Abstract LB-028: Mdm4 regulates mutant p53 stability in vivo

Abstract

Abstract The p53 tumor suppressor is maintained mainly at low physiological levels in normal cells by its two major inhibitors, Mdm2 and Mdm4. Mdm2 is an E3 ubiquitin ligase while Mdm4 lacks this activity. Deletion of either inhibitor results in p53-dependent embryonic lethality in mice. We have shown that Mdm2 binds and inhibits mutant p53R172H in a mouse model of Li-Fraumeni syndrome. We recently established that Mdm4, like Mdm2, regulates p53R172H stability in vivo, and that endogenous Mdm2 cannot compensate for this stabilization. Thus, mice that lack Mdm4 and are homozygous for the p53R172H allele have stabilized p53R172H and display accelerated tumor development and an increased range of tumor types, compared to p53R172H/R172H mice. Furthermore, we compared mutant mice with the loss of two different alleles of Mdm4 and observed a threshold for metastasis associated with higher p53R172H levels. These data support the gain-of-function hypothesis: high levels of mutant p53 increase the frequency of metastasis. We are currently analyzing mutant p53 target genes expression differences between the two Mdm4 alleles and Mdm2 to assess mutant p53 mode of regulation of these alleles. Citation Format: Molly Plehaty, Tara Srinivas, Wanida Stevens, Nema Sobhani, Tomoo Iwakuma, Brendan Podell, Farinaz Arbab, Tamara Terzian. Mdm4 regulates mutant p53 stability in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-028. doi:10.1158/1538-7445.AM2017-LB-028