Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden J M
Department of Medicine, University of Chicago, Illinois 60637, USA.
Nature. 1996 Jan 4;379(6560):81-5. doi: 10.1038/379081a0.
The basic/leucine zipper (bZip) transcription factor, CREB, binds to the CRE element (TGANNTCA). The transcriptional activity of CREB requires phosphorylation of the protein on a serine residue at position 119 (ref. 6). CREs are present in a number of T-cell genes but the precise role of CREB in T-cell differentiation and function was unknown. Here we show that resting thymocytes contain predominantly unphosphorylated (inactive) CREB, which is rapidly activated by phosphorylation on Ser 119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (CREBA119, with alanine at position 119) under the control of the T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T cells from these animals display a profound proliferative defect characterized by markedly decreased interleukin-2 production, G1 cell-cycle arrest and subsequent apoptotic death in response to a number of different activation signals. This proliferative defect is associated with the markedly reduced induction of c-jun, c-fos, Fra-2 and FosB following activation of the CREBA119 transgenic thymocytes. We propose that T-cell activation leads to the phosphorylation and activation of CREB, which in turn is required for normal induction of the transcription factor AP1 and subsequent interleukin-2 production and cell-cycle progression.
碱性/亮氨酸拉链（bZip）转录因子CREB可与CRE元件（TGANNTCA）结合。CREB的转录活性需要其119位丝氨酸残基发生磷酸化（参考文献6）。许多T细胞基因中都存在CRE元件，但CREB在T细胞分化和功能中的具体作用尚不清楚。在此我们发现，静息胸腺细胞主要含有未磷酸化（无活性）的CREB，胸腺细胞激活后，该蛋白可通过119位丝氨酸的磷酸化而迅速激活。在T细胞特异性CD2启动子/增强子控制下表达显性负性形式CREB（CREBA119，119位为丙氨酸）的转基因小鼠中，T细胞发育正常。相反，这些动物的胸腺细胞和T细胞表现出严重的增殖缺陷，其特征为白介素-2产生显著减少、G1期细胞周期停滞以及在多种不同激活信号刺激下随后发生凋亡性死亡。这种增殖缺陷与CREBA119转基因胸腺细胞激活后c-jun、c-fos、Fra-2和FosB的诱导显著减少有关。我们提出，T细胞激活导致CREB磷酸化并激活，这反过来对于转录因子AP1的正常诱导以及随后白介素-2的产生和细胞周期进程是必需的。
