Dual Defects Of Mdm2/Mdmx-P53 Pathways Cause Global Metabolic Disruption And Enhance Tumorigenesis

Although recent discoveries have linked the tumor suppressing functions of p53 to its regulation on cellular metabolism, the exact signaling pathways underlying how p53 is activated in response to various metabolism stresses, and how p53 coordinates the systemic metabolism homeostasis and further blocks tumorigenesis remain largely unclear. Previous studies have shown that the mice containing a single knock-in at cysteine residue 305 of MDM2 (MDM2C305F) is defective in ribosomal stress (RS) induced p53 activation and display severe nutrient shortage-induced hepatosteatosis. And very recently we found that in response to metabolic stress (MeS), AMPK directly phosphorylates serine 342 of MDMX, leading to p53 activation, which is defective in MDMX3SA mice harboring a mutant MDMX with S341A, S367A and S402A mutations. In the current study, we want to determine if the dual defects in the MDM2/MDMX-p53 pathways might thoroughly impair p539s ability to regulate metabolic homeostasis and thus favor metabolism-related tumorigenesis, by generating a double knock-in (DKI) MDMX3SA/MDM2C305F mouse line. Our results indicate that DKI mice on normal chow diet exhibit mild, but significant, metabolism abnormalities, including increased body weight, higher fasting-glucose level and impaired glucose tolerance, which is exacerbated by high-fat-diet feeding. Consistently, MEFs isolated from DKI mice possess higher capacity of differentiation into adipocytes, and less beige fat is induced in the subcutaneous white adipose tissue of DKI mice after chronic cold exposure. Furthermore, we observe that the survival rate of DKI mice is significantly lower compared to either control or single knock-in groups, which may be due to the higher morbidity of cancers in DKI mice, including hepatoma, lymphoma and lung carcinoma. Because of these observations, we further specifically investigate if dual defects of these p53 activation pathways will accelerate hepatocellular carcinogenesis or not. We indeed find that treatment of carcinogen DEN causes more and bigger tumor nodules in the liver of DKI mice. These results suggest that both RS-MDM2-p53 and MeS-MDMX-p53 pathways play important roles in regulation of global metabolism, and dual defects of these pathways benefit metabolism-related tumor formation and growth. Further study is required to establish the direct effect of the p53 pathway defects-mediated metabolic disruption on tumorigenesis, and determine the underlying mechanisms. Citation Format: Hua Lu, Yi-wei zhang, Peng Liao, Wenjuan Liao, Jiaxiang Chen, Shelya X. Zeng. Dual defects of MDM2/MDMX-p53 pathways cause global metabolic disruption and enhance tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 891.