Integration of calcineurin and MEF2 signals by the coactivator p300 duringT-cell apoptosis

T-cell antigen receptor (TCR)-induced thymocyte apoptosis is mediated by ca lcium-dependent signal transduction pathways leading to the transcriptional activation of members of the Nur77 family, The major calcium- and calcineu rin-responsive elements in the Nur77 promoter are binding sites for myocyte enhancer factor-2 (MEF2), It has been shown that nuclear factor of activat ed T cells (NFAT) interacts with MEF2D and enhances its transcriptional act ivity, offering a plausible mechanism of activation of MEF2D by calcineurin . We report here that NFATp synergizes with MEF2D to recruit the coactivato r p300 for the transcription of Nur77. Surprisingly, the enhancement of tra nscriptional activity of MEF2D by NFATp does not require its DNA-binding ac tivity, suggesting that NFATp acts as a coactivator for MEF2D, Transient co -expression of p300, MEF2D, NFATp and constitutively active calcineurin is sufficient to recapitulate TCR signaling for the selective induction of the endogenous Nur77 gene. These results implicate NFAT as an important mediat or of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-pro tein interaction with other transcription factors.