Suppression of p53 Activity through the Cooperative Action of Ski and Histone Deacetylase SIRT1
Suppression of p53 Activity through the Cooperative Action of Ski and Histone Deacetylase SIRT1
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DOI：
10.1074/jbc.m110.177683
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发表时间：
2011-02-25
影响因子：
4.8
通讯作者：
Imamura, Takeshi
中科院分区：
文献类型：
--
作者：
Inoue, Yasumichi;Iemura, Shun-ichiro;Imamura, Takeshi
Ski 最初被确定为癌基因，因为 Ski 过度表达会转化鸡和鹌鹑胚胎成纤维细胞。与这些提出的致癌作用一致，Ski 在各种人类肿瘤中过度表达。然而，Ski 在哺乳动物肿瘤发生中是否以及如何发挥作用尚未得到充分研究。在这里，我们证明 Ski 与 p53 相互作用并减弱 p53 的生物学功能。 Ski 过表达减弱了 p53 依赖性反式激活，而 Ski 敲低则增强了 p53 的转录活性。有趣的是，Ski 与组蛋白脱乙酰酶 SIRT1 结合并稳定 p53-SIRT1 相互作用，从而促进 p53 脱乙酰化，从而降低 p53 的 DNA 结合活性。与 Ski 灭活 p53 的能力一致，过表达 Ski 使细胞对基因毒性药物和 Nutlin-3 脱敏，Nutlin-3 是 Mdm2 的小分子拮抗剂，可稳定 p53 并激活 p53 通路，而敲除 Ski 则增加细胞对这些药物的敏感性。这些结果表明 Ski 负向调节 p53，并表明 p53-Ski-SIRT1 轴是癌症治疗的一个有吸引力的靶点。
Ski was originally identified as an oncogene based on the fact that Ski overexpression transformed chicken and quail embryo fibroblasts. Consistent with these proposed oncogenic roles, Ski is overexpressed in various human tumors. However, whether and how Ski functions in mammalian tumorigenesis has not been fully investigated. Here, we show that Ski interacts with p53 and attenuates the biological functions of p53. Ski overexpression attenuated p53-dependent transactivation, whereas Ski knockdown enhanced the transcriptional activity of p53. Interestingly, Ski bound to the histone deacetylase SIRT1 and stabilized p53-SIRT1 interaction to promote p53 deacetylation, which subsequently decreased the DNA binding activity of p53. Consistent with the ability of Ski to inactivate p53, overexpressing Ski desensitized cells to genotoxic drugs and Nutlin-3, a small-molecule antagonist of Mdm2 that stabilizes p53 and activates the p53 pathway, whereas knocking down Ski increased the cellular sensitivity to these agents. These results indicate that Ski negatively regulates p53 and suggest that the p53-Ski-SIRT1 axis is an attractive target for cancer therapy.