Alternative titles; symbols
HGNC Approved Gene Symbol: NFATC1
Cytogenetic location: 18q23 Genomic coordinates (GRCh38): 18:79,395,930-79,529,323 (from NCBI)
Antigen-specific immune responses are initiated by the interaction of the T-cell antigen receptor (TCR) with antigenic peptide bound to major histocompatibility complex proteins on the surface of antigen-presenting cells. Li et al. (1995) noted that the intracellular events that take place subsequent to TCR engagement lead to the transcriptional activation of genes involved in the functions of T lymphocytes. Analysis of the interleukin-2 (IL2; 147680) promoter, which is activated rapidly after TCR stimulation, showed 2 homologous regions that bind a complex induced upon TCR stimulation and whose induction is inhibited by the immunosuppressant agents cyclosporin A and FK506. This DNA-binding complex was designated nuclear factor of activated T cells (NFAT). Subsequent studies demonstrated that the NFAT complex consists of at least 2 components: a preexisting cytosolic component (NFATP, NFAT1, or NFATC2; 600490) that translocates to the nucleus upon TCR stimulation and an inducible nuclear component. Homodimers or heterodimers of FOS (164810) and JUN (165160) family proteins also combine to form NFAT. Common transcription factors involved in IL2 gene expression include OCT1 (164175), AP1 (165160), and NFKB (164011). For a review, see Horsley and Pavlath (2002).
Northrop et al. (1994) purified NFATC from bovine thymus and used the determined sequence of that protein to isolate human cDNA clones. The NFATC cDNA encodes a protein of 716 amino acids with a predicted mass of 77,870 Da. Expression of the full-length cDNA activates the IL2 promoter in non-T lymphocytes. They used transient transfection assays to show that a truncated NFATC cDNA encoding only amino acids 1 to 418 acted as a dominant negative, specifically blocking activation of the IL2 promoter in T lymphocytes. This suggested to them that NFATC is required for IL2 gene expression.
The cytosolic component of NFAT was purified biochemically by Li et al. (1995). The authors reported the partial cDNA cloning of the mouse homolog of the cytosolic component of the NFAT transcription complex (referred to by the authors as NFATC) and the human homolog of the mouse preexisting form (NFATP).
Park et al. (1996) isolated and characterized another human isoform, called NFATC-beta by them, from the Raji B cell line. (They referred to the isoform cloned by Northrop et al. (1994) as NFATC-alpha.) The predicted 827-amino acid sequence of NFATC-beta differs from that of NFATC-alpha in the first N-terminal 29 residues and contains an additional region of 142 residues at the C terminus. Northern blot analysis using a probe encompassing a common region of both isoforms showed 2 mRNA species of 2.7 and 4.5 kb, while an NFATC-beta-specific probe detected only the larger mRNA, which was preferentially expressed in the spleen.
By Northern blot analysis, Masuda et al. (1995) detected variable expression of NFATC1 transcripts at about 5.2 and 2.9 kb in nearly all tissues examined. Expression was highest in muscle, thymus, and leukocytes, and intermediate in spleen, prostate, testis, ovary, small intestine, colon, heart, placenta, lung, and pancreas. NFATC1 was not detected in brain, liver, or kidney.
Park et al. (1996) found that transient expression of NFATC-beta activated an IL2 NFAT-driven reporter gene, but did not bind to the kappa-3 element (an NFAT-binding site) in the tumor necrosis factor (TNF)-alpha (191160) promoter and did not activate transcription from the TNF-alpha promoter. Park et al. (1996) suggested that different members or isoforms of the NFAT gene family may regulate inducible expression of different cytokine genes.
The NFAT family of transcription factors regulates cytokine gene expression by binding to the promoter/enhancer regions of antigen-responsive genes, usually in cooperation with heterologous DNA-binding partners. By nuclear magnetic resonance spectroscopy, Zhou et al. (1998) determined the solution structure of the binary complex formed between the core DNA-binding domain of human NFATC1 and the 12-bp oligonucleotide duplex containing the ARRE2 DNA site from the IL2 promoter. The structure revealed that DNA binding induces the folding of key structural elements that are required for both sequence-specific recognition and the establishment of cooperative protein-protein contacts.
