NFAT5
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Location (UCSC) | Chr 16: 69.57 – 69.7 Mb | Chr 8: 108.02 – 108.11 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Nuclear factor of activated T-cells 5, also known as NFAT5 and sometimes TonEBP, is a human
The product of this gene is a member of the nuclear factors of activated T cells (NFAT) family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.[5]
Osmotic stress
Tissues that comprise the kidneys, skin, and eyes are often subjected to osmotic stresses. When the extracellular environment is
It has been shown that when NFAT5 is inhibited in renal and immune cells, these cells become significantly more susceptible to osmotic stress. NFAT5 deficient mice were found to suffer from massive cell loss in the renal medulla.[9] Additionally, mice expressing a dominant-negative form of NFAT5 in their eyes exhibited decreased viability under hypertonic extracellular environment.[10]
Structure
The
Mechanism of Activation
Although the precise mechanism by which osmotic stress is sensed by the cell is unclear, it has been suggested that Brx, a guanine nucleotide exchange factor (GEF) localized near the plasma membrane, is activated by osmotic stress through changes in the cytoskeleton structure. Alternatively, Brx may also be activated through changes in its interactions with possible osmosensor molecules at the cell membrane.[12] Upon Brx activation, the GEF domain of Brx facilitates activation of Rho-type small G proteins from its inactive GDP state to active GTP state. Additionally, activated Brx also recruits and physically interacts with JIP4, a p38 MAPK-specific scaffold protein. JIP4 binds to downstream kinases, MKK3 and MKK6.[13] This complex then activates p38 mitogen-activated protein kinase (MAPK). Activation of p38 MAPK is regulated by Cdc42 and Rac1. Activation of p38 MAPK is a necessary step for NFAT5 expression.[12]
It has been found that NFAT5 expression, following hyperosmolarity, depends on p38 mitogen-activated protein kinase (MAPK). The addition of a p38 MAPK inhibitor was found to correlate with decreased NFAT5 expression, even in the presence of osmotic stress signals.
Although the Brx-mediated activation of NFAT5 has only been examined in lymphocyte response to osmotic stress, it is hypothesized that this mechanism is a common one in other cell types.
Additional Roles
NFAT5 has also been implicated in other biological roles, such as in embryonic development. Mice in the embryonic stages with non-function NFAT5 exhibited reduced survivorship.
NFAT5 is also involved in cellular proliferation. NFAT5 mRNA expression is particularly high in proliferating cells. Inhibition of NFAT5 in embryonic fibroblasts resulted in cell cycle arrest.[8]
Although NFAT5 has been found to be important in other biological processes besides hyperosmotic stress response, the mechanism by which NFAT5 acts in these other processes are currently not well known.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000102908 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003847 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: NFAT5 nuclear factor of activated T-cells 5, tonicity-responsive".
- PMID 21209002.
- PMID 10051678.
- ^ PMID 18436816.
- ^ PMID 14983020.
- PMID 15774462.
- ^ PMID 10377394.
- ^ PMID 19211510.
- PMID 15767678.
Further reading
- López-Rodríguez C, Aramburu J, Rakeman AS, et al. (2001). "NF-AT5: the NF-AT family of transcription factors expands in a new direction". Cold Spring Harb. Symp. Quant. Biol. 64 (1): 517–26. PMID 11233530.
- Horsley V, Pavlath GK (2002). "NFAT: ubiquitous regulator of cell differentiation and adaptation". J. Cell Biol. 156 (5): 771–4. PMID 11877454.
- Nagase T, Ishikawa K, Suyama M, et al. (1999). "Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 5 (6): 355–64. PMID 10048485.
- Miyakawa H, Woo SK, Dahl SC, et al. (1999). "Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity". Proc. Natl. Acad. Sci. U.S.A. 96 (5): 2538–42. PMID 10051678.
- Lopez-Rodríguez C, Aramburu J, Rakeman AS, Rao A (1999). "NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7214–9. PMID 10377394.
- Zühlke C, Kiehl R, Johannsmeyer A, et al. (2000). "Isolation and characterization of novel CAG repeat containing genes expressed in human brain". DNA Seq. 10 (1): 1–6. PMID 10565538.
- Ko BC, Turck CW, Lee KW, et al. (2000). "Purification, identification, and characterization of an osmotic response element binding protein". Biochem. Biophys. Res. Commun. 270 (1): 52–61. PMID 10733904.
- Trama J, Lu Q, Hawley RG, Ho SN (2000). "The NFAT-related protein NFATL1 (TonEBP/NFAT5) is induced upon T cell activation in a calcineurin-dependent manner". J. Immunol. 165 (9): 4884–94. PMID 11046013.
- Hebinck A, Dalski A, Engel H, et al. (2000). "Assignment of transcription factor NFAT5 to human chromosome 16q22.1, murine chromosome 8D and porcine chromosome 6p1.4 and comparison of the polyglutamine domains". Cytogenet. Cell Genet. 90 (1–2): 68–70. S2CID 26169461.
- López-Rodríguez C, Aramburu J, Jin L, et al. (2001). "Bridging the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress". Immunity. 15 (1): 47–58. PMID 11485737.
- Dalski A, Schwinger E, Zühlke C (2001). "Genomic organization of the human NFAT5 gene: exon-intron structure of the 14-kb transcript and CpG-island analysis of the promoter region". Cytogenet. Cell Genet. 93 (3–4): 239–41. S2CID 20758948.
- Stroud JC, Lopez-Rodriguez C, Rao A, Chen L (2002). "Structure of a TonEBP-DNA complex reveals DNA encircled by a transcription factor". Nat. Struct. Biol. 9 (2): 90–4. S2CID 20918812.
- Ferraris JD, Williams CK, Persaud P, et al. (2002). "Activity of the TonEBP/OREBP transactivation domain varies directly with extracellular NaCl concentration". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 739–44. PMID 11792870.
- Merante F, Altamentova SM, Mickle DA, et al. (2002). "The characterization and purification of a human transcription factor modulating the glutathione peroxidase gene in response to oxygen tension". Mol. Cell. Biochem. 229 (1–2): 73–83. S2CID 24302120.
- Ko BC, Lam AK, Kapus A, et al. (2003). "Fyn and p38 signaling are both required for maximal hypertonic activation of the osmotic response element-binding protein/tonicity-responsive enhancer-binding protein (OREBP/TonEBP)". J. Biol. Chem. 277 (48): 46085–92. PMID 12359721.
- Kneitz C, Goller M, Tony H, et al. (2002). "The CD23b promoter is a target for NF-AT transcription factors in B-CLL cells". Biochim. Biophys. Acta. 1588 (1): 41–7. PMID 12379312.
- Nakayama M, Kikuno R, Ohara O (2003). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Res. 12 (11): 1773–84. PMID 12421765.
External links
- NFAT5+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: O94916 (Nuclear factor of activated T-cells 5) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.