers etc.) on the host's body. Their legs are long, the hind pair well adapted for jumping (vertically up to seven inches (18 cm); horizontally thirteen inches (33 cm)[1]) - around 200 times their own body length, making the flea the best jumper out of all animals (in comparison to body size). The flea body is hard, polished, and covered with many hairs and short spines directed backward[2], allowing the flea a smooth passage through the hairs of its host. Its tough body is able to withstand great pressure, likely an adaptation to survive scratching etc. Even hard squeezing between the fingers is normally insufficient to kill the flea; it may be necessary to crush them between the fingernails or roll them between the fingers.
Fleas lay tiny white oval shaped eggs. Their larvae are small and pale with bristles covering their worm-like body. They are without eyes, and have mouthparts adapted to chewing. While the adult flea's diet consists solely of blood, their larvae feed on various organic matter including the feces of mature fleas.[3] In the pupae phase the larvae are enclosed in a silken, debris covered cocoon.
# Life cycle and habitat
Fleas are holometabolous insects, going through the four life cycle stages of embryo, larva, pupa and imago (adult). The flea life cycle begins when the female lays after feeding. Adult fleas must feed on blood before they can become capable of reproduction.[2] Eggs are laid in batches of up to 20 or so, usually on the host itself, which easily roll onto the ground. As such, areas where the host rests and sleeps become one of the primary habitats of eggs and developing fleas. The eggs take around two days to two weeks to hatch[1].
Flea larvae emerge from the eggs to feed on any available organic material such as dead insects, feces and vegetable matter. They are blind and avoid sunlight, keeping to dark places like sand, cracks and crevices, and bedding. Given an adequate supply of food, larvae should pupate within 1-2 weeks. After going through three larval stages they spin a silken cocoon. After another week or two the adult flea is fully developed and ready to emerge from the cocoon. They may however remain resting during this period until they receive a signal that a host is near - vibrations (including sound), heat and carbon dioxide are all stimuli indicating the probable presence of a host.[1] Fleas are known to overwinter in the larval or pupal stages.
Once the flea reaches adulthood its primary goal is to find blood - adult fleas must feed on blood in order to reproduce[1]. Adult fleas only have around a week to find food once they emerge, though they can survive two months to a year between meals. A flea population is unevenly distributed, with 50 percent eggs, 35 percent larvae, 10 percent pupae and 5 percent adults.[1] Their total life cycle can take as little as two weeks, but may be lengthened to many months if conditions are favourable. Female fleas can lay 500 or more eggs over their life, allowing for phenomenal growth rates.
# Evolution and classification
Fleas are apparently related to scorpionflies[4], winged insects with good eyesight. The flightless snow flea with its rudimentary wings seems to be close to the common ancestor of the 2000 or so currently known varieties of flea, which split off in many directions around 160 million years ago.[4] Their evolution continued to produce adaptations for their specialized parasitic niche, such that they now have no wings and their eyes are covered over. The large number of flea species may be attributed to the wide variety of host species they feed on, which provides so many specific ecological niches to adapt to.
Flea systematics is not entirely fixed. While compared to many other insect groups fleas have been studied and classified fairly thoroughly, details still remain to be learned about the evolutionary relationships among the different flea lineages.
Infraorder Pulicomorpha
- Superfamily Pulicoidea
Family Tungidae – sticktight and chigoe fleas ("chiggers" of Latin America)
Family Pulicidae – common fleas
- Family Tungidae – sticktight and chigoe fleas ("chiggers" of Latin America)
- Family Pulicidae – common fleas
- Superfamily Malacopsylloidea
Family Malacopsyllidae
Family Rhopalopsyllidae – hosts: marsupials
- Family Malacopsyllidae
- Family Rhopalopsyllidae – hosts: marsupials
- Superfamily Vermipsylloidea
Family Vermipsyllidae – hosts: carnivores
- Family Vermipsyllidae – hosts: carnivores
- Superfamily Coptopsylloidea
Family Coptopsyllidae
- Family Coptopsyllidae
- Superfamily Ancistropsylloidea
Family Ancistropsyllidae
- Family Ancistropsyllidae
Infraorder Pygiopsyllomorpha
- Superfamily Pygiopsylloidea
Family Lycopsyllidae
Family Pygiopsyllidae
Family Stivaliidae
- Family Lycopsyllidae
- Family Pygiopsyllidae
- Family Stivaliidae
Infraorder Hystrichopsyllomorpha
- Superfamily Hystrichopsylloidea
Family Hystrichopsyllidae – hosts: rats and mice. Includes Ctenopsyllidae, Amphipsyllidae
Family Chimaeropsyllidae
- Family Hystrichopsyllidae – hosts: rats and mice. Includes Ctenopsyllidae, Amphipsyllidae
- Family Chimaeropsyllidae
- Superfamily Macropsylloidea
Family Macropsyllidae
- Family Macropsyllidae
- Superfamily Stephanocircidoidea
Family Stephanocircidae - hosts: rodents
- Family Stephanocircidae - hosts: rodents
Infraorder Ceratophyllomorpha
- Superfamily Ceratophylloidea
Family Ceratophyllidae - hosts: rodents and birds. Includes Dolichopsyllidae
Family Leptopsyllidae – hosts: mice and rats
Family Ischnopsyllidae – hosts: bats
Family Xiphiopsyllidae
- Family Ceratophyllidae - hosts: rodents and birds. Includes Dolichopsyllidae
- Family Leptopsyllidae – hosts: mice and rats
- Family Ischnopsyllidae – hosts: bats
- Family Xiphiopsyllidae
# Relationship with host
Fleas attack a wide variety of warm-blooded vertebrates including dogs, cats, humans, chickens, rabbits, squirrels, rats and mice. Fleas are a nuisance to their hosts, causing an itching sensation which in turn may result in the host attempting to remove the pest by biting, pecking, scratching etc the vicinity of the parasite. Fleas are not simply a source of annoyance, however. Some people and animals suffer allergic reactions to flea saliva resulting in rashes. Flea bites generally result in the formation of a slightly-raised swollen itching spot with a single puncture point at the center. The bites often appear in clusters or lines, and can remain itchy and inflamed for up to several weeks afterwards. Fleas can also lead to hair loss as a result of frequent scratching and biting by the animal, and can cause anemia in extreme cases.
Besides the problems posed by the creature itself, fleas can also act as a vector for disease. For example, fleas transmitted the bubonic plague between rodents and humans by carrying Yersinia pestis bacteria. Murine typhus (endemic typhus) fever, and in some cases Hymenolepiasis (tapeworm) can also be transmitted by fleas.
# Flea treatments
## For humans
The itching associated with flea bites can be treated with anti-itch creams, usually antihistaminics or hydrocortisone. Calamine lotion has been shown to lack any effect on itching.
## For pets
The fleas, their larvae, or their eggs can be controlled with insecticides. Lufenuron and fipronil are popular veterinary preparation that attacks the larval flea's ability to produce chitin. Flea medicines need to be used with care as many, especially the acetylcholinesterase inhibitors, also affect mammals. Popular brands include Bayer Advantage, Advantix, and Frontline.
## For the home
Combating a flea infestation in the home takes patience as for every flea found on an animal there are many more developing in the home. A spot-on insecticide, such as Advantage, Frontline or Revolution will kill the fleas on the pet and in turn the pet itself will be a roving fleatrap and mop up newly hatched fleas. The environment ought to be treated with a fogger containing an insect growth regulator, such as pyriproxyfen or methoprene to kill eggs and pupae, which are quite resistant against insecticides. Frequent vacuuming is also helpful.
Even though organophosphate-based insecticides are still sold as flea collars, flea powders and flea shampoos those are not recommended. Many strains of insects have become resistant against that class of compounds, and they display an unacceptably high level of toxicity against mammals.
# Other
The Moche people of ancient Peru worshipped nature.[5] They placed emphasis on animals and even depicted fleas in their art. [6] | https://www.wikidoc.org/index.php/Flea | |
5df5c972b480c5be5c80a1adef3363cd9357688f | wikidoc | Foot | Foot
The foot is a biological structure found in many animals that is used for locomotion. In many animals with feet, the foot is a separate organ at the terminal part of the leg made up of one or more segments or bones, generally including claws or nails.
# The human foot
## Anatomy
The major bones in the foot are:
- Phalanges: The bones in the toes are called phalanges.
- Metatarsals: The bones in the middle of the foot are called metatarsal bones.
- Cuneiforms: There are three bones in the middle of the foot, towards the centre of the body called cuneiforms.
- Cuboid: The bone sitting adjacent to the cuneiforms on the outside of the foot is called the cuboid.
- Navicular: This bone sits behind the cuneiforms.
- Talus: Also called the ankle bone, the talus sits directly behind the navicular.
- Calcaneus: Also called the heel bone, the calcaneus sits under the talus and behind the cuboid.
The foot also contains sesamoid bones in distal portion of the first metatarsal bone.
## Medical aspects
Due to their position and function, feet are exposed to a variety of potential infections and injuries, including athlete's foot, bunions, ingrown toenails, Morton's neuroma, plantar fasciitis, plantar warts and stress fractures. In addition, there are several genetic conditions that can affect the shape and function of the feet, including a club foot or flat feet.
A doctor who specializes in the treatment of the feet practices podiatry and is called a podiatrist. A pedorthist specializes in the use and modification of footwear to treat problems related to the lower limbs.
Reflexology is an alternative therapy which involves the stimulation of the nerves and skin of the feet to improve a person's health.
## Additional images
- A foot seen from the lateral view.
- Feet seen from the top.
- The soles of a male (left) and female (right) foot. | Foot
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The foot is a biological structure found in many animals that is used for locomotion. In many animals with feet, the foot is a separate organ at the terminal part of the leg made up of one or more segments or bones, generally including claws or nails.
# The human foot
## Anatomy
The major bones in the foot are:
- Phalanges: The bones in the toes are called phalanges.
- Metatarsals: The bones in the middle of the foot are called metatarsal bones.
- Cuneiforms: There are three bones in the middle of the foot, towards the centre of the body called cuneiforms.
- Cuboid: The bone sitting adjacent to the cuneiforms on the outside of the foot is called the cuboid.
- Navicular: This bone sits behind the cuneiforms.
- Talus: Also called the ankle bone, the talus sits directly behind the navicular.
- Calcaneus: Also called the heel bone, the calcaneus sits under the talus and behind the cuboid.
The foot also contains sesamoid bones in distal portion of the first metatarsal bone.
Template:Seealso
## Medical aspects
Due to their position and function, feet are exposed to a variety of potential infections and injuries, including athlete's foot, bunions, ingrown toenails, Morton's neuroma, plantar fasciitis, plantar warts and stress fractures. In addition, there are several genetic conditions that can affect the shape and function of the feet, including a club foot or flat feet.
A doctor who specializes in the treatment of the feet practices podiatry and is called a podiatrist. A pedorthist specializes in the use and modification of footwear to treat problems related to the lower limbs.
Reflexology is an alternative therapy which involves the stimulation of the nerves and skin of the feet to improve a person's health.
## Additional images
- A foot seen from the lateral view.
- Feet seen from the top.
- The soles of a male (left) and female (right) foot.
# External links
- Template:Dmoz
- American College of Foot and Ankle Surgeons
- American Academy of Podiatric Sports Medicine
- Association of Reflexologists
- Foot Health
- Epodiatry
- Foot Health Care
- Anatomical illustrations
Template:Human anatomical features
Template:Lower limb general
af:Voet
an:Piet
ast:Pie (anatomía)
ca:Peu
cy:Troed
de:Fuß
eo:Piedo
ko:발
it:Piede (anatomia)
he:כף רגל
la:Pes
lt:Pėda
ms:Kaki
nl:Voet (anatomie)
no:Fot (kroppsdel)
nn:Fot
oc:Pè
nds:Foot
qu:Chaki
simple:Foot
fi:Jalkaterä
sv:Fot
uk:Стопа (анатомія)
ur:فٹ
yi:פוס
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Foot | |
34de774145d3160feb5567c87be04af4570a9a1e | wikidoc | Frzb | Frzb
Frzb (pronounced like the sport 'ultimate frisbee') is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.
Frizzled is a tissue polarity gene in Drosophila melanogaster and encodes integral proteins that function as cell-surface receptors for Wnts called serpentine receptors. The integral membrane proteins contain a cysteine-rich domain thought to be the Wnt binding domain in extracellular region. The signals are initiated at the 7 transmembrane domain and transmitted through receptor coupling to G-proteins.
This protein is expressed in chondrocytes making it important in skeletal development in the embryo and fetus. Frzb is localized in the extracellular plasma membrane. Unlike frizzled, frzb lacks the 7 transmembrane domains normally found in G-protein-coupled receptors. It is still considered a homolog of frizzled because it contains a Cysteine Rich Domain (CRD), and because of its intracellular C-terminus which is crucial for signaling. The CRD is highly conserved in diverse proteins, such as receptor tyrosine kinases and functions as a ligand binding domain. The C-terminal is a carboxyl terminus located intracellularly and is required for canonical signaling.
The serpentine receptors (frzb) couple binds to ligand (Wnt protein) and activates G-proteins. A signal transduction cascade results in the secretion of first and second group antagonists. First group antagonists are composed of secreted Frizzled Related protein family (Sfrp) and Wnt inhibitory factor (Wif). Both Srfp and Wif bind directly to Wnt proteins blocking activation of the receptor. Second group of antagonists contains a class of Wnt inhibitory proteins known as Frizzled Receptor-like Proteins (FRPs). FRPs bind to the LRP (low-density-lipoprotein-related protein) co-receptors blocking activation of the Wnt signaling pathway.
One such pathway that involves Frizzled (Fz) family is the Wnt/β-Catenin (β-Cat) signaling. β-Cat is an intracellular signal that is held in check by axin. In this pathway, the activation of Wnt receptors can be transduced by the canonical pathway via a series of phosphorylation steps leading to stabilization and nuclear import of β-Cat into the nucleus where β-Cat associates with T-cell factor (TCF), a DNA-binding protein family. The β-Cat and TCF complex activates target genes of the Wnt pathway. In the absence of Wnt, β-Catenin is phosphorylated by complex containing GSK3 (glycogen synthase kinase 3) which targets β-Cat for protesosomal degradation. In the nucleus, members of the T-cell factor (TCF) family of DNA-binding proteins repress Wnt targets along with co-repressors such as Groucho (Gro).
If Wnt is present it binds to Fz-LRP receptors causing axin to bind to intracellular domain of LRP and Fz. Dishevelled (Dvl) is a protein required for Wnt-dependent inhibition complex. The combination of LRP-axin induces Dvl phosphorylation (P) which blocks the APC-axin-GSK3 complex from phosphorylating β-Cat. The accumulated β-Cat then enters the nucleus and converts TCF into a transcriptional activator.
Defects in Frzb are associated with female-specific osteoarthritis (OA) susceptibility which is the most prevalent form of arthritis and common cause of disability.
Frzb (known as Frzb1 or Sfrp3, Secreted Frizzled Related Protein 3) was initially identified as a chondrogenic factor during bone morphogenesis, and was described as a novel marker of the neural crest-derived mesenchymal cells that contribute to dental follicle formation, the future periodontium. | Frzb
Frzb (pronounced like the sport 'ultimate frisbee') is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.
Frizzled is a tissue polarity gene in Drosophila melanogaster and encodes integral proteins that function as cell-surface receptors for Wnts called serpentine receptors. The integral membrane proteins contain a cysteine-rich domain thought to be the Wnt binding domain in extracellular region. The signals are initiated at the 7 transmembrane domain and transmitted through receptor coupling to G-proteins.
This protein is expressed in chondrocytes making it important in skeletal development in the embryo and fetus. Frzb is localized in the extracellular plasma membrane. Unlike frizzled, frzb lacks the 7 transmembrane domains normally found in G-protein-coupled receptors. It is still considered a homolog of frizzled because it contains a Cysteine Rich Domain (CRD), and because of its intracellular C-terminus which is crucial for signaling. The CRD is highly conserved in diverse proteins, such as receptor tyrosine kinases and functions as a ligand binding domain. The C-terminal is a carboxyl terminus located intracellularly and is required for canonical signaling.
The serpentine receptors (frzb) couple binds to ligand (Wnt protein) and activates G-proteins. A signal transduction cascade results in the secretion of first and second group antagonists. First group antagonists are composed of secreted Frizzled Related protein family (Sfrp) and Wnt inhibitory factor (Wif). Both Srfp and Wif bind directly to Wnt proteins blocking activation of the receptor. Second group of antagonists contains a class of Wnt inhibitory proteins known as Frizzled Receptor-like Proteins (FRPs). FRPs bind to the LRP (low-density-lipoprotein-related protein) co-receptors blocking activation of the Wnt signaling pathway.
One such pathway that involves Frizzled (Fz) family is the Wnt/β-Catenin (β-Cat) signaling.[1] β-Cat is an intracellular signal that is held in check by axin. In this pathway, the activation of Wnt receptors can be transduced by the canonical pathway via a series of phosphorylation steps leading to stabilization and nuclear import of β-Cat into the nucleus where β-Cat associates with T-cell factor (TCF), a DNA-binding protein family. The β-Cat and TCF complex activates target genes of the Wnt pathway. In the absence of Wnt, β-Catenin is phosphorylated by complex containing GSK3 (glycogen synthase kinase 3) which targets β-Cat for protesosomal degradation. In the nucleus, members of the T-cell factor (TCF) family of DNA-binding proteins repress Wnt targets along with co-repressors such as Groucho (Gro).
If Wnt is present it binds to Fz-LRP receptors causing axin to bind to intracellular domain of LRP and Fz. Dishevelled (Dvl) is a protein required for Wnt-dependent inhibition complex. The combination of LRP-axin induces Dvl phosphorylation (P) which blocks the APC-axin-GSK3 complex from phosphorylating β-Cat. The accumulated β-Cat then enters the nucleus and converts TCF into a transcriptional activator.
Defects in Frzb are associated with female-specific osteoarthritis (OA) susceptibility which is the most prevalent form of arthritis and common cause of disability.
http://jcs.biologists.org/content/vol119/issue3/images/large/JCS02826F1.jpeg
Frzb (known as Frzb1 or Sfrp3, Secreted Frizzled Related Protein 3) was initially identified as a chondrogenic factor during bone morphogenesis, and was described as a novel marker of the neural crest-derived mesenchymal cells that contribute to dental follicle formation, the future periodontium[2]. | https://www.wikidoc.org/index.php/Frzb | |
b000c71a1ec945a64f2917a3078bd124d2a7ba79 | wikidoc | Fuel | Fuel
# Overview
Fuel is any material that is burnt or altered in order to obtain energy. Fuel releases its energy either through a chemical reaction means, such as combustion, or nuclear means, such as nuclear fission or nuclear fusion. An important property of a useful fuel is that its energy can be stored to be released only when needed, and that the release is controlled in such a way that the energy can be harnessed to produce work.
All carbon-based life forms—from microorganisms to animals and humans—depend on and use fuels as their source of energy. Their cells engage in an enzyme-mediated chemical process called metabolism that converts energy from food or solar power into a form that can be used to sustain life. Additionally, humans employ a variety of techniques to convert one form of energy into another, producing usable energy for purposes that go far beyond the energy needs of a human body. The application of energy released from fuels ranges from heat to cooking and from powering weapons to combustion and generation of electricity.
# Energy sources
All currently-known fuels ultimately derive their energy from a small number of sources. Much of the chemical energy produced by life forms, such as fossil fuels, is derived from the utilization of solar energy through photosynthesis. Solar energy in turn is generated by the thermonuclear fusion process at the core of the Sun. The radioactive isotopes used as fuel to power nuclear plants were formed in supernova explosions.
# Chemical
Chemical fuels are substances that generate energy by reacting with substances around them, most notably by the process of oxidization. These substances were the first fuels to be known and used by humans and are still the primary type of fuel used today.
## Biofuels
Biofuel can be broadly defined as solid, liquid, or gas fuel consisting of, or derived from biomass. Biomass can also be used directly for heating or power—known as biomass fuel. Biofuel can be produced from any carbon source that can be replenished rapidly e.g. plants. Many different plants and plant-derived materials are used for biofuel manufacture.
Perhaps the earliest fuel that was employed by humans is wood. Evidence shows controlled fire was used up to 1.5 million years ago at Swartkrans, South Africa. It is unknown which hominid species first used fire, as both Australopithecus and an early species of Homo were present at the sites. As a fuel, wood has remained in use up until the present day, although it has been superseded for many purposes by other sources. Wood has an energy density of 10–20 MJ/kg.
Recently biofuels have been developed for use in automotive transport (for example E10 fuel).
## Fossil fuels
Fossil fuels are hydrocarbons, primarily coal and petroleum (liquid petroleum or natural gas), formed from the fossilized remains of dead plants and animals by exposure to heat and pressure in the Earth's crust over hundreds of millions of years. In common parlance, the term fossil fuel also includes hydrocarbon-containing natural resources that are not derived entirely from biological sources, such as tar sands. These latter sources are properly known as mineral fuels.
Modern large-scale industrial development is based on fossil fuel use, which has largely supplanted water-driven mills, as well as the combustion of wood or peat for heat. With global modernization in the 20th and 21st centuries, the growth in energy production from fossil fuels, especially gasoline derived from oil, is one of the causes of major regional and global conflicts and environmental issues. A global movement toward the generation of renewable energy is therefore under way to help meet the increased global energy needs.
The burning of fossil fuels by humans is the largest source of emissions of carbon dioxide, which is one of the greenhouse gases that enhances radiative forcing and contributes to global warming. The atmospheric concentration of CO2, a greenhouse gas, is increasing, raising concerns that solar heat will be trapped and the average surface temperature of the Earth will rise in response.
# Nuclear
Nuclear fuel is any material that is consumed to derive nuclear energy. Technically speaking this definition includes all matter because any element will under the right conditions release nuclear energy, the only materials that are commonly referred to as nuclear fuels though are those that will produce energy without being placed under extreme duress.
## Fission
The most common type of nuclear fuel used by humans is heavy fissile elements that can be made to undergo nuclear fission chain reactions in a nuclear fission reactor; nuclear fuel can refer to the material or to physical objects (for example fuel bundles composed of fuel rods) composed of the fuel material, perhaps mixed with structural, neutron moderating, or neutron reflecting materials. The most common fissile nuclear fuels are 235U and 239Pu, and the actions of mining, refining, purifying, using, and ultimately disposing of these elements together make up the nuclear fuel cycle, which is important for its relevance to nuclear power generation and nuclear weapons.
## Fusion
Fuels that produce energy by the process of nuclear fusion are currently not utilized by man but are the main source of fuel for stars, the most powerful energy sources in nature. Fusion fuels tend to be light elements such as hydrogen which will combine easily.
In stars that undergo nuclear fusion, fuel consists of atomic nuclei that can release energy by the absorption of a proton or neutron. In most stars the fuel is provided by hydrogen, which can combine together to form helium through the proton-proton chain reaction or by the CNO cycle. When the hydrogen fuel is exhausted, nuclear fusion can continue with progressively heavier elements, although the net energy released is lower because of the smaller difference in nuclear binding energy. Once iron-56 or nickel-56 nuclei are produced, no further energy can be obtained by nuclear fusion as these have the highest nuclear binding energies.
# World trade
World Bank reported that the USA was the top fuel importer in 2005 followed by the EU and Japan.
# Use over time
The first use of fuel was the combustion of wood or sticks by Homo erectus near 2 million years ago.Template:Page number Throughout the majority of human history fuels derived from plants or animal fat were the only ones available for human use. Charcoal, a wood derivative, has been used since at least 6,000 BCE for smelting metals. It was only supplanted by coke, derived from coal, as the forests started to became depleted around the 18th century. Charcoal briquettes are now commonly used as a fuel for barbecue cooking.
Coal was first used as a fuel around 1000 BCE in China. With the
development of the steam engine in 1769, coal came into more common use as a power source. Coal was later used to drive ships and locomotives. By the 19th century, gas extracted from coal was being used for street lighting in London. In the 20th century, the primary use of coal is for the generation of electricity, providing 40% of the world's electrical power supply in 2005. | Fuel
# Overview
Fuel is any material that is burnt or altered in order to obtain energy.[1] Fuel releases its energy either through a chemical reaction means, such as combustion, or nuclear means, such as nuclear fission or nuclear fusion. An important property of a useful fuel is that its energy can be stored to be released only when needed, and that the release is controlled in such a way that the energy can be harnessed to produce work.
All carbon-based life forms—from microorganisms to animals and humans—depend on and use fuels as their source of energy. Their cells engage in an enzyme-mediated chemical process called metabolism that converts energy from food or solar power into a form that can be used to sustain life. [2] Additionally, humans employ a variety of techniques to convert one form of energy into another, producing usable energy for purposes that go far beyond the energy needs of a human body. The application of energy released from fuels ranges from heat to cooking and from powering weapons to combustion and generation of electricity.
# Energy sources
All currently-known fuels ultimately derive their energy from a small number of sources. Much of the chemical energy produced by life forms, such as fossil fuels, is derived from the utilization of solar energy through photosynthesis. Solar energy in turn is generated by the thermonuclear fusion process at the core of the Sun. The radioactive isotopes used as fuel to power nuclear plants were formed in supernova explosions.
# Chemical
Chemical fuels are substances that generate energy by reacting with substances around them, most notably by the process of oxidization. These substances were the first fuels to be known and used by humans and are still the primary type of fuel used today.
## Biofuels
Biofuel can be broadly defined as solid, liquid, or gas fuel consisting of, or derived from biomass. Biomass can also be used directly for heating or power—known as biomass fuel. Biofuel can be produced from any carbon source that can be replenished rapidly e.g. plants. Many different plants and plant-derived materials are used for biofuel manufacture.
Perhaps the earliest fuel that was employed by humans is wood. Evidence shows controlled fire was used up to 1.5 million years ago at Swartkrans, South Africa. It is unknown which hominid species first used fire, as both Australopithecus and an early species of Homo were present at the sites.[3] As a fuel, wood has remained in use up until the present day, although it has been superseded for many purposes by other sources. Wood has an energy density of 10–20 MJ/kg. [4]
Recently biofuels have been developed for use in automotive transport (for example E10 fuel).
## Fossil fuels
Fossil fuels are hydrocarbons, primarily coal and petroleum (liquid petroleum or natural gas), formed from the fossilized remains of dead plants and animals[5] by exposure to heat and pressure in the Earth's crust over hundreds of millions of years[6]. In common parlance, the term fossil fuel also includes hydrocarbon-containing natural resources that are not derived entirely from biological sources, such as tar sands. These latter sources are properly known as mineral fuels.
Modern large-scale industrial development is based on fossil fuel use, which has largely supplanted water-driven mills, as well as the combustion of wood or peat for heat. With global modernization in the 20th and 21st centuries, the growth in energy production from fossil fuels, especially gasoline derived from oil, is one of the causes of major regional and global conflicts and environmental issues. A global movement toward the generation of renewable energy is therefore under way to help meet the increased global energy needs.
The burning of fossil fuels by humans is the largest source of emissions of carbon dioxide, which is one of the greenhouse gases that enhances radiative forcing and contributes to global warming. The atmospheric concentration of CO2, a greenhouse gas, is increasing, raising concerns that solar heat will be trapped and the average surface temperature of the Earth will rise in response.
# Nuclear
Nuclear fuel is any material that is consumed to derive nuclear energy. Technically speaking this definition includes all matter because any element will under the right conditions release nuclear energy, the only materials that are commonly referred to as nuclear fuels though are those that will produce energy without being placed under extreme duress.
## Fission
The most common type of nuclear fuel used by humans is heavy fissile elements that can be made to undergo nuclear fission chain reactions in a nuclear fission reactor; nuclear fuel can refer to the material or to physical objects (for example fuel bundles composed of fuel rods) composed of the fuel material, perhaps mixed with structural, neutron moderating, or neutron reflecting materials. The most common fissile nuclear fuels are 235U and 239Pu, and the actions of mining, refining, purifying, using, and ultimately disposing of these elements together make up the nuclear fuel cycle, which is important for its relevance to nuclear power generation and nuclear weapons.
## Fusion
Fuels that produce energy by the process of nuclear fusion are currently not utilized by man but are the main source of fuel for stars, the most powerful energy sources in nature. Fusion fuels tend to be light elements such as hydrogen which will combine easily.
In stars that undergo nuclear fusion, fuel consists of atomic nuclei that can release energy by the absorption of a proton or neutron. In most stars the fuel is provided by hydrogen, which can combine together to form helium through the proton-proton chain reaction or by the CNO cycle. When the hydrogen fuel is exhausted, nuclear fusion can continue with progressively heavier elements, although the net energy released is lower because of the smaller difference in nuclear binding energy. Once iron-56 or nickel-56 nuclei are produced, no further energy can be obtained by nuclear fusion as these have the highest nuclear binding energies.[7]
# World trade
World Bank reported that the USA was the top fuel importer in 2005 followed by the EU and Japan.[citation needed]
# Use over time
The first use of fuel was the combustion of wood or sticks by Homo erectus near 2 million years ago.[8]Template:Page number Throughout the majority of human history fuels derived from plants or animal fat were the only ones available for human use. Charcoal, a wood derivative, has been used since at least 6,000 BCE for smelting metals. It was only supplanted by coke, derived from coal, as the forests started to became depleted around the 18th century. Charcoal briquettes are now commonly used as a fuel for barbecue cooking.[9]
Coal was first used as a fuel around 1000 BCE in China. With the
development of the steam engine in 1769, coal came into more common use as a power source. Coal was later used to drive ships and locomotives. By the 19th century, gas extracted from coal was being used for street lighting in London. In the 20th century, the primary use of coal is for the generation of electricity, providing 40% of the world's electrical power supply in 2005.[10] | https://www.wikidoc.org/index.php/Fuel | |
d2ceaee753e6917382bf2d78ac8bcf484c1ae1b8 | wikidoc | G6PC | G6PC
Glucose-6-phosphatase, catalytic subunit (glucose 6-phosphatase alpha) is an enzyme that in humans is encoded by the G6PC gene.
Glucose-6-phosphatase is an integral membrane protein of the endoplasmic reticulum that catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate. It is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Defects in the enzyme cause glycogen storage disease type I (von Gierke disease).
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | G6PC
Glucose-6-phosphatase, catalytic subunit (glucose 6-phosphatase alpha) is an enzyme that in humans is encoded by the G6PC gene.[1][2]
Glucose-6-phosphatase is an integral membrane protein of the endoplasmic reticulum that catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate. It is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Defects in the enzyme cause glycogen storage disease type I (von Gierke disease).[2]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/G6PC | |
0ff9fa565ba608f1f614687b850c4898e1d06e57 | wikidoc | GAB2 | GAB2
GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.
GAB2 is a docking protein with a conserved, folded PH domain attached to the membrane and a large disordered region, which hosts interactions with signaling molecules. It is a member of the GAB/DOS family localized on the internal membrane of the cell. It mediates the interaction between receptor tyrosine kinases (RTKs) and non-RTK receptors serving as the gateway into the cell for activation of SHP2, Phosphatidylinositol 3-kinase (PI3K), Grb2, ERK, and AKT and acting as one of the first steps in these signaling pathways. GAB2 has been shown to be important in physiological functions such as growth in bone marrow and cardiac function. GAB2 has also been associated with many diseases including leukemia and Alzheimer's disease.
# Discovery
GAB proteins were one of the first docking proteins identified in the mammalian signal transduction pathway. GAB2 along with many other adaptor, scaffold, and docking proteins, was discovered in the mid-1990s during the isolation and cloning of protein tyrosine kinase substrates and association partners. GAB2 was initially discovered as a binding protein and substrate of protein tyrosine phosphatase Shp2/PTPN11. Two other groups later cloned GAB2 by searching DNA database for protein with sequence homology to GAB1.
# Structure
GAB2 is a large multi-site docking protein (LMD) of about 100kD that has a folded N-terminal domain attached to an extended, disordered C-terminal tail rich in short linear motifs. LMDs are docking proteins that function as platforms mediating interaction between different signaling pathways and assisting with signal integration. The N-terminal is characterized by a Pleckstrin Homology (PH) domain that is the most highly conserved region between all members of the GAB family of proteins. (GAB1, GAB2, GAB3 and GAB4) GAB2 is an Intrinsically disordered protein, meaning that beyond the folded N-terminal region, the C-terminal region extends out into the cytoplasm with little or no secondary structure. The disordered region of the protein however may not be as disordered as was initially expected, as sequencing has revealed significant similarity between the “disordered” regions of GAB orthologs in different species.
The PH domain of GAB2 recognizes phosphatidylinositol 3,4,5-triphosphate(PIP3) in the membrane and is responsible for localizing the GAB protein on the intracellular surface of the membrane and in regions where the cell contacts another cell. Some evidence also suggests that the PH domain plays a role in some signal regulation as well.
Adjacent to the PH domain is a central, proline-rich domain that contains many PXXP motifs for binding to the SH3 domains of signaling molecules such as Grb2 (from which the name “Grb2-associated binding” protein, GAB, comes). It is hypothesized that binding sites in this region may be used in indirect mechanisms pairing the GAB2 protein to receptor tyrosine kinases. It is on the C-terminal tail that the various conserved protein binding motifs and phosphorylation sites of GAB2 are found. GAB2 binds to the SH2 domains of such signaling molecules as SHP2 and PI3K. By binding to the p85 subunit of PI3K, and continuing this signaling pathway GAB provides positive feedback for the creation of PIP3, produced as a result of the PI3K pathway, which binds to GAB2 in the membrane and promotes activation of more PI3Ks. Discovery of multiple binding sites in GAB proteins has led to the N-terminal folding nucleation (NFN) hypothesis for the structure of the disordered region. This theory suggests that the disordered domain is looped back to connect to the N-terminal, structured region several times to make the protein more compact. This would assist in promoting interactions between molecules bound to GAB and resisting degradation.
# Function
GAB2 mediates the interactions between receptor tyrosine kinases (RTK) or non-RTK receptors, such as G protein coupled receptors, cytokine receptors, multichain immune recognition receptors and integrins, and the molecules of the intracellular signaling pathways. By providing a platform to host a wide array of interactions from extracellular inputs to intracellular pathways, GAB proteins can act as a gatekeeper to the cell, modulating and integrating signals as they pass them along, to control the functional state within the cell.
Mutagenesis and Binding assays have helped to identify which molecules and what pathways are downstream of GAB2. The two main pathways of GAB proteins are SHP2 and PI3K. GAB protein binding to SHP2 molecules acts as an activator whose main effect is the activation of the ERK/MAPK pathway. There are also, however, other pathways that are activated by this interaction such as the pathways c-Kit-induced Rac activation and β1-integrin. PI3K activation by GAB2 promotes cell growth.
