NFAT Transcription Factors

The nuclear factor of activated T cells (NFAT) family of transcription factors consists of five family members, four of which are regulated by calcium/calcineurin (NFATc1, -2, -3, and -4) and one of which is calcium/calcineurin independent (NFAT5). Although calcineurin is highly conserved from yeast and humans, NFATc1 through 4 transcription factors appeared later during evolution, with the rise of chordates. The NFAT signaling pathway was first described in T cells. However, most cell types express one or more isoforms of NFAT. Indeed, these proteins have been shown to play a critical role in such diverse processes as the development of skeletal muscle, cartilage, the central nervous system (CNS), and the cardiovascular system. In this chapter, we review evidence for the role of NFAT in endothelial cell (EC) biology. Of particular interest is the recent finding that NFAT signaling in ECs is tightly regulated by a negative feedback inhibitor, the Down syndrome critical region (DSCR)-1. STRUCTURE OF NUCLEAR FACTOR OF ACTIVATED T CELLS NFAT proteins contain a highly conserved DNA-binding domain that is similar to the DNA-binding domain of the Rel family of transcription factors (Figure 92.1). Indeed, all five members of the NFAT family may be classified as members of the extended nuclear factor (NF)-κB/Rel family (1). In contrast to canonical Rel-containing factors, the Rel binding domain of NFAT binds weakly as a monomer or dimer. Instead, NFAT cooperates with other transcription factors to upregulate target genes (discussed in the next section). In addition to the DNA-binding domain, NFAT proteins contain a regulatory domain, which mediates transactivation, and docking sites for calcineurin (CnA) and NFAT kinases.