The activation of NFAT proteins is controlled by calcineurin (see 114105), the calmodulin-dependent phosphatase. Aramburu et al. (1998) identified a short conserved sequence in the NFATC1 protein (residues 114-126) that targets calcineurin to NFAT. Mutation of a single residue in this sequence impairs the calcineurin-mediated dephosphorylation and nuclear translocation of NFATC2. Peptides spanning the region inhibit the ability of calcineurin to bind to and dephosphorylate NFAT proteins, without affecting the phosphatase activity of calcineurin against other substrates. When expressed intracellularly, a corresponding peptide inhibits NFAT dephosphorylation, nuclear translocation, and NFAT-mediated expression in response to stimulation. Thus, disruption of the enzyme-substrate docking interaction that directs calcineurin to NFAT can effectively block NFAT-dependent functions.
Semsarian et al. (1999) and Musaro et al. (1999) independently showed that IGF1 (147440) stimulates skeletal muscle hypertrophy and a switch to glycolytic metabolism by activating calcineurin and inducing the nuclear translocation of transcription factor NFATC1. Musaro et al. (1999) demonstrated that either IGF1 or activated calcineurin induces expression of transcription factor GATA2 (137295), which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of NFATC1.
Pahwa et al. (1989) described a child with severe combined immunodeficiency with a normal number of circulating T cells and poor T-lymphocyte proliferation to mitogens, which was corrected in vitro and in vivo by recombinant IL2. Further studies showed that the patient's T lymphocytes were defective in the expression of IL2, IL3, IL4, and IL5 mRNAs, indicating decreased transcription of the corresponding genes. The expression by T lymphocytes of other cytokines such as granulocyte/macrophage colony-stimulating factor (CSF2; 138960) and interleukin-6 (IL6; 147620), both of which are not T-lymphocyte-restricted, was not affected (Chatila et al., 1990). Castigli et al. (1993) demonstrated that the patient's T lymphocytes had an abnormality in the binding activity of NFAT, suggesting that a primary defect in this complex may underlie the multiple lymphokine deficiency in this patient.
Helicobacter pylori vacuolating cytotoxin VacA induces cellular vacuolation in epithelial cells. Gebert et al. (2003) found that VacA could efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest. VacA interfered with the T cell receptor/IL2 signaling pathway at the level of the calcium-calmodulin-dependent phosphatase calcineurin. Nuclear translocation of NFAT was abrogated, resulting in downregulation of IL2 transcription. VacA partially mimicked the activity of the immunosuppressive drug FK506 by possibly inducing a local immune suppression, explaining the extraordinary chronicity of Helicobacter pylori infections.
Neal and Clipstone (2003) found that expression of a constitutively active Nfatc1 mutant (caNfatc1) inhibited differentiation of mouse 3T3-L1 cells into mature adipocytes by preventing expression of the critical proadipogenic transcription factors Ppar-gamma (PPARG; 601487) and Cebpa (116897). The 3T3-L1 cells expressing caNfatc1 adopted morphologic changes and a transformed cell phenotype, including loss of contact-dependent growth, reduced serum growth requirements, and protection from growth factor withdrawal-induced apoptosis. The authors found that caNfatc1 induced production of 1 or more heat-labile factors that acted in an autocrine fashion to promote cell survival and proliferation and inhibit the ability to undergo terminal differentiation into mature adipocytes. In addition, expression of caNfatc1 in 3T3-L1 cells promoted anchorage-independent cell growth and formation of tumors in athymic nude mice.
Ikeda et al. (2004) generated transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage and found that they developed severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL (602642)-induced osteoclast differentiation in vitro. Overexpression of NFATC2 or NFATC1 promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.