The effects of all the pathways activated by GAB proteins are not known, but it is easy to see that amplification of signal can progress quickly and these proteins can have large effects on the state of the cell. While not lethal, GAB2 deficient knockout mice do exhibit phenotypic side-effects. These include weak allergic reactions, reduced mast cell growth in bone marrow and osteopetrosis. Knockout mice have also been used to show the importance of GAB2 in maintenance of cardiac function. A paracrine factor, NRG1 β, utilizes GAB2 to activate the ERK and AKT pathways in the heart to produce angiopoietin 1.
# Interactions
The C-terminal tail of GAB2 acts as a site for multiple phosphorylation of tyrosine kinases. It acts as a docking station for the Src homology 2(SH2) domain that is contained in the adaptor protein families Crk, Grb2, and Nck. These adaptor proteins then couple to enzymes to amplify different cellular signals. GAB2 may also bind directly to SH2-containing enzymes, such as PI3K, to produce such signals.
GAB2 has been shown to interact with:
## AKT1
Through the PI3K signaling pathway, PI3K activates the serine/threonine protein kinase (AKT), which in turn through phosphorylation inactivates GSK3. This in turn causes the phosphorylation of tau and amyloid production.
## CRKL
CT10 regulator of kinase (Crk) is also known as the breast cancer anti-oestrogen resistance protein. It plays a role in both fibroblast formation and breast cancer. The YXXP binding motif is required for the association of CRKL and GAB2. This leads to the activation of c-Jun N-terminal kinase(JNK) as part of the JNK signaling pathway.
## Grb2
Upon stimulation by growth hormone, insulin, epidermal growth factor (EFG), etc., the GAB2 protein can be recruited from the cytoplasm to the cell membrane, where it forms a complex with Grb2 and SHC. The interaction between GAB2 and Grb2 requires a PX3RX2KP motif in order to produce a regulatory signal. The activated GAB2 can now recruit SH2 domain-containing molecules, such as SHP2 or PI3K to activate signaling pathways.
## PI3K
The p85 subunit of PI3K (or PIK3) possessed the SH2 domain required to be activated by GAB2. The activation of the PI3K signaling pathway produces increased amyloid production and microglia-mediated inflammation. The immunoglobulin receptor FceRI requires GAB2 as a necessity for mast cells to activate PI3K receptor to create an allergic response. In a study of knockout mice lacking the GAB2 gene, subjects experienced impaired allergic reactions, including passive cutaneous and systemic anaphylaxis. PI3K is found to be mutated in most breast cancer subtypes. Sufficient GAB2 expression by these cancerous subtypes proves necessary in order to sustain a cancerous phenotype.
## PLCG2
The erythropoietin hormone (Epo) is responsible for the regulation and proliferation of erythrocytes. Epo is able to self phosphorylate, which causes recruitment of SH2 proteins. An activated complex of GAB2, SHC, and SHP2 is required for binding of Phospholipase C gamma 2 (PLCG2) through its SH2 domain, which activates PIP3.
## PTPN11
Protein tyrosine phosphatase non-receptor 11 (PTPN11) interaction with GAB2 is part of the Ras pathway. Mutations found in PTPN11 cause disruption in the binding to GAB2, which in turn impairs correct cellular growth. Thirty-five percent of patients diagnosed with JMML show activating mutations in PTPN11.
## RICS
GC-GAP is part of the Rho GTP-ase activating protein family (RICS). It contains a highly proline-rich motifs that allow favorable interactions with GAB2. GC-GAP is responsible for the proliferation of astroglioma cells.
## SHC1
The interaction between GAB2 and Grb2 at the cell membrane recruits another adaptor protein, the Src homology domain-containing transforming protein 1 (SHC1), before being able to recruit SH2 domain-containing molecules.
# Clinical Implications
## Alzheimer's Disease
Ten SNPs of GAB2 have been associated with late-onset Alzheimer's disease (LOAD). However, this association is found only in APOE ε4 carriers. In LOAD brains, GAB2 is overexpressed in neurons, tangle-bearing neurons, and dystrophic neuritis.
GAB2 has been indicated in playing a role in the pathogenesis of Alzheimer's disease via its interaction with tau and amyloid precursor proteins. GAB2 may prevent neuronal tangle formation characteristic of LOAD by reducing phosphorylation of tau protein via the activation of the PI3K signaling pathway, which activates Akt. Akt inactivates Gsk3, which is responsible for tau phosphorylation. Mutations in GAB2 could affect Gsk3-dependent phosphorylation of tau and the formation of neurofibrillary tangles. Interactions between GAB2-Grb2 and APP are enhanced in AD brains, suggesting an involvement of this coupling in the neuropathogenesis of AD.
## Cancer
GAB2 has been linked to the oncogenesis of many cancers including colon, gastric, breast, and ovarian cancer. Studies suggest that GAB2 is used to amplify the signal of many RTKs implicated in breast cancer development and progression.
GAB2 has been particularly characterized for its role in leukemia. In chronic myelogenous leukemia (CML), GAB2 interacts with the Bcr-Abl complex and is instrumental in maintaining the oncogenic properties of the complex. The Grb2/GAB2 complex is recruited to phosphorylated Y177 of the Bcr-Abl complex leading to Bcr-Abl-mediated transformation and leukemogenesis. GAB2 also plays a role in juvenile myelomonocytic leukemia (JMML). Studies have shown the protein’s involvement in the disease via the Ras pathway. In addition, GAB2 appears to play an important role in PTPN11 mutations associated with JMML. | GAB2
GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.[1][2][3][4]
GAB2 is a docking protein with a conserved, folded PH domain attached to the membrane and a large disordered region, which hosts interactions with signaling molecules. It is a member of the GAB/DOS family localized on the internal membrane of the cell. It mediates the interaction between receptor tyrosine kinases (RTKs) and non-RTK receptors serving as the gateway into the cell for activation of SHP2, Phosphatidylinositol 3-kinase (PI3K), Grb2, ERK, and AKT and acting as one of the first steps in these signaling pathways. GAB2 has been shown to be important in physiological functions such as growth in bone marrow and cardiac function. GAB2 has also been associated with many diseases including leukemia and Alzheimer's disease.
# Discovery
GAB proteins were one of the first docking proteins identified in the mammalian signal transduction pathway.[5] GAB2 along with many other adaptor, scaffold, and docking proteins, was discovered in the mid-1990s during the isolation and cloning of protein tyrosine kinase substrates and association partners.[5] GAB2 was initially discovered as a binding protein and substrate of protein tyrosine phosphatase Shp2/PTPN11.[1] Two other groups later cloned GAB2 by searching DNA database for protein with sequence homology to GAB1.[2][3]
# Structure
GAB2 is a large multi-site docking protein (LMD) of about 100kD that has a folded N-terminal domain attached to an extended, disordered C-terminal tail rich in short linear motifs. LMDs are docking proteins that function as platforms mediating interaction between different signaling pathways and assisting with signal integration.[6] The N-terminal is characterized by a Pleckstrin Homology (PH) domain that is the most highly conserved region between all members of the GAB family of proteins. (GAB1, GAB2, GAB3 and GAB4) GAB2 is an Intrinsically disordered protein, meaning that beyond the folded N-terminal region, the C-terminal region extends out into the cytoplasm with little or no secondary structure.[6] The disordered region of the protein however may not be as disordered as was initially expected, as sequencing has revealed significant similarity between the “disordered” regions of GAB orthologs in different species.
The PH domain of GAB2 recognizes phosphatidylinositol 3,4,5-triphosphate(PIP3) in the membrane and is responsible for localizing the GAB protein on the intracellular surface of the membrane and in regions where the cell contacts another cell. Some evidence also suggests that the PH domain plays a role in some signal regulation as well.[7]
Adjacent to the PH domain is a central, proline-rich domain that contains many PXXP motifs for binding to the SH3 domains of signaling molecules such as Grb2 (from which the name “Grb2-associated binding” protein, GAB, comes). It is hypothesized that binding sites in this region may be used in indirect mechanisms pairing the GAB2 protein to receptor tyrosine kinases.[7] It is on the C-terminal tail that the various conserved protein binding motifs and phosphorylation sites of GAB2 are found. GAB2 binds to the SH2 domains of such signaling molecules as SHP2 and PI3K. By binding to the p85 subunit of PI3K, and continuing this signaling pathway GAB provides positive feedback for the creation of PIP3, produced as a result of the PI3K pathway, which binds to GAB2 in the membrane and promotes activation of more PI3Ks. Discovery of multiple binding sites in GAB proteins has led to the N-terminal folding nucleation (NFN) hypothesis for the structure of the disordered region. This theory suggests that the disordered domain is looped back to connect to the N-terminal, structured region several times to make the protein more compact. This would assist in promoting interactions between molecules bound to GAB and resisting degradation.[6]
# Function
GAB2 mediates the interactions between receptor tyrosine kinases (RTK) or non-RTK receptors, such as G protein coupled receptors, cytokine receptors, multichain immune recognition receptors and integrins, and the molecules of the intracellular signaling pathways.[6] By providing a platform to host a wide array of interactions from extracellular inputs to intracellular pathways, GAB proteins can act as a gatekeeper to the cell, modulating and integrating signals as they pass them along, to control the functional state within the cell.[6]
Mutagenesis and Binding assays have helped to identify which molecules and what pathways are downstream of GAB2. The two main pathways of GAB proteins are SHP2 and PI3K. GAB protein binding to SHP2 molecules acts as an activator whose main effect is the activation of the ERK/MAPK pathway. There are also, however, other pathways that are activated by this interaction such as the pathways c-Kit-induced Rac activation and β1-integrin. PI3K activation by GAB2 promotes cell growth.
[5] The effects of all the pathways activated by GAB proteins are not known, but it is easy to see that amplification of signal can progress quickly and these proteins can have large effects on the state of the cell. While not lethal, GAB2 deficient knockout mice do exhibit phenotypic side-effects. These include weak allergic reactions, reduced mast cell growth in bone marrow and osteopetrosis.[6] Knockout mice have also been used to show the importance of GAB2 in maintenance of cardiac function. A paracrine factor, NRG1 β, utilizes GAB2 to activate the ERK and AKT pathways in the heart to produce angiopoietin 1.[5]
# Interactions
The C-terminal tail of GAB2 acts as a site for multiple phosphorylation of tyrosine kinases. It acts as a docking station for the Src homology 2(SH2) domain that is contained in the adaptor protein families Crk, Grb2, and Nck. These adaptor proteins then couple to enzymes to amplify different cellular signals. GAB2 may also bind directly to SH2-containing enzymes, such as PI3K, to produce such signals.[6]
GAB2 has been shown to interact with:
## AKT1
Through the PI3K signaling pathway, PI3K activates the serine/threonine protein kinase (AKT), which in turn through phosphorylation inactivates GSK3. This in turn causes the phosphorylation of tau and amyloid production.[8][9]
## CRKL
CT10 regulator of kinase (Crk) is also known as the breast cancer anti-oestrogen resistance protein.[6] It plays a role in both fibroblast formation and breast cancer. The YXXP binding motif is required for the association of CRKL and GAB2. This leads to the activation of c-Jun N-terminal kinase(JNK) as part of the JNK signaling pathway.[9][10]
## Grb2
Upon stimulation by growth hormone, insulin, epidermal growth factor (EFG), etc., the GAB2 protein can be recruited from the cytoplasm to the cell membrane, where it forms a complex with Grb2 and SHC. The interaction between GAB2 and Grb2 requires a PX3RX2KP motif in order to produce a regulatory signal. The activated GAB2 can now recruit SH2 domain-containing molecules, such as SHP2 or PI3K to activate signaling pathways.[2][8][9][11]
## PI3K
The p85 subunit of PI3K (or PIK3) possessed the SH2 domain required to be activated by GAB2. The activation of the PI3K signaling pathway produces increased amyloid production and microglia-mediated inflammation.[9] The immunoglobulin receptor FceRI requires GAB2 as a necessity for mast cells to activate PI3K receptor to create an allergic response. In a study of knockout mice lacking the GAB2 gene, subjects experienced impaired allergic reactions, including passive cutaneous and systemic anaphylaxis.[12] PI3K is found to be mutated in most breast cancer subtypes. Sufficient GAB2 expression by these cancerous subtypes proves necessary in order to sustain a cancerous phenotype.[6][8][10]
## PLCG2
The erythropoietin hormone (Epo) is responsible for the regulation and proliferation of erythrocytes. Epo is able to self phosphorylate, which causes recruitment of SH2 proteins. An activated complex of GAB2, SHC, and SHP2 is required for binding of Phospholipase C gamma 2 (PLCG2) through its SH2 domain, which activates PIP3.[13]
## PTPN11
Protein tyrosine phosphatase non-receptor 11 (PTPN11) interaction with GAB2 is part of the Ras pathway. Mutations found in PTPN11 cause disruption in the binding to GAB2, which in turn impairs correct cellular growth. Thirty-five percent of patients diagnosed with JMML show activating mutations in PTPN11.[2][8][10][13][14]
## RICS
GC-GAP is part of the Rho GTP-ase activating protein family (RICS). It contains a highly proline-rich motifs that allow favorable interactions with GAB2. GC-GAP is responsible for the proliferation of astroglioma cells.[15]
## SHC1
The interaction between GAB2 and Grb2 at the cell membrane recruits another adaptor protein, the Src homology domain-containing transforming protein 1 (SHC1), before being able to recruit SH2 domain-containing molecules.[8][13][15]
# Clinical Implications
## Alzheimer's Disease
Ten SNPs of GAB2 have been associated with late-onset Alzheimer's disease (LOAD).[16] However, this association is found only in APOE ε4 carriers.[17] In LOAD brains, GAB2 is overexpressed in neurons, tangle-bearing neurons, and dystrophic neuritis.[9][17]
GAB2 has been indicated in playing a role in the pathogenesis of Alzheimer's disease via its interaction with tau and amyloid precursor proteins.[9] GAB2 may prevent neuronal tangle formation characteristic of LOAD by reducing phosphorylation of tau protein via the activation of the PI3K signaling pathway, which activates Akt. Akt inactivates Gsk3, which is responsible for tau phosphorylation.[9] Mutations in GAB2 could affect Gsk3-dependent phosphorylation of tau and the formation of neurofibrillary tangles.[9][17][18] Interactions between GAB2-Grb2 and APP are enhanced in AD brains, suggesting an involvement of this coupling in the neuropathogenesis of AD.[9]
## Cancer
GAB2 has been linked to the oncogenesis of many cancers including colon, gastric, breast, and ovarian cancer.[6][14] Studies suggest that GAB2 is used to amplify the signal of many RTKs implicated in breast cancer development and progression.[5]
GAB2 has been particularly characterized for its role in leukemia. In chronic myelogenous leukemia (CML), GAB2 interacts with the Bcr-Abl complex and is instrumental in maintaining the oncogenic properties of the complex.[6][14][19] The Grb2/GAB2 complex is recruited to phosphorylated Y177 of the Bcr-Abl complex leading to Bcr-Abl-mediated transformation and leukemogenesis.[5] GAB2 also plays a role in juvenile myelomonocytic leukemia (JMML). Studies have shown the protein’s involvement in the disease via the Ras pathway.[14] In addition, GAB2 appears to play an important role in PTPN11 mutations associated with JMML.[14] | https://www.wikidoc.org/index.php/GAB2 | |
5a9936ea14f797fbc8f489e8611ee333ed674565 | wikidoc | GAIL | GAIL
GAIL (India) Limited, is India's largest natural gas transportation company, integrating all aspects of the Natural Gas value chain.
# History
The company (previously known as Gas Authority of India Ltd) is India's principal gas transmission and marketing company, was set up by the Government of India in August 1984 to create gas sector infrastructure.
GAIL commissioned 2800-km Hazira-Vijaipur-Jagdishpur (HVJ) pipeline in 1991. During 1991-93, three LPG plants were constructed and some regional pipelines acquired, enabling GAIL to begin its gas transportation in various parts of India.
GAIL began its city gas distribution in New Delhi in 1997 by setting up nine CNG stations.
In 1999, GAIL set up northern India's only petrochemical plant at Pata.
# Trivia
GAIL is listed by Forbes as one of the world's 2,000 largest public companies in 2007. | GAIL
Template:Infobox Company
GAIL (India) Limited, is India's largest natural gas transportation company, integrating all aspects of the Natural Gas value chain.
# History
The company (previously known as Gas Authority of India Ltd) is India's principal gas transmission and marketing company, was set up by the Government of India in August 1984 to create gas sector infrastructure.
GAIL commissioned 2800-km Hazira-Vijaipur-Jagdishpur (HVJ) pipeline in 1991. During 1991-93, three LPG plants were constructed and some regional pipelines acquired, enabling GAIL to begin its gas transportation in various parts of India.
GAIL began its city gas distribution in New Delhi in 1997 by setting up nine CNG stations.
In 1999, GAIL set up northern India's only petrochemical plant at Pata.
# Trivia
GAIL is listed by Forbes as one of the world's 2,000 largest public companies in 2007. [1] | https://www.wikidoc.org/index.php/GAIL | |
81e57e23660dac3bf361e221436f5393e160adb9 | wikidoc | GAS1 | GAS1
Growth arrest-specific protein 1 is a protein that in humans is encoded by the GAS1 gene.
# Function
Growth arrest-specific 1 plays a role in growth suppression. GAS1 blocks entry to S phase and prevents cycling of normal and transformed cells. Gas1 is a putative tumor suppressor gene.
# Discovery
The mouse cells, which appear the growth-arrested, were observed expression of Growth Arrest Specific-1 gene (GAS1). In 1988, Gas-1 was first defined as one of six genes that block transcriptional up-regulation of the NIH3T3 cell cycle from G0 to S phase. Most of scientist have proved that overexpressed gas1 has the function of inhibiting tumor growth and progression in gliomas. Furthermore, GAS1 gene was also thought to contribute to recurrence and metastasized prediction in colon cancer.
# Gene location of GAS1
GAS-1 gene has been identified as a putative tumor suppressor collocates on chromosome 9q21.3-22.1 where was considered to be a fragile site. In 1994, 29 metaphases were analyzed by Del Sal G et al, and 102 fluorescent signals were observed during the experiment. The results showed that 84 (82%) expression rate of the fluorescent signal on chromosome 9. Furthermore, the peak signal density of the fluorescent also observed occurring in the q21.3-22.1 region. In addition, the inexpression of the fluorescent signal cluster on any other chromosome further demonstrates Gas1 gene specifically expresses on chromosome 9q21.3-22.1.
# GAS1 characteristic
345 amino acids were confirmed to constitute mature Gas-1 gene. Asn117 and an aminated Ser318 are two particular position which result in discovering of the one N-glycosylation site and potential signal peptide, respectively.
## Gene structure
Gas-1 gene has been confirmed to be highly similar to the GFRα1 gene (28% similarity) while the Gas1 only consists of two domains which is different from the GFRα1-3 that composes of three domains. Although the structure of GAS1 gene is similar to GFRαs, the function of GAS1 is largely different from GFRαs since the GAS 1 gene has the ability of binding RET in a ligand independent manner. Since the structure similarity between GAS1 and GFRαs, the ancestor of GFRα proteins was suspected to be the GAS1. In regard to the secondary structure, most of mammalian Gas1 gene’s secondary structure were identified to be mostly α-helical and to have a long unstructured C-terminal domain
# Gene expression
GAS1 protein widespread distributed in adult mammalian CNS ( central nervous system). Adult mouse brain has been described expressing GAS1 mRNA, and the experiment of Natanael Zarco et al further corroborated this description. Western blot analysis is the main method which has been used in their practical and plays an significant role in successfully determining the distribution of the protein in the adult central nervous system (CNS). Olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord has been identified as the specific expression parts of GAS1. Despite the pattern of expression in Astrocyte cells was more limited than in neurons, the gas1 was also found expressing in that part.
# Function
GAS1 was identified as a pleiotropic protein with the function of the cell arrest and apoptosis. Except that, the nervous system and other amount of organs can also be largely influenced by the abnormal Gas1 gene. The reason of this dual function is likely caused by its ability of interacting with the inhibited signaling cascade which induced by GNDF (glial cell-line derived neurotrophic factor). Additionally, GAS1 has been proved can largely influence the developmental state of the organs. During the development stage of the GAS1, it has been suggested that development GAS1 can not only inhibit cell proliferation but also control the cell death as well as growth of the cerebellum. The signal emission of GAS 1 protein associate with two different types of transmembrane receptor protein, including RET and the Hedgehog receptor protein, GAS1 is therefore determined as a kind of multifunctional protein. The Hedgehog signaling pathway is known as an essential part in the body which largely influences the body development, and cancer progression since the Sonic hedgehog can be connected by GAS1 directly, and lead to active of the signaling pathway.
## Associated diseases
### Kidney hypoplasia
The GAS1 gene plays a significant role in Kidney development. Conserved DNA binding motif, which is located in the Gas1 promoter, is directly bind by the WT1, and then the Gas1 mRNA is activated to transcript to the NPCs. The WT1 has been confirmed as a necessary part for expressing Gas1 in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. In humans, fetal period is the most significant time point for inducting a new nephrons, no matter what kind of mammals, once the NPCS disappeared, there is no possibility for inducing the new nephrons.
# Gene mutation
Gas1 gene has been mapped by the method of in situ hybridization to human chromosome bands 9q21.3-q22, a fragile site where frequently deleted in human tumors, especially acute myeloid leukemia and bladder tumors. The deletion region of early superficial bladder cancer indicated that the frequent (50%) deletion of tumor suppressor genes was located between 9q22 and 9p12-13, an area that spanned the GAS1 gene position and could be a starting event for bladder cancer disease. However, a study that has been done by Simoneau et al indicates that there is no mutations in the gas1 gene in 14 primary bladder carcinomas and 10 bladder carcinoma cell lines, which means the mutation of gas1 is not the main reason in causing the pathogenesis. | GAS1
Growth arrest-specific protein 1 is a protein that in humans is encoded by the GAS1 gene.[1][2]
# Function
Growth arrest-specific 1 plays a role in growth suppression. GAS1 blocks entry to S phase and prevents cycling of normal and transformed cells. Gas1 is a putative tumor suppressor gene.[2]
# Discovery
The mouse cells, which appear the growth-arrested, were observed expression of Growth Arrest Specific-1 gene (GAS1)[1]. In 1988, Gas-1 was first defined as one of six genes that block transcriptional up-regulation of the NIH3T3 cell cycle from G0 to S phase[2]. Most of scientist have proved that overexpressed gas1 has the function of inhibiting tumor growth and progression in gliomas. Furthermore, GAS1 gene was also thought to contribute to recurrence and metastasized prediction in colon cancer.
# Gene location of GAS1
GAS-1 gene has been identified as a putative tumor suppressor collocates on chromosome 9q21.3-22.1 where was considered to be a fragile site.[3] In 1994, 29 metaphases were analyzed by Del Sal G et al, and 102 fluorescent signals were observed during the experiment. The results showed that 84 (82%) expression rate of the fluorescent signal on chromosome 9[4]. Furthermore, the peak signal density of the fluorescent also observed occurring in the q21.3-22.1 region.[4] In addition, the inexpression of the fluorescent signal cluster on any other chromosome further demonstrates Gas1 gene specifically expresses on chromosome 9q21.3-22.1.[4]
# GAS1 characteristic
345 amino acids were confirmed to constitute mature Gas-1 gene. Asn117 and an aminated Ser318 are two particular position which result in discovering of the one N-glycosylation site and potential signal peptide, respectively.[5]
## Gene structure
Gas-1 gene has been confirmed to be highly similar to the GFRα1 gene (28% similarity) while the Gas1 only consists of two domains which is different from the GFRα1-3 that composes of three domains.[6] Although the structure of GAS1 gene is similar to GFRαs, the function of GAS1 is largely different from GFRαs since the GAS 1 gene has the ability of binding RET in a ligand independent manner[7]. Since the structure similarity between GAS1 and GFRαs, the ancestor of GFRα proteins was suspected to be the GAS1[7]. In regard to the secondary structure, most of mammalian Gas1 gene’s secondary structure were identified to be mostly α-helical and to have a long unstructured C-terminal domain[6]
# Gene expression
GAS1 protein widespread distributed in adult mammalian CNS ( central nervous system). Adult mouse brain has been described expressing GAS1 mRNA, and the experiment of Natanael Zarco et al further corroborated this description.[8] Western blot analysis is the main method which has been used in their practical and plays an significant role in successfully determining the distribution of the protein in the adult central nervous system (CNS).[8] Olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord has been identified as the specific expression parts of GAS1.[8] Despite the pattern of expression in Astrocyte cells was more limited than in neurons, the gas1 was also found expressing in that part.
# Function
GAS1 was identified as a pleiotropic protein with the function of the cell arrest and apoptosis. Except that, the nervous system and other amount of organs can also be largely influenced by the abnormal Gas1 gene. The reason of this dual function is likely caused by its ability of interacting with the inhibited signaling cascade which induced by GNDF (glial cell-line derived neurotrophic factor)[8]. Additionally, GAS1 has been proved can largely influence the developmental state of the organs.[9] During the development stage of the GAS1, it has been suggested that development GAS1 can not only inhibit cell proliferation but also control the cell death as well as growth of the cerebellum.[5] The signal emission of GAS 1 protein associate with two different types of transmembrane receptor protein, including RET and the Hedgehog receptor protein[10], GAS1 is therefore determined as a kind of multifunctional protein. The Hedgehog signaling pathway is known as an essential part in the body which largely influences the body development, and cancer progression since the Sonic hedgehog can be connected by GAS1 directly, and lead to active of the signaling pathway.[11]
## Associated diseases
### Kidney hypoplasia
The GAS1 gene plays a significant role in Kidney development. Conserved DNA binding motif, which is located in the Gas1 promoter, is directly bind by the WT1, and then the Gas1 mRNA is activated to transcript to the NPCs.[12] The WT1 has been confirmed as a necessary part for expressing Gas1 in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs.[12] In humans, fetal period is the most significant time point for inducting a new nephrons, no matter what kind of mammals, once the NPCS disappeared, there is no possibility for inducing the new nephrons.[12]
# Gene mutation
Gas1 gene has been mapped by the method of in situ hybridization to human chromosome bands 9q21.3-q22[4], a fragile site where frequently deleted in human tumors, especially acute myeloid leukemia and bladder tumors.[13] The deletion region of early superficial bladder cancer indicated that the frequent (50%) deletion of tumor suppressor genes was located between 9q22 and 9p12-13, an area that spanned the GAS1 gene position and could be a starting event for bladder cancer disease.[14] However, a study that has been done by Simoneau et al indicates that there is no mutations in the gas1 gene in 14 primary bladder carcinomas and 10 bladder carcinoma cell lines, which means the mutation of gas1 is not the main reason in causing the pathogenesis. | https://www.wikidoc.org/index.php/GAS1 | |
1fdefb0f807c72357cffb7ac510d97918f7912ab | wikidoc | GAS5 | GAS5
Growth arrest-specific 5 is a non-protein coding RNA that in humans is encoded by the GAS5 gene.
GAS5 noncoding RNA, which accumulates in growth arrested cells, acts as a decoy hormone response element for the glucocorticoid receptor (GR) and hence blocks the upregulation of gene expression by activated GR.
A number of studies have linked GAS5 to apoptosis and it may play a role in the progression of some types of cancer.
The GAS5 introns host several snoRNA sequences, including SNORD81, SNORD47, SNORD80, SNORD79, SNORD78, SNORD44, SNORD77, SNORD76, SNORD75 and SNORD74. These intronic sequences are more conserved than the exons of the host gene, these sorts of genes are often called "inside-out genes".
It was recently discovered that the nonsense-mediated degradation pathway can regulate the function of the GAS5 in mammalian cells.
# Transcriptions
GeneID: 60674 GAS5 growth arrest specific 5 (non-protein coding). "This gene produces a spliced long non-coding RNA and is a member of the 5' terminal oligo-pyrimidine class of genes. It is a small nucleolar RNA host gene, containing multiple C/D box snoRNA genes in its introns. Part of the secondary RNA structure of the encoded transcript mimics glucocorticoid response element (GRE) which means it can bind to the DNA binding domain of the glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1). This action blocks the glucocorticoid receptor from being activated and thereby stops it from regulating the transcription of its target genes. This transcript is also thought to regulate the transcriptional activity of other receptors, such as androgen, progesterone and mineralocorticoid receptors, that can bind to its GRE mimic region. Multiple functions have been associated with this transcript, including cellular growth arrest and apoptosis. It has also been identified as a potential tumor suppressor, with its down-regulation associated with cancer in multiple different tissues." | GAS5
Associate Editor(s)-in-Chief: Henry A. Hoff
Growth arrest-specific 5 is a non-protein coding RNA that in humans is encoded by the GAS5 gene.[1][2]
GAS5 noncoding RNA, which accumulates in growth arrested cells, acts as a decoy hormone response element for the glucocorticoid receptor (GR) and hence blocks the upregulation of gene expression by activated GR.[3][4]
A number of studies have linked GAS5 to apoptosis and it may play a role in the progression of some types of cancer.[5][6][7]
The GAS5 introns host several snoRNA sequences, including SNORD81, SNORD47, SNORD80, SNORD79, SNORD78, SNORD44, SNORD77, SNORD76, SNORD75 and SNORD74.[2][8][9][10] These intronic sequences are more conserved than the exons of the host gene, these sorts of genes are often called "inside-out genes".[11]
It was recently discovered that the nonsense-mediated degradation pathway can regulate the function of the GAS5 in mammalian cells.[12]
# Transcriptions
GeneID: 60674 GAS5 growth arrest specific 5 (non-protein coding). "This gene produces a spliced long non-coding RNA and is a member of the 5' terminal oligo-pyrimidine class of genes. It is a small nucleolar RNA host gene, containing multiple C/D box snoRNA genes in its introns. Part of the secondary RNA structure of the encoded transcript mimics glucocorticoid response element (GRE) which means it can bind to the DNA binding domain of the glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1). This action blocks the glucocorticoid receptor from being activated and thereby stops it from regulating the transcription of its target genes. This transcript is also thought to regulate the transcriptional activity of other receptors, such as androgen, progesterone and mineralocorticoid receptors, that can bind to its GRE mimic region. Multiple functions have been associated with this transcript, including cellular growth arrest and apoptosis. It has also been identified as a potential tumor suppressor, with its down-regulation associated with cancer in multiple different tissues."[13] | https://www.wikidoc.org/index.php/GAS5 | |
107ec63dd4eb7fbd66288c701f43fec2d5804680 | wikidoc | GAS6 | GAS6
Growth arrest-specific 6, also known as GAS6, is a human gene coding for the Gas6 protein. It is similar to the Protein S with the same domain organization and 43% amino acid identity. It was originally found as a gene upregulated by growth arrested fibroblasts.
# Function
Gas6 is a gamma-carboxyglutamic acid (Gla) domain-containing protein thought to be involved in the stimulation of cell proliferation.
# Interactions
Gas6 has been shown to interact with AXL receptor tyrosine kinase, MerTK and TYRO3.
The presence of Gla needs a vitamin K-dependent enzymatic reaction that carboxylates the gamma carbon of certain glutamic residues of the protein during its production in the endoplasmic reticulum. | GAS6
Growth arrest-specific 6, also known as GAS6, is a human gene coding for the Gas6 protein. It is similar to the Protein S with the same domain organization and 43% amino acid identity. It was originally found as a gene upregulated by growth arrested fibroblasts.
# Function
Gas6 is a gamma-carboxyglutamic acid (Gla) domain-containing protein thought to be involved in the stimulation of cell proliferation.[1]
# Interactions
Gas6 has been shown to interact with AXL receptor tyrosine kinase, MerTK and TYRO3.[2][3]
The presence of Gla needs a vitamin K-dependent enzymatic reaction that carboxylates the gamma carbon of certain glutamic residues of the protein during its production in the endoplasmic reticulum. | https://www.wikidoc.org/index.php/GAS6 | |
6d87d55c3aa9a88e0c6b448528eba308e6bcd294 | wikidoc | GBP2 | GBP2
Interferon-induced guanylate-binding protein 2 is a protein that in humans is encoded by the GBP2 gene. GBP2 is a gene related to the superfamily of large GTPases which can be induced mainly by interferon gamma.
# Localization
GBP2 gene is located in a various compartment in the cell: nucleus, cytosol and cytoskeleton and also the dimer GBP2-GBP5 localise to the Golgi apparatus.
In addition ,the Isoprenylation is required to regulate the intracellular localization and the membrane association of GBP2.
# Activation
The murine GBP2 gene is not just highly activated by the interferon-gamma during macrophages activation but also by the stimulation of Toll-like receptors, Tumor necrosis factor (TNF) and Interleukin 1 beta.
# Expression
After the stimulation of interferon gamma, GPB2 murine is expressed in the innate and adaptive immune cells.
# Structure
Sequence analysis of GBP2 showed the presence of an RNA binding domain which comprises a three RNA recognition motifs (RRM) and SR domain. The amino terminus of GBp2 shares a four Arg-Gly-Gly (RGG) repeat motifs and nine serine residues in the context of arginine/serine motifs.
The SR domain of GBP2 is a phosphorylation site for SR specific protein kinase SRPK (sky1) which lead a nuclear localization of GBP2.
The porcine GBP2 present a high similarity regarding the N-terminal which present a globular domain and contain the GTPase function. However, the C-terminal present a helical domain which is less conserved.
# Interaction
GBP2 gene can interact with the RNA via the domain RRM1 and RRM2. The RRM2 domain can recognize the core motif GGUC present in the RNA. Besides, a new type of RRM domain are identified and can interact with THO/TREX complex.
GBp2 gene can cooperate with TREX (transcription- export) complex; a multimeric complex has different transcription factor and exports factors such as Yra1 and Sub2.
# Function
Interferons are cytokines that have antiviral effects and inhibit tumor cell proliferation. They induce a large number of genes in their target cells, including those coding for the guanylate-binding proteins (GBPs). GBPs are characterized by their ability to specifically bind guanine nucleotides (GMP, GDP, and GTP). The protein encoded by this gene is a GTPase that converts GTP to GDP and GMP. In addition, GBP2 gene can be a relationship between cell surface receptor and intracellular effectors which can transmit extracellular information into the cells as well as an intracellular signal transduction protein.
A study on the bovine GBP2 gene showed the importance of GBP2 in the regulation of cell proliferation and the resistance to the pathogen infection such as an Exhibition of antiviral activity against influenza virus.
