Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis
Menée in vitro et à l'aide de modèles murins de cancer induit par les espèces réactives de l'oxygène, cette étude met en évidence un mécanisme par lequel la phosphorylation de la protéine Mdm2 par la kinase Akt, en réduisant l'expression de la protéine p53 impliquée dans la réponse au stress oxydant, favorise la prolifération cellulaire et la tumorigenèse
We demonstrate that Akt phosphorylation of Mdm2 protein at Ser183 inhibits p53-mediated senescence and promotes ROS-induced tumorigenesis. Thus, different effector kinases can modify Mdm2 and selectively regulate the p53-mediated response to stress. Our study suggests that targeted inhibition of Mdm2 Ser183 phosphorylation would activate p53-mediated senescence and delay tumor progression.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 KrasG12D-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.All study data are included in the article and supporting information.