Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis.
Loretah ChibayaBaktiar O KarimHong ZhangStephen N JonesPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- dna damage
- oxidative stress
- cell proliferation
- induced apoptosis
- signaling pathway
- protein kinase
- diabetic rats
- bone marrow
- cell cycle arrest
- pi k akt
- ischemia reperfusion injury
- endoplasmic reticulum stress
- cell cycle
- cell death
- mouse model
- high glucose
- dendritic cells
- metabolic syndrome
- squamous cell carcinoma
- adipose tissue
- drug induced
- insulin resistance
- amino acid