Transcriptional regulation by calcium, calcineurin, and NFAT.
By P. Hogan, Lin Chen, J. Nardone, Anjana Rao. Genes & Development, 2003
2,034 citations recorded by the source corpus.
The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFATrelated protein represented in the Drosophila genome. NFAT5 is identical to TonEBP (tonicity element binding protein), a transcription factor crucial for cellular responses to hypertonic stress (Lopez-Rodriguez et al. 1999; Miyakawa et al. 1999). We focus here on the remaining four NFAT proteins (NFAT1–NFAT4, also known as NFATc1–c4; see Table 1), referring to them collectively as NFAT. The distinguishing feature of NFAT is its regulation by Ca and the Ca/calmodulin-dependent serine phosphatase calcineurin. NFAT proteins are phosphorylated and reside in the cytoplasm in resting cells; upon stimulation, they are dephosphorylated by calcineurin, translocate to the nucleus, and become transcriptionally active, thus providing a direct link between intracellular Ca signaling and gene expression. NFAT activity is further modulated by additional inputs from diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In the first part of this review, we describe the influence of these multiple inputs on the nuclear–cytoplasmic distribution and transcriptional function of NFAT. Recent structural data emphasize the remarkable versatility of NFAT binding to DNA. At composite NFAT:AP-1 elements found in the regulatory regions of many target genes, NFAT proteins bind cooperatively with an unrelated transcription factor, AP-1 (Fos–Jun; Chen et al. 1998). At DNA elements that resemble NF B sites, NFAT proteins bind DNA as dimers (Giffin et al. 2003; Jin et al. 2003). In the second section of this review, we describe these two modes of DNA binding by NFAT. NFAT also acts synergistically with transcription factors other than Fos and Jun, but the structural basis for synergy remains unknown. Drawing on published structures, we discuss the potential cooperation of NFAT with other classes of DNA-binding proteins. It is clear that NFAT activates transcription of a large number of genes during an effective immune response (Rao et al. 1997; Kiani et al. 2000; Serfling et al. 2000; Macian et al. 2001). In the third part of this review, we present information obtained from these studies, highlighting experimental and bioinformatics approaches to identifying NFAT target genes. We discuss the finding that NFAT and NFAT–Fos–Jun complexes activate distinct subsets of target genes in lymphocytes (Macian et al. 2002). We also describe a novel aspect of gene regulation by NFAT, in which this transcription factor participates in an early phase of chromatin remodeling that occurs at specific genetic loci in differentiating T cells (Avni et al. 2002). There is evidence that NFAT regulates cell differentiation programs in cell types other than immune cells (Crabtree and Olson 2002; Horsley and Pavlath 2002; Graef et al. 2003; Hill-Eubanks et al. 2003). In the last section of this review, we select three differentiation programs—fiber-type specification in differentiated skeletal muscle, cardiac valve development, and osteoclast differentiation—for detailed consideration. We evaluate the evidence for NFAT involvement, point out novel cellular and molecular mechanisms that might regulate this familiar transcription factor, and discuss how NFAT exerts its biological effects. Because the phenotypes of NFAT knockout mice have been reviewed elsewhere (Crabtree and Olson 2002; Horsley and Pavlath 2002), we refer to them only as necessary to illustrate specific points.
Subfields: Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/d16c5903dd209b9775b618c8ea8b74466fdd42eb
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Citations in the corpus
- Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI (2010, background): “However, store release by itself does not elevate [Ca]i sufficiently to promote long-term immune responses: Cytokine production, for instance, requires sustained calcineurin activation to support the prolonged nuclear residence of NFAT necessary for effective transcriptional activity (7, 15).”
- Mapping pathways and phenotypes by systematic gene overexpression. (2006, background): “…kinases in budding yeast is analogous to the regulation of the mammalian functional homolog of Crz1p; nuclear export of NFAT responds to phosphorylation by multiple kinases , including casein kinase I, GSK3, PKA, and the MAP kinases p38 and JNK, depending on the NFAT isoform (Hogan et al., 2003).”
- cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action (2010, background): “Evidence is mounting that cGMP activation of PKGI and the resulting reduction in intracellular calcium blunts expression of genes associated with cardiomyocyte hypertrophy, perhaps in part through diminished calcineurin activity (Hogan et al., 2003; Koitabashi et al., 2010); however, other pathways ”
- METHAMPHETAMINE TOXICITY AND MESSENGERS OF DEATH (2009, background): “Because NFATs are known to participate in the regulation of Ca2+ and calcineurin-mediated transcriptional activity in the nervous system (Hogan et al., 2003) and because pretreatment with SCH23390 also blocked METH-induced increase in calcineurin expression and NFAT nuclear translocation (Jayanthi e”
- Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems (2007, background): “The NFAT family of transcription factors was originally discovered in T cells, but they are involved in the regulation of various biological system”
- NFAT proteins: key regulators of T-cell development and function (2005, background): “At least one NFAT family member is expressed by almost every cell type that has been examined, including other cells of the immune system and non-immune cell”
- Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation (2017, background): “Moreover, NFATc1 regulates not only osteoblasts and bone formation but also the activation and development of diverse cells in other biological systems such as the immune, cardiovascular, and skeletal muscular systems (Hogan et al., 2003; Koga et al., 2005).”
- TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion (2019, methodology): “We used the calcineurin inhibitor cyclosporin A (CsA) to assess the involvement of NFAT transcription factors, which are induced by calcium influx and calcineurin activation (23, 24).”
- Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival (2008, background): “NFATs reside within the cytoplasm in an inactive, phosphorylated state but, following an increase in [Ca 2+ ] i , activated calcineurin dephosphorylates NFAT proteins, allowing them to enter the nucleus and regulate expression of their target gene”
- The transcription factor NFAT promotes exhaustion of activated CD8+ T cells (2015, neutral): “The ability to participate inmultiple transcriptional complexes allows NFAT to contribute to different transcriptional programs depending on the cell type and signaling context in which it is activated (Hogan et al., 2003).”
- Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. (2012, background): “In contrast, in vivo, MSKs, possibly through CREB regulation, may act redundantly as negative regulators of innate immunity (6, 56) (section IVC1).”
- Cell and Molecular Biology (2009, background): “Calcineurin can dephosphorylate (activate) NFAT, which otherwise remains inactivated in a multiphosphorylated form in the cytoplasm (Hogan et al., 2003; Masuda et al., 1998).”