We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote Kras^G12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.

我们之前已经表明，ATM 和 c-Abl 对 Mdm2 的磷酸化可调节 Mdm2-p53 信号传导并改变小鼠 DNA 损伤的影响，包括电离辐射诱导的骨髓衰竭和肿瘤发生。在这里，我们研究了另一种 DNA 损伤效应激酶 Akt 对 Mdm2 磷酸化的生理影响。令人惊讶的是，Mdm2 的 Akt 磷酸化不会改变 p53 介导的电离辐射在细胞或小鼠中的作用，而是调节 p53 对氧化应激的反应。Mdm2 丝氨酸残基 183 的 Akt 磷酸化可增加核 Mdm2 的稳定性，降低 p53 水平，并防止暴露于活性氧化物质 (ROS) 的原代细胞衰老。使用 ROS 诱导癌症的多个小鼠模型，我们表明 Akt 对 Mdm2 的磷酸化可减少衰老以促进 Kras ^G12D-驱动的肺癌和致癌物引起的乳头状瘤和肝细胞癌。总的来说，我们记录了 Akt-Mdm2-p53 信号在调节细胞生长和肿瘤发生以响应氧化应激的独特生理作用。