p53-Dependent Translational Control of Senescence and Transformation via 4E-BPs
p53-Dependent Translational Control of Senescence and Transformation via 4E-BPs
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DOI：
10.1016/j.ccr.2009.09.025
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发表时间：
2009-11-03
期刊：
影响因子：
50.3
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Petroulakis, Emmanuel;Parsyan, Armen;Sonenberg, Nahum
eIF 4 E是mRNA 5'帽结合翻译起始因子，在许多癌症中过表达，并与肿瘤发生和衰老的潜在机制有关。4 E-BP（eIF 4 E结合蛋白）抑制eIF 4 E活性，从而作为eIF 4 E依赖性途径的抑制剂。在这里，我们表明，肿瘤发生增加p53基因敲除小鼠缺乏4 E-BP 1和4 E-BP 2。然而，缺乏4 E-BP但表达p53的原代成纤维细胞经历过早衰老并抵抗癌基因驱动的转化。因此，p53状态控制4 E-BP依赖性衰老和转化。有趣的是，4 E-BP通过p53稳定蛋白Gas 2的翻译控制参与衰老。我们的数据表明4 E-BP在衰老和肿瘤发生中的作用，并强调了p53介导的衰老机制，通过4 E-BP依赖性途径。
eIF4E, the mRNA 5' cap-binding translation initiation factor, is overexpressed in numerous cancers and is implicated in mechanisms underlying oncogenesis and senescence. 4E-BPs (eIF4E-binding proteins) inhibit eIF4E activity, and thereby act as suppressors of eIF4E-dependent pathways. Here, we show that tumorigenesis is increased in p53 knockout mice that lack 4E-BP1 and 4E-BP2. However, primary fibroblasts lacking 4E-BPs, but expressing p53, undergo premature senescence and resist oncogene-driven transformation. Thus, the p53 status governs 4E-BP-dependent senescence and transformation. Intriguingly, the 4E-BPs engage in senescence via translational control of the p53-stabilizing protein, Gas2. Our data demonstrate a role for 4E-BPs in senescence and tumorigenesis and highlight a p53-mediated mechanism of senescence through a 4E-BP-dependent pathway.