通过4E-BP蛋白实现的p53依赖的衰老和转化的翻译调控

p53-dependent translational control of senescence and transformation via 4E-BPs.

作者信息

Petroulakis Emmanuel, Parsyan Armen, Dowling Ryan J O, LeBacquer Olivier, Martineau Yvan, Bidinosti Michael, Larsson Ola, Alain Tommy, Rong Liwei, Mamane Yaël, Paquet Marilene, Furic Luc, Topisirovic Ivan, Shahbazian David, Livingstone Mark, Costa-Mattioli Mauro, Teodoro Jose G, Sonenberg Nahum

机构信息

Department of Biochemistry & Goodman Cancer Center, McGill University, Montreal, Quebec, H3G 1Y6, Canada.

出版信息

Cancer Cell. 2009 Nov 6;16(5):439-46. doi: 10.1016/j.ccr.2009.09.025.

DOI:10.1016/j.ccr.2009.09.025

PMID:19878875

Abstract

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.

摘要

真核生物翻译起始因子4E（eIF4E）是一种mRNA 5'帽结合翻译起始因子，在多种癌症中过度表达，并与肿瘤发生和衰老的潜在机制有关。4E结合蛋白（4E-BPs）抑制eIF4E活性，从而作为eIF4E依赖性途径的抑制因子。在此，我们表明，在缺乏4E-BP1和4E-BP2的p53基因敲除小鼠中，肿瘤发生增加。然而，缺乏4E-BPs但表达p53的原代成纤维细胞会过早衰老，并抵抗癌基因驱动的转化。因此，p53状态决定了4E-BP依赖性衰老和转化。有趣的是，4E-BPs通过对p53稳定蛋白Gas2的翻译控制参与衰老过程。我们的数据证明了4E-BPs在衰老和肿瘤发生中的作用，并突出了一种通过4E-BP依赖性途径的p53介导的衰老机制。