NFAT1 C-terminal domains are necessary but not sufficient for inducing cell death

• Published in: PloS one Vol. 7; no. 10; p. e47868
• Main Authors: Faget, Douglas V, Lucena, Pedro I, Robbs, Bruno K, Viola, João P B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26-10-2012; Public Library of Science (PLoS)
• Subjects: Amino acids; Animals; Apoptosis; Apoptosis - genetics; Biochemistry; Biology; Blotting, Western; Cancer; Cell cycle; Cell death; Cellular biology; Conservation; Conserved sequence; Cytokines; Deoxyribonucleic acid; DNA; DNA binding proteins; DNA Primers - genetics; Electrophoretic Mobility Shift Assay; Fibroblasts; Gene expression; Gene Expression Regulation - genetics; Gene regulation; Genetic transformation; Gentian Violet; Homology; Ligands; Localization; Lymphocytes; Mice; Mortality; Multigene Family - genetics; Next-generation sequencing; NF-AT protein; NF-AT1 protein; NFATC Transcription Factors - genetics; NIH 3T3 Cells; Plasmids - genetics; Protein Structure, Tertiary; Proteins; Rodents; Signal transduction; Similarity; T cells; Trans-Activators - genetics; Transcription (Genetics); Transcription factors; Transformation; Brazil; Rio de Janeiro Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047868

The proteins belonging to the nuclear factor of activated T cells (NFAT) family of transcription factors are expressed in several cell types and regulate genes involved in differentiation, cell cycle and apoptosis. NFAT proteins share two conserved domains, the NFAT-homology region (NHR) and a DNA-binding domain (DBD). The N- and C-termini display two transactivation domains (TAD-N and TAD-C) that have low sequence similarity. Due to the high sequence conservation in the NHR and DBD, NFAT members have some overlapping roles in gene regulation. However, several studies have shown distinct roles for NFAT proteins in the regulation of cell death. The TAD-C shows low sequence similarity among NFAT family members, but its contribution to specific NFAT1-induced phenotypes is poorly understood. Here, we described at least two regions of NFAT1 TAD-C that confer pro-apoptotic activity to NFAT1. These regions extend from amino acids 699 to 734 and 819 to 850 of NFAT1. We also showed that the NFAT1 TAD-C is unable to induce apoptosis by itself and requires a functional DBD. Furthermore, we showed that when fused to NFAT1 TAD-C, NFAT2, which is associated with cell transformation, induces apoptosis in fibroblasts. Together, these results suggest that the NFAT1 TAD-C includes NFAT death domains that confer to different NFAT members the ability to induce apoptosis.