Xiong Lei, Kou Fei, Yang Ying, Wu Jiarui
Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
J Cell Biol. 2007 Sep 10;178(6):995-1007. doi: 10.1083/jcb.200703044.
Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer cell growth and survival and has been implicated in cancer pathophysiology and treatment. Here we report a novel function for IGF-1R in p53-dependent apoptotic response. We show that inhibition or loss of IGF-1R activity reduces translational synthesis of p53 and Mdm2 protein. Notably, IGF-1R inhibition increases p53 protein stability by reducing p53 ubiquitination and maintains p53 at low levels by decreasing p53 synthesis, thus rendering p53 insensitive to stabilization after DNA damage. The accumulation and apoptosis of DNA-damage-induced p53 is therefore reduced in Igf-1r(-/-) mouse embryonic fibroblasts or tumor cells treated with the IGF-1R inhibitor. Furthermore, we find that inhibition of IGF-1R reduces p53 and Mdm2 translation through a gene-specific mechanism mediated by the respective 5' untranslated region of p53 and mdm2 messenger RNA. The eukaryotic translation initiation factor 4F complex is also involved in this translational inhibition. These results demonstrate an unexpected role for translational control by IGF-1R in p53-mediated apoptosis.
胰岛素样生长因子1受体（IGF-1R）在癌细胞的生长和存活中起着重要作用，并且与癌症的病理生理学及治疗相关。在此，我们报告IGF-1R在p53依赖的凋亡反应中的一种新功能。我们发现IGF-1R活性的抑制或缺失会降低p53和Mdm2蛋白的翻译合成。值得注意的是，IGF-1R抑制通过减少p53泛素化增加p53蛋白稳定性，并通过降低p53合成将p53维持在低水平，从而使p53在DNA损伤后对稳定化不敏感。因此，在用IGF-1R抑制剂处理的Igf-1r(-/-)小鼠胚胎成纤维细胞或肿瘤细胞中，DNA损伤诱导的p53的积累和凋亡减少。此外，我们发现抑制IGF-1R通过由p53和mdm2信使核糖核酸各自的5'非翻译区介导的基因特异性机制减少p53和Mdm2的翻译。真核翻译起始因子4F复合物也参与这种翻译抑制。这些结果证明了IGF-1R在p53介导的凋亡中的翻译控制具有意想不到的作用。