Koga et al. (2005) found that overexpression of Nfatc1 stimulated osterix (OSX, or SP7; 606633)-dependent activation of the Col1a1 (120150) promoter in mice. Electrophoretic mobility shift assay detected a complex between Nfat and Osx that bound DNA containing SP1 (189906)-binding sites. Koga et al. (2005) concluded that NFAT and OSX cooperatively control osteoblastic bone formation.
Kim et al. (2005) found that Nfatc1 induced expression of Oscar (606862) by binding directly to specific sites in its promoter region during mouse osteoclast differentiation. Nfatc1, Mitf (156845), and Pu.1 (SPI1; 165170) acted synergistically to stimulate Oscar promoter activity with involvement of the Mkk6 (MAP2K6; 601254)/p38 (MAPK14; 600289) signaling pathway.
Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A (600855), that lie within the Down syndrome (190685) critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease.
Huang et al. (2008) found that Homer2 (604799) and Homer3 (604800), members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of NFAT and by competing with calcineurin (see 114105). Homer-NFAT binding was also antagonized by active serine-threonine kinase AKT (AKT1; 164730), thereby enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice, which also developed autoimmune-like pathology. Huang et al. (2008) concluded that their results demonstrate a further means by which costimulatory signals are regulated to control self-reactivity.
Horsley et al. (2008) showed that Nfatc1 was expressed exclusively in mouse hair follicle stem cells, and using gain- and loss-of-function approaches, they showed that Nfatc1 inhibited stem cell activation. Nfatc1-mediated quiescence involved transcriptional repression of Cdk4 (123829), a gene required for progression through the G1/S phase of the cell cycle. Nfatc1 expression was activated by BMP signaling (see BMP1; 112264).
Calabria et al. (2009) showed that all 4 NFAT family members, including Nfatc1, were expressed in rat skeletal muscle. The NFAT proteins shuttled between nucleus and cytoplasm in response to plasma membrane electrical activity, and different combinations of NFAT proteins controlled specific transcription in slow or fast muscle fibers.
Wu et al. (2010) reported that the genetic and pharmacologic suppression of calcineurin (601302)/NFAT function promotes tumor formation in mouse skin and in xenografts, in immune-compromised mice, of H-ras(V12) (190020.0001)-expressing primary human keratinocytes, or keratinocyte-derived squamous cell carcinoma cells. Calcineurin/NFAT inhibition counteracts p53 (191170)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3 (603148), a member of the 'enlarged' AP1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumors, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, Wu et al. (2010) concluded that intact calcineurin/NFAT signaling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.
Using an integrative genomics approach, Lee et al. (2010) identified DSCR1 (RCAN1) as an NFAT-dependent injury-response gene in mouse smooth muscle cells (SMC). Induction of DSCR1 inhibited calcineurin/NFAT signaling through a negative feedback mechanism. DSCR1 overexpression attenuated NFAT transcriptional activity and COX2 (PTGS2; 600262) protein expression, whereas knockdown of endogenous DSCR1 enhanced NFAT transcriptional activity. Lee et al. (2010) concluded that DSCR1 is a novel NFAT-dependent, injury-inducible, early gene that may serve to negatively regulate SMC phenotypic switching.
Using real-time RT-PCR, Youn et al. (2012) found that Jmjd5 (611917) expression decreased during osteoclast differentiation in mouse RAW264 cells. Knockdown of Jmjd5 accelerated osteoclast maturation. Jmjd5 interacted directly with the osteoclastogenic transcription factor Nfatc1 and downregulated its transcriptional activity. In vitro assays revealed that Jmjd5 downregulated Nfatc1 by inducing hydroxylation of an Nfatc1 C-terminal domain, targeting Nfatc1 for interaction with the E3 ubiquitin ligase Vhl (608537) and proteasome-mediated degradation.
