Transcriptional regulation by calcium, calcineurin, and NFAT

  1. Patrick G. Hogan1,
  2. Lin Chen3,
  3. Julie Nardone1, and
  4. Anjana Rao1,2,4
  1. 1 The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. 2 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
  3. 3 Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215, USA

This extract was created in the absence of an abstract.

The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NFκB family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFAT-related 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 (López-Rodríguez 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.

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Table 1.

List of NFAT proteins

The distinguishing feature of NFAT is its regulation by Ca2+ and the Ca2+/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 Ca2+ 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 NFκB 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, …

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