GPB2 Promote an oxidative killing and deliver antimicrobial peptides to autophagolysosomal, providing broad host protection against different pathogen classes. During a viral infection, GBPs Family(GBP1, GBP2 and GBP5) play a vital role to activate canonical and non-canonical inflammasome to response to a pathogen infection via chlamydia muridarum.
# Clinical significance
## Gene Mutation
A missense mutation of the GBP2 (A907G) has been identified in patients of a migraine. In the first step can lead to vasomotor dysfunction and then headaches.
## Breast cancer
GBP2 is considered as a control factor for the proliferation and spreading in the tumor cell. The high expression of GBP2 is associated with a better diagnosis of breast cancer. P53 can upregulate GBP2 and play an essential role in the tumor development by inhibition of metalloproteinase MM9 as well as NF-Kappa B and Rac protein.
The transcriptional level of GBP2 is also regulated by two transcription factor STAT1 and IRF1. GBP2 expression have a strong correlation with T cell metagene which seems an association with the infiltration of T cell in the breast cancer.
However, a recent study showed that GBP2 can regulate dynamin-related protein 1 (Drp1) to block the translocation of Drp1 to the mitochondria which lead to an attenuation of the Drp1 dependent mitochondrial fission and also an invasion of breast cancer cells. | GBP2
Interferon-induced guanylate-binding protein 2 is a protein that in humans is encoded by the GBP2 gene.[1][2] GBP2 is a gene related to the superfamily of large GTPases which can be induced mainly by interferon gamma.[3]
# Localization
GBP2 gene is located in a various compartment in the cell: nucleus, cytosol and cytoskeleton and also the dimer GBP2-GBP5 localise to the Golgi apparatus.[4]
In addition ,the Isoprenylation is required to regulate the intracellular localization and the membrane association of GBP2.[5]
# Activation
The murine GBP2 gene is not just highly activated by the interferon-gamma during macrophages activation but also by the stimulation of Toll-like receptors, Tumor necrosis factor (TNF) and Interleukin 1 beta.[6]
# Expression
After the stimulation of interferon gamma, GPB2 murine is expressed in the innate and adaptive immune cells.[7]
# Structure
Sequence analysis of GBP2 showed the presence of an RNA binding domain which comprises a three RNA recognition motifs (RRM) and SR domain. The amino terminus of GBp2 shares a four Arg-Gly-Gly (RGG) repeat motifs and nine serine residues in the context of arginine/serine motifs.[8]
The SR domain of GBP2 is a phosphorylation site for SR specific protein kinase SRPK (sky1) which lead a nuclear localization of GBP2.[8]
The porcine GBP2 present a high similarity regarding the N-terminal which present a globular domain and contain the GTPase function. However, the C-terminal present a helical domain which is less conserved.[9]
# Interaction
GBP2 gene can interact with the RNA via the domain RRM1 and RRM2. The RRM2 domain can recognize the core motif GGUC present in the RNA. Besides, a new type of RRM domain are identified and can interact with THO/TREX complex.[10]
GBp2 gene can cooperate with TREX (transcription- export) complex; a multimeric complex has different transcription factor and exports factors such as Yra1 and Sub2.[10]
# Function
Interferons are cytokines that have antiviral effects and inhibit tumor cell proliferation. They induce a large number of genes in their target cells, including those coding for the guanylate-binding proteins (GBPs). GBPs are characterized by their ability to specifically bind guanine nucleotides (GMP, GDP, and GTP). The protein encoded by this gene is a GTPase that converts GTP to GDP and GMP.[2] In addition, GBP2 gene can be a relationship between cell surface receptor and intracellular effectors which can transmit extracellular information into the cells as well as an intracellular signal transduction protein.[11]
A study on the bovine GBP2 gene showed the importance of GBP2 in the regulation of cell proliferation and the resistance to the pathogen infection such as an Exhibition of antiviral activity against influenza virus.[7]
GPB2 Promote an oxidative killing and deliver antimicrobial peptides to autophagolysosomal, providing broad host protection against different pathogen classes. During a viral infection, GBPs Family(GBP1, GBP2 and GBP5) play a vital role to activate canonical and non-canonical inflammasome to response to a pathogen infection via chlamydia muridarum.[12]
# Clinical significance
## Gene Mutation
A missense mutation of the GBP2 (A907G) has been identified in patients of a migraine. In the first step can lead to vasomotor dysfunction and then headaches.[11]
## Breast cancer
GBP2 is considered as a control factor for the proliferation and spreading in the tumor cell. The high expression of GBP2 is associated with a better diagnosis of breast cancer. P53 can upregulate GBP2 and play an essential role in the tumor development by inhibition of metalloproteinase MM9 as well as NF-Kappa B and Rac protein.[13]
The transcriptional level of GBP2 is also regulated by two transcription factor STAT1 and IRF1. GBP2 expression have a strong correlation with T cell metagene which seems an association with the infiltration of T cell in the breast cancer.[13]
However, a recent study showed that GBP2 can regulate dynamin-related protein 1 (Drp1) to block the translocation of Drp1 to the mitochondria which lead to an attenuation of the Drp1 dependent mitochondrial fission and also an invasion of breast cancer cells.[14] | https://www.wikidoc.org/index.php/GBP2 | |
d8903d80ef9035414d3147467a2c7e54f5bc7910 | wikidoc | GBX2 | GBX2
Homeobox protein GBX-2 is a protein that in humans is encoded by the GBX2 gene.
# Function
Gastrulation Brain Homeobox 2 (GBX2) is a homeobox gene involved in the normal development of rhombomeres 1-3 which is the mid/hindbrain region. This gene is a dosage dependent transcription factor involved in the regulation of proper expression of other genes. GBX2 expression occurs during gastrulation and continues to be expressed in the later stages of embryogenesis. During these different stages, GBX2 is responsible for several important processes. In the neural plate stage GBX2 is required in order for the anterior hindbrain precursors to survive and form correctly. Also at this stage in development GBX2 is required for the proper regulation of different gene expression needed for the early establishment of A/P patterning in the neural plate. In the early stages of brain morphogenesis GBX2 is required for both the normal development of the anterior hindbrain and the proper formation of the mid/hindbrain organizer. Because of the effects on the mid/hindbrain organizer, GBX2 is involved in the positioning of the expression domain for isthmic FGF8. Since this is a dosage dependent gene, the different amounts of gene present in certain location can cause different outcomes. FGF8 is affected by the different dosages in the location it is expressed. The absence of GBX2 causes FGF8 expression is shifted caudally and over expression of GBX2 causes FGF8 expression to be shifted rostrally. Not all of the rhombomeres GBX2 is expressed in require the same strictness of dose regulation. Of the three, rhombomere 2 has the most strict dose requirements.
# Animal studies
Knockout of the GBX2 gene causes the failure of many structures to form, such as the isthmic nuclei, the cerebellum, motor nerve V and many other derivatives of rhombomeres 1-3. GBX2 gene knockout embryos will continue to develop and will reach full term pregnancy. The babies are born but if there is a lack of GBX2 expression all will die soon after birth.
Knockdown of the gbx2 gene leads to a truncated anterior hindbrain as well as abnormal clusters of cell bodies in r2 and r3 which are associated with problems in cranial nerve V. It has been shown that any structures derived from r1-r3 will be adversely affected by mutations or deficiencies in gbx2. These structures include the aortic arch and right Subclavian artery which, when improperly developed, can lead to cardiovascular defects in addition to craniofacial defects from improper development of cranial nerve V. | GBX2
Homeobox protein GBX-2 is a protein that in humans is encoded by the GBX2 gene.[1][2][3]
# Function
Gastrulation Brain Homeobox 2 (GBX2) is a homeobox gene involved in the normal development of rhombomeres 1-3 which is the mid/hindbrain region. This gene is a dosage dependent transcription factor involved in the regulation of proper expression of other genes. GBX2 expression occurs during gastrulation and continues to be expressed in the later stages of embryogenesis. During these different stages, GBX2 is responsible for several important processes. In the neural plate stage GBX2 is required in order for the anterior hindbrain precursors to survive and form correctly. Also at this stage in development GBX2 is required for the proper regulation of different gene expression needed for the early establishment of A/P patterning in the neural plate. In the early stages of brain morphogenesis GBX2 is required for both the normal development of the anterior hindbrain and the proper formation of the mid/hindbrain organizer. Because of the effects on the mid/hindbrain organizer, GBX2 is involved in the positioning of the expression domain for isthmic FGF8. Since this is a dosage dependent gene, the different amounts of gene present in certain location can cause different outcomes. FGF8 is affected by the different dosages in the location it is expressed. The absence of GBX2 causes FGF8 expression is shifted caudally and over expression of GBX2 causes FGF8 expression to be shifted rostrally. Not all of the rhombomeres GBX2 is expressed in require the same strictness of dose regulation. Of the three, rhombomere 2 has the most strict dose requirements.
# Animal studies
Knockout of the GBX2 gene causes the failure of many structures to form, such as the isthmic nuclei, the cerebellum, motor nerve V and many other derivatives of rhombomeres 1-3. GBX2 gene knockout embryos will continue to develop and will reach full term pregnancy. The babies are born but if there is a lack of GBX2 expression all will die soon after birth.[4][5]
Knockdown of the gbx2 gene leads to a truncated anterior hindbrain as well as abnormal clusters of cell bodies in r2 and r3 which are associated with problems in cranial nerve V. It has been shown that any structures derived from r1-r3 will be adversely affected by mutations or deficiencies in gbx2. These structures include the aortic arch and right Subclavian artery which, when improperly developed, can lead to cardiovascular defects in addition to craniofacial defects from improper development of cranial nerve V.[6] | https://www.wikidoc.org/index.php/GBX2 | |
fcf97f6a073c4940d4105ac6f806ff5efe5da510 | wikidoc | GCLC | GCLC
Glutamate—cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the GCLC gene.
# Function
Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. The gene encoding the catalytic subunit encodes a protein of 367 amino acids with a calculated molecular weight of 72.773 kDa and maps to chromosome 6. The regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Deficiency of gamma-glutamylcysteine synthetase in human is associated with enzymopathic hemolytic anemia.
# Model organisms
Model organisms have been used in the study of GCLC function. A conditional knockout mouse line, called Gclctm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed. | GCLC
Glutamate—cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the GCLC gene.[1][2]
# Function
Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. The gene encoding the catalytic subunit encodes a protein of 367 amino acids with a calculated molecular weight of 72.773 kDa and maps to chromosome 6. The regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Deficiency of gamma-glutamylcysteine synthetase in human is associated with enzymopathic hemolytic anemia.[2]
# Model organisms
Model organisms have been used in the study of GCLC function. A conditional knockout mouse line, called Gclctm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[5] | https://www.wikidoc.org/index.php/GCLC | |
4b9b1210ca38d7a27a5aa5113589c457ac4484cf | wikidoc | GCS1 | GCS1
Mannosyl-oligosaccharide glucosidase is an enzyme that in humans is encoded by the MOGS gene.
Glucosidase I is the first enzyme in the N-linked oligosaccharide processing pathway. GCS1 cleaves the distal alpha-1,2-linked glucose residue from the Glc(3)-Man(9)-GlcNAc(2) oligosaccharide precursor. GCS1 is located in the lumen of the endoplasmic reticulum.
GCS1 may also refer to "generative cell specific 1", also called HAP2 (hapless2), a gene of lower eukaryotes which is thought to be responsible for gametes fusion . | GCS1
Mannosyl-oligosaccharide glucosidase is an enzyme that in humans is encoded by the MOGS gene.[1][2][3]
Glucosidase I is the first enzyme in the N-linked oligosaccharide processing pathway. GCS1 cleaves the distal alpha-1,2-linked glucose residue from the Glc(3)-Man(9)-GlcNAc(2) oligosaccharide precursor. GCS1 is located in the lumen of the endoplasmic reticulum.[3]
GCS1 may also refer to "generative cell specific 1", also called HAP2 (hapless2), a gene of lower eukaryotes which is thought to be responsible for gametes fusion .[4]
. | https://www.wikidoc.org/index.php/GCS1 | |
dc6cdb316f94781c4af81b3f04c362dfd6969379 | wikidoc | GCSH | GCSH
Glycine cleavage system H protein, mitochondrial (abbreviated as GCSH) is a protein that in humans is encoded by the GCSH gene. Degradation of glycine is brought about by the glycine cleavage system (GCS), which is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein; this protein), T protein (a tetrahydrofolate-requiring aminomethyltransferase enzyme), and L protein (a lipoamide dehydrogenase). The H protein shuttles the methylamine group of glycine from the P protein to the T protein. The protein encoded by GCSH gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding,have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.
# Function
The glycine cleavage system (GCS) is the major physiological pathway for glycine degradation in mammals and is confined to mitochondria of the liver, kidney, small intestine, pituitary, thyroid glands, and brain. The P-protein is a pyridoxal phosphate-dependent glycine decarboxylase that transfers the methylamine moiety of glycine to one of the thiol groups in the lipoyl component of H-protein, a hydrogen-carrier protein and the second component of the complex. The T-protein catalyzes the release of ammonia and transfer of the one-carbon fragment from the intermediate lipoyl residue to tetrahydrofolate, while the L-protein, a lipoamide dehydrogenase, catalyzes the oxidation of the dihydrolipoyl residue of H-protein and reduction of NAD.
# Structure
## Gene
Human GCSH gene has 5 exons spanning 13.5kb and resides on chromosome 16 at q23.2.
## Protein
The GCSH is a heat-stable small protein with a covalently attached lipoic acid prosthetic group which interacts with the three enzymes during the catalysis. The chemically determined amino acid sequence revealed that chicken H-protein is composed of 125 amino acids with a lipoic acid prosthetic group at lysine 59 (Lys59). Because of its restricted tissue expression in humans, H-protein purified from chicken liver has been routinely used for the assay. The H-protein comprises a mitochondrial targeting sequence and a mature mitochondrial matrix protein sequence. Its activation in vivo requires the attachment of a lipoic acid prosthetic group at Lys59 of the mature protein. The matrix protein sequence is highly conserved and chicken H-protein has 85.6% amino acid sequence similarity to the human form.
# Clinical significance
Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism caused by deficiency in the glycine cleavage system (GCS). Enzymatic analysis has identified three metabolic lesions in NKH, deficiencies of P-, T-, and H-proteins. The first mutation identified in NKH was in the P-protein gene. Subsequently, some patients were found to have mutations in the T-protein gene. The structure, polymorphism, and expression of GCSH could facilitate the molecular analysis of patients with variant forms of NKH that are caused by H-protein deficiency.
# Interactions
GCSH has been shown to interact with the other glycine cleavage system protein components: P protein, T protein and L protein. | GCSH
Glycine cleavage system H protein, mitochondrial (abbreviated as GCSH) is a protein that in humans is encoded by the GCSH gene.[1][2][3] Degradation of glycine is brought about by the glycine cleavage system (GCS), which is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein; this protein), T protein (a tetrahydrofolate-requiring aminomethyltransferase enzyme), and L protein (a lipoamide dehydrogenase).[3] The H protein shuttles the methylamine group of glycine from the P protein to the T protein. The protein encoded by GCSH gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein.[4] Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[5] Two transcript variants, one protein-coding and the other probably not protein-coding,have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.[6]
# Function
The glycine cleavage system (GCS) is the major physiological pathway for glycine degradation in mammals and is confined to mitochondria of the liver, kidney, small intestine, pituitary, thyroid glands, and brain.[7] The P-protein is a pyridoxal phosphate-dependent glycine decarboxylase that transfers the methylamine moiety of glycine to one of the thiol groups in the lipoyl component of H-protein, a hydrogen-carrier protein and the second component of the complex. The T-protein catalyzes the release of ammonia and transfer of the one-carbon fragment from the intermediate lipoyl residue to tetrahydrofolate, while the L-protein, a lipoamide dehydrogenase, catalyzes the oxidation of the dihydrolipoyl residue of H-protein and reduction of NAD.[8]
# Structure
## Gene
Human GCSH gene has 5 exons spanning 13.5kb and resides on chromosome 16 at q23.2.[4]
## Protein
The GCSH is a heat-stable small protein with a covalently attached lipoic acid prosthetic group which interacts with the three enzymes during the catalysis. The chemically determined amino acid sequence revealed that chicken H-protein is composed of 125 amino acids with a lipoic acid prosthetic group at lysine 59 (Lys59).[2] Because of its restricted tissue expression in humans, H-protein purified from chicken liver has been routinely used for the assay.[9] The H-protein comprises a mitochondrial targeting sequence and a mature mitochondrial matrix protein sequence. Its activation in vivo requires the attachment of a lipoic acid prosthetic group at Lys59 of the mature protein.[4] The matrix protein sequence is highly conserved and chicken H-protein has 85.6% amino acid sequence similarity to the human form.[10]
# Clinical significance
Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism caused by deficiency in the glycine cleavage system (GCS).[11] Enzymatic analysis has identified three metabolic lesions in NKH, deficiencies of P-, T-, and H-proteins.[6] The first mutation identified in NKH was in the P-protein gene.[12] Subsequently, some patients were found to have mutations in the T-protein gene.[13] The structure, polymorphism, and expression of GCSH could facilitate the molecular analysis of patients with variant forms of NKH that are caused by H-protein deficiency.[4]
# Interactions
GCSH has been shown to interact with the other glycine cleavage system protein components: P protein, T protein and L protein.[4][6] | https://www.wikidoc.org/index.php/GCSH | |
14262c9a7e600600726123832a48d6127bedd667 | wikidoc | GDF2 | GDF2
Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.
# Structure
GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminal transforming growth factor beta superfamily domain (325–428). GDF2 (BMP9) is secreted as a pro-complex consisting of the BMP9 growth factor dimer non-covalently bound to two BMP9 prodomain molecules in an open-armed conformation.
# Function
GDF2 has a role in inducing and maintaining the ability of embryonic basal forebrain cholinergic neurons (BFCN) to respond to a neurotransmitter called acetylcholine; BFCN are important for the processes of learning, memory and attention. GDF2 is also important for the maturation of BFCN. Another role of GDF2 has been recently suggested. GDF2 is a potent inducer of hepcidin (a cationic peptide that has antimicrobial properties) in liver cells (hepatocytes) and can regulate iron metabolism. The physiological receptor of GDF2 is thought to be activin receptor-like kinase 1, ALK1 (also called ACVRL1), an endothelial-specific type I receptor of the TGF-beta receptor family. Endoglin, a type I membrane glycoprotein that forms the TGF-beta receptor complex, is a co-receptor of ALK1 for GDF2/BMP-9 binding. Mutations in ALK1 and endoglin cause hereditary hemorrhagic telangiectasia (HHT), a rare but life-threatening genetic disorder that leads to abnormal blood vessel formation in multiple tissues and organs of the body.
GDF2 is one of the most potent BMPs to induce orthotopic bone formation in vivo. BMP3, a blocker of most BMPs seems not to affect GDF2.
GDF2 induces the differentiation of mesenchymal stem cells (MSCs) to an osteoblast lineage. The Smad signaling pathway of GDF2 target HEY1 inducing the differentiation by up regulating it. Augmented expression of HEY1 increase the mineralization of the cells. RUNX2 is another factor who's up regulate by GDF2. This factor is known to be essential for osteoblastic differentiation.
# Interactions
The signaling complex for bone morphogenetic proteins (BMP) start with a ligand binding with a high affinty type I receptor (ALK1-7) followed by the recruitment of a type II receptor(ActRIIA, ActRIIB, BMPRII). The first receptor kinase domain is then trans-phosphorylated by the apposed, activating type II receptor kinase domain. GDF2 binds ALK1 and ActRIIB with the highest affinity in the BMPs, it also binds, with a lower affinity ALK2, also known has Activin A receptor, type I (ACVR1), and the other type II receptors BMPRII and ActRIIA. GDF2 and BMP10 are the only ligands from the TGF-β superfamily that can bind to both type I and II receptors with equally high affinity. This non-discriminative formation of the signaling complex open the possibility of a new mechanism. In cell type with low expression level of ActRIIB, GDF2 might still signal due to its affinity to ALK1, then form complex with type II receptors.
# Associate Disease
Mutations in GDF2 have been identified in patients with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia.
# Signaling
Like other BMPs, GDF2 binding to its receptors triggers the phosphorylation of the R-Smads, Smad1,5,8. The activation of this pathway has been documented in all cellular types analyzed up to date, including hepatocytes and HCC cells. GDF2 also triggers Smad-2/Smad-3 phosphorylation in different endothelial cell types.
Another pathway for GDF2 is the induced non-canonical one. Little is known about this type of pathway in GDF2. GDF2 activate JNK in osteogenic differentiation of mesenchymal progenitor cells (MPCs). GDF2 also triggers p38 and ERK activation who will modulate de Smad pathway, p38 increase the phosphorylation of Smad 1,5,8 by GDF2 whereas ERK has the opposite effect.
The transcriptional factor p38 activation induced by GDF2 has been documented in other cell types such as osteosarcoma cells, human osteoclasts derived from cord blood monocytes, and dental follicle stem cells. | GDF2
Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene.[1] GDF2 belongs to the transforming growth factor beta superfamily.
# Structure
GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminal transforming growth factor beta superfamily domain (325–428).[2] GDF2 (BMP9) is secreted as a pro-complex consisting of the BMP9 growth factor dimer non-covalently bound to two BMP9 prodomain molecules in an open-armed conformation.[3]
# Function
GDF2 has a role in inducing and maintaining the ability of embryonic basal forebrain cholinergic neurons (BFCN) to respond to a neurotransmitter called acetylcholine; BFCN are important for the processes of learning, memory and attention.[4] GDF2 is also important for the maturation of BFCN.[4] Another role of GDF2 has been recently suggested. GDF2 is a potent inducer of hepcidin (a cationic peptide that has antimicrobial properties) in liver cells (hepatocytes) and can regulate iron metabolism.[5] The physiological receptor of GDF2 is thought to be activin receptor-like kinase 1, ALK1 (also called ACVRL1), an endothelial-specific type I receptor of the TGF-beta receptor family.[6] Endoglin, a type I membrane glycoprotein that forms the TGF-beta receptor complex, is a co-receptor of ALK1 for GDF2/BMP-9 binding. Mutations in ALK1 and endoglin cause hereditary hemorrhagic telangiectasia (HHT), a rare but life-threatening genetic disorder that leads to abnormal blood vessel formation in multiple tissues and organs of the body.[7]
GDF2 is one of the most potent BMPs to induce orthotopic bone formation in vivo. BMP3, a blocker of most BMPs seems not to affect GDF2.[8]
GDF2 induces the differentiation of mesenchymal stem cells (MSCs) to an osteoblast lineage. The Smad signaling pathway of GDF2 target HEY1 inducing the differentiation by up regulating it.[9] Augmented expression of HEY1 increase the mineralization of the cells. RUNX2 is another factor who's up regulate by GDF2. This factor is known to be essential for osteoblastic differentiation.[10]
# Interactions
The signaling complex for bone morphogenetic proteins (BMP) start with a ligand binding with a high affinty type I receptor (ALK1-7) followed by the recruitment of a type II receptor(ActRIIA, ActRIIB, BMPRII). The first receptor kinase domain is then trans-phosphorylated by the apposed, activating type II receptor kinase domain.[11] GDF2 binds ALK1 and ActRIIB with the highest affinity in the BMPs, it also binds, with a lower affinity ALK2, also known has Activin A receptor, type I (ACVR1), and the other type II receptors BMPRII and ActRIIA.[11][12] GDF2 and BMP10 are the only ligands from the TGF-β superfamily that can bind to both type I and II receptors with equally high affinity.[11] This non-discriminative formation of the signaling complex open the possibility of a new mechanism. In cell type with low expression level of ActRIIB, GDF2 might still signal due to its affinity to ALK1, then form complex with type II receptors.[11]
# Associate Disease
Mutations in GDF2 have been identified in patients with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia.[13]
# Signaling
Like other BMPs, GDF2 binding to its receptors triggers the phosphorylation of the R-Smads, Smad1,5,8. The activation of this pathway has been documented in all cellular types analyzed up to date, including hepatocytes and HCC cells.[14][15] GDF2 also triggers Smad-2/Smad-3 phosphorylation in different endothelial cell types.[16][17]
Another pathway for GDF2 is the induced non-canonical one. Little is known about this type of pathway in GDF2. GDF2 activate JNK in osteogenic differentiation of mesenchymal progenitor cells (MPCs). GDF2 also triggers p38 and ERK activation who will modulate de Smad pathway, p38 increase the phosphorylation of Smad 1,5,8 by GDF2 whereas ERK has the opposite effect.[17]
The transcriptional factor p38 activation induced by GDF2 has been documented in other cell types such as osteosarcoma cells,[18] human osteoclasts derived from cord blood monocytes,[19] and dental follicle stem cells.[20] | https://www.wikidoc.org/index.php/GDF2 | |
c52f86f199cdff26bed7a10744f55592ff4a9e17 | wikidoc | GDF3 | GDF3
Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 (found in frogs) and GDF1.
# Tissue distribution
Expression of GDF3 occurs in ossifying bone during embryonic development and in the brain, thymus, spleen, bone marrow and adipose tissue of adults.
# Function
GDF3 is a bi-functional protein that has some intrinsic activity and also modulate other TGF-β superfamily members, e.g. potentiates the activity of NODAL. It may also inhibit other TGF-β superfamily members (i.e. BMPs), thus regulating the balance between different modes of TGF-beta signaling. It has been shown to negatively and positively control differentiation of embryonic stem cells in mice and humans. This molecule plays a role in mesoderm and definitive endoderm formation during the pre-gastrulation stages of development. | GDF3
Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene.[1] GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 (found in frogs) and GDF1.[1]
# Tissue distribution
Expression of GDF3 occurs in ossifying bone during embryonic development and in the brain, thymus, spleen, bone marrow and adipose tissue of adults.[2][3]
# Function
GDF3 is a bi-functional protein that has some intrinsic activity and also modulate other TGF-β superfamily members, e.g. potentiates the activity of NODAL. It may also inhibit other TGF-β superfamily members (i.e. BMPs), thus regulating the balance between different modes of TGF-beta signaling.[4] It has been shown to negatively and positively control differentiation of embryonic stem cells in mice and humans.[5] This molecule plays a role in mesoderm and definitive endoderm formation during the pre-gastrulation stages of development.[2] | https://www.wikidoc.org/index.php/GDF3 | |
4678b20a84bcf85fa4890889d56071c7be13e011 | wikidoc | GDF5 | GDF5
Growth/differentiation factor 5 is a protein that in humans is encoded by the GDF5 gene.
The protein encoded by this gene is closely related to the bone morphogenetic protein (BMP) family and is a member of the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site which is cleaved to produce a mature protein containing seven conserved cysteine residues. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Mutations in this gene are associated with acromesomelic dysplasia, Hunter-Thompson type; brachydactyly, type C; and osteochondrodysplasia, Grebe type. These associations confirm that the gene product plays a role in skeletal development.
Growth differentiation factor 5 (GDF5) is a protein belonging to the transforming growth factor beta superfamily that is expressed in the developing central nervous system, and has a role in skeletal and joint development. It also increases the survival of neurones that respond to the neurotransmitter dopamine, and is a potential therapeutic molecule associated with Parkinson's disease. | GDF5
Growth/differentiation factor 5 is a protein that in humans is encoded by the GDF5 gene.[1][2][3]
The protein encoded by this gene is closely related to the bone morphogenetic protein (BMP) family and is a member of the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site which is cleaved to produce a mature protein containing seven conserved cysteine residues. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Mutations in this gene are associated with acromesomelic dysplasia, Hunter-Thompson type; brachydactyly, type C; and osteochondrodysplasia, Grebe type. These associations confirm that the gene product plays a role in skeletal development.[3]
Growth differentiation factor 5 (GDF5) is a protein belonging to the transforming growth factor beta superfamily that is expressed in the developing central nervous system,[4] and has a role in skeletal and joint development.[5][6][7] It also increases the survival of neurones that respond to the neurotransmitter dopamine, and is a potential therapeutic molecule associated with Parkinson's disease.[8] | https://www.wikidoc.org/index.php/GDF5 | |
5b2ccd5f1a3553280f3454e1317750a84fdd7047 | wikidoc | GDF6 | GDF6
Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.
# Function
GDF6 belongs to the transforming growth factor beta superfamily and may regulate patterning of the ectoderm by interacting with bone morphogenetic proteins, and control eye development.
Growth differentiation factor 6 (GDF6) is a regulatory protein associated with growth and differentiation of developing embryos. GDF6 is encoded by the GDF6 gene. It is a member the transforming growth factor beta superfamily which is a group of proteins involved in early regulation of cell growth and development. GDF6 has been shown to play an important role in the patterning of the epidermis and bone and joint formation. GDF6 induces genes related to the development of the epidermis and can bind directly to noggin, a gene that controls neural development, to block its effect. GDF6 interacts with bone morphogenetic proteins (BMPs) to form heterodimers that may work to regulate neural induction and patterning in developing embryos. By developing a GDF6 “knockout” model, scientists repressed expression of GDF6 in developing mice embryos. Through this experiment, the scientists were able to directly link GDF6 with several skull and vertebral joint disorders, such as scoliosis and chondrodysplasia, Grebe type.
# Clinical significance
GDF6 is recurrently amplified and specifically expressed in 80% of the melanomas. Patients with less GDF6 had a lower risk of metastasis and a higher chance of survival. Since GDF6 expression is very low or undetectable in most healthy adult tissues its inhibition could be used to treat this lethal disease. | GDF6
Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.[1]
# Function
GDF6 belongs to the transforming growth factor beta superfamily and may regulate patterning of the ectoderm by interacting with bone morphogenetic proteins,[2] and control eye development.[3][4]
Growth differentiation factor 6 (GDF6) is a regulatory protein associated with growth and differentiation of developing embryos. GDF6 is encoded by the GDF6 gene. It is a member the transforming growth factor beta superfamily which is a group of proteins involved in early regulation of cell growth and development. GDF6 has been shown to play an important role in the patterning of the epidermis[5] and bone and joint formation.[6] GDF6 induces genes related to the development of the epidermis and can bind directly to noggin, a gene that controls neural development, to block its effect.[5] GDF6 interacts with bone morphogenetic proteins (BMPs) to form heterodimers that may work to regulate neural induction and patterning in developing embryos.[5] By developing a GDF6 “knockout” model, scientists repressed expression of GDF6 in developing mice embryos. Through this experiment, the scientists were able to directly link GDF6 with several skull and vertebral joint disorders, such as scoliosis and chondrodysplasia, Grebe type.[6]
# Clinical significance
GDF6 is recurrently amplified and specifically expressed in 80% of the melanomas. Patients with less GDF6 had a lower risk of metastasis and a higher chance of survival. Since GDF6 expression is very low or undetectable in most healthy adult tissues its inhibition could be used to treat this lethal disease.[7][unreliable medical source] | https://www.wikidoc.org/index.php/GDF6 | |
01960ec86f97d1c8ffd039d85402a72fecce1fd9 | wikidoc | GDI1 | GDI1
Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the GDI1 gene.
# Function
GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI1 is expressed primarily in neural and sensory tissues. Mutations in GDI1 have been linked to X-linked nonspecific mental retardation.
Rab GTPases cycles between the cytosolic compartment, where it is bound to a protein called GDI (GDP Dissociation Inhibitor), and the membrane, where it interacts with a receptor, a nucleotide exchange factor, a GAP (GTPase Activating Protein) and probably other factors that link it to the appropriate SNARE. GDI is non-specific with respect to the rab it binds. However, the exchanger, receptor and GAP, are rab specific.
# Interactions
GDI1 has been shown to interact with CDC42. | GDI1
Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the GDI1 gene.[1][2]
# Function
GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI1 is expressed primarily in neural and sensory tissues. Mutations in GDI1 have been linked to X-linked nonspecific mental retardation.[3]
Rab GTPases cycles between the cytosolic compartment, where it is bound to a protein called GDI (GDP Dissociation Inhibitor), and the membrane, where it interacts with a receptor, a nucleotide exchange factor, a GAP (GTPase Activating Protein) and probably other factors that link it to the appropriate SNARE. GDI is non-specific with respect to the rab it binds. However, the exchanger, receptor and GAP, are rab specific.
# Interactions
GDI1 has been shown to interact with CDC42.[4] | https://www.wikidoc.org/index.php/GDI1 | |
bc53eec0a655ad387e5dd8dd0e2424f902a23d47 | wikidoc | GFER | GFER
Growth factor, augmenter of liver regeneration (ERV1 homolog, S. cerevisiae), also known as GFER, or Hepatopoietin is a protein which in humans is encoded by the GFER gene. This gene is also known as essential for respiration and vegatative growth, augmenter of liver regeneration, and growth factor of Erv1-like/Hepatic regenerative stimulation substance.
# Structure
The GFER gene is located on the p arm of chromosome 16 at position 13.3 and it spans 3,600 base pairs. The GFER gene produces a 15.4 kDa protein composed of 130 amino acids. The structure of the protein is a homodimer which has been found to be fairly similar to the scERV1 protein of yeast.
# Genomics
The gene resides on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1). The putative gene product is 42% similar to the scERV1 protein of yeast. The human gene has three exons: the first encodes a 5' untranslated region and the first part of the protein; the second encodes the bulk of the protein; and the third the remainder.
# Molecular biology
Proteins of the ERV1/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses for which the sequence data are available. All possess a C-X-X-C motif within a ~100 amino acid domain
# Function
The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver. It has also been called hepatic regenerative stimulation substance (HSS). The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle. The human gene is both the structural and functional homolog of the yeast scERV1 gene.
This protein interacts with Mia40 during the import of intermembrane space proteins including the small Tim proteins Cox17 and Cox19 both of which have disulfide bonds.
# Clinical Significance
Mutations in GFER has been shown to result in Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay (MPMCHD). MPMCHD is a disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay.
# Interactions
GFER has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5 and BNIPL. | GFER
Growth factor, augmenter of liver regeneration (ERV1 homolog, S. cerevisiae), also known as GFER, or Hepatopoietin is a protein which in humans is encoded by the GFER gene. This gene is also known as essential for respiration and vegatative growth, augmenter of liver regeneration, and growth factor of Erv1-like/Hepatic regenerative stimulation substance. [1][2][3]
# Structure
The GFER gene is located on the p arm of chromosome 16 at position 13.3 and it spans 3,600 base pairs.[1] The GFER gene produces a 15.4 kDa protein composed of 130 amino acids.[4][5] The structure of the protein is a homodimer which has been found to be fairly similar to the scERV1 protein of yeast.[6]
# Genomics
The gene resides on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1). The putative gene product is 42% similar to the scERV1 protein of yeast. The human gene has three exons: the first encodes a 5' untranslated region and the first part of the protein; the second encodes the bulk of the protein; and the third the remainder.
