Abstract 125: The DNp73 isoform provides novel insights into the regulation of p53 by BRCA1 to favor cell survival over cell death

Abstract

Abstract BRCA1, the first breast cancer susceptibility gene to be identified, remains an enigma. Many roles have been ascribed to BRCA1 including DNA repair, cell cycle checkpoint activation, transcriptional regulation and chromatin remodeling. We have previously established that BRCA1 overexpression induces the stabilization of p53 without activating pro-apoptotic targets of p53, and that BRCA1 can protect cells from DNA damage-induced p53-dependent cell death. This seems to be specific to pro-apoptotic targets because p53 is still able to activate target genes involved in cell cycle arrest or DNA repair. In our efforts to understand this phenomenon, we have found that BRCA1 induces many of the same post-translational modifications that DNA damage induces including key phosphorylations and the acetylation of lysine 120 of p53, known to be important for apoptosis. Moreover, BRCA1-stabilized p53 localizes to the promoter regions of pro-apoptotic target genes whose expression is not upregulated. We hypothesized that p53 family members p63 and/or p73 may regulate the selectivity of p53 action in response to BRCA1. Unexpectedly, we found that BRCA1 upregulates DNp73 expression, an isoform of the p53 family member p73 lacking the transactivation domain, that has been previously implicated in cell survival. This observation has important implications for understanding the selectivity of p53-dependent transcription as well as the tumor suppressive action of BRCA1 that favors DNA repair over cell death. Our ongoing studies are evaluating the effects of the BRCA1-induced DNp73 isoform on interactions between p53 and p53 family members that regulate the genes involved in cell fate. These findings unravel a novel mechanism by which the selectivity of p53-dependent gene expression is regulated BRCA1 and further unravels the complex nature of these p53 and BRCA1 tumor suppressor pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 125.