Abstract 4627: Mutant p53 regulation in a Li-Fraumeni mouse model

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 a E3 ubiquitin ligase while Mdm4 binds to p53 and inhibits its transactivation activity. Deletion of either inhibitor results in p53-dependent embryonic lethality in mice. p53 is one of the most commonly mutated genes in human cancer. While we have gained considerable knowledge about wild-type p53 regulation and mode of action, our understanding of the oncogenic activity of mutant p53 lags behind. We know that mutant p53 is regulated in the same manner as wild-type p53. In a mouse model of Li-Fraumeni syndrome, Mdm2 binds and inhibits the hot spot mutant p53R172H (p53R175H in humans). Here we show that Mdm4, like Mdm2, regulates p53R172H stability in vivo, and that endogenous Mdm2 cannot compensate for this stabilization. Thus, mutant p53 mice that lack Mdm4 have stable high levels of p53R172H and display accelerated tumor development and an increased range of tumor types, compared to mutant p53 mice. Furthermore, when we compared mutant mice with the loss of two different alleles of both negative regulators, Mdm2 and Mdm4, we observed an even higher level of p53. This finding reveals that several tissues can tolerate high expression of oncogenic p53 and indicates a collaborative activity of these inhibitors in regulating mutant p53. The analysis of these mice uncovered new and unexpected functions of mutant p53 that we will discuss for the first time at the AACR 2019 meeting. Citation Format: Tamara Terzian, Molly Plehaty, Nema Sobhani, Wanida Stevens, Stefan Marasligiller, Tara Srinivas, Rohan Mylavarapu, Yvonne Clarke, Farinaz Arbab, Brendon Podell, Roderick Bronson. Mutant p53 regulation in a Li-Fraumeni mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4627.