Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun
Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun
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DOI：
10.1093/emboj/19.17.4783
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发表时间：
2000-09-01
期刊：
影响因子：
11.4
通讯作者：
Rao, AJN
中科院分区：
文献类型：
--
作者：
Macián, F;García-Rodríguez, C;Rao, AJN
活化T细胞核因子（NFAT）与AP - 1（Fos - Jun）蛋白在复合的NFAT - AP - 1 DNA元件上的协同作用构成了一种强大的机制，用于在基因表达调控中整合钙和蛋白激酶C/Ras通路的信号。在此我们报道，NFAT可在T细胞中诱导某些基因的表达，而无需Fos和Jun的协同募集。利用无法与Fos - Jun二聚体相互作用但在DNA结合或转录活性方面不受影响的NFAT1突变蛋白，我们表明白细胞介素（IL）- 2、粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）、IL - 3、IL - 4、巨噬细胞炎性蛋白1α（MIP1α）和Fas配体mRNA的表达绝对依赖于NFAT和Fos - Jun之间的协同作用；相反，NFAT可诱导肿瘤坏死因子α（TNFα）mRNA和IL - 13启动子活性，而无需募集Fos和Jun。此外，我们表明NFAT - Fos - Jun的协同作用对于引发活化诱导的细胞死亡的NFAT依赖性程序也是必不可少的。我们的结果支持这样一种假设：即使在单一细胞类型中，NFAT的激活也可引发两种不同的基因表达生物学程序，这些程序依赖于或不依赖于NFAT - AP - 1的协同作用。
Cooperation between nuclear factor of activated T cells (NFAT) and AP-1 (Fos-Jun) proteins on composite NFAT-AP-1 DNA elements constitutes a powerful mechanism for signal integration of the calcium and protein kinase C/Ras pathways in the regulation of gene expression. sere we report that NFAT can induce expression of certain genes in T cells without the need for cooperative recruitment of Fos and Jun. Using NFAT1 mutant proteins that are unable to interact with Fos-Jun dimers but are unaffected in DNA binding or transcriptional activity, we show that expression of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-4, MIP1 alpha and Fas ligand mRNAs is absolutely dependent on cooperation between NFAT and Fos-Jun; in contrast, NFAT induces tumor necrosis factor alpha (TNF alpha) mRNA and IL-13 promoter activity without any necessity to recruit Fos and Jun. Furthermore, we show that NFAT-Fos-Jun cooperation is also essential to elicit the NFAT-dependent program of activation-induced cell death. Our results support the hypothesis that even in a single cell type, NFAT activation can evoke two distinct biological programs of gene expression, dependent or independent of NFAT-AP-1 cooperation.