The p53 mRNA-Mdm2 Interaction Controls Mdm2 Nuclear Trafficking and Is Required for p53 Activation following DNA Damage

Abstract

The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway. The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA. The physiological role and regulation of Mdm2's dual function toward p53 is not known. Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction. This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation. Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage. These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA.

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…92 A second promoter, P1, regulates MDM2 levels under 'non-stressed' conditions, and PTEN is a major ligand suppressing basal MDM2 expression levels. 93 Although Gajjer et al 94 found MDM2 to suppress p53 protein levels under non-stressed conditions, following ATM-dependent phosphorylation of MDM2 at serine 395, the MDM2 protein became a stabilizer of p53 mRNA in response to stress. The potential impact of these findings yet remains to be settled.…”

Association Between MDM2 SNP309 T>G and Risk of Gastric Cancer: A Meta-analysis

“…MDM2 regulates P53 by binding to its N terminus and promoting either p53 monoubiquitination and nuclear export or p53 polyubiquitination and degradation by the 26S proteasomal pathway; besides, MDM2 could regulate p53 via its interaction with L26 or directly by binding to the p53 mRNA (Gajjar et al, 2012). The polymorphism 309 T>G, found in the MDM2 promoter, was reported to increase the affinity of transcriptional activator Sp1, thus resulting in the higher expression of MDM2 and subsequent disturbance of MDM2-P53 feedback loop balance (Stommel et al, 2005).…”

Association Between MDM2 Promoter SNP309 T/G Polymorphism and Liver Cancer Risk - a Meta-analysis

“…MDM2 protein is a direct negative regulator for the p53 tumor suppressor protein, which accounts for 50% of human cancers after loss of MDM2 function (Stommel and Wahl, 2005;Gajjar et al, 2012). This increase in MDM2 results in the direct inhibition of p53 transcriptional activity, enabling damaged cell to escape the cell-cycle checkpoint and become carcinogenic (Dongiovanni et al, 2010;Embade et al, 2012).…”

“…This increase in MDM2 results in the direct inhibition of p53 transcriptional activity, enabling damaged cell to escape the cell-cycle checkpoint and become carcinogenic (Dongiovanni et al, 2010;Embade et al, 2012). Overexpression of MDM2 by up to four-fold in transgenic mice harboring wild-type p53 can lead to carcinogenesis (Stommel and Wahl, 2005;Gajjar et al, 2012). These findings suggest that MDM2 may play an important role in cancer development and progression (Jung et al, 2010;Embade et al, 2012).…”