Through the use of mapping panels of human/Chinese hamster and mouse/rodent cell hybrids, Li et al. (1995) mapped the human and mouse NFATC1 genes to the respective chromosomes 18. By analysis of a chromosome 18 radiation hybrid panel, human NFATC1 gene was localized to the 18q terminus, closely linked to STS marker D18S497. The mouse Nfatc gene was sublocalized to chromosome band 18E4 by fluorescence in situ hybridization.
Whereas Nfatc1-deficient mice have impaired proliferative and Th2-like responses, Nfatc2-deficient mice have modestly enhanced responses with Th2-like characteristics. By fetal liver chimerization in Rag2 (179616)-deficient hosts, Peng et al. (2001) generated mice whose lymphocytes were deficient in both transcription factors. Functional analysis showed that the double knockout (DKO) mice had reasonable proliferative responses and expression of activation markers but were incapable of producing a wide range of cytokines, with the exception of weak production of IL5 (147850), and of expressing CD40 ligand (CD40LG; 300386) and CD95 ligand (CD95L; 134638) or allogeneic cytotoxicity. Analysis of serum immunoglobulins revealed significantly elevated amounts of IgG1 and IgE, isotypes typically associated with Th2-like immune responses, in DKO mice. The results suggested that NFATC1 and NFATC2 are essential for the maintenance of B-cell homeostasis and differentiation, but are dispensable for T-cell inflammatory activity, as measured by lymphoproliferation and activation marker expression.
Chang et al. (2004) showed that initiation of heart valve morphogenesis in mice required Cnb1 (601302), Nfatc2, Nfatc3 (602698), and Nfatc4 (602699) to repress Vegf (192240) expression in the myocardium underlying the site of prospective valve formation. Repression of Vegf at mouse embryonic day 9 (E9) was essential for endocardial cells to transform into mesenchymal cells. Later, at E11, Cnb1/Nfatc1 signaling was required in the endocardium, adjacent to the earlier myocardial site of NFAT action, to direct valvular elongation and refinement. Chang et al. (2004) concluded that NFAT signaling functions sequentially from myocardium to endocardium within a valvular morphogenetic field to initiate and perpetuate embryonic valve formation. They found that this mechanism also operates in zebrafish, indicating a conserved role for calcineurin/NFAT signaling in vertebrate heart valve morphogenesis.
Winslow et al. (2006) found that mice expressing a constitutively nuclear Nfatc1 variant (Nfatc1-nuc) developed abnormally high bone mass. Nfatc1-nuc mice had massive osteoblast overgrowth, enhanced osteoblast proliferation, and coordinated changes in expression of Wnt signaling components. In contrast, viable Nfatc1-deficient mice showed defects in skull bone formation and impaired osteoclast development. Nfatc1-nuc mice had increased osteoclastogenesis despite normal levels of Rankl and Opg (TNFRSF11B ;602643), indicating that an additional NFAT-regulated mechanism influences osteoclastogenesis in vivo. Winslow et al. (2006) found that calcineurin/Nfatc signaling in osteoblasts controlled expression of chemoattractants and attracted monocytic osteoclast precursors, thereby coupling bone formation and bone resorption.
Heit et al. (2006) showed that mice with a beta-cell specific deletion of the calcineurin phosphatase regulatory subunit Cnb1 developed age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content, and hypoinsulinemia. Moreover, beta-cells lacking Cnb1 had a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active Nfatc1 in Cnb1-deficient beta-cells rescued these defects and prevented diabetes.
By generating Dtx1 -/- mice, Hsiao et al. (2009) determined that Dtx1 is important in T-cell anergy and that it is a target of Nfat. Immunoblot analysis showed Dtx1 upregulation in anergic T cells. Mutation analysis with deletion of N- or C-terminal portions of Dtx1 indicated that T-cell activation was inhibited by Dtx1 in both E3-dependent and E3-independent mechanisms. Mice lacking Dtx1 have increased T-cell activation and systemic autoimmune disease. Hsiao et al. (2009) concluded that DTX1 contributes to T-cell tolerance.
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