Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms
Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms
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DOI：
10.1126/science.286.5443.1358
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发表时间：
1999-11-12
期刊：
影响因子：
56.9
通讯作者：
Greenberg, ME
中科院分区：
文献类型：
--
作者：
Bonni, A;Brunet, A;Greenberg, ME
研究了Ras丝裂原活化蛋白激酶(MAPK)信号通路介导生长因子依赖的细胞存活的机制。在体外和体内，MAPK激活的蛋白激酶RSKs催化丝氨酸112处促凋亡蛋白BAD的磷酸化。RSK诱导的丝氨酸112位BAD的磷酸化抑制了BAD介导的神经元凋亡。已知的RSK还能使转录因子CREB(cAMP反应元件结合蛋白)在丝氨酸133处磷酸化。激活的CREB可促进细胞存活，抑制CREB丝氨酸133位的磷酸化可引发细胞凋亡。这些发现表明，MAPK信号通路通过双重机制促进细胞存活，包括细胞死亡机制的一个组成部分的翻译后修饰和失活以及促进生存基因的转录增加。
A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.