# Molecular biology
Proteins of the ERV1/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses for which the sequence data are available. All possess a C-X-X-C motif within a ~100 amino acid domain
# Function
The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver. It has also been called hepatic regenerative stimulation substance (HSS). The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle. The human gene is both the structural and functional homolog of the yeast scERV1 gene.[1]
This protein interacts with Mia40 during the import of intermembrane space proteins including the small Tim proteins Cox17 and Cox19 both of which have disulfide bonds.
# Clinical Significance
Mutations in GFER has been shown to result in Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay (MPMCHD). MPMCHD is a disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay.
# Interactions
GFER has been shown to interact with COP9 constitutive photomorphogenic homolog subunit 5[7] and BNIPL.[8] | https://www.wikidoc.org/index.php/GFER | |
03e2025c610fd7b7de2beda85faf18ed6308f384 | wikidoc | GFM1 | GFM1
Elongation factor G 1, mitochondrial is a protein that in humans is encoded by the GFM1 gene.
Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known.
# Model organisms
Model organisms have been used in the study of GFM1 function. A conditional knockout mouse line, called Gfm1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and decreased circulating amylase levels were observed in male animals. | GFM1
Elongation factor G 1, mitochondrial is a protein that in humans is encoded by the GFM1 gene.[1][2][3]
Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known.[3]
# Model organisms
Model organisms have been used in the study of GFM1 function. A conditional knockout mouse line, called Gfm1tm1a(EUCOMM)Wtsi[10][11] 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.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on mutant mice and three significant abnormalities were observed.[8] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and decreased circulating amylase levels were observed in male animals.[8] | https://www.wikidoc.org/index.php/GFM1 | |
7d03cd34f808158256bb07d2a3139af9d3b35d70 | wikidoc | GGA1 | GGA1
ADP-ribosylation factor-binding protein GGA1 is a protein that in humans is encoded by the GGA1 gene.
This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) protein family. Members of this family are ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Interactions
GGA1 has been shown to interact with Sortilin 1, BACE2, RABEP1 and ARF3. | GGA1
ADP-ribosylation factor-binding protein GGA1 is a protein that in humans is encoded by the GGA1 gene.[1][2][3]
This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) protein family. Members of this family are ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.[4]
# Interactions
GGA1 has been shown to interact with Sortilin 1,[5] BACE2,[6] RABEP1[7] and ARF3.[8][9] | https://www.wikidoc.org/index.php/GGA1 | |
c53ced1003b325491d359dd27810892899cac28c | wikidoc | GGA2 | GGA2
ADP-ribosylation factor-binding protein GGA2 is a protein that in humans is encoded by the GGA2 gene.
# Function
This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly.
# Interactions
GGA2 has been shown to interact with RABEP1, Sortilin 1, BACE2 and CLINT1. | GGA2
ADP-ribosylation factor-binding protein GGA2 is a protein that in humans is encoded by the GGA2 gene.[1][2][3]
# Function
This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly.[3]
# Interactions
GGA2 has been shown to interact with RABEP1,[4] Sortilin 1,[5][6] BACE2[7] and CLINT1.[8][9] | https://www.wikidoc.org/index.php/GGA2 | |
72835ccd7a8d55303d46d267c76a1e670257360b | wikidoc | GIT2 | GIT2
ARF GTPase-activating protein GIT2 is an enzyme that in humans is encoded by the GIT2 gene.
# Function
This gene encodes a member of the GIT protein family. GIT proteins interact with G protein-coupled receptor kinases and possess ADP-ribosylation factor (ARF) GTPase-activating protein (GAP) activity. This gene undergoes extensive alternative splicing; although ten transcript variants have been described, the full length sequence has been determined for only four variants. The various isoforms have functional differences, with respect to ARF GAP activity and to G protein-coupled receptor kinase 2 binding.
# Model organisms
Model organisms have been used in the study of GIT2 function. A conditional knockout mouse line, called Git2Gt(XG510)Byg 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. Mice lacking Git2 had no significant defects in viability or fertility, so further tests were carried out and four significant phenotypes were reported:
- Mutant mice had differences in their clinical blood chemistry compared to wildtype control mice.
- Mutant male mice had a decrease in white blood cell count.
- An increased thickness in hippocampus was observed.
- Mutant female mice were slower to respond to heat when placed on a hotplate.
# Interactions
GIT2 has been shown to interact with GIT1. | GIT2
ARF GTPase-activating protein GIT2 is an enzyme that in humans is encoded by the GIT2 gene.[1][2][3]
# Function
This gene encodes a member of the GIT protein family. GIT proteins interact with G protein-coupled receptor kinases and possess ADP-ribosylation factor (ARF) GTPase-activating protein (GAP) activity. This gene undergoes extensive alternative splicing; although ten transcript variants have been described, the full length sequence has been determined for only four variants. The various isoforms have functional differences, with respect to ARF GAP activity and to G protein-coupled receptor kinase 2 binding.[3]
# Model organisms
Model organisms have been used in the study of GIT2 function. A conditional knockout mouse line, called Git2Gt(XG510)Byg[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Mice lacking Git2 had no significant defects in viability or fertility,[17][18] so further tests were carried out and four significant phenotypes were reported:[9][16]
- Mutant mice had differences in their clinical blood chemistry compared to wildtype control mice.
- Mutant male mice had a decrease in white blood cell count.
- An increased thickness in hippocampus was observed.
- Mutant female mice were slower to respond to heat when placed on a hotplate.
# Interactions
GIT2 has been shown to interact with GIT1.[19] | https://www.wikidoc.org/index.php/GIT2 | |
b116f4b80b02149d412b95e62c4dd6756c7f98ac | wikidoc | GJA1 | GJA1
Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the GJA1 gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular communication (GJIC) between cells to regulate cell death, proliferation, and differentiation. As a result of its function, GJA1 is implicated in many biological processes, including muscle contraction, embryonic development, inflammation, and spermatogenesis, as well as diseases, including oculodentodigital dysplasia (ODDD), heart malformations, and cancers.
# Structure
Connexin-43 is a 43.0 kDa protein composed of 382 amino acids. GJA1 contains a long C-terminal tail, an N-terminal domain, and multiple transmembrane domains. The protein passes through the phospholipid bilayer four times, leaving its C- and N-terminals exposed to the cytoplasm. The C-terminal tail is composed of 50 amino acids and includes post-translational modification sites, as well as binding sites for transcription factors, cytoskeleton elements, and other proteins. As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of the GJA1 gene encoding this tail is highly conserved, indicating that it is either resistant to mutations or becomes lethal when mutated. Meanwhile, the N-terminal domain is involved in channel gating and oligomerization and, thus, may control the switch between the channel’s open and closed states. The transmembrane domains form the gap junction channel while the extracellular loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.
The connexin-43 internal ribosome entry site is an RNA element present in the 5' UTR of the mRNA of GJA1. This internal ribosome entry site (IRES) allows cap independent translation during conditions such as heat shock and stress.
# Function
As a member of the connexin family, GJA1 is a component of gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small ions and secondary messengers, to maintain homeostasis.
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.
It is the major protein in heart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart. Despite its key role in the heart and other vital organs, GJA1 has a short half-life (only two to four hours), indicating that the protein undergoes daily turnover in the heart and may be highly abundant or compensated with other connexins.
GJA1 is also largely involved in embryonic development. For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta.
Furthermore, GJA1 is expressed in many immune cells, such as eosinophils and T cells, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an inflammatory response.
In addition, GJA1 can be found in the Leydig cells and seminiferous tubules between Sertoli cells and spermatogonia or primary spermatocytes, where it plays a key role in spermatogenesis and testis development through controlling the tight junction proteins in the blood-testis barrier.
While it is a channel protein, GJA1 can also perform channel-independent functions. In the cytoplasm, the protein regulates the microtubule network and, by extension, cell migration and polarity. This function has been observed in brain and heart development, as well as wound-healing in endothelial cells. GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.
# Clinical significance
Mutations in this gene have been associated with ODDD; craniometaphyseal dysplasia; sudden infant death syndrome, which is linked to cardiac arrhythmia; Hallermann–Streiff syndrome; and heart malformations, such as viscero-atrial heterotaxia. There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD. Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes. It is paradoxical, however, that patients with an array of somatic mutations in GJA1 most often do not present with cardiac arrhythmias, even though connexin-43 is the most abundant protein forming gap junctional pores in cardiomyocytes and are essential for normal action potential propagation.
Notably, GJA1 expression has been associated with a wide variety of cancers, including nasopharyngeal carcinoma, meningioma, hemangiopericytoma, liver tumor, colon cancer, esophageal cancer, breast cancer, mesothelioma, glioblastoma, lung cancer, adrenocortical tumors, renal cell cancer, cervical carcinoma, ovarian carcinoma, endometrial carcinoma, prostate cancer, thyroid carcinoma, and testis cancer. Its role in controlling cell motility and polarity was thought to contribute to cancer development and metastasis, though its role as a gap junction protein may also be involved. Moreover, the cytoprotective effects of this protein can promote tumor cell survival in radiotherapy treatments, while silencing its gene increases radiosensitivity. As a result, GJA1 may serve as a target for improving the success of radiotherapeutic treatment of cancer. As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.
Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such as Cx40, which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere. Thus, a more effective approach entails designing a miRNA through antisense oligonucleotides, transfection, or infection to knock down only mutant GJA1 mRNA, thus allowing the expression of wildtype GJA1 and retaining normal phenotype.
# Interactions
Gap junction protein, alpha 1 has been shown to interact with:
- Cx37,
- Cx40,
- Cx45,
- MAPK7,
- Caveolin 1,
- Tight junction protein 1
- CSNK1D, and
- PTPmu (PTPRM). | GJA1
Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the GJA1 gene on chromosome 6.[1][2][3] As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular communication (GJIC) between cells to regulate cell death, proliferation, and differentiation.[4] As a result of its function, GJA1 is implicated in many biological processes, including muscle contraction, embryonic development, inflammation, and spermatogenesis, as well as diseases, including oculodentodigital dysplasia (ODDD), heart malformations, and cancers.[3][5][6]
# Structure
Connexin-43 is a 43.0 kDa protein composed of 382 amino acids.[7] GJA1 contains a long C-terminal tail, an N-terminal domain, and multiple transmembrane domains. The protein passes through the phospholipid bilayer four times, leaving its C- and N-terminals exposed to the cytoplasm.[8] The C-terminal tail is composed of 50 amino acids and includes post-translational modification sites, as well as binding sites for transcription factors, cytoskeleton elements, and other proteins.[8][9] As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of the GJA1 gene encoding this tail is highly conserved, indicating that it is either resistant to mutations or becomes lethal when mutated. Meanwhile, the N-terminal domain is involved in channel gating and oligomerization and, thus, may control the switch between the channel’s open and closed states. The transmembrane domains form the gap junction channel while the extracellular loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.[8]
The connexin-43 internal ribosome entry site is an RNA element present in the 5' UTR of the mRNA of GJA1. This internal ribosome entry site (IRES) allows cap independent translation during conditions such as heat shock and stress.[10]
# Function
As a member of the connexin family, GJA1 is a component of gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small ions and secondary messengers, to maintain homeostasis.[3][8][11]
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.[3][5][8]
It is the major protein in heart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart.[3] Despite its key role in the heart and other vital organs, GJA1 has a short half-life (only two to four hours), indicating that the protein undergoes daily turnover in the heart and may be highly abundant or compensated with other connexins.[8]
GJA1 is also largely involved in embryonic development.[3][4] For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta.[4]
Furthermore, GJA1 is expressed in many immune cells, such as eosinophils and T cells, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an inflammatory response.[6]
In addition, GJA1 can be found in the Leydig cells and seminiferous tubules between Sertoli cells and spermatogonia or primary spermatocytes, where it plays a key role in spermatogenesis and testis development through controlling the tight junction proteins in the blood-testis barrier.
While it is a channel protein, GJA1 can also perform channel-independent functions. In the cytoplasm, the protein regulates the microtubule network and, by extension, cell migration and polarity.[5][9] This function has been observed in brain and heart development, as well as wound-healing in endothelial cells.[9] GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.[11]
# Clinical significance
Mutations in this gene have been associated with ODDD; craniometaphyseal dysplasia; sudden infant death syndrome, which is linked to cardiac arrhythmia; Hallermann–Streiff syndrome; and heart malformations, such as viscero-atrial heterotaxia.[3][5][8][12] There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD.[8] Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes.[8] It is paradoxical, however, that patients with an array of somatic mutations in GJA1 most often do not present with cardiac arrhythmias, even though connexin-43 is the most abundant protein forming gap junctional pores in cardiomyocytes and are essential for normal action potential propagation.[13]
Notably, GJA1 expression has been associated with a wide variety of cancers, including nasopharyngeal carcinoma, meningioma, hemangiopericytoma, liver tumor, colon cancer, esophageal cancer, breast cancer, mesothelioma, glioblastoma, lung cancer, adrenocortical tumors, renal cell cancer, cervical carcinoma, ovarian carcinoma, endometrial carcinoma, prostate cancer, thyroid carcinoma, and testis cancer.[5] Its role in controlling cell motility and polarity was thought to contribute to cancer development and metastasis, though its role as a gap junction protein may also be involved.[5][11] Moreover, the cytoprotective effects of this protein can promote tumor cell survival in radiotherapy treatments, while silencing its gene increases radiosensitivity. As a result, GJA1 may serve as a target for improving the success of radiotherapeutic treatment of cancer.[11] As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.[5]
Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such as Cx40, which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere.[8] Thus, a more effective approach entails designing a miRNA through antisense oligonucleotides, transfection, or infection to knock down only mutant GJA1 mRNA, thus allowing the expression of wildtype GJA1 and retaining normal phenotype.[5][8]
# Interactions
Gap junction protein, alpha 1 has been shown to interact with:
- Cx37,[8]
- Cx40,[8]
- Cx45,[8]
- MAPK7,[14]
- Caveolin 1,[15]
- Tight junction protein 1[16]
- CSNK1D,[17] and
- PTPmu (PTPRM).[18] | https://www.wikidoc.org/index.php/GJA1 | |
31d9d26123902726b602a0eb075eddc4591ef678 | wikidoc | GJB2 | GJB2
Gap junction beta-2 protein (GJB2), also known as connexin 26 (Cx26) — is a protein that in humans is encoded by the GJB2 gene.
# Clinical significance
Defects in this gene lead to the most common form of congenital deafness in developed countries, called DFNB1 (also known as connexin 26 deafness or GJB2-related deafness).
Connexin 26 also plays a role in tumor suppression through mediation of the cell cycle. The abnormal expression of Cx26, correlated with several types of human cancers, may serve as a prognostic factor for cancers such as colorectal cancer, breast cancer, and bladder cancer. Furthermore, Cx26 over-expression is suggested to promote cancer development by facilitating cell migration and invasion and by stimulating the self-perpetuation ability of cancer stem cells.
# Function
Gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels. Proteins, called connexins, purified from fractions of enriched gap junctions from different tissues differ. The connexins are designated by their molecular mass. Another system of nomenclature divides gap junction proteins into two categories, alpha and beta, according to sequence similarities at the nucleotide and amino acid levels. For example, CX43 (GJA1) is designated alpha-1 gap junction protein, whereas GJB1 (CX32), and GJB2 (CX26; this protein) are called beta-1 and beta-2 gap junction proteins, respectively. This nomenclature emphasizes that GJB1 and GJB2 are more homologous to each other than either of them is to gap junction protein, alpha GJA1. | GJB2
Gap junction beta-2 protein (GJB2), also known as connexin 26 (Cx26) — is a protein that in humans is encoded by the GJB2 gene.
# Clinical significance
Defects in this gene lead to the most common form of congenital deafness in developed countries, called DFNB1 (also known as connexin 26 deafness or GJB2-related deafness).[1]
Connexin 26 also plays a role in tumor suppression through mediation of the cell cycle.[2] The abnormal expression of Cx26, correlated with several types of human cancers, may serve as a prognostic factor for cancers such as colorectal cancer,[3] breast cancer,[4] and bladder cancer.[5] Furthermore, Cx26 over-expression is suggested to promote cancer development by facilitating cell migration and invasion[6] and by stimulating the self-perpetuation ability of cancer stem cells.[7]
# Function
Gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels. Proteins, called connexins, purified from fractions of enriched gap junctions from different tissues differ. The connexins are designated by their molecular mass. Another system of nomenclature divides gap junction proteins into two categories, alpha and beta, according to sequence similarities at the nucleotide and amino acid levels. For example, CX43 (GJA1) is designated alpha-1 gap junction protein, whereas GJB1 (CX32), and GJB2 (CX26; this protein) are called beta-1 and beta-2 gap junction proteins, respectively. This nomenclature emphasizes that GJB1 and GJB2 are more homologous to each other than either of them is to gap junction protein, alpha GJA1.[8] | https://www.wikidoc.org/index.php/GJB2 | |
15ca2d2ea39091554d506a5fe78055cf711fc20f | wikidoc | GJB6 | GJB6
Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene. Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear. Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness. Mutations in this gene are associated with Clouston syndrome (i.e., hydrotic ectodermal dysplasia).
# Function
The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel.
Connexin 30 is prevalent in the two distinct gap junction systems found in the cochlea: the epithelial cell gap junction network, which couple non-sensory epithelial cells, and the connective tissue gap junction network, which couple connective tissue cells. Gap junctions serve the important purpose of recycling potassium ions that pass through hair cells during mechanotransduction back to the endolymph.
Connexin 30 has been found to be co-localized with connexin 26. Cx30 and Cx26 have also been found to form heteromeric and heterotypic channels. The biochemical properties and channel permeabilities of these more complex channels differ from homotypic Cx30 or Cx26 channels. Overexpression of Cx30 in Cx30 null mice restored Cx26 expression and normal gap junction channel functioning and calcium signaling, but it is described that Cx26 expression is altered in Cx30 null mice. The researchers hypothesized that co-regulation of Cx26 and Cx30 is dependent on phospholipase C signaling and the NF-κB pathway.
The cochlea contains two cell types, auditory hair cells for mechanotransduction and supporting cells. Gap junction channels are only found between cochlear supporting cells. While gap junctions in the inner ear are critically involved in potassium recycling to the endolymph, connexin expression in the supporting cells surrounding the organ of Corti have been found to support epithelial tissue lesion repair following loss of sensory hair cells. An experiment with Cx30 null mice found deficits in lesion closure and repair of the organ of Corti following hair cell loss, suggesting that Cx30 has a role in regulating lesion repair response.
# Clinical Significance
## Auditory
Connexin 26 and connexin 30 are commonly accepted to be the predominant gap junction proteins in the cochlea. Genetic knockout experiments in mice has shown that knockout of either Cx26 or Cx30 produces deafness. However, recent research suggests that Cx30 knockout produces deafness due to subsequent downregulation of Cx26, and one mouse study found that a Cx30 mutation that preserves half of Cx26 expression found in normal Cx30 mice resulted in unimpaired hearing. The lessened severity of Cx30 knockout in comparison to Cx26 knockout is supported by a study examining the time course and patterns of hair cell degeneration in the cochlea. Cx26 null mice displayed more rapid and widespread cell death than Cx30 null mice. The percent hair cell loss was less widespread and frequent in the cochleas of Cx30 null mice. | GJB6
Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene.[1][2][3] Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear.[4] Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness.[5] Mutations in this gene are associated with Clouston syndrome (i.e., hydrotic ectodermal dysplasia).
# Function
The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel.[supplied by OMIM][3]
Connexin 30 is prevalent in the two distinct gap junction systems found in the cochlea: the epithelial cell gap junction network, which couple non-sensory epithelial cells, and the connective tissue gap junction network, which couple connective tissue cells. Gap junctions serve the important purpose of recycling potassium ions that pass through hair cells during mechanotransduction back to the endolymph.[6]
Connexin 30 has been found to be co-localized with connexin 26.[7] Cx30 and Cx26 have also been found to form heteromeric and heterotypic channels. The biochemical properties and channel permeabilities of these more complex channels differ from homotypic Cx30 or Cx26 channels.[8] Overexpression of Cx30 in Cx30 null mice restored Cx26 expression and normal gap junction channel functioning and calcium signaling, but it is described that Cx26 expression is altered in Cx30 null mice. The researchers hypothesized that co-regulation of Cx26 and Cx30 is dependent on phospholipase C signaling and the NF-κB pathway.[9]
The cochlea contains two cell types, auditory hair cells for mechanotransduction and supporting cells. Gap junction channels are only found between cochlear supporting cells.[10] While gap junctions in the inner ear are critically involved in potassium recycling to the endolymph, connexin expression in the supporting cells surrounding the organ of Corti have been found to support epithelial tissue lesion repair following loss of sensory hair cells. An experiment with Cx30 null mice found deficits in lesion closure and repair of the organ of Corti following hair cell loss, suggesting that Cx30 has a role in regulating lesion repair response.[11]
# Clinical Significance
## Auditory
Connexin 26 and connexin 30 are commonly accepted to be the predominant gap junction proteins in the cochlea. Genetic knockout experiments in mice has shown that knockout of either Cx26 or Cx30 produces deafness.[12][13] However, recent research suggests that Cx30 knockout produces deafness due to subsequent downregulation of Cx26, and one mouse study found that a Cx30 mutation that preserves half of Cx26 expression found in normal Cx30 mice resulted in unimpaired hearing.[14] The lessened severity of Cx30 knockout in comparison to Cx26 knockout is supported by a study examining the time course and patterns of hair cell degeneration in the cochlea. Cx26 null mice displayed more rapid and widespread cell death than Cx30 null mice. The percent hair cell loss was less widespread and frequent in the cochleas of Cx30 null mice.[15] | https://www.wikidoc.org/index.php/GJB6 | |
92f1255f729ce24c79d89432d33750df72bb332b | wikidoc | GJC2 | GJC2
Gap junction gamma-2 (GJC2), also known as connexin-46.6 (Cx46.6) and connexin-47 (Cx47) and gap junction alpha-12 (GJA12), is a protein that in humans is encoded by the GJC2 gene.
# Function
This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans.
# Clinical significance
Homozygous or compound heterozygous defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1.
Heterozygous missense mutations in this same gene cause pubertal onset hereditary lymphedema. | GJC2
Gap junction gamma-2 (GJC2), also known as connexin-46.6 (Cx46.6) and connexin-47 (Cx47) and gap junction alpha-12 (GJA12), is a protein that in humans is encoded by the GJC2 gene.[1]
# Function
This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans.[1]
# Clinical significance
Homozygous or compound heterozygous defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1.[1]
Heterozygous missense mutations in this same gene cause pubertal onset hereditary lymphedema. | https://www.wikidoc.org/index.php/GJC2 | |
a66dead200a38418b0c12fc36b377f7ea5d1b8fb | wikidoc | GJC3 | GJC3
Gap junction gamma-3, also known as connexin-29 (Cx29) or gap junction epsilon-1 (GJE1), is a protein that in humans is encoded by the GJC3 gene.
GJC3 is a conexin.
# Function
This gene encodes a gap junction protein. The encoded protein is known as a connexin, most of which form gap junctions that provide direct connections between neighboring cells. However, Cx29, which is highly expressed in myelin-forming glial cells of the CNS and PNS, has not been documented to form gap junctions in any cell type. In both PNS and CNS myelinated axons, Cx29 is precisely colocalized with Kv1.2 voltage-gated K+ channels, where both proteins are concentrated in the juxtaparanode and along the inner mesaxon. By freeze-fracture immunogold labeling electron microscopy, Cx29 is identified in abundant "rosettes" of transmembrane protein particles in the innermost layer of myelin, directly apposed to equally abundant immunogold-labeled Kv1.1 potassium channels, both in the juxtaparanodal axolemma and along the inner mesaxon. A role in K+ handling during saltatory conduction is implied but not yet demonstrated.
# Clinical significance
Mutations in this gene have been reported to be associated with nonsyndromic hearing loss. | GJC3
Gap junction gamma-3, also known as connexin-29 (Cx29) or gap junction epsilon-1 (GJE1), is a protein that in humans is encoded by the GJC3 gene.[1]
GJC3 is a conexin.
# Function
This gene encodes a gap junction protein. The encoded protein is known as a connexin, most of which form gap junctions that provide direct connections between neighboring cells.[1] However, Cx29, which is highly expressed in myelin-forming glial cells of the CNS and PNS, has not been documented to form gap junctions in any cell type. In both PNS and CNS myelinated axons, Cx29 is precisely colocalized with Kv1.2 voltage-gated K+ channels, where both proteins are concentrated in the juxtaparanode and along the inner mesaxon.[2] By freeze-fracture immunogold labeling electron microscopy, Cx29 is identified in abundant "rosettes" of transmembrane protein particles in the innermost layer of myelin, directly apposed to equally abundant immunogold-labeled Kv1.1 potassium channels, both in the juxtaparanodal axolemma and along the inner mesaxon.[3] A role in K+ handling during saltatory conduction is implied but not yet demonstrated.
# Clinical significance
Mutations in this gene have been reported to be associated with nonsyndromic hearing loss.[1] | https://www.wikidoc.org/index.php/GJC3 | |
c51402624bc49d8a002e50ae123144fd3fc6c39c | wikidoc | GLB1 | GLB1
Galactosidase, beta 1, also known as GLB1, is a protein which in humans is encoded by the GLB1 gene.
The GLB1 protein is a beta-galactosidase that cleaves the terminal beta-galactose from ganglioside substrates and other glycoconjugates. The GLB1 gene also encodes an elastin binding protein.
In corn (Zea mays), Glb1 is a gene coding for the storage protein globulin.
# Clinical significance
GM1-gangliosidosis is a lysosomal storage disease that can be caused by a deficiency of β-galactosidase (GLB1). Some cases of Morquio syndrome B have been shown to be due to GLP1 mutations that cause patients to have abnormal elastic fibers.
# Elastin receptor
The RNA transcript of the GLB1 gene is alternatively spliced and produces 2 mRNAs. The 2.5-kilobase transcript encodes the beta-galactosidase enzyme of 677 amino acids. The alternative 2.0-kb mRNA encodes a beta-galactosidase-related protein (S-Gal) that is only 546 amino acids long and that has no enzymatic activity. The S-Gal protein does bind elastin and fragments of elastin that are generated by proteolysis.
The S-Gal protein is a peripheral membrane protein that functions as part of an elastin receptor complex on the surface of cells. The elastin receptor complex includes S-Gal, neuraminidase and Cathepsin A. When elastin-derived peptides bind to the S-Gal protein then the associated neuraminidase enzyme activity is activated and responding cells can have altered signal transduction involving extracellular signal-regulated kinases and regulated matrix metallopeptidase production. Elastin-derived peptides are chemotactic for some cell types and can alter cell cycle progression. The ability of the GLB1-derived elastin binding protein and the elastin receptor complex to influence cell proliferation appears to be indirect and involve removal of sialic acid from extracellular and cell surface proteins such as growth factor receptors.
The S-Gal protein functions during the normal assembly of elastin into extracellular elastic fibers. Elastin is initially present as newly synthesized tropoelastin which can be found in association with S-Gal. The enzymatic activity of neuraminidase in the elastin receptor complex is involved in the release of tropoelastin molecules from the S-Gal chaperone. Cathepsin A is also required for normal elastin biosynthesis. | GLB1
Galactosidase, beta 1, also known as GLB1, is a protein which in humans is encoded by the GLB1 gene.[1][2]
The GLB1 protein is a beta-galactosidase that cleaves the terminal beta-galactose from ganglioside substrates and other glycoconjugates.[3] The GLB1 gene also encodes an elastin binding protein.[4]
In corn (Zea mays), Glb1 is a gene coding for the storage protein globulin.
# Clinical significance
GM1-gangliosidosis is a lysosomal storage disease that can be caused by a deficiency of β-galactosidase (GLB1). Some cases of Morquio syndrome B have been shown to be due to GLP1 mutations that cause patients to have abnormal elastic fibers.[5]
# Elastin receptor
The RNA transcript of the GLB1 gene is alternatively spliced and produces 2 mRNAs. The 2.5-kilobase transcript encodes the beta-galactosidase enzyme of 677 amino acids. The alternative 2.0-kb mRNA encodes a beta-galactosidase-related protein (S-Gal) that is only 546 amino acids long and that has no enzymatic activity. The S-Gal protein does bind elastin and fragments of elastin that are generated by proteolysis.[6]
The S-Gal protein is a peripheral membrane protein that functions as part of an elastin receptor complex on the surface of cells.[7] The elastin receptor complex includes S-Gal, neuraminidase and Cathepsin A. When elastin-derived peptides bind to the S-Gal protein then the associated neuraminidase enzyme activity is activated and responding cells can have altered signal transduction involving extracellular signal-regulated kinases and regulated matrix metallopeptidase production. Elastin-derived peptides are chemotactic for some cell types[8] and can alter cell cycle progression.[9] The ability of the GLB1-derived elastin binding protein and the elastin receptor complex to influence cell proliferation appears to be indirect and involve removal of sialic acid from extracellular and cell surface proteins such as growth factor receptors.
The S-Gal protein functions during the normal assembly of elastin into extracellular elastic fibers. Elastin is initially present as newly synthesized tropoelastin which can be found in association with S-Gal. The enzymatic activity of neuraminidase in the elastin receptor complex is involved in the release of tropoelastin molecules from the S-Gal chaperone.[10] Cathepsin A is also required for normal elastin biosynthesis.[11] | https://www.wikidoc.org/index.php/GLB1 | |
3e221e19086cb74191cf2ba6be78884b0cb42a6e | wikidoc | GLI1 | GLI1
Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.
# Function
The Gli proteins are the effectors of Hedgehog (Hh) signaling and have been shown to be involved in cell fate determination, proliferation and patterning in many cell types and most organs during embryo development. In the developing spinal cord the target genes of Gli proteins, that are themselves transcription factors, are arranged into a complex gene regulatory network that translates the extracellular concentration gradient of Sonic hedgehog into different cell fates along the dorsoventral axis.
The Gli transcription factors activate/inhibit transcription by binding to Gli responsive genes and by interacting with the transcription complex. The Gli transcription factors have DNA binding zinc finger domains which bind to consensus sequences on their target genes to initiate or suppress transcription. Yoon showed that mutating the Gli zinc finger domain inhibited the proteins effect proving its role as a transcription factor. Gli proteins have an 18-amino acid region highly similar to the α-helical herpes simplex viral protein 16 activation domain. This domain contains a consensus recognition element for the human TFIID TATA box-binding protein associated factor TAFII31. Other proteins such as Missing in Metastasis (MIM/BEG4) have been shown to potentiate the effects of the Gli transcription factors on target gene transcription. Gli and MIM have been shown to act synergistically to induce epidermal growth and MIM + Gli1 overexpressing grafts show similar growth patterns to Shh grafts.
# Gli family
There are three members of the family; Gli1, Gli2 and Gli3 which are all transcription factors mediating the Hh pathway. The GLI1, GLI2, and GLI3 genes encode transcription factors which all contain conserved tandem C2-H2 zinc finger domains and a consensus histidine/cysteine linker sequence between zinc fingers. This Gli motif is related to those of Kruppel which is a Drosophila segmentation gene of the gap class. In transgenic mice, mutant Gli1 lacking the zinc fingers does not induce Sonic Hedgehog (Shh) targets. The conserved stretch of 9 amino acids connects the C-terminal histidine of one finger to the N-terminal cysteine of the next. The GLI consensus finger amino acid sequence is JXCX3GCX3X5LX2HX4HGEKP. The Gli1 and Gli2 protein zinc finger DNA binding domain have been shown to bind to the DNA consensus GLI binding site GACCACCCA.
Gli Proteins transcriptional regulation is tissue specific for many targets. For example, Gli1 in primary keratinocytes upregulates FOXM1 whereas in mesenchymal C3H10T1/2 cells it has been shown to upregulate platelet-derived growth factor receptor PDGFRa.
Human Gli1 encodes a transcription activator involved in development that is a known oncogene. It has been found that N-terminal regions of Gli1 recruit histone deacetylase complexes via SuFu, which are involved in DNA folding in chromosomes. This may negatively regulate transcription indicating Gli1 could act as transcriptional inhibitor as well as an activator. The human GLI1 promoter region is regulated by a 1.4 kb 5’ region including a 5’ flanking sequence, an untranslated exon and 425bp of the first intron. Numerous proteins such as Sp1, USF1, USF2, and Twist are also involved in Gli1 promoter regulation. During mouse embryo development Gli1 expression can be detected in the gut mesoderm, ventral neural tube, ependymal layer of the spinal cord, forebrain, midbrain, cerebellum, and in sites of endochondral bone formation. Some of the downstream gene targets of human Gli1 include regulators of the cell cycle and apoptosis such as cyclin D2 and plakoglobin respectively. Gli1 also upregulates FoxM1 in BCC. Gli1 expression can also mimic Shh expression in certain cell types.
# Isolation
GLI1 was originally isolated from a glioma tumour and has been found to be up regulated in many tumors including muscle, brain and skin tumors such as Basal cell carcinoma (BCC).
DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.
Shh and the Gli genes are normally expressed in hair follicles, and skin tumours expressing Gli1 may arise from hair follicles. The level of Gli1 expression correlates with the tumor grade in bone and soft tissue sarcomas. Transgenic mice and frogs overexpressing Gli1 develop BCC like tumours as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas, and trichoblastomas. Expression of Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. This suggests that overexpressed Gli1 alone is probably sufficient for tumour development Mutations leading to the expression of Gli1 in basal cells are thus predicted to induce BCC formation.
