Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis.

Autor:	Chibaya L; Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655., Karim B; Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Zhang H; Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655., Jones SN; Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655; stephen.jones2@nih.gov.; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655.; Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 26; Vol. 118 (4).
DOI:	10.1073/pnas.2003193118
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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