Youn H D, Chatila T A, Liu J O
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
EMBO J. 2000 Aug 15;19(16):4323-31. doi: 10.1093/emboj/19.16.4323.
T-cell antigen receptor (TCR)-induced thymocyte apoptosis is mediated by calcium-dependent signal transduction pathways leading to the transcriptional activation of members of the Nur77 family. The major calcium- and calcineurin-responsive elements in the Nur77 promoter are binding sites for myocyte enhancer factor-2 (MEF2). It has been shown that nuclear factor of activated T cells (NFAT) interacts with MEF2D and enhances its transcriptional activity, offering a plausible mechanism of activation of MEF2D by calcineurin. We report here that NFATp synergizes with MEF2D to recruit the coactivator p300 for the transcription of Nur77. Surprisingly, the enhancement of transcriptional activity of MEF2D by NFATp does not require its DNA-binding activity, 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 mediator of T-cell apoptosis and suggest that NFAT is capable of integrating the calcineurin signaling pathway and other pathways through direct protein-protein interaction with other transcription factors.
T细胞抗原受体（TCR）诱导的胸腺细胞凋亡是由钙依赖性信号转导途径介导的，该途径导致Nur77家族成员的转录激活。Nur77启动子中的主要钙和钙调神经磷酸酶反应元件是心肌细胞增强因子2（MEF2）的结合位点。已经表明，活化T细胞核因子（NFAT）与MEF2D相互作用并增强其转录活性，为钙调神经磷酸酶激活MEF2D提供了一种合理的机制。我们在此报告，NFATp与MEF2D协同作用，募集共激活因子p300以进行Nur77的转录。令人惊讶的是，NFATp对MEF2D转录活性的增强并不需要其DNA结合活性，这表明NFATp作为MEF2D的共激活因子发挥作用。p300、MEF2D、NFATp和组成型活性钙调神经磷酸酶的瞬时共表达足以重现TCR信号传导，用于内源性Nur77基因的选择性诱导。这些结果表明NFAT是T细胞凋亡的重要介质，并表明NFAT能够通过与其他转录因子的直接蛋白质-蛋白质相互作用整合钙调神经磷酸酶信号通路和其他通路。