# Interactions
GLI1 has been shown to interact with:
- SAP18,
- STK36,
- SUFU, and
- ZIC1. | GLI1
Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.[1]
# Function
The Gli proteins are the effectors of Hedgehog (Hh) signaling and have been shown to be involved in cell fate determination, proliferation and patterning in many cell types and most organs during embryo development.[2] In the developing spinal cord the target genes of Gli proteins, that are themselves transcription factors, are arranged into a complex gene regulatory network that translates the extracellular concentration gradient of Sonic hedgehog into different cell fates along the dorsoventral axis.[3]
The Gli transcription factors activate/inhibit transcription by binding to Gli responsive genes and by interacting with the transcription complex. The Gli transcription factors have DNA binding zinc finger domains which bind to consensus sequences on their target genes to initiate or suppress transcription.[4] Yoon[5] showed that mutating the Gli zinc finger domain inhibited the proteins effect proving its role as a transcription factor. Gli proteins have an 18-amino acid region highly similar to the α-helical herpes simplex viral protein 16 activation domain. This domain contains a consensus recognition element for the human TFIID TATA box-binding protein associated factor TAFII31.[5] Other proteins such as Missing in Metastasis (MIM/BEG4) have been shown to potentiate the effects of the Gli transcription factors on target gene transcription. Gli and MIM have been shown to act synergistically to induce epidermal growth and MIM + Gli1 overexpressing grafts show similar growth patterns to Shh grafts.[6]
# Gli family
There are three members of the family; Gli1, Gli2 and Gli3 which are all transcription factors mediating the Hh pathway. The GLI1, GLI2, and GLI3 genes encode transcription factors which all contain conserved tandem C2-H2 zinc finger domains and a consensus histidine/cysteine linker sequence between zinc fingers. This Gli motif is related to those of Kruppel which is a Drosophila segmentation gene of the gap class.[7] In transgenic mice, mutant Gli1 lacking the zinc fingers does not induce Sonic Hedgehog (Shh) targets.[8] The conserved stretch of 9 amino acids connects the C-terminal histidine of one finger to the N-terminal cysteine of the next. The GLI consensus finger amino acid sequence is [Y/F]JXCX3GCX3[F/Y]X5LX2HX4H[T/S]GEKP.[7] The Gli1 and Gli2 protein zinc finger DNA binding domain have been shown to bind to the DNA consensus GLI binding site GACCACCCA.
[9]
Gli Proteins transcriptional regulation is tissue specific for many targets. For example, Gli1 in primary keratinocytes upregulates FOXM1[10] whereas in mesenchymal C3H10T1/2 cells it has been shown to upregulate platelet-derived growth factor receptor PDGFRa.[11]
Human Gli1 encodes a transcription activator involved in development that is a known oncogene.[5][12] It has been found that N-terminal regions of Gli1 recruit histone deacetylase complexes via SuFu, which are involved in DNA folding in chromosomes.[13] This may negatively regulate transcription indicating Gli1 could act as transcriptional inhibitor as well as an activator.[14] The human GLI1 promoter region is regulated by a 1.4 kb 5’ region including a 5’ flanking sequence, an untranslated exon and 425bp of the first intron. Numerous proteins such as Sp1, USF1, USF2, and Twist are also involved in Gli1 promoter regulation.[15][16][17] During mouse embryo development Gli1 expression can be detected in the gut mesoderm, ventral neural tube, ependymal layer of the spinal cord, forebrain, midbrain, cerebellum, and in sites of endochondral bone formation.[18][19][20] Some of the downstream gene targets of human Gli1 include regulators of the cell cycle and apoptosis such as cyclin D2 and plakoglobin respectively.[21] Gli1 also upregulates FoxM1 in BCC.[10] Gli1 expression can also mimic Shh expression in certain cell types.[22]
# Isolation
GLI1 was originally isolated from a glioma tumour and has been found to be up regulated in many tumors including muscle, brain and skin tumors such as Basal cell carcinoma (BCC).[23]
DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.[24]
Shh and the Gli genes are normally expressed in hair follicles, and skin tumours expressing Gli1 may arise from hair follicles. The level of Gli1 expression correlates with the tumor grade in bone and soft tissue sarcomas.[25] Transgenic mice and frogs overexpressing Gli1 develop BCC like tumours as well as other hair follicle-derived neoplasias, such as trichoepitheliomas, cylindromas, and trichoblastomas.[22][26] Expression of Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1. This suggests that overexpressed Gli1 alone is probably sufficient for tumour development[26][27] Mutations leading to the expression of Gli1 in basal cells are thus predicted to induce BCC formation.[22]
# Interactions
GLI1 has been shown to interact with:
- SAP18,[28]
- STK36,[29]
- SUFU,[30][31][32] and
- ZIC1.[33] | https://www.wikidoc.org/index.php/GLI1 | |
fafb80d87423eddab3450a8f9024751fa548da57 | wikidoc | GLI2 | GLI2
Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.
GLI2 belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis.
# Isoforms
There are four isoforms: Gli2 alpha, beta, gamma and delta.
# Structure
C-terminal activator and N-terminal repressor regions have been identified in both Gli2 and Gli3. However, the N-terminal part of human Gli2 is much smaller than its mouse or frog homologs, suggesting that it may lack repressor function.
# Function
Gli2 affects ventroposterior mesodermal development by regulating at least three different genes; Wnt genes involved in morphogenesis, Brachyury genes involved in tissue specification and Xhox3 genes involved in positional information. The anti-apoptotic protein BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1 – but not Gli3, which may lead to carcinogenesis. Additionally, in the amphibian model organism Xenopus laevis, it has been shown that Gli2 plays a key role in the induction, specification, migration and differentiation of the neural crest. In this context, Gli2 is responding to the Indian Hedgehog signaling pathway.
It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus. This suggests that in mouse embryogenesis, Gli1 and Gli2 regulate a similar set of target genes. Mutations do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent. Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development. Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of
epidermal differentiation. There is a significant level of crosstalk and functional overlap between the Gli TFs. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically normal. However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally and Gli3 dorsally in transgenic mice. Gli2 null mice embryos develop neural tube defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs. Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level. These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumors form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous keratinocytes develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma (BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastomas, cylindromas and hamartomas but rarely developed BCCs. Gli2 is expressed in the
interfollicular epidermis and the outer root sheath of hair follicles in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.
# Clinical significance
Mutations of the GLI2 gene are associated with several phenotypes including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B.
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other.
# Cis-regulatory catalog of GLI2
Minhas et al. 2015 have recently elucidated a subset of cis-regulatory elements controlling GLI2 expression. They have shown that conserved non-coding elements (CNEs) from the intron of GLI2 gene act as tissue-specific enhancers and reporter gene expression induced by these elements correlates with previously reported endogenous gli2 expression in zebrafish. The regulatory activities of these elements are observed in several embryonic domains, including neural tube and pectoral fin. | GLI2
Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene.[1] The protein encoded by this gene is a transcription factor.[2]
GLI2 belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis.[3]
# Isoforms
There are four isoforms: Gli2 alpha, beta, gamma and delta.[4]
# Structure
C-terminal activator and N-terminal repressor regions have been identified in both Gli2 and Gli3.[5] However, the N-terminal part of human Gli2 is much smaller than its mouse or frog homologs, suggesting that it may lack repressor function.
# Function
Gli2 affects ventroposterior mesodermal development by regulating at least three different genes; Wnt genes involved in morphogenesis, Brachyury genes involved in tissue specification and Xhox3 genes involved in positional information.[6] The anti-apoptotic protein BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1 – but not Gli3, which may lead to carcinogenesis.[7] Additionally, in the amphibian model organism Xenopus laevis, it has been shown that Gli2 plays a key role in the induction, specification, migration and differentiation of the neural crest.[8] In this context, Gli2 is responding to the Indian Hedgehog signaling pathway.[9]
It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus. This suggests that in mouse embryogenesis, Gli1 and Gli2 regulate a similar set of target genes. Mutations do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent.[7] Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development.[10] Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of
epidermal differentiation.[11] There is a significant level of crosstalk and functional overlap between the Gli TFs. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically normal.[10] However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally and Gli3 dorsally in transgenic mice.[12] Gli2 null mice embryos develop neural tube defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs.[13] Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level.[10][14][15] These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumors form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.[16]
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous keratinocytes develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma (BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastomas, cylindromas and hamartomas but rarely developed BCCs.[17] Gli2 is expressed in the
interfollicular epidermis and the outer root sheath of hair follicles in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.[18]
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.[4]
# Clinical significance
Mutations of the GLI2 gene are associated with several phenotypes including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B.[3]
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.[11]
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other.
# Cis-regulatory catalog of GLI2
Minhas et al. 2015 have recently elucidated a subset of cis-regulatory elements controlling GLI2 expression. They have shown that conserved non-coding elements (CNEs) from the intron of GLI2 gene act as tissue-specific enhancers and reporter gene expression induced by these elements correlates with previously reported endogenous gli2 expression in zebrafish. The regulatory activities of these elements are observed in several embryonic domains, including neural tube and pectoral fin.[19] | https://www.wikidoc.org/index.php/GLI2 | |
81d8c079ae2c345610aa240c572fdd0b0751d6b8 | wikidoc | GLI3 | GLI3
Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.
This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH1) gene expression. It is also thought to play a role during embryogenesis.
# Role in development
Gli3 is a known transcriptional repressor but may also have a positive transcriptional function. Gli3 represses dHand and Gremlin, which are involved in developing digits. There is evidence that Shh-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of Ci. Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly. In the developing mouse limb bud, Gli3 derepression predominately regulates Shh target genes.
# Disease association
Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.
There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene.
# Interactions with Gli1 and Gli2
The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCCs. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation.
Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death, respectively, but not the formation of BCC. This suggests that overexpression of more than one Gli protein is not necessary for BCC formation.
# Interactions
GLI3 has been shown to interact with CREBBP SUFU, ZIC1, and ZIC2. | GLI3
Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.[1][2]
This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH1) gene expression. It is also thought to play a role during embryogenesis.[2]
# Role in development
Gli3 is a known transcriptional repressor but may also have a positive transcriptional function.[3][4] Gli3 represses dHand and Gremlin, which are involved in developing digits.[5] There is evidence that Shh-controlled processing (e.g., cleavage) regulates transcriptional activity of Gli3 similarly to that of Ci.[4] Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly.[6][7][8][9][10] In the developing mouse limb bud, Gli3 derepression predominately regulates Shh target genes.[11]
# Disease association
Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B.[2] DNA copy-number alterations that contribute to increased conversion of the oncogenes Gli1–3 into transcriptional activators by the Hedgehog signaling pathway are included in a genome-wide pattern, which was found to be correlated with an astrocytoma patient’s outcome.[12]
There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene.[13]
# Interactions with Gli1 and Gli2
The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCCs. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation.[14]
Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death, respectively, but not the formation of BCC. This suggests that overexpression of more than one Gli protein is not necessary for BCC formation.
# Interactions
GLI3 has been shown to interact with CREBBP[15] SUFU,[16] ZIC1,[17] and ZIC2.[17] | https://www.wikidoc.org/index.php/GLI3 | |
ca2a50387a9fe9311c124b8b687435106dc6b3eb | wikidoc | GLMN | GLMN
Glomulin is a protein that in humans is encoded by the GLMN gene.
This gene encodes a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex. The protein is essential for normal development of the vasculature and mutations in this gene have been associated with glomuvenous malformations, also called glomangiomas. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined.
# Interactions
GLMN has been shown to interact with FKBP52, C-Met and FKBP1A. | GLMN
Glomulin is a protein that in humans is encoded by the GLMN gene.[1][2]
This gene encodes a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex. The protein is essential for normal development of the vasculature and mutations in this gene have been associated with glomuvenous malformations, also called glomangiomas. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined.[2]
# Interactions
GLMN has been shown to interact with FKBP52,[1][3] C-Met[4] and FKBP1A.[1][3] | https://www.wikidoc.org/index.php/GLMN | |
01eb933d75e8944bfc9f38b5142b51069cf87d4e | wikidoc | GLS2 | GLS2
Glutaminase 2 (liver, mitochondrial) is a protein that in humans is encoded by the GLS2 gene.
# Structure
The GLS2 gene is on the 12th chromosome in humans, with its specific location being 12q13.3. It contains 19 exons.
# Function
GLS2 is a part of the glutaminase family. The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms.
# Clinical significance
GLS2 has interesting molecular relationships with tumor progression and cancer. Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. Additionally, silencing of GLS and overexpression of GLS2 genes cooperate in decreasing the proliferation and viability of glioblastoma cells. | GLS2
Glutaminase 2 (liver, mitochondrial) is a protein that in humans is encoded by the GLS2 gene.[1]
# Structure
The GLS2 gene is on the 12th chromosome in humans, with its specific location being 12q13.3. It contains 19 exons.[1]
# Function
GLS2 is a part of the glutaminase family. The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms.
# Clinical significance
GLS2 has interesting molecular relationships with tumor progression and cancer. Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma.[2] Additionally, silencing of GLS and overexpression of GLS2 genes cooperate in decreasing the proliferation and viability of glioblastoma cells.[3] | https://www.wikidoc.org/index.php/GLS2 | |
76153162792d43f3b9129ebaf8e5f4afe0c6bb4d | wikidoc | GM2A | GM2A
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the GM2A gene.
# Function
The protein encoded by this gene is a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme β-hexosaminidase A. β-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines.
GM2A is a lipid transfer protein that stimulates the enzymatic processing of gangliosides, and also T-cell activation through lipid presentation. This protein binds molecules of ganglioside GM2, extracts them from membranes, and presents them to beta-hexosaminidase A for cleavage of N-acetyl-D-galactosamine and conversion to GM3.
It was identified as a member of ML domain family of proteins involved in innate immunity and lipid metabolism in the SMART database.
# Regulation
In melanocytic cells GM2A gene expression may be regulated by MITF.
# Clinical significance
Mutations in this gene, inherited in an autosomal recessive pattern, result in GM2-gangliosidosis, AB variant, a rare GM2 gangliosidosis that has symptoms and pathology identical with Tay-Sachs disease and Sandhoff disease.
GM2A mutations are rarely reported, and the cases that are observed often occur with consanguineous parents or in genetically isolated populations.
Because AB variant is so rarely diagnosed, even in infants, it is likely that most mutations of GM2A are fatal in the fetus in homozygotes and genetic compounds, and thus are never observed clinically. | GM2A
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the GM2A gene.[1][2]
# Function
The protein encoded by this gene is a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme β-hexosaminidase A. β-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines.
GM2A is a lipid transfer protein that stimulates the enzymatic processing of gangliosides, and also T-cell activation through lipid presentation. This protein binds molecules of ganglioside GM2, extracts them from membranes, and presents them to beta-hexosaminidase A for cleavage of N-acetyl-D-galactosamine and conversion to GM3.
It was identified as a member of ML domain family of proteins involved in innate immunity and lipid metabolism in the SMART database.
[2].
# Regulation
In melanocytic cells GM2A gene expression may be regulated by MITF.[3]
# Clinical significance
Mutations in this gene, inherited in an autosomal recessive pattern, result in GM2-gangliosidosis, AB variant, a rare GM2 gangliosidosis that has symptoms and pathology identical with Tay-Sachs disease and Sandhoff disease.[4]
GM2A mutations are rarely reported, and the cases that are observed often occur with consanguineous parents or in genetically isolated populations.[5]
Because AB variant is so rarely diagnosed, even in infants, it is likely that most mutations of GM2A are fatal in the fetus in homozygotes and genetic compounds, and thus are never observed clinically. | https://www.wikidoc.org/index.php/GM2A | |
1960663a727fbd61d95368323d00a9969a61d07c | wikidoc | GNAQ | GNAQ
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Together with GNA11 (its paralogue), it functions as a Gq alpha subunit.
# Function
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways. Receptor activation catalyzes the exchange of GDP for GTP bound to the inactive G protein alpha subunit resulting in a conformational change and dissociation of the complex. The G protein alpha and beta-gamma subunits are capable of regulating various cellular effectors. Activation is terminated by a GTPase intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediates stimulation of phospholipase C-beta (MIM 600230).
Mutations in this gene have been found associated to cases of Sturge-Weber syndrome and port-wine stains.
# Interactions
GNAQ has been shown to interact with:
- Beta adrenergic receptor kinase,
- Bruton's tyrosine kinase,
- RGS16,
- RGS4
- RIC8A, and
- Sodium-hydrogen antiporter 3 regulator 1. | GNAQ
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene.[1] Together with GNA11 (its paralogue), it functions as a Gq alpha subunit.[2]
# Function
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways. Receptor activation catalyzes the exchange of GDP for GTP bound to the inactive G protein alpha subunit resulting in a conformational change and dissociation of the complex. The G protein alpha and beta-gamma subunits are capable of regulating various cellular effectors. Activation is terminated by a GTPase intrinsic to the G-alpha subunit. G-alpha-q is the alpha subunit of one of the heterotrimeric GTP-binding proteins that mediates stimulation of phospholipase C-beta (MIM 600230).[supplied by OMIM][3]
Mutations in this gene have been found associated to cases of Sturge-Weber syndrome and port-wine stains.[4]
# Interactions
GNAQ has been shown to interact with:
- Beta adrenergic receptor kinase,[5]
- Bruton's tyrosine kinase,[6]
- RGS16,[7]
- RGS4[7][8]
- RIC8A,[9][10] and
- Sodium-hydrogen antiporter 3 regulator 1.[11] | https://www.wikidoc.org/index.php/GNAQ | |
30217fc288f79aa8c77477009bee7ce1563cd004 | wikidoc | GNAZ | GNAZ
Guanine nucleotide-binding protein G(z) subunit alpha is a protein that in humans is encoded by the GNAZ gene.
# Function
The protein encoded by this gene is a member of a G protein subfamily that mediates signal transduction in pertussis toxin-insensitive systems. This encoded protein may play a role in maintaining the ionic balance of perilymphatic and endolymphatic cochlear fluids.
# Interactions
GNAZ has been shown to interact with EYA2, RGS20 and RGS19. | GNAZ
Guanine nucleotide-binding protein G(z) subunit alpha is a protein that in humans is encoded by the GNAZ gene.[1][2]
# Function
The protein encoded by this gene is a member of a G protein subfamily that mediates signal transduction in pertussis toxin-insensitive systems. This encoded protein may play a role in maintaining the ionic balance of perilymphatic and endolymphatic cochlear fluids.[2]
# Interactions
GNAZ has been shown to interact with EYA2,[3] RGS20[4][5] and RGS19.[3][6] | https://www.wikidoc.org/index.php/GNAZ | |
6de7c256e134e7b6eda0d7f28177afeb1347b2be | wikidoc | GNB1 | GNB1
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 is a protein that in humans is encoded by the GNB1 gene.
# Function
Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. This gene uses alternative polyadenylation signals.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
GNB1 has been shown to interact with GNG4. | GNB1
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 is a protein that in humans is encoded by the GNB1 gene.[1]
# Function
Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. This gene uses alternative polyadenylation signals.[1][2]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
GNB1 has been shown to interact with GNG4.[3][4] | https://www.wikidoc.org/index.php/GNB1 | |
2f61ef2cb0087e23284e4dba23e96779445f2265 | wikidoc | GNB5 | GNB5
Guanine nucleotide-binding protein subunit beta-5 is a protein that in humans is encoded by the GNB5 gene. Alternatively spliced transcript variants encoding different isoforms exist.
# Function
Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors.
GNB5 has been shown to differentially control RGS protein stability and membrane anchor binding, and therefore is involved in the control of complex neuronal G protein signaling pathways.
# Interactions
GNB5 has been shown to interact with:
- GNG7,
- GNG13,
- RGS7 and
- RGS9. | GNB5
Guanine nucleotide-binding protein subunit beta-5 is a protein that in humans is encoded by the GNB5 gene.[1] Alternatively spliced transcript variants encoding different isoforms exist.[2]
# Function
Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors.[2]
GNB5 has been shown to differentially control RGS protein stability and membrane anchor binding, and therefore is involved in the control of complex neuronal G protein signaling pathways.[3]
# Interactions
GNB5 has been shown to interact with:
- GNG7,[4]
- GNG13,[5]
- RGS7[6][7] and
- RGS9.[3] | https://www.wikidoc.org/index.php/GNB5 | |
628fd7c7933ce07b0bea1c4f5a1acd20c1944e47 | wikidoc | GNG2 | GNG2
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 is a protein that in humans is encoded by the GNG2 gene.
Heterotrimeric G proteins play vital roles in cellular responses to external signals. The specificity of a G protein-receptor interaction is primarily mediated by the gamma subunit.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | GNG2
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 is a protein that in humans is encoded by the GNG2 gene.[1][2]
Heterotrimeric G proteins play vital roles in cellular responses to external signals. The specificity of a G protein-receptor interaction is primarily mediated by the gamma subunit.[supplied by OMIM][2]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/GNG2 | |
39b1b97064c2afd1df8c8ff3929127face6ad322 | wikidoc | GNLY | GNLY
Granulysin, also known as GNLY, is a protein which in humans is encoded by the GNLY gene.
# Function
Granulysin is a protein present in cytotoxic granules of cytotoxic T cells and natural killer cells. Granulysin is a member of the saposin-like protein (SAPLIP) family and is released from cytotoxic T cells upon antigen stimulation. Granulysin has antimicrobial activity against M. tuberculosis and other organisms. Granulysin is alternatively spliced, resulting in the NKG5 and 519 transcripts.
Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed “late” (3–5 days) after activation of human peripheral blood mononuclear cells. Granulysin is present in cytolytic granules of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Granulysin is made as a 15 kD molecule, and a portion of it is cleaved at both the amino and carboxy termini into a 9 kD form. The 9 kD form is released by receptor-mediated granule exocytosis while the 15 kD form is constitutively secreted. Recombinant 9 kD granulysin is broadly cytolytic against tumors and microbes, including gram positive and gram negative bacteria, fungi/yeast and parasites. 9kD granulysin is also a chemoattractant for T lymphocytes, monocytes, and other inflammatory cells and activates the expression of a number of cytokines, including RANTES, MCP-1, MCP-3, MIP-1α, IL-10, IL-1, IL-6 and IFNα. Mice do not have a granulysin homolog, but transgenic mice expressing human granulysin have been engineered. Granulysin has been implicated in a myriad of diseases including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies. | GNLY
Granulysin, also known as GNLY, is a protein which in humans is encoded by the GNLY gene.[1]
# Function
Granulysin is a protein present in cytotoxic granules of cytotoxic T cells and natural killer cells. Granulysin is a member of the saposin-like protein (SAPLIP) family and is released from cytotoxic T cells upon antigen stimulation. Granulysin has antimicrobial activity against M. tuberculosis and other organisms. Granulysin is alternatively spliced, resulting in the NKG5 and 519 transcripts.[1]
Granulysin is a cytolytic and proinflammatory molecule first identified by a screen for genes expressed “late” (3–5 days) after activation of human peripheral blood mononuclear cells.[2] Granulysin is present in cytolytic granules of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Granulysin is made as a 15 kD molecule, and a portion of it is cleaved at both the amino and carboxy termini into a 9 kD form. The 9 kD form is released by receptor-mediated granule exocytosis while the 15 kD form is constitutively secreted. Recombinant 9 kD granulysin is broadly cytolytic against tumors and microbes, including gram positive and gram negative bacteria, fungi/yeast and parasites.[3] 9kD granulysin is also a chemoattractant for T lymphocytes, monocytes, and other inflammatory cells and activates the expression of a number of cytokines, including RANTES, MCP-1, MCP-3, MIP-1α, IL-10, IL-1, IL-6 and IFNα.[4] Mice do not have a granulysin homolog, but transgenic mice expressing human granulysin have been engineered.[5] Granulysin has been implicated in a myriad of diseases including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies.[6] | https://www.wikidoc.org/index.php/GNLY | |
2b53f53ceb382a06960b1ac968f98f73c863ed70 | wikidoc | GNMT | GNMT
Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.
# Discovery
The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver. However, this enzyme was not purified until 1972 in the rabbit liver by Kerr. In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT. The human GMNT gene was cloned in 2000 by Chen and coworkers.
# Tissue distribution
GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver. In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney. GNMT is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas. The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa. GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum. The presence of GNMT in these cells suggests that this enzyme may play a role in secretion.
# Structure
The properties of GNMT protein from rabbits, rats and humans, either purified from liver/pancreas, or expressed in Escherichia coli, have been well characterized. All GNMTs have very similar molecular and kinetic properties. Comparison of the cDNA and protein sequences of human, rabbit, pig and rat GNMTs shows similarities of over 84% at the nucleotide level and about 90% at the amino acid level. All GNMTs are 130 kDa tetramers consisting of four identical subunits, each having a Mr of 32 kDa. The structure of recombinant rat, mouse and human GNMTs have been solved. The four nearly spherical subunits are arranged to form a flat and square tetramer with a large hole in the center. The active sites are located in the near center of each subunit.
# Function
Glycine N-methyltransferase catalyzes the synthesis of N-methylglycine (sarcosine) from glycine using S-adenosylmethionine(SAM) (AdoMet) as the methyl donor. GNMT acts as an enzyme to regulate the ratio of S-adenosylmethionine(SAM) to S-adenosylhomocysteine (SAH) (AdoHcy) and participates in the detoxification pathway in liver cells. GNMT competes with tRNA methyltransferases for SAM and the product, S-adenosylhomocysteine (SAH), is a potent inhibitor of tRNA methyltransferases and a relatively weak inhibitor of GNMT. GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions. GNMT is therefore likely to regulate cellular methylation capacity. An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme. Thus, GNMT has been proposed to link the de novo synthesis of methyl groups to the ratio of SAM to SAH, which in turn serves as a bridge between methionine and one-carbon metabolism.
In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein. The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases, which therefore suggests that GNMT may be capable of capturing unidentified chemicals as a part of a detoxification process. Therefore, GNMT has been proposed to be a protein with diverse functionality.
# Clinical significance
GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin.
There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis.
# Inducer
The glycoside natural product 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) isolated from Paeonia lactiflora, an Asian flower plant, induces GNMT mRNA and protein expression in Huh7 human hepatoma cells. | GNMT
Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.[1][2][3]
# Discovery
The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver.[4] However, this enzyme was not purified until 1972 in the rabbit liver by Kerr.[5] In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT.[6] The human GMNT gene was cloned in 2000 by Chen and coworkers.[2]
# Tissue distribution
GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver.[7] In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney.[5] GNMT is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas.[7] The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa.[7] GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum.[8] The presence of GNMT in these cells suggests that this enzyme may play a role in secretion.
# Structure
The properties of GNMT protein from rabbits, rats and humans, either purified from liver/pancreas, or expressed in Escherichia coli, have been well characterized. All GNMTs have very similar molecular and kinetic properties.[7][9][10][11][12] Comparison of the cDNA and protein sequences of human, rabbit, pig and rat GNMTs shows similarities of over 84% at the nucleotide level and about 90% at the amino acid level. All GNMTs are 130 kDa tetramers consisting of four identical subunits, each having a Mr of 32 kDa.[11] The structure of recombinant rat, mouse and human GNMTs have been solved.[13][14] The four nearly spherical subunits are arranged to form a flat and square tetramer with a large hole in the center. The active sites are located in the near center of each subunit.
# Function
Glycine N-methyltransferase catalyzes the synthesis of N-methylglycine (sarcosine) from glycine using S-adenosylmethionine(SAM) (AdoMet) as the methyl donor. GNMT acts as an enzyme to regulate the ratio of S-adenosylmethionine(SAM) to S-adenosylhomocysteine (SAH) (AdoHcy)[15] and participates in the detoxification pathway in liver cells.[3] GNMT competes with tRNA methyltransferases for SAM and the product, S-adenosylhomocysteine (SAH), is a potent inhibitor of tRNA methyltransferases and a relatively weak inhibitor of GNMT.[5] GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions.[15] GNMT is therefore likely to regulate cellular methylation capacity.[15][16] An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme.[17] Thus, GNMT has been proposed to link the de novo synthesis of methyl groups to the ratio of SAM to SAH, which in turn serves as a bridge between methionine and one-carbon metabolism.[15][17]
In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein.[18] The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases,[13] which therefore suggests that GNMT may be capable of capturing unidentified chemicals as a part of a detoxification process. Therefore, GNMT has been proposed to be a protein with diverse functionality.[19]
# Clinical significance
GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin.[20]
There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis.[21]
# Inducer
The glycoside natural product 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) isolated from Paeonia lactiflora, an Asian flower plant, induces GNMT mRNA and protein expression in Huh7 human hepatoma cells.[22] | https://www.wikidoc.org/index.php/GNMT | |
2e024de43b9cc01ef16e8f8e15d9a94f12ca7bb4 | wikidoc | GOPC | GOPC
Golgi-associated PDZ and coiled-coil motif-containing protein is a protein that in humans is encoded by the GOPC gene.
PIST is a PDZ domain-containing Golgi protein. PDZ domains contain approximately 90 amino acids and bind the extreme C terminus of proteins in a sequence-specific manner.
# Interactions
GOPC has been shown to interact with GRID2, BECN1, RHOQ,ACCN3, Cystic fibrosis transmembrane conductance regulator and CSPG5. | GOPC
Golgi-associated PDZ and coiled-coil motif-containing protein is a protein that in humans is encoded by the GOPC gene.[1][2][3]
PIST is a PDZ domain-containing Golgi protein. PDZ domains contain approximately 90 amino acids and bind the extreme C terminus of proteins in a sequence-specific manner.[supplied by OMIM][3]
# Interactions
GOPC has been shown to interact with GRID2,[4] BECN1,[4] RHOQ,[1]ACCN3,[5] Cystic fibrosis transmembrane conductance regulator[6][7] and CSPG5.[8] | https://www.wikidoc.org/index.php/GOPC | |
70d0712d3b3c2d52d7e0089d2723fae972920a88 | wikidoc | GOT1 | GOT1
Aspartate aminotransferase, cytoplasmic is an enzyme that in humans is encoded by the GOT1 gene.
Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | GOT1
Aspartate aminotransferase, cytoplasmic is an enzyme that in humans is encoded by the GOT1 gene.[1][2]
Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology.[2]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/GOT1 | |
aa1ee15bdee0aad2a9637bf1072f11d864de705f | wikidoc | GOT2 | GOT2
Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology. GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.
# Structure
GOT2 is a dimer containing two identical subunits that hold overlapping subunit regions. The top and sides of the enzyme are made up of helices, while the bottom is formed by strands of beta sheets and extended hairpin loops. The subunit itself can be categorized into four different parts: a large domain, which binds pyridoxal-P, a small domain, an NH2-terminal arm, and a bridge across two domains, which is formed by residues 48-75 and 301-358. Virtually ubiquitous in eukaryotic cells, GOT2 nucleic acid and protein sequences are highly conserved, and its 5’regulatory regions in genomic DNA resemble those of typical house-keeping genes in that, e.g.,they lack a TATA box. The GOT2 gene is also located on 16q21 and has an exon count of 10.
# Function
In order to produce the energy needed for everyday activities, our body needs to go through the process of glycolysis, which breaks down glucose into pyruvate. In this pathway, one very important part is the reduction of NAD+ to NADH and then the rapid oxidation of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of the electron transport chain, but the transfer of NADH into the mitochondria from the cytosol is impossible, due to the impermeability of the inner mitochondrial membrane to NADH. Therefore, the malate-aspartate shuttle is needed to transfer reducing equivalents across the mitochondrial membrane for energy production. GOT2 and another enzyme, MDH, are essential for the functioning of the shuttle. GOT2 converts oxaloacetate into aspartate by transamination. This aspartate as well as alpha-ketoglutarate return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively.
Another function of GOT2 is that it is believed to transaminate kynurenine into kynurenic acid (KYNA) in the brain. The KYNA made by the GOT2 is thought to be an important factor in brain pathology. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of the neurotoxicity caused by mitochondrial poisons, such as otenone, malonate, 1-methyl-4-phenylpyridinium, and 3-nitropropionic acid.
# Clinical Significance
In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy, biosynthesis, and redox needs. Therefore, the malate-aspartate shuttle promotes the net transfer of cytosolic NADH into mitochondria to ensure a high rate of glycolysis in diverse cancer cell lines. In a study completed in 2008, inhibiting the malate-aspartate shuttle was found to impair the glycolysis process and essentially decreased breast adenocarcinoma cell proliferation. Furthermore, knocking down GOT2 and GOT1 has also been reported to inhibit cell proliferation and colony formation in pancreatic cancer cell lines, suggesting that the GOT enzyme is essential for maintaining a high rate of glycolysis to support rapid tumor cell growth. Also, both glucose and glutamine increase GOT2 3K acetylation in PANC-1 cells and that GOT2 3K acetylation plays a critical role in coordinating glucose and glutamine uptake to provide energy and support cell proliferation and tumor growth. This implies that inhibiting GOT2 3K acetylation may merit exploration as a therapeutic agent especially for pancreatic cancer.
# Interactions
GOT2 has been seen to interact with:
- oxaloacetate
- kynurenine
- aspartate
- alpha-ketoglutarate
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | GOT2
Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology.[1] GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.
# Structure
GOT2 is a dimer containing two identical subunits that hold overlapping subunit regions. The top and sides of the enzyme are made up of helices, while the bottom is formed by strands of beta sheets and extended hairpin loops. The subunit itself can be categorized into four different parts: a large domain, which binds pyridoxal-P, a small domain, an NH2-terminal arm, and a bridge across two domains, which is formed by residues 48-75 and 301-358.[2] Virtually ubiquitous in eukaryotic cells, GOT2 nucleic acid and protein sequences are highly conserved, and its 5’regulatory regions in genomic DNA resemble those of typical house-keeping genes in that, e.g.,they lack a TATA box.[3] The GOT2 gene is also located on 16q21 and has an exon count of 10.[1]
# Function
In order to produce the energy needed for everyday activities, our body needs to go through the process of glycolysis, which breaks down glucose into pyruvate. In this pathway, one very important part is the reduction of NAD+ to NADH and then the rapid oxidation of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of the electron transport chain, but the transfer of NADH into the mitochondria from the cytosol is impossible, due to the impermeability of the inner mitochondrial membrane to NADH. Therefore, the malate-aspartate shuttle is needed to transfer reducing equivalents across the mitochondrial membrane for energy production. GOT2 and another enzyme, MDH, are essential for the functioning of the shuttle. GOT2 converts oxaloacetate into aspartate by transamination. This aspartate as well as alpha-ketoglutarate return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively.[4]
Another function of GOT2 is that it is believed to transaminate kynurenine into kynurenic acid (KYNA) in the brain. The KYNA made by the GOT2 is thought to be an important factor in brain pathology. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of the neurotoxicity caused by mitochondrial poisons, such as otenone, malonate, 1-methyl-4-phenylpyridinium, and 3-nitropropionic acid.[5]
# Clinical Significance
In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy, biosynthesis, and redox needs. Therefore, the malate-aspartate shuttle promotes the net transfer of cytosolic NADH into mitochondria to ensure a high rate of glycolysis in diverse cancer cell lines. In a study completed in 2008, inhibiting the malate-aspartate shuttle was found to impair the glycolysis process and essentially decreased breast adenocarcinoma cell proliferation. Furthermore, knocking down GOT2 and GOT1 has also been reported to inhibit cell proliferation and colony formation in pancreatic cancer cell lines, suggesting that the GOT enzyme is essential for maintaining a high rate of glycolysis to support rapid tumor cell growth. Also, both glucose and glutamine increase GOT2 3K acetylation in PANC-1 cells and that GOT2 3K acetylation plays a critical role in coordinating glucose and glutamine uptake to provide energy and support cell proliferation and tumor growth. This implies that inhibiting GOT2 3K acetylation may merit exploration as a therapeutic agent especially for pancreatic cancer.[4]
# Interactions
GOT2 has been seen to interact with:
- oxaloacetate
- kynurenine
- aspartate
- alpha-ketoglutarate
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/GOT2 | |
453fda6413b39c20c4181529767de7e85c683910 | wikidoc | GPER | GPER
G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.
