Abstract B07: Gain of function activities of p53R245W in a conditional knock-in mouse model

Abstract

Abstract Missense mutations of the p53 tumor suppressor gene are present in more than 50% of human tumors. Emerging evidence suggests that p53 missense mutations in human cancer patients are associated with the poor prognosis and drug resistance due to their gain-of-function (GOF) properties, rather than just the loss of normal p53 function. Interestingly, these missense mutations have been shown to contribute to tumor progression by different mechanisms: interactions with Smad and SREBPs, modulation of EGFR/integrin signaling, and inhibition of p63 and p73 tumor suppressors. Combined, these studies suggest that the GOF of p53 missense mutations may be dependent on cell contexts and mutation types. Of particular interest, the p53R248W mutation is one of the most frequent missense mutation among human cancer patients; yet to date a mouse model that faithfully mimics this mutation does not exist. Additionally, the majority of human cancers evolve from somatic inactivation of p53 and current mouse models do not mimic somatic mutation of p53. Thus, we generated a conditional p53WMR245/+ knock-in mouse model, which normally expresses wild type p53, but produces p53R245W by Cre-mediated deletion of wild type p53 sequences. Germ line mutation of p53R245W/+ can rescue the early embryonic lethality of Mdm2 and Mdm4 null alleles like p53 null. Preliminary analyses of p53R245W/+ cohorts indicate differences in tumor spectrum in comparison to p53+/- and p53R172H/+ mice. Somatic mutation of p53R245W has also been performed to examine germ line versus somatic differences in tumor development. This study will help us understand the in vivo contributions of different p53 missense mutations to tumorigenesis, as well as the genetic alterations that occur during tumor evolution initiated by both germ line and somatic p53 mutations. Citation Format: Shunbin Xiong, Yun Zhang, Guillermina Lozano. Gain of function activities of p53R245W in a conditional knock-in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B07.