# Discovery
The classical estrogen receptors first characterized in 1958 are water-soluble proteins located in the interior of cells that are activated by estrogenenic hormones such as estradiol and several of its metabolites such as estrone or estriol. These proteins belong to the nuclear hormone receptor class of transcription factors that regulate gene transcription. Since it takes time for genes to be transcribed into RNA and translated into protein, the effects of estrogens binding to these classical estrogen receptors is delayed. However, estrogens are also known to have effects that are too fast to be caused by regulation of gene transcription. In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) family, GPR30 also binds with high affinity to estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor (GPER). Unlike the other members of the GPCR family, which reside in the outer membrane of cells, GPER is localized in the endoplasmic reticulum.
# Ligands
GPER binds estradiol though not other endogenous estrogens, such as estrone or estriol, nor for other endogenous steroids, including progesterone, testosterone, and cortisol. Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone. Niacin and nicotinamide bind to the receptor in vitro with very low affinity. CCL18 has been identified as an endogenous antagonist of the GPER.
# Function
This protein is a member of the rhodopsin-like family of G protein-coupled receptors and is a multi-pass membrane protein that localizes to the endoplasmic reticulum. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol. The distribution of GPER is well established in the rodent, with high expression observed in the hypothalamus, pituitary gland, adrenal medulla, kidney medulla and developing follicles of the ovary.
# Animal studies
## Reproductive tissue
GPER is expressed in the breasts, and activation by estradiol produces cell proliferation in both normal and malignant breast epithelial tissue. However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice. This indicates that although GPER and ERβ play a modulatory role in breast development, ERα is the main receptor responsible for estrogen-mediated breast tissue growth. GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis. GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.
## Cardiovascular effects
GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol. GPER also regulates components of the renin–angiotensin system, which also controls blood pressure, and is required for superoxide-mediated cardiovascular function and aging.
## Central nervous system activity
GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol. Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic. There is a high expression of GPER, as well as ERβ, in oxytocin neurons in various parts of the hypothalamus, including the paraventricular nucleus and the supraoptic nucleus. It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system, for instance, rapidly increasing oxytocin receptor expression. Estradiol has also been found to increase oxytocin levels and release in the medial preoptic area and medial basal hypothalamus, actions that may be mediated by activation of GPER and/or ERβ. Estradiol, as well as tamoxifen and fulvestrant, have been found to rapidly induce lordosis through activation of GPER in the arcuate nucleus of the hypothalamus of female rats.
## Metabolic roles
Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure. Male GPER knockout mice are observed to have increased growth, body fat, insulin resistance and glucose intolerance, dyslipidemia, increased osteoblast function (mineralization), resulting in higher bone mineral density and trabecular bone volume, and persistent growth plate activity resulting in longer bones.
# Clinical significance
GPER plays a role in breast cancer progression and tamoxifen resistance. GPER has also been proposed as a biomarker in triple-negative breast cancer. In patients with endometrial cancer GPER it is overexpressed and its associated with poor survival. In other tumors, there is still a controversy over the role of GPER. For example in ovarian cancer, some studies indicate a link between GPER expression and poor prognosis, while other studies do not. | GPER
G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene.[1] GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.
# Discovery
The classical estrogen receptors first characterized in 1958[2] are water-soluble proteins located in the interior of cells that are activated by estrogenenic hormones such as estradiol and several of its metabolites such as estrone or estriol. These proteins belong to the nuclear hormone receptor class of transcription factors that regulate gene transcription. Since it takes time for genes to be transcribed into RNA and translated into protein, the effects of estrogens binding to these classical estrogen receptors is delayed. However, estrogens are also known to have effects that are too fast to be caused by regulation of gene transcription.[3] In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) family, GPR30 also binds with high affinity to estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor (GPER). Unlike the other members of the GPCR family, which reside in the outer membrane of cells, GPER is localized in the endoplasmic reticulum.[3]
# Ligands
GPER binds estradiol though not other endogenous estrogens, such as estrone or estriol, nor for other endogenous steroids, including progesterone, testosterone, and cortisol.[4][5][6][7] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone.[8][9] Niacin and nicotinamide bind to the receptor in vitro with very low affinity.[10][11] CCL18 has been identified as an endogenous antagonist of the GPER.[12]
# Function
This protein is a member of the rhodopsin-like family of G protein-coupled receptors and is a multi-pass membrane protein that localizes to the endoplasmic reticulum. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus.[4] This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol.[13] The distribution of GPER is well established in the rodent, with high expression observed in the hypothalamus, pituitary gland, adrenal medulla, kidney medulla and developing follicles of the ovary.[14]
# Animal studies
## Reproductive tissue
GPER is expressed in the breasts, and activation by estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[15][16] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[15] This indicates that although GPER and ERβ play a modulatory role in breast development, ERα is the main receptor responsible for estrogen-mediated breast tissue growth.[15] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[17][18][19][20] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[20]
## Cardiovascular effects
GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol.[21] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[22][23] and is required for superoxide-mediated cardiovascular function and aging.[24]
## Central nervous system activity
GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[25][26][27] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[28] There is a high expression of GPER, as well as ERβ, in oxytocin neurons in various parts of the hypothalamus, including the paraventricular nucleus and the supraoptic nucleus.[27][29] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[27][29] for instance, rapidly increasing oxytocin receptor expression.[30] Estradiol has also been found to increase oxytocin levels and release in the medial preoptic area and medial basal hypothalamus, actions that may be mediated by activation of GPER and/or ERβ.[30] Estradiol, as well as tamoxifen and fulvestrant, have been found to rapidly induce lordosis through activation of GPER in the arcuate nucleus of the hypothalamus of female rats.[31][32]
## Metabolic roles
Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[33] Male GPER knockout mice are observed to have increased growth, body fat, insulin resistance and glucose intolerance, dyslipidemia, increased osteoblast function (mineralization), resulting in higher bone mineral density and trabecular bone volume, and persistent growth plate activity resulting in longer bones.[34][35]
# Clinical significance
GPER plays a role in breast cancer progression and tamoxifen resistance.[16] GPER has also been proposed as a biomarker in triple-negative breast cancer.[16] In patients with endometrial cancer GPER it is overexpressed and its associated with poor survival.[36] In other tumors, there is still a controversy over the role of GPER. For example in ovarian cancer, some studies indicate a link between GPER expression and poor prognosis, while other studies do not.[36] | https://www.wikidoc.org/index.php/GPER | |
b63799e302b9ac1e31c136447359df6942a0d1c6 | wikidoc | GPVI | GPVI
Glycoprotein VI (platelet) also known as GPVI is a glycoprotein receptor for collagen which is expressed in platelets. In humans, glycoprotein VI is encoded by the GPVI gene.
GPVI was first cloned in 2000 by several groups including that of Martine Jandrot-Perrus from INSERM.
# Function
Glycoprotein VI (GP6) is a 58-kD platelet membrane glycoprotein that plays a crucial role in the collagen-induced activation and aggregation of platelets. Upon injury to the vessel wall and subsequent damage to the endothelial lining, exposure of the subendothelial matrix to blood flow results in deposition of platelets. Collagen fibers are the most thrombogenic macromolecular components of the extracellular matrix, with collagen types I, III, and VI being the major forms found in blood vessels. Platelet interaction with collagen occurs as a 2-step procedure: (1) the initial adhesion to collagen is followed by (2) an activation step leading to platelet secretion, recruitment of additional platelets, and aggregation. In physiologic conditions, the resulting platelet plug is the initial hemostatic event limiting blood loss. However, exposure of collagen after rupture of atherosclerotic plaques is a major stimulus of thrombus formation associated with myocardial infarction or stroke.
Complete or partial deficiency of GPVI in humans is a rare condition presenting as a mild bleeding disorder.
# Interactions
GPVI has been shown to interact with LYN. | GPVI
Glycoprotein VI (platelet) also known as GPVI is a glycoprotein receptor for collagen which is expressed in platelets. In humans, glycoprotein VI is encoded by the GPVI gene.[1]
GPVI was first cloned in 2000 by several groups including that of Martine Jandrot-Perrus from INSERM.
# Function
Glycoprotein VI (GP6) is a 58-kD platelet membrane glycoprotein that plays a crucial role in the collagen-induced activation and aggregation of platelets. Upon injury to the vessel wall and subsequent damage to the endothelial lining, exposure of the subendothelial matrix to blood flow results in deposition of platelets. Collagen fibers are the most thrombogenic macromolecular components of the extracellular matrix, with collagen types I, III, and VI being the major forms found in blood vessels. Platelet interaction with collagen occurs as a 2-step procedure: (1) the initial adhesion to collagen is followed by (2) an activation step leading to platelet secretion, recruitment of additional platelets, and aggregation. In physiologic conditions, the resulting platelet plug is the initial hemostatic event limiting blood loss. However, exposure of collagen after rupture of atherosclerotic plaques is a major stimulus of thrombus formation associated with myocardial infarction or stroke.[2][3]
Complete or partial deficiency of GPVI in humans is a rare condition presenting as a mild bleeding disorder.
# Interactions
GPVI has been shown to interact with LYN.[4] | https://www.wikidoc.org/index.php/GPVI | |
fc2233d171215715f0dd46d046d5d283984e7a2f | wikidoc | GPX1 | GPX1
Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.
# Structure
This gene encodes a member of the glutathione peroxidase family, consisting of eight known glutathione peroxidases (GPx1-8) in humans. Mammalian Gpx1 (this gene), Gpx2, Gpx3, and Gpx4 have been shown to be selenium-containing enzymes, whereas Gpx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon. In addition to the UGA-codon, a cis-acting element in the mRNA, called SECIS, binds SBP2 to recruit other proteins, such as eukaryotic elongation factor selenocysteine-tRNA specific, to form the complex responsible for the recoding process.
The protein encoded by this gene forms a homotetramer structure. As with other glutathione peroxidases, GPx1 has a conserved catalytic tetrad composed of Sec or Cys, Gln, Trp, and Asn, where the Sec is surrounded by four arginines (R 57, 103, 184, 185; bovine numbering) and a lysine of an adjacent subunit (K 91'). These 5 residues bind glutathione (GSH) and are only present in GPx1.
Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
Glutathione peroxidase 1 is characterized in a polyalanine sequence polymorphism in the N-terminal region, which includes three alleles with five, six or seven alanine (Ala) repeats in this sequence. The allele with five Ala repeats is significantly associated with breast cancer risk.
# Function
GPX1 is ubiquitously expressed in many tissues, where it protects cells from oxidative stress. Within cells, it localizes to the cytoplasm and mitochondria. As a glutathione peroxidase, GPx1 functions in the detoxification of hydrogen peroxide, specifically by catalyzing the reduction of hydrogen peroxide to water. The glutathione peroxidase also catalyzes the reduction of other organic hydroperoxides, such as lipid peroxides, to the corresponding alcohols. GPx1 typically uses glutathione (GSH) as the reductant, but when glutathione synthetase (GSS) is, as in brain mitochondria, γ-glutamylcysteine can serve as the reductant instead. The protein encoded by this gene protects from CD95-induced apoptosis in cultured breast cancer cells and inhibits 5-lipoxygenase in blood cells, and its overexpression delays endothelial cell death and increases resistance to toxic challenges, especially oxidative stress. This protein is one of only a few proteins known in higher vertebrates to contain selenocysteine, which occurs at the active site of glutathione peroxidase and is coded by the nonsense (stop) codon TGA.
GPX1 forms a highly reactive selenenic acid intermediate, providing insight into the way that the protein environment stabilizes these intermediates and paving the way for new therapeutics. Selenenic acid is protected by the protein environment from reactive groups within the protein. The mechanism of action is based on selenenic acid reacting with the amid or amine bond of another protein, forming a senyladmide bond, suggesting a role for this bond new bond in protecting the reactivity of GPX1.
# Animal studies
GPX1 helps to prevent cardiac dysfunction after ischemia-reperfusion injuries. Mitochondrial ROS production and oxidative mtDNA damage is increased during reoxygenation in the GPX1 knockout mice, in addition to structural abnormalities in cardiac mitochondria and myocytes, suggesting GPX1 may play an important role in protecting cardiac mitochondria from reoxygenation damage in vivo.
In GPX1 (-/-) mice, oxidant formation is increased, endothelial NO synthase is deregulated, and adhesion of leukocytes to cultured endothelial cells is increased. Experimental GPX1 deficiency amplifies certain aspects of aging, namely endothelial dysfunction, vascular remodeling, and invasion of leukocytes in cardiovascular tissue.
# Clinical significance
The GPx1 allele with five Ala repeats is significantly associated with breast cancer risk.
Kocabasoglu, et al., sought to investigate connections between oxidative stress genes, including GPX1, and Panic Disorder, an anxiety disorder characterized by random and unexpected attacks of intense fear. Although the GPX1 Pro198Leu polymorphism, in general, did not significantly correlate with panic disorder risk, the study found a plausible association of the C allele of the GPX1 Pro198Leu polymorphism, found to be more frequent in the female cohort, with PD development.
Ergen and colleagues analyzed gene expression of oxidative stress genes, specifically GPX1, in colorectal tumors in comparison to healthy colorectal tissues. ELISA was utilized to quantify GPX1 protein expression levels in both tissue types, highlighting a 2-fold decrease in tumor tissue (p<0.05).
In esophageal cancer, Chen and colleagues found that vitamin D, a known suppressor of GPX1 expression via the NF-kB signaling pathway, could help to decrease the proliferative, migratory, and invasive capabilities of esophageal cancer cells. Unlike in colorectal cancer, GPX1 expression in esophageal cancer cells is thought to drive aggressive growth and metastasis, but Vitamin D-mediated decrease in GPX1 prevents such growth.
In a study looking at gene polymorphisms of GPX1 and other oxidative stress genes in relation to prevalence of Type 2 diabetes mellitus, Banerjee, et al, found that while no association was found in expression of most GPX1 polymorphisms and risk of Type 2 diabetes mellitus, having the C allele of GPX1 led to a 1.362 times higher risk of the disease, highlighting the importance of finding individuals in the population with this gene variant to help treat them early on.
Recent work by Alan M. Diamond and colleagues has shown that allelic variations of GPX1, like the codon 198 polymorphism that results in leucine or proline and an increase in alanine repeat codons, can result in different localization levels in MCF-7 human breast carcinoma cells. For instance, the allele expressing the leucine-198 polymorphism and 7 alanine repeats generates GPX-1 localization that is disproportionately in the cytoplasm as compared to other allelic variants. To further understand the effects of these variants on GPX-1 function, mutant GPX-1 with mitochondrial localization sequences were generated and the GPX-1 infused cells were analyzed for their response to oxidative stress, energy metabolism and cancer-associated signaling molecules. Ultimately, GPX-1 variants heavily influenced cellular biology, suggesting that different GPX-1 variants affect cancer risk differently.
An analysis of GPX1 expression in oligodendrocytes from patients with major depressive disorder and control patients showed that GPX1 levels were significantly decreased in patients with the disorder, but not in their astrocytes. Shortening of telomeres and decreased expression of telomerase were also evident in these oligodendrocytes, but not in the astrocytes in these patients. This suggests that decreased oxidative stress protection, as observed by decreased GPX1 levels, and decreased telomerase expression may help give rise to telomere shortening in patients suffering from MDD.
# Interactions
GPX1 has been shown to interact with ABL and GSH.
A recently discovered suppressor for GPX1 is S-adenosylhomocysteine, which when accumulated in endothelial cells can cause tRNA(Sec) hypomethylation, reducing the expression of GPX1 and other selenoproteins. The decreased GPX-1 expression can then lead to inflammatory activating of endothelial cells, helping give rise to a proatherogenic endothelial phenotype. | GPX1
Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3.[1] This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.[2]
# Structure
This gene encodes a member of the glutathione peroxidase family, consisting of eight known glutathione peroxidases (GPx1-8) in humans. Mammalian Gpx1 (this gene), Gpx2, Gpx3, and Gpx4 have been shown to be selenium-containing enzymes, whereas Gpx6 is a selenoprotein in humans with cysteine-containing homologues in rodents.[2][3][4] In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon.[2][5] In addition to the UGA-codon, a cis-acting element in the mRNA, called SECIS, binds SBP2 to recruit other proteins, such as eukaryotic elongation factor selenocysteine-tRNA specific, to form the complex responsible for the recoding process.[4]
The protein encoded by this gene forms a homotetramer structure. As with other glutathione peroxidases, GPx1 has a conserved catalytic tetrad composed of Sec or Cys, Gln, Trp, and Asn, where the Sec is surrounded by four arginines (R 57, 103, 184, 185; bovine numbering) and a lysine of an adjacent subunit (K 91'). These 5 residues bind glutathione (GSH) and are only present in GPx1.[3]
Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]
Glutathione peroxidase 1 is characterized in a polyalanine sequence polymorphism in the N-terminal region, which includes three alleles with five, six or seven alanine (Ala) repeats in this sequence. The allele with five Ala repeats is significantly associated with breast cancer risk.[2]
# Function
GPX1 is ubiquitously expressed in many tissues, where it protects cells from oxidative stress.[3][4] Within cells, it localizes to the cytoplasm and mitochondria.[3] As a glutathione peroxidase, GPx1 functions in the detoxification of hydrogen peroxide, specifically by catalyzing the reduction of hydrogen peroxide to water. The glutathione peroxidase also catalyzes the reduction of other organic hydroperoxides, such as lipid peroxides, to the corresponding alcohols.[2][3][6] GPx1 typically uses glutathione (GSH) as the reductant, but when glutathione synthetase (GSS) is, as in brain mitochondria, γ-glutamylcysteine can serve as the reductant instead.[3] The protein encoded by this gene protects from CD95-induced apoptosis in cultured breast cancer cells and inhibits 5-lipoxygenase in blood cells, and its overexpression delays endothelial cell death and increases resistance to toxic challenges, especially oxidative stress.[4][6][7][8] This protein is one of only a few proteins known in higher vertebrates to contain selenocysteine, which occurs at the active site of glutathione peroxidase and is coded by the nonsense (stop) codon TGA.[2][4]
GPX1 forms a highly reactive selenenic acid intermediate, providing insight into the way that the protein environment stabilizes these intermediates and paving the way for new therapeutics. Selenenic acid is protected by the protein environment from reactive groups within the protein. The mechanism of action is based on selenenic acid reacting with the amid or amine bond of another protein, forming a senyladmide bond, suggesting a role for this bond new bond in protecting the reactivity of GPX1.[9]
# Animal studies
GPX1 helps to prevent cardiac dysfunction after ischemia-reperfusion injuries. Mitochondrial ROS production and oxidative mtDNA damage is increased during reoxygenation in the GPX1 knockout mice, in addition to structural abnormalities in cardiac mitochondria and myocytes, suggesting GPX1 may play an important role in protecting cardiac mitochondria from reoxygenation damage in vivo.[10]
In GPX1 (-/-) mice, oxidant formation is increased, endothelial NO synthase is deregulated, and adhesion of leukocytes to cultured endothelial cells is increased. Experimental GPX1 deficiency amplifies certain aspects of aging, namely endothelial dysfunction, vascular remodeling, and invasion of leukocytes in cardiovascular tissue.[11]
# Clinical significance
The GPx1 allele with five Ala repeats is significantly associated with breast cancer risk.[2]
Kocabasoglu, et al., sought to investigate connections between oxidative stress genes, including GPX1, and Panic Disorder, an anxiety disorder characterized by random and unexpected attacks of intense fear. Although the GPX1 Pro198Leu polymorphism, in general, did not significantly correlate with panic disorder risk, the study found a plausible association of the C allele of the GPX1 Pro198Leu polymorphism, found to be more frequent in the female cohort, with PD development.[12]
Ergen and colleagues analyzed gene expression of oxidative stress genes, specifically GPX1, in colorectal tumors in comparison to healthy colorectal tissues. ELISA was utilized to quantify GPX1 protein expression levels in both tissue types, highlighting a 2-fold decrease in tumor tissue (p<0.05).[13]
In esophageal cancer, Chen and colleagues found that vitamin D, a known suppressor of GPX1 expression via the NF-kB signaling pathway, could help to decrease the proliferative, migratory, and invasive capabilities of esophageal cancer cells. Unlike in colorectal cancer, GPX1 expression in esophageal cancer cells is thought to drive aggressive growth and metastasis, but Vitamin D-mediated decrease in GPX1 prevents such growth.[14]
In a study looking at gene polymorphisms of GPX1 and other oxidative stress genes in relation to prevalence of Type 2 diabetes mellitus, Banerjee, et al, found that while no association was found in expression of most GPX1 polymorphisms and risk of Type 2 diabetes mellitus, having the C allele of GPX1 led to a 1.362 times higher risk of the disease, highlighting the importance of finding individuals in the population with this gene variant to help treat them early on.[15]
Recent work by Alan M. Diamond and colleagues has shown that allelic variations of GPX1, like the codon 198 polymorphism that results in leucine or proline and an increase in alanine repeat codons, can result in different localization levels in MCF-7 human breast carcinoma cells. For instance, the allele expressing the leucine-198 polymorphism and 7 alanine repeats generates GPX-1 localization that is disproportionately in the cytoplasm as compared to other allelic variants. To further understand the effects of these variants on GPX-1 function, mutant GPX-1 with mitochondrial localization sequences were generated and the GPX-1 infused cells were analyzed for their response to oxidative stress, energy metabolism and cancer-associated signaling molecules. Ultimately, GPX-1 variants heavily influenced cellular biology, suggesting that different GPX-1 variants affect cancer risk differently.[16]
An analysis of GPX1 expression in oligodendrocytes from patients with major depressive disorder and control patients showed that GPX1 levels were significantly decreased in patients with the disorder, but not in their astrocytes. Shortening of telomeres and decreased expression of telomerase were also evident in these oligodendrocytes, but not in the astrocytes in these patients. This suggests that decreased oxidative stress protection, as observed by decreased GPX1 levels, and decreased telomerase expression may help give rise to telomere shortening in patients suffering from MDD.[17]
# Interactions
GPX1 has been shown to interact with ABL and GSH.[3][18]
A recently discovered suppressor for GPX1 is S-adenosylhomocysteine, which when accumulated in endothelial cells can cause tRNA(Sec) hypomethylation, reducing the expression of GPX1 and other selenoproteins. The decreased GPX-1 expression can then lead to inflammatory activating of endothelial cells, helping give rise to a proatherogenic endothelial phenotype.[19] | https://www.wikidoc.org/index.php/GPX1 | |
9bf440d98587a5c7809e34f5f4748826b1589a3b | wikidoc | GPX4 | GPX4
Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.
# Function
The antioxidant enzyme glutathione peroxidase 4 (GPx4) belongs to the family of glutathione peroxidases, which consists of 8 known mammalian isoenzymes (GPx1-8). Gpx4 catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides at the expense of reduced glutathione and functions in the protection of cells against oxidative stress. The oxidized form of glutathione (glutathione disulfide), which is generated during the reduction of hydroperoxides by GPx4, is recycled by glutathione reductase and NADPH/H+. GPx4 differs from the other GPx family members in terms of its monomeric structure, a less restricted dependence on glutathione as reducing substrate, and the ability to reduce lipid-hydroperoxides inside biological membranes.
Inactivation of GPX4 leads to an accumulation of lipid peroxides, resulting in ferroptotic cell death. Mutations in GPX4 cause spondylometaphyseal dysplasia .
# Structure
Mammalian GPx1, GPx2, GPx3, and GPx4 (this protein) have been shown to be selenium-containing enzymes, whereas GPx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon. GPx4 shares the amino acid motif of selenocysteine, glutamine, and tryptophane (catalytic triad) with other glutathione peroxidases.
# Reaction mechanism
GPx4 catalyzes the following reaction:
- 2 glutathione + lipid–hydroperoxide → glutathione disulfide + lipid–alcohol + H2O
This reaction occurs at the selenocysteine within the catalytic center of GPx4. During the catalytic cycle of GPx4, the active selenol (-SeH) is oxidized by peroxides to selenenic acid (-SeOH), which is then reduced with glutathione (GSH) to an intermediate selenodisulfide (-Se-SG). GPx4 is eventually reactivated by a second glutathione molecule, releasing glutathione disulfide (GS-SG).
# Subcellular distribution of isoforms
In mouse and rat, three distinct GPx4 isoforms with different subcellular localization are produced through alternative splicing and transcription initiation; cytosolic GPx4, mitochondrial GPx4 (mGPx4), and nuclear GPx4 (nGPx4). Cytosolic GPx4 has been identified as the only GPx4 isoform being essential for embryonic development and cell survival. The GPx4 isoforms mGPx4 and nGPx4 have been implicated in spermatogenesis and male fertility. In humans, experimental evidence for alternative splicing exists; alternative transcription initiation and the cleavage sites of the mitochondrial and nuclear transit peptides need to be experimentally verified.
# Animal models
Knockout mice of GPX4 die at embryonic day 8
and conditional inducible deletion in adult mice (neurons) results in degeneration and death in less than a month. Targeted disruption of the mitochondrial GPx4 isoform (mGPx4) caused infertility in male mice and disruption of the nuclear GPx4 isoform (nGPx4) reduced the structural stability of sperm chromatin, yet both knockout mouse models (for mGPx4 and nGPx4) were fully viable. Surprisingly, knockout of GPX4 heterozygously in mice (GPX4+/−) increases their median life span. Knockout studies with GPx1, GPx2, or GPx3 deficient mice showed that cytosolic GPx4 is so far the only glutathione peroxidase that is indispensable for embryonic development and cell survival. As mechanisms to dispose of both hydrogen peroxide and lipid hydroperoxides are essential to life, this indicates that in contrast to the multiple metabolic pathways that can be utilised to dispose of hydrogen peroxide, pathways for the disposal of lipid hydroperoxides are limited.
While mammals have only one copy of the GPX4 gene, fish have two copies, GPX4a and GPX4b. The GPX4's appear to play a greater role in the fish GPX system than in mammals. For example, in fish GPX4 activity contributes to a greater extent to total GPX activity, GPX4a is the most highly expressed selenoprotein mRNA (in contrast to mammals where it is GPX1 mRNA) and GPX4a appears to be highly inducible to changes within the cellular environment, such as changes in methylmercury and selenium status. | GPX4
Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene.[1] GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.
# Function
The antioxidant enzyme glutathione peroxidase 4 (GPx4) belongs to the family of glutathione peroxidases, which consists of 8 known mammalian isoenzymes (GPx1-8). Gpx4 catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides at the expense of reduced glutathione and functions in the protection of cells against oxidative stress. The oxidized form of glutathione (glutathione disulfide), which is generated during the reduction of hydroperoxides by GPx4, is recycled by glutathione reductase and NADPH/H+. GPx4 differs from the other GPx family members in terms of its monomeric structure, a less restricted dependence on glutathione as reducing substrate, and the ability to reduce lipid-hydroperoxides inside biological membranes.
Inactivation of GPX4 leads to an accumulation of lipid peroxides, resulting in ferroptotic cell death.[2][3] Mutations in GPX4 cause spondylometaphyseal dysplasia .[4]
# Structure
Mammalian GPx1, GPx2, GPx3, and GPx4 (this protein) have been shown to be selenium-containing enzymes, whereas GPx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. In selenoproteins, the 21st amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon. GPx4 shares the amino acid motif of selenocysteine, glutamine, and tryptophane (catalytic triad) with other glutathione peroxidases.
# Reaction mechanism
GPx4 catalyzes the following reaction:
- 2 glutathione + lipid–hydroperoxide → glutathione disulfide + lipid–alcohol + H2O
This reaction occurs at the selenocysteine within the catalytic center of GPx4. During the catalytic cycle of GPx4, the active selenol (-SeH) is oxidized by peroxides to selenenic acid (-SeOH), which is then reduced with glutathione (GSH) to an intermediate selenodisulfide (-Se-SG). GPx4 is eventually reactivated by a second glutathione molecule, releasing glutathione disulfide (GS-SG).
# Subcellular distribution of isoforms
In mouse and rat, three distinct GPx4 isoforms with different subcellular localization are produced through alternative splicing and transcription initiation; cytosolic GPx4, mitochondrial GPx4 (mGPx4), and nuclear GPx4 (nGPx4). Cytosolic GPx4 has been identified as the only GPx4 isoform being essential for embryonic development and cell survival. The GPx4 isoforms mGPx4 and nGPx4 have been implicated in spermatogenesis and male fertility.[5] In humans, experimental evidence for alternative splicing exists; alternative transcription initiation and the cleavage sites of the mitochondrial and nuclear transit peptides need to be experimentally verified.[6]
# Animal models
Knockout mice of GPX4 die at embryonic day 8[7][8]
and conditional inducible deletion in adult mice (neurons) results in degeneration and death in less than a month.[9] Targeted disruption of the mitochondrial GPx4 isoform (mGPx4) caused infertility in male mice and disruption of the nuclear GPx4 isoform (nGPx4) reduced the structural stability of sperm chromatin, yet both knockout mouse models (for mGPx4 and nGPx4) were fully viable. Surprisingly, knockout of GPX4 heterozygously in mice (GPX4+/−) increases their median life span.[10] Knockout studies with GPx1, GPx2, or GPx3 deficient mice showed that cytosolic GPx4 is so far the only glutathione peroxidase that is indispensable for embryonic development and cell survival. As mechanisms to dispose of both hydrogen peroxide and lipid hydroperoxides are essential to life, this indicates that in contrast to the multiple metabolic pathways that can be utilised to dispose of hydrogen peroxide, pathways for the disposal of lipid hydroperoxides are limited.
While mammals have only one copy of the GPX4 gene, fish have two copies, GPX4a and GPX4b.[11] The GPX4's appear to play a greater role in the fish GPX system than in mammals. For example, in fish GPX4 activity contributes to a greater extent to total GPX activity,[12] GPX4a is the most highly expressed selenoprotein mRNA (in contrast to mammals where it is GPX1 mRNA)[13] and GPX4a appears to be highly inducible to changes within the cellular environment, such as changes in methylmercury and selenium status.[14] | https://www.wikidoc.org/index.php/GPX4 | |
ca6c6b6e55ae8556dfaceed8ada14c7d95e89124 | wikidoc | GRAP | GRAP
GRB2-related adapter protein is a protein that in humans is encoded by the GRAP gene.
This gene encodes a member of the GRB2/Sem5 (C. elegans homolog)/Drk (Drosophila homolog) family. This member functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain.
# Interactions
GRAP has been shown to interact with Linker of activated T cells. | GRAP
GRB2-related adapter protein is a protein that in humans is encoded by the GRAP gene.[1][2][3]
This gene encodes a member of the GRB2/Sem5 (C. elegans homolog)/Drk (Drosophila homolog) family. This member functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain.[3]
# Interactions
GRAP has been shown to interact with Linker of activated T cells.[4][5] | https://www.wikidoc.org/index.php/GRAP | |
2e5e26d44b1cbc82a26f87c1deb304f725839f95 | wikidoc | GRB2 | GRB2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.
The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the sem-5 gene of Caenorhabditis elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.
# Function and expression
Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that targeted gene disruption of Grb2 in mice is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain. Grb2 has two closely related proteins with similar domain organizations, Gads and Grap. Gads and Grap are expressed specifically in hematopoietic cells and function in the coordination of tyrosine kinase mediated signal transduction.
# Domains
The SH2 domain of Grb2 binds to phosphorylated tyrosine-containing peptides on receptors or scaffold proteins with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine (see ).
The N-terminal SH3 domain binds to proline-rich peptides and can bind to the Ras-guanine exchange factor SOS.
The C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1.
# Interactions
Grb2 has been shown to interact with:
- ADAM15,
- Abl gene,
- Arachidonate 5-lipoxygenase,
- B-cell linker,
- BCAR1,
- BCR gene,
- Beta-2 adrenergic receptor,
- C-Met,
- CBLB,
- CD117,
- CD22,
- CD28,
- CDKN1B,
- CRK,
- Cbl gene,
- Colony stimulating factor 1 receptor,
- DCTN1,
- DNM1,
- Dock180,
- Dystroglycan,
- EPH receptor A2,
- ETV6,
- Epidermal growth factor receptor,
- Erythropoietin receptor,
- FRS2,
- Fas ligand,
- GAB1,
- GAB2,
- Glycoprotein 130,
- Granulocyte colony-stimulating factor receptor,
- HER2/neu,
- HNRNPC,
- Huntingtin,
- INPP5D,
- IRS1,
- ITK,
- Janus kinase 1,
- Janus kinase 2,
- KHDRBS1,
- Linker of activated T cells,
- Lymphocyte cytosolic protein 2,
- MAP2,
- MAP3K1
- MAP4K1,
- MED28,
- MST1R,
- MUC1,
- Mitogen-activated protein kinase 9,
- NCKIPSD,
- NEU3,
- PDGFRB,
- PIK3R1,
- PLCG1,
- PRKAR1A,
- PTK2,
- PTPN11,
- PTPN12,
- PTPN1,
- PTPN6,
- PTPRA,
- RAPGEF1,
- RET proto-oncogene,
- SH2B1,
- SH3KBP1,
- SHC1,
- SOS1,
- Src,
- Syk,
- TNK2,
- TrkA,
- VAV1,
- VAV2,
- VAV3, and
- Wiskott-Aldrich syndrome protein. | GRB2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.[1][2]
The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the sem-5 gene of Caenorhabditis elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.[3]
# Function and expression
Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that targeted gene disruption of Grb2 in mice is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain. Grb2 has two closely related proteins with similar domain organizations, Gads and Grap. Gads and Grap are expressed specifically in hematopoietic cells and function in the coordination of tyrosine kinase mediated signal transduction.
# Domains
The SH2 domain of Grb2 binds to phosphorylated tyrosine-containing peptides on receptors or scaffold proteins with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine (see [2]).
The N-terminal SH3 domain binds to proline-rich peptides and can bind to the Ras-guanine exchange factor SOS.
The C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1.[4]
# Interactions
Grb2 has been shown to interact with:
- ADAM15,[5]
- Abl gene,[6][7]
- Arachidonate 5-lipoxygenase,[8][9]
- B-cell linker,[10][11][12][13]
- BCAR1,[14][15]
- BCR gene,[16][17][18][19][20][21]
- Beta-2 adrenergic receptor,[22]
- C-Met,[23][24]
- CBLB,[25][26][27]
- CD117,[28][29][30]
- CD22,[31][32]
- CD28,[33][34]
- CDKN1B,[35]
- CRK,[36][37][38]
- Cbl gene,[25][39][40][41][42][43][44][45][46][47][48][49][50]
- Colony stimulating factor 1 receptor,[51]
- DCTN1,[52]
- DNM1,[53][54]
- Dock180,[55][56]
- Dystroglycan,[57]
- EPH receptor A2,[58]
- ETV6,[16]
- Epidermal growth factor receptor,[2][59][60][61][62][63][64][65][66][67]
- Erythropoietin receptor,[28][68]
- FRS2,[40][69][70][71]
- Fas ligand,[72][73]
- GAB1,[59][74][75]
- GAB2,[16][76][77]
- Glycoprotein 130,[78]
- Granulocyte colony-stimulating factor receptor,[79]
- HER2/neu,[61][80][81]
- HNRNPC,[82]
- Huntingtin,[83]
- INPP5D,[84]
- IRS1,[85][86][87]
- ITK,[88][89]
- Janus kinase 1,[85][90]
- Janus kinase 2,[85][91]
- KHDRBS1,[42][59][92]
- Linker of activated T cells,[93][94][95]
- Lymphocyte cytosolic protein 2,[39][74][96][97][98]
- MAP2,[99][100]
- MAP3K1[101]
- MAP4K1,[102][103][104][105]
- MED28,[106]
- MST1R,[107][108]
- MUC1,[109]
- Mitogen-activated protein kinase 9,[110][111]
- NCKIPSD,[112][113]
- NEU3,[114]
- PDGFRB,[67][115][116]
- PIK3R1,[117][118]
- PLCG1,[119][120][121]
- PRKAR1A,[64]
- PTK2,[14][122][123][124][125]
- PTPN11,[79][116][126][127][128][129][130][131][132]
- PTPN12,[133]
- PTPN1,[134][135]
- PTPN6,[41][127][136]
- PTPRA,[137][138][139]
- RAPGEF1,[140][141]
- RET proto-oncogene,[142][143]
- SH2B1,[144][145]
- SH3KBP1,[146][147]
- SHC1,[17][41][43][60][86][126][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162]
- SOS1,[17][38][40][41][42][43][54][59][60][66][96][109][120][154][161][163][164][165][166][167][168]
- Src,[41][169]
- Syk,[41][127]
- TNK2,[148][170]
- TrkA,[171][172]
- VAV1,[78][163][173][174]
- VAV2,[60][80]
- VAV3,[60][175] and
- Wiskott-Aldrich syndrome protein.[176][177] | https://www.wikidoc.org/index.php/GRB2 | |
a6ed00edecbaa6c3de84d7584b842e296f8eb394 | wikidoc | GRB7 | GRB7
Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the GRB7 gene.
# Function
The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with epidermal growth factor receptor (EGFR) and ephrin receptors. The protein plays a role in the integrin signaling pathway and cell migration by binding with focal adhesion kinase (FAK). Alternative splicing results in multiple transcript variants encoding different isoforms, although the full-length natures of only two of the variants have been determined to date.
# Clinical significance
GRB7 is an SH2-domain adaptor protein that binds to receptor tyrosine kinases and provides the intra-cellular direct link to the Ras proto-oncogene.
Human GRB7 is located on the long arm of chromosome 17, next to the ERBB2 (alias HER2/neu) proto-oncogene.
These two genes are commonly co-amplified (present in excess copies) in breast cancers.
GRB7 thought to be involved in migration, is well known to be over-expressed in testicular germ cell tumors, esophageal cancers, and gastric cancers.
# Interactions
GRB7 has been shown to interact with:
- EPH receptor B1,
- Insulin receptor,
- PTK2,
- RET proto-oncogene, and
- Rnd1
# Model organisms
Model organisms have been used in the study of GRB7 function. A conditional knockout mouse line called Grb7tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | GRB7
Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the GRB7 gene.[1][2]
# Function
The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with epidermal growth factor receptor (EGFR) and ephrin receptors. The protein plays a role in the integrin signaling pathway and cell migration by binding with focal adhesion kinase (FAK). Alternative splicing results in multiple transcript variants encoding different isoforms, although the full-length natures of only two of the variants have been determined to date.[1]
# Clinical significance
GRB7 is an SH2-domain adaptor protein that binds to receptor tyrosine kinases and provides the intra-cellular direct link to the Ras proto-oncogene.
Human GRB7 is located on the long arm of chromosome 17, next to the ERBB2 (alias HER2/neu) proto-oncogene.
These two genes are commonly co-amplified (present in excess copies) in breast cancers.
GRB7 thought to be involved in migration[citation needed], is well known to be over-expressed in testicular germ cell tumors, esophageal cancers, and gastric cancers.
# Interactions
GRB7 has been shown to interact with:
- EPH receptor B1,[3]
- Insulin receptor,[4]
- PTK2,[5]
- RET proto-oncogene,[6] and
- Rnd1[7]
# Model organisms
Model organisms have been used in the study of GRB7 function. A conditional knockout mouse line called Grb7tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[8] Male and female animals underwent a standardized phenotypic screen[9] to determine the effects of deletion.[10][11][12][13] Additional screens performed: - In-depth immunological phenotyping[14] | https://www.wikidoc.org/index.php/GRB7 | |
bc0af8cfe81e3159f458b3b150542940a1b71afa | wikidoc | GYPA | GYPA
Glycophorin A (MNS blood group), also known as GYPA, is a protein which in humans is encoded by the GYPA gene. GYPA has also recently been designated CD235a (cluster of differentiation 235a).
# Function
Glycophorins A (GYPA; this protein) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens, that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta; also, Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB.
# Genomics
GypA, GypB and GypE are members of the same family and are located on the long arm of chromosome 4 (chromosome 4q31). The family evolved via two separate gene duplication events. The initial duplication gave rise to two genes one of subsequently evolved into GypA and the other which give rise via a second duplication event to GypB and GypE. These events appear to have occurred within a relatively short time span. The second duplication appears to have occurred via an unequal crossing over event.
The GypA gene itself consists of 7 exons and has 97% sequence homology with GypB and GypE from the 5' untranslated transcription region (UTR) to the coding sequence encoding the first 45 amino acids. The exon at this point encodes the transmembrane domain. Within the intron downstream of this pint is an Alu repeat. The cross over event which created the genes ancestral to
GypA and GypB/E occurred within this region.
GypA can be found in all primates. GypB can be found only in gorillas and some of the higher primates suggesting that the duplication events occurred only recently.
# Molecular biology
There are about one million copies of this protein per erythrocyte.
# Blood groups
The MNS blood group was the second set of antigens discovered. M and N were identified in 1927 by Landsteiner and Levine. S and s in were described later in 1947.
The frequencies of these antigens are
- M: 78% Caucasian; 74% Negroid
- N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
# Molecular medicine
## Transfusion medicine
The M and N antigens differ at two amino acid residues: the M allele has serine at position 1 (C at nucleotide 2) and glycine at position 5 (G at nucleotide 14) while the N allele has leucine at position 1 (T at nucleotide 2) and glutamate at position 5 (A at nucleotide 14). Both glycophorin A and B bind the Vicia graminea anti-N lectin.
There are about 40 known variants in the MNS blood group system. These have arisen largely as a result of mutations within the 4 kb region coding for the extracellular domain. These include the antigens Mg, Dantu, Henshaw (He), Miltenberger, Nya, Osa, Orriss (Or), Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system. In chimpanzees M reacts strong but N only weakly.
## Null mutants
In individuals who lack both glycophorin A and B the phenotype has been designated Mk.
## Dantu antigen
The Dantu antigen was described in 1984. The Dantu antigen has an apparent molecular weight of 29 kiloDaltons (kDa) and 99 amino acids. The first 39 amino acids of the Dantu antigen are derived from glycophorin B and residues 40-99 are derived from glycophorin A. Dantu is associated with very weak s antigen, a protease-resistant N antigen and either very weak or no U antigen. There are at least three variants: MD, NE and Ph. The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.
## Henshaw antigen
The Henshaw (He) antigen is due to a mutation of the N terminal region. There are three differences in the first three amino acid residues: the usual form has Tryptophan1-Serine-Threonine-Serine-Glycine5 while Henshaw has Leucine1-Serine-Threonine-Threonine-Glutamate5. This antigen is rare in Caucasians but occurs at a frequency of 2.1% in US and UK of African origin. It occurs at the rate of 7.0% in blacks in Natal and 2.7% in West Africans. At least 3 variants of this antigen have been identified.
## Miltenberger subsystem
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut) now has 11 recognised phenotypes numbered I to XI (The antigen 'Mur' is named after to the patient the original serum was isolated from - a Mrs Murrel.) The name originally given to this complex refers to the reaction erythrocytes gave to the standard Miltenberger antisera used to test them. The subclasses were based on additional reactions with other standard antisera.
Mi-I (Mia), Mi-II(Vw), Mi-VII and Mi-VIII are carried on glycophorin A. Mi-I is due to a mutation at amino acid 28 (threonine to methionine: C→T at nucleotide 83) resulting in a loss of the glycosylation at the asparagine26 residue. Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83). Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine26 residue. This alteration in glycoslation is detectable by the presence of a new 32kDa glycoprotein stainable with PAS. Mi-VII is due to a double mutation in glycophorin A converting an arginine residue into a threonine residue and a tyrosine residue into a serine at the positions 49 and 52 respectively. The threonine-49 residue is glycosylated. This appears to be the origin of one of the Mi-VII specific antigens (Anek) which is known to lie between residues 40-61 of glycophorin A and comprises sialic acid residue(s) attached to O-glycosidically linked oligosaccharide(s). This also explains the loss of a high frequency antigen ((EnaKT)) found in normal glycophorin A which is located within the residues 46-56. Mi-VIII is due to a mutation at amino acid residue 49 (arginine->threonine). M-VIII shares the Anek determinant with MiVII. Mi-III, Mi-VI and Mi-X are due to rearrangements of glycophorin A and B in the order GlyA (alpha)-GlyB (delta)-GlyA (alpha). Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene. Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes. The MiV and MiV(J.L.) genes are arranged in the same 5' alpha-delta 3' frame whereas Sta gene is in a reciprocal 5'delta-alpha 3' configuration.
The incidence of Mi-I in Thailand is 9.7%.
Peptide constructs representative of Mia mutations MUT and MUR have been attached onto red blood cells (known as kodecytes) and are able to detect antibodies against these Miltenberger antigens
Although uncommon in Caucasians (0.0098%) and Japanese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwanese aboriginal tribes (up to 90%). In contrast its frequency is 2-3% in Han Taiwanese (Minnan). The Mi-III phenotype occurs in 6.28% of Hong Kong Chinese.
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark.
## Stone's antigen
Stones (Sta) has been shown to be the product of a hybrid gene of which the 5'-half is derived from the glycophorin B whereas the 3'-half is derived from the glycophorin A. Several isoforms are known. This antigen is now considered to be part of the Miltenberger complex.
## Sat antigen
A related antigen is Sat. This gene has six exons of which exon I to exon IV are identical to the N allele of glycophorin A whereas its 3' portion, including exon V and exon VI, are derived from the glycophorin B gene. The mature protein SAT protein contains 104 amino acid residues.
## Orriss antigen
Orriss (Or) appears to be a mutant of glyphorin A but its precise nature has not yet been determined.
## Mg antigen
The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.
## Os antigen
Osa (MNS38) is due to a mutation at nucleotide 273 (C->T) lying within exon 3 resulting in the replacement of a proline residue with a serine.
## Ny antigen
Nya (MNS18) is due to a mutation at nucleotide 194 (T->A) which results in the substitution of an aspartate residue with a glutamate.
## Reactions
Anti-M although occurring naturally has rarely been implicated in transfusion reactions. Anti-N is not considered to cause transfusion reactions. Severe reactions have been reported with anti-Miltenberger. Anti Mi-I (Vw) and Mi-III has been recognised as a cause of haemolytic disease of the newborn. Raddon has been associated with severe transfusion reactions.
# Relevance for infection
The Wright b antigen (Wrb) is located on glycophorin A and acts as a receptor for the malaria parasite Plasmodium falciparum. Cells lacking glycophorins A (Ena) are resistant to invasion by this parasite.
The erythrocyte binding antigen 175 of P. falciparum recognises the terminal Neu5Ac(alpha 2-3)Gal-sequences of glycophorin A.
Several viruses bind to glycophorin A including hepatitis A virus (via its capsid), bovine parvovirus , Sendai virus , influenza A and B , group C rotavirus , encephalomyocarditis virus and reovirus es. | GYPA
Glycophorin A (MNS blood group), also known as GYPA, is a protein which in humans is encoded by the GYPA gene.[1] GYPA has also recently been designated CD235a (cluster of differentiation 235a).
# Function
Glycophorins A (GYPA; this protein) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens, that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta; also, Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB.[1]
# Genomics
GypA, GypB and GypE are members of the same family and are located on the long arm of chromosome 4 (chromosome 4q31). The family evolved via two separate gene duplication events. The initial duplication gave rise to two genes one of subsequently evolved into GypA and the other which give rise via a second duplication event to GypB and GypE. These events appear to have occurred within a relatively short time span. The second duplication appears to have occurred via an unequal crossing over event.
The GypA gene itself consists of 7 exons and has 97% sequence homology with GypB and GypE from the 5' untranslated transcription region (UTR) to the coding sequence encoding the first 45 amino acids. The exon at this point encodes the transmembrane domain. Within the intron downstream of this pint is an Alu repeat. The cross over event which created the genes ancestral to
GypA and GypB/E occurred within this region.
GypA can be found in all primates. GypB can be found only in gorillas and some of the higher primates suggesting that the duplication events occurred only recently.
# Molecular biology
There are about one million copies of this protein per erythrocyte. [Reference needed]
# Blood groups
The MNS blood group was the second set of antigens discovered. M and N were identified in 1927 by Landsteiner and Levine. S and s in were described later in 1947.
The frequencies of these antigens are
- M: 78% Caucasian; 74% Negroid
- N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
# Molecular medicine
## Transfusion medicine
The M and N antigens differ at two amino acid residues: the M allele has serine at position 1 (C at nucleotide 2) and glycine at position 5 (G at nucleotide 14) while the N allele has leucine at position 1 (T at nucleotide 2) and glutamate at position 5 (A at nucleotide 14). Both glycophorin A and B bind the Vicia graminea anti-N lectin.
There are about 40 known variants in the MNS blood group system. These have arisen largely as a result of mutations within the 4 kb region coding for the extracellular domain. These include the antigens Mg, Dantu, Henshaw (He), Miltenberger, Nya, Osa, Orriss (Or), Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system.[2] In chimpanzees M reacts strong but N only weakly.
## Null mutants
In individuals who lack both glycophorin A and B the phenotype has been designated Mk.[3]
## Dantu antigen
The Dantu antigen was described in 1984.[4] The Dantu antigen has an apparent molecular weight of 29 kiloDaltons (kDa) and 99 amino acids. The first 39 amino acids of the Dantu antigen are derived from glycophorin B and residues 40-99 are derived from glycophorin A. Dantu is associated with very weak s antigen, a protease-resistant N antigen and either very weak or no U antigen. There are at least three variants: MD, NE and Ph.[5] The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.[6]
## Henshaw antigen
The Henshaw (He) antigen is due to a mutation of the N terminal region. There are three differences in the first three amino acid residues: the usual form has Tryptophan1-Serine-Threonine-Serine-Glycine5 while Henshaw has Leucine1-Serine-Threonine-Threonine-Glutamate5. This antigen is rare in Caucasians but occurs at a frequency of 2.1% in US and UK of African origin. It occurs at the rate of 7.0% in blacks in Natal[7] and 2.7% in West Africans.[8] At least 3 variants of this antigen have been identified.
## Miltenberger subsystem
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut)[9] now has 11 recognised phenotypes numbered I to XI (The antigen 'Mur' is named after to the patient the original serum was isolated from - a Mrs Murrel.) The name originally given to this complex refers to the reaction erythrocytes gave to the standard Miltenberger antisera used to test them. The subclasses were based on additional reactions with other standard antisera.
Mi-I (Mia), Mi-II(Vw), Mi-VII and Mi-VIII are carried on glycophorin A. Mi-I is due to a mutation at amino acid 28 (threonine to methionine: C→T at nucleotide 83) resulting in a loss of the glycosylation at the asparagine26 residue.[10][11] Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83).[11] Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine26 residue. This alteration in glycoslation is detectable by the presence of a new 32kDa glycoprotein stainable with PAS.[12] Mi-VII is due to a double mutation in glycophorin A converting an arginine residue into a threonine residue and a tyrosine residue into a serine at the positions 49 and 52 respectively.[13] The threonine-49 residue is glycosylated. This appears to be the origin of one of the Mi-VII specific antigens (Anek) which is known to lie between residues 40-61 of glycophorin A and comprises sialic acid residue(s) attached to O-glycosidically linked oligosaccharide(s). This also explains the loss of a high frequency antigen ((EnaKT)) found in normal glycophorin A which is located within the residues 46-56. Mi-VIII is due to a mutation at amino acid residue 49 (arginine->threonine).[14] M-VIII shares the Anek determinant with MiVII.[15] Mi-III, Mi-VI and Mi-X are due to rearrangements of glycophorin A and B in the order GlyA (alpha)-GlyB (delta)-GlyA (alpha).[16] Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene.[17] Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes.[18] The MiV and MiV(J.L.) genes are arranged in the same 5' alpha-delta 3' frame whereas Sta gene is in a reciprocal 5'delta-alpha 3' configuration.
The incidence of Mi-I in Thailand is 9.7%.[19]
Peptide constructs representative of Mia mutations MUT and MUR have been attached onto red blood cells (known as kodecytes) and are able to detect antibodies against these Miltenberger antigens[20][21][22]
Although uncommon in Caucasians (0.0098%) and Japanese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwanese aboriginal tribes (up to 90%). In contrast its frequency is 2-3% in Han Taiwanese (Minnan). The Mi-III phenotype occurs in 6.28% of Hong Kong Chinese.[23]
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark.[24]
## Stone's antigen
Stones (Sta) has been shown to be the product of a hybrid gene of which the 5'-half is derived from the glycophorin B whereas the 3'-half is derived from the glycophorin A. Several isoforms are known. This antigen is now considered to be part of the Miltenberger complex.
## Sat antigen
A related antigen is Sat. This gene has six exons of which exon I to exon IV are identical to the N allele of glycophorin A whereas its 3' portion, including exon V and exon VI, are derived from the glycophorin B gene. The mature protein SAT protein contains 104 amino acid residues.
## Orriss antigen
Orriss (Or) appears to be a mutant of glyphorin A but its precise nature has not yet been determined.[25]
## Mg antigen
The Mg antigen is carried on glycophorin A and lacks three O-glycolated side chains.[26]
## Os antigen
Osa (MNS38) is due to a mutation at nucleotide 273 (C->T) lying within exon 3 resulting in the replacement of a proline residue with a serine.[27]
## Ny antigen
Nya (MNS18) is due to a mutation at nucleotide 194 (T->A) which results in the substitution of an aspartate residue with a glutamate.[27]
## Reactions
Anti-M although occurring naturally has rarely been implicated in transfusion reactions. Anti-N is not considered to cause transfusion reactions. Severe reactions have been reported with anti-Miltenberger. Anti Mi-I (Vw) and Mi-III has been recognised as a cause of haemolytic disease of the newborn.[28] Raddon has been associated with severe transfusion reactions.[29]
# Relevance for infection
The Wright b antigen (Wrb) is located on glycophorin A and acts as a receptor for the malaria parasite Plasmodium falciparum.[30] Cells lacking glycophorins A (Ena) are resistant to invasion by this parasite.[31]
The erythrocyte binding antigen 175 of P. falciparum recognises the terminal Neu5Ac(alpha 2-3)Gal-sequences of glycophorin A.[32]
Several viruses bind to glycophorin A including hepatitis A virus (via its capsid),[33] bovine parvovirus ,[34] Sendai virus ,[35] influenza A and B ,[36] group C rotavirus ,[37] encephalomyocarditis virus [38] and reovirus es.[39] | https://www.wikidoc.org/index.php/GYPA | |
ca9f5ef07db9ce50a1f6a1af8a71cf6e04a8165f | wikidoc | GYPB | GYPB
Glycophorin B (MNS blood group) (gene designation GYPB) also known as sialoglycoprotein delta and SS-active sialoglycoprotein is a protein which in humans is encoded by the GYPB gene. GYPB has also recently been designated CD235b (cluster of differentiation 235b).
# Function
Glycophorin A (GYPA) and B (GYPB; this protein) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups respectively. In addition to the M or N and S or s antigens, that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include the Miltenberger (Mi) complex and several isoforms of Stones (Sta); also Dantu, Sat, Henshaw (He or MNS6), Mg and deletion variants Ena, S-s-U- and Mk. Most of these are the result of gene recombinations between GYPA and GYPB.
# Genomics
The gene is located on the long arm of chromosome 4 (4q28-q31) and has 5 exons. It was first sequenced in 1987 the peptide sequence of 72 amino acids having been determined earlier that year.
The gene has 97% sequence homology with the glycophorin A gene from the 5' UTR approximately 1 kilobase upstream from the exon encoding the transmembrane regions to the portion of the coding sequence encoding the first 45 amino acids. There is a signal sequence of 19 amino acid residues. The leader peptide differs by one amino acid and the next 26 amino acids are identical. Amino acids 27-55 of glycophorin A are absent from glycophorin B. This section includes an N-glycosylation site. Only O-glycosylation sites are found on glycoprotein B and these are linked via serine or threonine. Residues 80-100 of glycophorin A and 51-71 of glycophorin B are very similar. The intervening residues in contrast differ significantly. The antigenic determinant for the blood group Ss is located at residue 29 where S has a methionine and s a threonine. This is due to a mutation at nucleotide 143 (C->T). The S antigen is also known as MSN3 and the s antigen as MNS4.
It seems likely that this gene evolved by gene duplication and subsequent mutation of glycophorin A. The transition site from homologous to nonhomologous sequences can be localized within Alu repeat sequences.
# Molecular biology
There are ~80000 copies of glycophorin B per erythrocyte. Both glycophorin A and B are expressed on the renal endothelium and epithelium.
The first 40 amino acids of the mature protein are extracellular. The next 22 form a transmembrane segment and the remainder are intra cellular.
# Blood groups
The MNS blood group was the second set of antigens discovered. M and N were identified in 1927 by Landsteiner and Levine. S and s in were described later in 1947
The frequencies of these antigens are
- M: 78% Caucasian; 74% Negroid
- N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
# Molecular medicine
## Transfusion medicine
The M and N antigens differ at two amino acid residues: the M allele has serine at position 1 (C at nucleotide 2) and glycine at position 5 (G at nucleotide 14) while the N allele has leucine at position 1 (T at nucleotide 2) and glutamate at position 5 (A at nucleotide 14)
Glycophorin B carries the blood group antigens N, Ss and U. Both glycophorin A and B bind the Vicia graminea anti-N lectin. S and s antigens are not affected by treatment with trypsin or sialidase but are destroyed or much depressed by treatment with papain, pronase or alpha-chymotrypsin.
There are about 40 known variants in the MNS blood group system. These have arisen largely as a result of mutations within the 4 kb region coding for the extracellular domain. These include the antigens Mv, Dantu, Henshaw (He), Orriss (Or), Miltenberger, Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system. In chimpanzees M reacts strong but N only weakly.
## Null mutants
Individuals who lack GypB have the phenotype S-s-U-. This may occur at frequencies of 20% in some African pygmies.
In individuals who lack both glycophorin A and B the phenotype has been designated Mk.
## Dantu antigen
The Dantu antigen was described in 1984. The Dantu antigen has an apparent molecular weight of 29 kiloDaltons (kDa) and 99 amino acids. The first 39 amino acids of the Dantu antigen are derived from glycophorin B and residues 40-99 are derived from glycophorin A. Dantu is associated with very weak s antigen, a protease-resistant N antigen and either very weak or no U antigen. There are at least three variants: MD, NE and Ph. The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.
## Henshaw antigen
The Henshaw (He) antigen is due to a mutation of the N terminal region. There are three differences in the first three amino acid residues: the usual form has Tryptophan1-Serine-Threonine-Serine-Glycine5 while Henshaw has Leucine1-Serine-Threonine-Threonine-Glutamate5. This antigen is rare in Caucasians but occurs at a frequency of 2.1% in US and UK of African origin. It occurs at the rate of 7.0% in blacks in Natal and 2.7% in West Africans. At least 3 variants of this antigen have been identified.
## Miltenberger subsystem
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut) now has 11 recognised phenotypes numbered I to XI (The antigen 'Mur' is named after to the patient the original serum was isolated from - a Mrs Murrel.) The name originally given to this complex refers to the reaction erythrocytes gave to the standard Miltenberger antisera used to test them. The subclasses were based on additional reactions with other standard antisera.
Mi-I (Mia), Mi-II(Vw), Mi-VII and Mi-VIII are carried on glycophorin A. Mi-I is due to a mutation at amino acid 28 (threonine to methionine: C->T at nucleotide 83) resulting in a loss of the glycosylation at the asparagine26 residue. Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83). Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine26 residue. This alteration in glycosylation is detectable by the presence of a new 32kDa glycoprotein stainable with PAS. Mi-VII is due to a double mutation in glycophorin A converting an arginine residue into a threonine residue and a tyrosine residue into a serine at the positions 49 and 52 respectively. The threonine-49 residue is glycosylated. This appears to be the origin of one of the Mi-VII specific antigens (Anek) which is known to lie between residues 40-61 of glycophorin A and comprises sialic acid residue(s) attached to O-glycosidically linked oligosaccharide(s). This also explains the loss of a high frequency antigen ((EnaKT)) found in normal glycophorin A which is located within the residues 46-56. Mi-VIII is due to a mutation at amino acid residue 49 (arginine->threonine). M-VIII shares the Anek determinant with MiVII. Mi-III, Mi-VI and Mi-X are due to rearrangements of glycophorin A and B in the order GlyA (alpha)-GlyB (delta)-GlyA (alpha). Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene. Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes. The MiV and MiV(J.L.) genes are arranged in the same 5' alpha-delta 3' frame whereas Sta gene is in a reciprocal 5'delta-alpha 3' configuration.
Although uncommon in Caucasians (0.0098%) and Japanese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwanese aboriginal tribes (up to 90%). In contrast its frequency is 2-3% in Han Taiwanese (Minnan). The Mi-III phenotype occurs in 6.28% of Hong Kong Chinese.
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark.
## Stone's antigen
Stones (Sta) has been shown to be the product of a hybrid gene of which the 5'-half is derived from the glycophorin B whereas the 3'-half is derived from the glycophorin A. Several isoforms are known. This antigen is now considered to be part of the Miltenberger complex.
## Sat antigen
A related antigen is Sat. This gene has six exons of which exon I to exon IV are identical to the N allele of glycophorin A whereas its 3' portion, including exon V and exon VI, are derived from the glycophorin B gene. The mature protein SAT protein contains 104 amino acid residues.
## Orissa antigen
Orriss (Or) appears to be a mutant of glyphorin A but its precise nature has not yet been determined.
## Transfusion reactions
Both anti-S and anti-s have been implicated in transfusion reactions and haemolytic disease of the newborn. Anti-M although occurring naturally has rarely been implicated in transfusion reactions. Anti-N is not considered to cause transfusion reactions. Severe reactions have been reported with anti-U and anti-Miltenberger. Anti Mi-I (Vw) and Mi-III has been recognised as a cause of haemolytic disease of the newborn. Raddon has been associated with severe transfusion reactions.
# Other areas
Glycophorin B acts as a receptor for erythrocyte binding Ligand (EBl-1) of Plasmodium falciparum involved in malaria. Both the Dantu and the S-s-U- cells phenotypes have been shown to be protective against P. falciparum infection while the Henshaw phenotype is not protective.
Influenza A and B bind to glycophorin B. | GYPB
Glycophorin B (MNS blood group) (gene designation GYPB) also known as sialoglycoprotein delta and SS-active sialoglycoprotein is a protein which in humans is encoded by the GYPB gene.[1] GYPB has also recently been designated CD235b (cluster of differentiation 235b).
# Function
Glycophorin A (GYPA) and B (GYPB; this protein) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups respectively. In addition to the M or N and S or s antigens, that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include the Miltenberger (Mi) complex and several isoforms of Stones (Sta); also Dantu, Sat, Henshaw (He or MNS6), Mg and deletion variants Ena, S-s-U- and Mk. Most of these are the result of gene recombinations between GYPA and GYPB.[1]
# Genomics
The gene is located on the long arm of chromosome 4 (4q28-q31) and has 5 exons. It was first sequenced in 1987[2] the peptide sequence of 72 amino acids having been determined earlier that year.
The gene has 97% sequence homology with the glycophorin A gene from the 5' UTR approximately 1 kilobase upstream from the exon encoding the transmembrane regions to the portion of the coding sequence encoding the first 45 amino acids. There is a signal sequence of 19 amino acid residues. The leader peptide differs by one amino acid and the next 26 amino acids are identical. Amino acids 27-55 of glycophorin A are absent from glycophorin B. This section includes an N-glycosylation site. Only O-glycosylation sites are found on glycoprotein B and these are linked via serine or threonine. Residues 80-100 of glycophorin A and 51-71 of glycophorin B are very similar. The intervening residues in contrast differ significantly. The antigenic determinant for the blood group Ss is located at residue 29 where S has a methionine and s a threonine. This is due to a mutation at nucleotide 143 (C->T). The S antigen is also known as MSN3 and the s antigen as MNS4.
It seems likely that this gene evolved by gene duplication and subsequent mutation of glycophorin A. The transition site from homologous to nonhomologous sequences can be localized within Alu repeat sequences.
# Molecular biology
There are ~80000 copies of glycophorin B per erythrocyte. Both glycophorin A and B are expressed on the renal endothelium and epithelium.
The first 40 amino acids of the mature protein are extracellular. The next 22 form a transmembrane segment and the remainder are intra cellular.
# Blood groups
The MNS blood group was the second set of antigens discovered. M and N were identified in 1927 by Landsteiner and Levine. S and s in were described later in 1947
The frequencies of these antigens are
- M: 78% Caucasian; 74% Negroid
- N: 72% Caucasian; 75% Negroid
- S: 55% Caucasian; 31% Negroid
- s: 89% Caucasian; 93% Negroid
# Molecular medicine
## Transfusion medicine
The M and N antigens differ at two amino acid residues: the M allele has serine at position 1 (C at nucleotide 2) and glycine at position 5 (G at nucleotide 14) while the N allele has leucine at position 1 (T at nucleotide 2) and glutamate at position 5 (A at nucleotide 14)
Glycophorin B carries the blood group antigens N, Ss and U. Both glycophorin A and B bind the Vicia graminea anti-N lectin. S and s antigens are not affected by treatment with trypsin or sialidase but are destroyed or much depressed by treatment with papain, pronase or alpha-chymotrypsin.
There are about 40 known variants in the MNS blood group system. These have arisen largely as a result of mutations within the 4 kb region coding for the extracellular domain. These include the antigens Mv, Dantu, Henshaw (He), Orriss (Or), Miltenberger, Raddon (FR) and Stones (Sta). Chimpanzees also have an MN blood antigen system.[3] In chimpanzees M reacts strong but N only weakly.
## Null mutants
Individuals who lack GypB have the phenotype S-s-U-. This may occur at frequencies of 20% in some African pygmies.
In individuals who lack both glycophorin A and B the phenotype has been designated Mk.[4]
## Dantu antigen
The Dantu antigen was described in 1984.[5] The Dantu antigen has an apparent molecular weight of 29 kiloDaltons (kDa) and 99 amino acids. The first 39 amino acids of the Dantu antigen are derived from glycophorin B and residues 40-99 are derived from glycophorin A. Dantu is associated with very weak s antigen, a protease-resistant N antigen and either very weak or no U antigen. There are at least three variants: MD, NE and Ph.[6] The Dantu phenotype occurs with a frequency of Dantu phenotype is ~0.005 in American Blacks and < 0.001 in Germans.[7]
## Henshaw antigen
The Henshaw (He) antigen is due to a mutation of the N terminal region. There are three differences in the first three amino acid residues: the usual form has Tryptophan1-Serine-Threonine-Serine-Glycine5 while Henshaw has Leucine1-Serine-Threonine-Threonine-Glutamate5. This antigen is rare in Caucasians but occurs at a frequency of 2.1% in US and UK of African origin. It occurs at the rate of 7.0% in blacks in Natal[8] and 2.7% in West Africans.[9] At least 3 variants of this antigen have been identified.
## Miltenberger subsystem
The Miltenberger (Mi) subsystem originally consisting of five phenotypes (Mia, Vw, Mur, Hil and Hut)[10] now has 11 recognised phenotypes numbered I to XI (The antigen 'Mur' is named after to the patient the original serum was isolated from - a Mrs Murrel.) The name originally given to this complex refers to the reaction erythrocytes gave to the standard Miltenberger antisera used to test them. The subclasses were based on additional reactions with other standard antisera.
Mi-I (Mia), Mi-II(Vw), Mi-VII and Mi-VIII are carried on glycophorin A. Mi-I is due to a mutation at amino acid 28 (threonine to methionine: C->T at nucleotide 83) resulting in a loss of the glycosylation at the asparagine26 residue.[11][12] Mi-II is due to a mutation at amino acid 28 (threonine to lysine:C->A at nucleotide 83). Similar to the case of Mi-I this mutation results in a loss of the glycosylation at the asparagine26 residue. This alteration in glycosylation is detectable by the presence of a new 32kDa glycoprotein stainable with PAS.[13] Mi-VII is due to a double mutation in glycophorin A converting an arginine residue into a threonine residue and a tyrosine residue into a serine at the positions 49 and 52 respectively.[14] The threonine-49 residue is glycosylated. This appears to be the origin of one of the Mi-VII specific antigens (Anek) which is known to lie between residues 40-61 of glycophorin A and comprises sialic acid residue(s) attached to O-glycosidically linked oligosaccharide(s). This also explains the loss of a high frequency antigen ((EnaKT)) found in normal glycophorin A which is located within the residues 46-56. Mi-VIII is due to a mutation at amino acid residue 49 (arginine->threonine).[15] M-VIII shares the Anek determinant with MiVII.[16] Mi-III, Mi-VI and Mi-X are due to rearrangements of glycophorin A and B in the order GlyA (alpha)-GlyB (delta)-GlyA (alpha).[17] Mil-IX in contrast is a reverse alpha-delta-alpha hybrid gene.[18] Mi-V, MiV(J.L.) and Sta are due to unequal but homologous crossing-over between alpha and delta glycophorin genes.[19] The MiV and MiV(J.L.) genes are arranged in the same 5' alpha-delta 3' frame whereas Sta gene is in a reciprocal 5'delta-alpha 3' configuration.[20]
Although uncommon in Caucasians (0.0098%) and Japanese (0.006%), the frequency of Mi-III is exceptionally high in several Taiwanese aboriginal tribes (up to 90%). In contrast its frequency is 2-3% in Han Taiwanese (Minnan). The Mi-III phenotype occurs in 6.28% of Hong Kong Chinese.[21]
Mi-IX (MNS32) occurs with a frequency of 0.43% in Denmark.[22]
## Stone's antigen
Stones (Sta) has been shown to be the product of a hybrid gene of which the 5'-half is derived from the glycophorin B whereas the 3'-half is derived from the glycophorin A. Several isoforms are known. This antigen is now considered to be part of the Miltenberger complex.
## Sat antigen
A related antigen is Sat. This gene has six exons of which exon I to exon IV are identical to the N allele of glycophorin A whereas its 3' portion, including exon V and exon VI, are derived from the glycophorin B gene. The mature protein SAT protein contains 104 amino acid residues.
## Orissa antigen
Orriss (Or) appears to be a mutant of glyphorin A but its precise nature has not yet been determined.[23]
## Transfusion reactions
Both anti-S and anti-s have been implicated in transfusion reactions and haemolytic disease of the newborn. Anti-M although occurring naturally has rarely been implicated in transfusion reactions. Anti-N is not considered to cause transfusion reactions. Severe reactions have been reported with anti-U and anti-Miltenberger. Anti Mi-I (Vw) and Mi-III has been recognised as a cause of haemolytic disease of the newborn.[24] Raddon has been associated with severe transfusion reactions.[25]
# Other areas
Glycophorin B acts as a receptor for erythrocyte binding Ligand (EBl-1) of Plasmodium falciparum involved in malaria.[26] Both the Dantu and the S-s-U- cells phenotypes have been shown to be protective against P. falciparum infection while the Henshaw phenotype is not protective.[27][28]
Influenza A and B bind to glycophorin B.[16] | https://www.wikidoc.org/index.php/GYPB | |
83e9b80404422ef8063ce52789451bad8b20dc04 | wikidoc | Gill | Gill
A gill is a respiration organ that functions for the extraction of oxygen from water and the excretion of carbon dioxide. Unlike many small aquatic animals, which can absorb oxygen through the entire surface of their bodies, more complex aquatic organisms have gills specially formed to present an adequate surface area to the external environment. Gills are usually thin plates of tissue, branches, or slender tufted processes and, with the exception of some aquatic insects, they contain blood or coelomic fluid, which exchanges gases through their thin walls. Oxygen is carried by the blood to other parts of the body. Carbon dioxide passes from the blood through the thin gill tissue into the water. Gills or gill-like organs, located in different parts of the body, are found in various groups of animalia. These include mollusks, crustaceans, insects, fish, and amphibians.
# Invertebrate gills
Respiration in Echinodermata (includes starfish and sea urchins) is done through a very primitive version of gills called papulli, thin protuberances on the surface of the body containing diverticula of the water vascular system. In crustaceans, mollusks and some insects, they are tufted or plate-like structures at the surface of the body in which blood circulates.
The gills of other insects are of the tracheal kind and also include both thin plates and tufted structures, and, in the larval dragon fly, the wall of the caudal end of the alimentary tract (rectum) is richly supplied with tracheae as a rectal gill. Water pumped into and out of the rectum provide oxygen to the closed tracheae. In the aquatic insects, a unique type of respiratory organ is used, the tracheal gill, which contains air tubes. The oxygen in these tubes is renewed through the gills.
## Physical gills
Physical gills are a type of structural adaptation common among some types of aquatic insects, in which atmospheric oxygen is held within an area into which the spiracles open. The structure (often called a plastron) typically consists of dense patches of hydrophobic setae on the body, which prevent water entry into the spiracles. The physical properties of the interface between the trapped air bubble and the surrounding water function so as to accomplish gas exchange through the spriacles, almost as if the insect were in atmospheric air. Carbon dioxide diffuses out into the surrounding water due to its high solubility, while oxygen diffuses into the bubble, as the concentration within the bubble has been reduced by respiration, and nitrogen also diffuses out as its tension has been increased. Oxygen diffuses into the bubble at a higher rate than Nitrogen diffuses out. However, water surrounding the insect can become oxygen-depleted if there is no water movement, so many aquatic insects in still water actively direct a flow of water over their bodies.
The physical gill mechanism allows aquatic insects with plastrons to remain constantly submerged. Examples include many beetles in the family Elmidae, aquatic weevils, and true bugs in the family Aphelocheiridae.
# Vertebrate gills
Gills of vertebrates are developed in the walls of the pharynx along a series of gill slits opening to the exterior. In fish, the gills are located on both sides of the pharynx. Gills are made of filaments which help increase surface area for oxygen exchange. In bony fish, the gills are covered by a bony cover called an operculum. When a fish breathes, it opens its mouth at regular times and draws in a mouthful of water. It then draws the sides of its throat together, forcing the water through the gill openings. The water passes over the gills on the outside. Valves inside the mouth keep the water from escaping through the mouth again. The operculum can be very important in adjusting the pressure of water inside of the pharynx to allow proper ventilation of the gills. Lampreys and sharks lack an operculum, they have multiple gill openings. Also, they must use different methods to force water over the gills. In sharks and rays, this ventilation of the gills is achieved either by the use of spiracles or ram ventilation (ventilation by constantly swimming).
In most species, a countercurrent exchange system is employed to enhance the diffusion of substances in and out of the gill, with blood and water flowing in opposite directions to each other. Water taken into the mouth passes out of the slits, bathing the gills as it passes.
Some fish utilize the gills for the excretion of electrolytes. Gills' large surface area tends to create a problem for fish seeking to regulate the osmolarity of their internal fluids. Saltwater is less dilute than these internal fluids; as a consequence, saltwater fish lose large quantities of water osmotically through their gills. To regain the water, they drink large amounts of seawater and excrete the salt. Freshwater is more dilute than the internal fluids of fish, however, so freshwater fish gain water osmotically through their gills.
The gill slits of fish are believed to be the evolutionary ancestors of the tonsils, thymus gland, and Eustachian tubes, as well as many other structures derived from the embryonic branchial pouches. In some amphibians, the gills occupy the same position on the body but protrude as external tufts.
## Branchia
Branchia (pl. branchiæ) is the name given by the Ancient Greek naturalists to the gills of fish. Galen observed that they are full of little foramina, big enough to admit gasses, but too fine to give passage to water. Pliny the Elder held that fish respired by their gills, but observed that Aristotle was of another opinion.
The word branchia comes from the Greek Template:Polytonic, "gills", plural of Template:Polytonic (in singular, meaning a fin). | Gill
A gill is a respiration organ that functions for the extraction of oxygen from water and the excretion of carbon dioxide. Unlike many small aquatic animals, which can absorb oxygen through the entire surface of their bodies, more complex aquatic organisms have gills specially formed to present an adequate surface area to the external environment. Gills are usually thin plates of tissue, branches, or slender tufted processes and, with the exception of some aquatic insects, they contain blood or coelomic fluid, which exchanges gases through their thin walls. Oxygen is carried by the blood to other parts of the body. Carbon dioxide passes from the blood through the thin gill tissue into the water. Gills or gill-like organs, located in different parts of the body, are found in various groups of animalia. These include mollusks, crustaceans, insects, fish, and amphibians.
# Invertebrate gills
Respiration in Echinodermata (includes starfish and sea urchins) is done through a very primitive version of gills called papulli, thin protuberances on the surface of the body containing diverticula of the water vascular system. In crustaceans, mollusks and some insects, they are tufted or plate-like structures at the surface of the body in which blood circulates.
The gills of other insects are of the tracheal kind and also include both thin plates and tufted structures, and, in the larval dragon fly, the wall of the caudal end of the alimentary tract (rectum) is richly supplied with tracheae as a rectal gill. Water pumped into and out of the rectum provide oxygen to the closed tracheae. In the aquatic insects, a unique type of respiratory organ is used, the tracheal gill, which contains air tubes. The oxygen in these tubes is renewed through the gills.
## Physical gills
Physical gills are a type of structural adaptation common among some types of aquatic insects, in which atmospheric oxygen is held within an area into which the spiracles open. The structure (often called a plastron) typically consists of dense patches of hydrophobic setae on the body, which prevent water entry into the spiracles. The physical properties of the interface between the trapped air bubble and the surrounding water function so as to accomplish gas exchange through the spriacles, almost as if the insect were in atmospheric air. Carbon dioxide diffuses out into the surrounding water due to its high solubility, while oxygen diffuses into the bubble, as the concentration within the bubble has been reduced by respiration, and nitrogen also diffuses out as its tension has been increased. Oxygen diffuses into the bubble at a higher rate than Nitrogen diffuses out. However, water surrounding the insect can become oxygen-depleted if there is no water movement, so many aquatic insects in still water actively direct a flow of water over their bodies.
The physical gill mechanism allows aquatic insects with plastrons to remain constantly submerged. Examples include many beetles in the family Elmidae, aquatic weevils, and true bugs in the family Aphelocheiridae.
# Vertebrate gills
Gills of vertebrates are developed in the walls of the pharynx along a series of gill slits opening to the exterior. In fish, the gills are located on both sides of the pharynx. Gills are made of filaments which help increase surface area for oxygen exchange. In bony fish, the gills are covered by a bony cover called an operculum. When a fish breathes, it opens its mouth at regular times and draws in a mouthful of water. It then draws the sides of its throat together, forcing the water through the gill openings. The water passes over the gills on the outside. Valves inside the mouth keep the water from escaping through the mouth again. The operculum can be very important in adjusting the pressure of water inside of the pharynx to allow proper ventilation of the gills. Lampreys and sharks lack an operculum, they have multiple gill openings. Also, they must use different methods to force water over the gills. In sharks and rays, this ventilation of the gills is achieved either by the use of spiracles or ram ventilation (ventilation by constantly swimming).
In most species, a countercurrent exchange system is employed to enhance the diffusion of substances in and out of the gill, with blood and water flowing in opposite directions to each other. Water taken into the mouth passes out of the slits, bathing the gills as it passes.
Some fish utilize the gills for the excretion of electrolytes. Gills' large surface area tends to create a problem for fish seeking to regulate the osmolarity of their internal fluids. Saltwater is less dilute than these internal fluids; as a consequence, saltwater fish lose large quantities of water osmotically through their gills. To regain the water, they drink large amounts of seawater and excrete the salt. Freshwater is more dilute than the internal fluids of fish, however, so freshwater fish gain water osmotically through their gills.
The gill slits of fish are believed to be the evolutionary ancestors of the tonsils, thymus gland, and Eustachian tubes, as well as many other structures derived from the embryonic branchial pouches. In some amphibians, the gills occupy the same position on the body but protrude as external tufts.
## Branchia
Branchia (pl. branchiæ) is the name given by the Ancient Greek naturalists to the gills of fish. Galen observed that they are full of little foramina, big enough to admit gasses, but too fine to give passage to water. Pliny the Elder held that fish respired by their gills, but observed that Aristotle was of another opinion.[1]
The word branchia comes from the Greek Template:Polytonic, "gills", plural of Template:Polytonic (in singular, meaning a fin).[2] | https://www.wikidoc.org/index.php/Gill | |
62b36a5f13a6f1feaec19dad9de87c8f57475317 | wikidoc | Gli2 | Gli2
Gli2 is a transcriptional activator and repressor of which there are four isoforms; Gli2 alpha, beta, gamma and delta. C-terminal transcriptional activator and N-terminal repressor regions have been identified in both Gli2 and Gli3. However, the N-terminal part of human Gli2 is much smaller than its mouse or frog homologs, suggesting that it may lack repressor function. Gli2 affects ventroposterior mesodermal development by regulating at least three different genes; Wnt genes involved in morphogenesis, Brachyruy genes involved in tissue specification and Xhox3 genes involved in positional information. The anti-apoptotic protein BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1 – but not Gli3, which may lead to carcinogenesis. It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus. This suggests that in mouse embryogenesis, Gli1 and Gli2 regulate a similar set of target genes. Mutations do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent. Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development. Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of epidermal differentiation.
There is a significant level of cross talk and functional overlap between the Gli TFs. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically normal. However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally and Gli3 dorsally in transgenic mice. Gli2 null mice embryos develop neural tube defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Interestingly Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs. Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level. These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Interestingly, transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumors form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous keratinocytes develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma (BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastomas, cylindromas and hamartomas but rarely developed BCCs. Gli2 is expressed in the interfollicular epidermis and the outer root sheath of hair follicles in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other. | Gli2
Gli2 is a transcriptional activator and repressor of which there are four isoforms; Gli2 alpha, beta, gamma and delta.[1] C-terminal transcriptional activator and N-terminal repressor regions have been identified in both Gli2 and Gli3.[2] However, the N-terminal part of human Gli2 is much smaller than its mouse or frog homologs, suggesting that it may lack repressor function. Gli2 affects ventroposterior mesodermal development by regulating at least three different genes; Wnt genes involved in morphogenesis, Brachyruy genes involved in tissue specification and Xhox3 genes involved in positional information.[3] The anti-apoptotic protein BCL-2 is up regulated by Gli2 and, to a lesser extent, Gli1 – but not Gli3, which may lead to carcinogenesis[4]. It has been shown in mouse models that Gli1 can compensate for knocked out Gli2 function when expressed from the Gli2 locus. This suggests that in mouse embryogenesis, Gli1 and Gli2 regulate a similar set of target genes. Mutations do develop later in development suggesting Gli1/Gli2 transcriptional regulation is context dependent.[5] Gli2 and Gli3 are important in the formation and development of lung, trachea and oesophagus tissue during embryo development.[6] Studies have also shown that GLI2 plays a dual role as activator of keratinocyte proliferation and repressor of epidermal differentiation.[7]
There is a significant level of cross talk and functional overlap between the Gli TFs. Gli2 has been shown to compensate for the loss of Gli1 in transgenic Gli1-/- mice which are phenotypically normal.[8] However, loss of Gli3 leads to abnormal patterning and loss of Gli2 affects the development of ventral cell types, most significantly in the floor plate. Gli2 has been shown to compensate for Gli1 ventrally and Gli3 dorsally in transgenic mice.[9] Gli2 null mice embryos develop neural tube defects which, can be rescued by overexpression of Gli1 (Jacob and Briscoe, 2003). Interestingly Gli1 has been shown to induce the two GLI2 α/β isoforms.
Transgenic double homozygous Gli1-/- and Gli2-/- knockout mice display serious central nervous system and lung defects have small lungs, undescended testes, and a hopping gait as well as an extra postaxial nubbin on the limbs.[10] Gli2-/- and Gli3-/- double homozygous transgenic mice are not viable and do not survive beyond embryonic level.[11][12][13] These studies suggest overlapping roles for Gli1 with Gli2 and Gli2 with Gli3 in embryonic development.
Interestingly, transgenic Gli1-/- and Gli2-/- mice have a similar phenotype to transgenic Gli1 gain of function mice. This phenotype includes failure to thrive, early death, and a distended gut although no tumors form in transgenic Gli1-/- and Gli2-/- mice. This could suggest that overexpression of human Gli1 in the mouse may have led to a dominant negative rather than a gain-of-function phenotype.[14][15]
Transgenic mice over-expressing the transcription factor Gli2 under the K5 promoter in cutaneous keratinocytes develop multiple skin tumours on the ears, tail, trunk and dorsal aspect of the paw, resembling those of basal cell carcinoma (BCC). Unlike Gli1 transgenic mice, Gli2 transgenic mice only developed BCC-like tumors. Transgenic mice with N-terminal deletion of Gli2, developed the benign trichoblastomas, cylindromas and hamartomas but rarely developed BCCs.[16] Gli2 is expressed in the interfollicular epidermis and the outer root sheath of hair follicles in normal human skin. This is significant as Shh regulates hair follicle growth and morphogenesis. When inappropriately activated causes hair follicle derived tumors, the most clinically significant being the BCC.[17]
Of the four Gli2 isoforms the expression of Gli2beta mRNA was increased the most in BCCs. Gli2beta is an isoform spliced at the first splicing site which contains a repression domain and consists of an intact activation domain. Overexpression of this Gli2 splice variant may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.[18]
In human keratinocytes Gli2 activation upregulates a number of genes involved in cell cycle progression including E2F1, CCND1, CDC2 and CDC45L. Gli2 is able to induce G1–S phase progression in contact-inhibited keratinocytes which may drive tumour development.[19]
Although both Gli1 and Gl12 have been implicated it is unclear whether one or both are needed for carcinogenesis. However, due to feed back loops, one may directly or indirectly induce the other. | https://www.wikidoc.org/index.php/Gli2 | |
f69421dae6b8752f055d784d5ad2f9e171d20ca2 | wikidoc | Gli3 | Gli3
Gli3 is a known transcriptional repressor but may also have a positive transcriptional function. Gli3 represses dHand and Germlin which are involved in developing digits There is evidence that Shh-controlled processing (e.g cleavage) regulates transcriptional activity of Gli3 similarly to that of CI. Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly. There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene.
The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCC's. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation.
Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death respectively but not the formation of BCC. This suggests that over expression of more that one Gli protein is not necessary for BCC formation. | Gli3
Gli3 is a known transcriptional repressor but may also have a positive transcriptional function.[1][2] Gli3 represses dHand and Germlin which are involved in developing digits[3] There is evidence that Shh-controlled processing (e.g cleavage) regulates transcriptional activity of Gli3 similarly to that of CI.[4] Gli3 mutant mice have many abnormalities including CNS and lung defects and limb polydactyly.[5][6][7][8] There is evidence that the autosomal dominant disorder Greig cephalopolysyndactyly syndrome (GCPS) that affects limb and craniofacial development in humans is caused by a translocations within the GLI3 gene.[9]
The independent overexpression Gli1 and Gli2 in mice models to lead to formation of basal cell carcinoma (BCC). Gli1 knockout is shown to lead to similar embryonic malformations as Gli1 overexpressions but not the formation of BCC's. Overexpression of Gli3 in transgenic mice and frogs does not lead to the development of BCC-like tumors and is not thought to play a role in tumor BCC formation.[10]
Gli1 and Gli2 overexpression leads to BCC formation in mouse models and a one step model for tumour formation has been suggested in both cases. This also indicates that Gli1 and/or Gli2 overexpression is vital in BCC formation. Co-overexpression of Gli1 with Gli2 and Gli2 with Gli3 leads to transgenic mice malformations and death respectively but not the formation of BCC. This suggests that over expression of more that one Gli protein is not necessary for BCC formation. | https://www.wikidoc.org/index.php/Gli3 | |
d543b1b95d1759674eb780b3a06438d00e338967 | wikidoc | Gram | Gram
The gram (sometimes gramme in British English, although gram prevails), (Greek/Latin root grámma); symbol g, is a unit of mass.
Originally defined as "the absolute weight of a volume of pure water equal to the cube of the hundredth part of a metre, and at the temperature of melting ice" (later 4 °C), a gram is now defined as one one-thousandth of the SI base unit, the kilogram, or 1×10-3 kg, which itself is defined as being equal to the mass of a physical prototype preserved by the International Bureau of Weights and Measures.
# Examples
All masses are approximate:
- Plastic pen cap (Bic): 1 gram
- A single Smartie: 1 gram
- Paper clip: 0.5 grams to 1.5 grams
- 1 US banknote (any denomination): 1 gram
- 1 litre of air: 1.2 grams
- A teaspoon of salt: 4.745 grams
- Typical sheet of A4 paper: 5 grams (if 80 g/m²)
- United States nickel: 5 grams (very accurate when new)
# Other abbreviations
The International System of Units abbreviation for the gram is g, and follows the numeric value with a space, as in "200 g". In some fields and regions, the international standard symbols for units are used quite strictly, in particular in technical and scientific publications and in legally regulated product labels. In other contexts (e.g., grocery market traders), a wide range of other abbreviations can also be encountered, such as gr, gm, grm, gms, grms.
# History
It was the base unit of mass in the original French metric system and the later centimetre-gram-second (CGS) system of units. The word originates from late Latin gramma – a small weight.
# Uses
The gram is today the most widely used unit of measurement for non-liquid ingredients in cooking and grocery shopping worldwide. For food products that are typically sold in quantities far less than 1 kg, the unit price is normally given per 100 g.
Most standards and legal requirements for nutrition labels on food products require relative contents to be stated per 100 g of the product, such that the resulting figure can also be read as a percentage.
# SI multiples
Because SI prefixes may not be concatenated (serially linked) within the name or symbol for a unit of measure, SI prefixes are used with the gram, not the kilogram, which already has a prefix as part of its name. For instance, one-millionth of a kilogram is 1 mg (one milligram), not 1 µkg (one microkilogram).
- When the Greek lowercase “µ” (mu) in the symbol of microgram is typographically unavailable, it is occasionally—although not properly—replaced by Latin lowercase “u”.
- The microgram is often abbreviated “mcg”, particularly in pharmaceutical and nutritional supplement labeling, to avoid confusion since the “µ” prefix is not well recognized outside of technical disciplines. Note however, that the abbreviation “mcg”, is also the symbol for an obsolete CGS unit of measure known as the “millicentigram,” which is equal to 10 µg.
- The unit name “megagram” is rarely used, and even then, typically only in technical fields in contexts where especially rigorous consistency with the units of measure is desired. For most purposes, the term “tonne,” or “metric ton” is instead used. Further, whereas unit name “megatonne” or “megaton” (Mt) is often used in popular literature on global climate change, the equivalent value in scientific literature on the subject is the “teragram” (Tg).
# Conversion factors
- 1 grain = 0.06479891 gram
- 1 ounce (avoirdupois) = 28.349523125 grams
- 1 ounce (troy) = 31.1034768 grams | Gram
Template:Units
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The gram (sometimes gramme in British English, although gram prevails), (Greek/Latin root grámma); symbol g, is a unit of mass.
Originally defined as "the absolute weight of a volume of pure water equal to the cube of the hundredth part of a metre, and at the temperature of melting ice"[1] (later 4 °C), a gram is now defined as one one-thousandth of the SI base unit, the kilogram, or 1×10-3 kg, which itself is defined as being equal to the mass of a physical prototype preserved by the International Bureau of Weights and Measures.
# Examples
All masses are approximate:
- Plastic pen cap (Bic): 1 gram
- A single Smartie: 1 gram
- Paper clip: 0.5 grams to 1.5 grams
- 1 US banknote (any denomination): 1 gram[2]
- 1 litre of air: 1.2 grams
- A teaspoon of salt: 4.745 grams
- Typical sheet of A4 paper: 5 grams (if 80 g/m²)
- United States nickel: 5 grams (very accurate when new)[3]
# Other abbreviations
The International System of Units abbreviation for the gram is g, and follows the numeric value with a space, as in "200 g"[4][5]. In some fields and regions, the international standard symbols for units are used quite strictly, in particular in technical and scientific publications and in legally regulated product labels. In other contexts (e.g., grocery market traders), a wide range of other abbreviations can also be encountered, such as gr, gm, grm, gms, grms.
# History
It was the base unit of mass in the original French metric system and the later centimetre-gram-second (CGS) system of units. The word originates from late Latin gramma – a small weight.
# Uses
The gram is today the most widely used unit of measurement for non-liquid ingredients in cooking and grocery shopping worldwide. For food products that are typically sold in quantities far less than 1 kg, the unit price is normally given per 100 g.
Most standards and legal requirements for nutrition labels on food products require relative contents to be stated per 100 g of the product, such that the resulting figure can also be read as a percentage.
# SI multiples
Because SI prefixes may not be concatenated (serially linked) within the name or symbol for a unit of measure, SI prefixes are used with the gram, not the kilogram, which already has a prefix as part of its name.[6] For instance, one-millionth of a kilogram is 1 mg (one milligram), not 1 µkg (one microkilogram).
Template:SI multiples
- When the Greek lowercase “µ” (mu) in the symbol of microgram is typographically unavailable, it is occasionally—although not properly—replaced by Latin lowercase “u”.
- The microgram is often abbreviated “mcg”, particularly in pharmaceutical and nutritional supplement labeling, to avoid confusion since the “µ” prefix is not well recognized outside of technical disciplines.[7] Note however, that the abbreviation “mcg”, is also the symbol for an obsolete CGS unit of measure known as the “millicentigram,” which is equal to 10 µg.
- The unit name “megagram” is rarely used, and even then, typically only in technical fields in contexts where especially rigorous consistency with the units of measure is desired. For most purposes, the term “tonne,” or “metric ton” is instead used. Further, whereas unit name “megatonne” or “megaton” (Mt) is often used in popular literature on global climate change, the equivalent value in scientific literature on the subject is the “teragram” (Tg).
# Conversion factors
- 1 grain = 0.06479891 gram
- 1 ounce (avoirdupois) = 28.349523125 grams
- 1 ounce (troy) = 31.1034768 grams | https://www.wikidoc.org/index.php/Gram | |
903de87ce1dd3b70faf76fb346168bc62fd87364 | wikidoc | Gurn | Gurn
A gurn is a distorted facial expression, and a verb to describe the action. A typical gurn might involve projecting the lower jaw as far forward and up as possible, and covering the upper lip with the lower lip.
The English Dialect Dictionary, compiled by Joseph Wright, defines the word gurn as 'to snarl as a dog; to look savage; to distort the countenance', while the Oxford English Dictionary suggests the derivation may originally be Scottish, related to 'grin'. In Northern Ireland the verb 'gurn' means, 'to cry', hence crying in Northern Ireland is often called gurnin.
The term is also used to describe the facial expressions of people under the influence of the drug ecstasy and other stimulants. Sufferers often complain of 'hamster cheeks' and 'Forsyth chin'. The following day is especially uncomfortable - chewing becomes difficult and even speaking is a chore.
# Gurning contests
Gurning contests are a rural English tradition and were once common at travelling sideshow]s, fairs and freak shows. They are still held regularly in some villages, and the contestants traditionally frame their faces through a horse collar - known as 'gurnin' through a braffin'. The World Gurning Championship is held annually in Egremont, Cumbria as one part of the Egremont Crab Fair. Those with the greatest gurn capabilities are often those with no teeth, as this provides greater room to move the jaw further up. In some cases the elderly or otherwise toothless can be capable of spectacular gurns covering the entire nose.
In Australia the most common form of gurning is the "duck face", with many areas holding local annual competitions for this form of facial expression. The "duck face" has been brought into mainstream culture by such people as TV's Kath and Kim, and is characterised by pursed lips and raised eyebrows.
# Notes
- ↑ Guide to Traditional Customs of Britain/Brian Shuel/National Trust/1985/ISBN 0-86350-051-X | Gurn
A gurn is a distorted facial expression, and a verb to describe the action. A typical gurn might involve projecting the lower jaw as far forward and up as possible, and covering the upper lip with the lower lip.
The English Dialect Dictionary, compiled by Joseph Wright, defines the word gurn as 'to snarl as a dog; to look savage; to distort the countenance', while the Oxford English Dictionary suggests the derivation may originally be Scottish, related to 'grin'. In Northern Ireland the verb 'gurn' means, 'to cry', hence crying in Northern Ireland is often called gurnin.
The term is also used to describe the facial expressions of people under the influence of the drug ecstasy and other stimulants. Sufferers often complain of 'hamster cheeks' and 'Forsyth chin'. The following day is especially uncomfortable - chewing becomes difficult and even speaking is a chore.
# Gurning contests
Gurning contests are a rural English tradition and were once common at travelling sideshow]s, fairs and freak shows. They are still held regularly in some villages[1], and the contestants traditionally frame their faces through a horse collar - known as 'gurnin' through a braffin'. The World Gurning Championship is held annually in Egremont, Cumbria as one part of the Egremont Crab Fair. [1] Those with the greatest gurn capabilities are often those with no teeth, as this provides greater room to move the jaw further up. In some cases the elderly or otherwise toothless can be capable of spectacular gurns covering the entire nose.
In Australia the most common form of gurning is the "duck face", with many areas holding local annual competitions for this form of facial expression. The "duck face" has been brought into mainstream culture by such people as TV's Kath and Kim, and is characterised by pursed lips and raised eyebrows.
# Notes
- ↑ Guide to Traditional Customs of Britain/Brian Shuel/National Trust/1985/ISBN 0-86350-051-X
# External links
- Cumbria traditions
- BBC: In Pictures - World Gurning Championship
- ABSFG/Worldwide online gurning contests
de:Grimasse
it:Smorfia (espressione facciale)
sv:Grimas
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Gurn | |
141d818cd13031588797be0da3bd0f1075c81cea | wikidoc | H1N2 | H1N2
H1N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). It is currently endemic in both human and pig populations.
H1N1, H1N2, and H3N2 are the only known Influenza A virus subtypes currently circulating among humans.
The new A(H1N2) strain appears to have resulted from the reassortment of the genes of the currently circulating influenza A(H1N1) and A(H3N2) subtypes. The hemagglutinin protein of the A(H1N2) virus is similar to that of the currently circulating A(H1N1) viruses and the neuraminidase protein is similar to that of the current A(H3N2) viruses.
It is unknown where the A(H1N2) virus originated, but on February 6 2002, the World Health Organization (WHO) in Geneva and the Public Health Laboratory Service (PHLS) in the United Kingdom reported the identification influenza A(H1N2) virus from humans in England, Israel, and Egypt. In addition to the virus isolates reported by WHO and PHLS, the Centers for Disease Control and Prevention has identified influenza A(H1N2) virus from patient specimens collected during the 2001-2002 and 2002-2003 seasons. Influenza A(H1N2) viruses have circulated transiently in the past. Between December 1988 and March 1989, 19 influenza A(H1N2) virus isolates were identified in 6 cities in China, but the virus did not spread further.
The H1N2 virus is not very different from the currently circulating influenza viruses. The H1 protein of the H1N2 virus is like the H1 protein of the currently circulating H1N1 viruses and the N2 protein is similar to the N2 protein in the currently circulating H3N2 viruses. The difference is that we don't commonly see the H1 and N2 proteins on the same virus.
The A(H1N2) virus is not causing a more severe illness than other influenza viruses, and no unusual increases in influenza activity have been associated with the A(H1N2) virus. Because both the hemagglutinin and neuraminidase protein on the A(H1N2) virus closely matches the hemagglutinin and neuraminidase proteins of viruses included in the current influenza vaccine, the vaccine should provide good protection against influenza A(H1N2) virus as well as protection against the currently circulating A(H1N1), A(H3N2), and B viruses.
# Sources
- Questions and Answers About Influenza A(H1N2) Viruses This is the source of most of this article.
- Phylogenetic analysis of H1N2 isolates of influenza A virus from pigs in the United States
- CDC | H1N2
H1N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). It is currently endemic in both human and pig populations.
H1N1, H1N2, and H3N2 are the only known Influenza A virus subtypes currently circulating among humans.
The new A(H1N2) strain appears to have resulted from the reassortment of the genes of the currently circulating influenza A(H1N1) and A(H3N2) subtypes. The hemagglutinin protein of the A(H1N2) virus is similar to that of the currently circulating A(H1N1) viruses and the neuraminidase protein is similar to that of the current A(H3N2) viruses.
It is unknown where the A(H1N2) virus originated, but on February 6 2002, the World Health Organization (WHO) in Geneva and the Public Health Laboratory Service (PHLS) in the United Kingdom reported the identification influenza A(H1N2) virus from humans in England, Israel, and Egypt. In addition to the virus isolates reported by WHO and PHLS, the Centers for Disease Control and Prevention has identified influenza A(H1N2) virus from patient specimens collected during the 2001-2002 and 2002-2003 seasons. Influenza A(H1N2) viruses have circulated transiently in the past. Between December 1988 and March 1989, 19 influenza A(H1N2) virus isolates were identified in 6 cities in China, but the virus did not spread further.
The H1N2 virus is not very different from the currently circulating influenza viruses. The H1 protein of the H1N2 virus is like the H1 protein of the currently circulating H1N1 viruses and the N2 protein is similar to the N2 protein in the currently circulating H3N2 viruses. The difference is that we don't commonly see the H1 and N2 proteins on the same virus.
The A(H1N2) virus is not causing a more severe illness than other influenza viruses, and no unusual increases in influenza activity have been associated with the A(H1N2) virus. Because both the hemagglutinin and neuraminidase protein on the A(H1N2) virus closely matches the hemagglutinin and neuraminidase proteins of viruses included in the current influenza vaccine, the vaccine should provide good protection against influenza A(H1N2) virus as well as protection against the currently circulating A(H1N1), A(H3N2), and B viruses.
Template:CDC
# Sources
- Questions and Answers About Influenza A(H1N2) Viruses This is the source of most of this article.
- Phylogenetic analysis of H1N2 isolates of influenza A virus from pigs in the United States
- CDC
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/H1N2 | |
5edf470ae760262545b749c190badc49078e480d | wikidoc | H3N8 | H3N8
H3N8 is a subtype of the species Influenza A virus (sometimes called bird flu virus). H3N8 is now endemic in birds, horses and dogs.
H3N8 is suspected of causing a human pandemic in either 1889 or 1900. Sources differ; some say the 1889 pandemic was caused H2N2. The experts also differ on exactly how sure we can be that either were involved.
It was the subtype that was responsible for over one-forth of the flu infections in wild ducks in a 1997 study. | H3N8
Template:Flu
H3N8 is a subtype of the species Influenza A virus (sometimes called bird flu virus). H3N8 is now endemic in birds, horses and dogs.
H3N8 is suspected of causing a human pandemic in either 1889 or 1900. Sources differ; some say the 1889 pandemic was caused H2N2. The experts also differ on exactly how sure we can be that either were involved.[1]
It was the subtype that was responsible for over one-forth of the flu infections in wild ducks in a 1997 study.[2] | https://www.wikidoc.org/index.php/H3N8 |
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