Abstract IA4: Deconstructing p53 pathways in vivo

The activation of the p53 protein by cellular stress signals is fundamental for tumor suppression but also promotes pathological states, such as provoking the side effects of genotoxic cancer therapies. To better understand the mechanisms of p53 action in different contexts, we have leveraged both mouse genetic and genomic approaches. First, we have used mouse genetics to define transcriptional programs involved in p53 function in different in vivo settings, specifically by generating a panel of p53 transcriptional activation domain mutant knock-in mouse strains. These include strains expressing p53 mutants in the first (p5325,26), second (p5353,54), or both transactivation domains (p5325,26,53,54). We have observed that p5325,26 is severely compromised for transactivation of most classical p53 target genes, but retains the ability to activate a subset of p53 targets, while p5325,26,53,54 lacks transactivation activity completely. Interestingly, although unable to induce apoptosis or cell cycle arrest in response to acute DNA damage signals, p5325,26 retains full activity in suppressing cancers of a wide range of types, indicating that robust transactivation of most canonical p53 targets is dispensable for tumor suppression. Importantly, as p5325,26 activates only a subset of p53-dependent genes, yet retains tumor suppressor activity, it has helped to define a small set of novel p53-inducible tumor suppression-associated genes, which we are currently analyzing in detail. Second, we have utilized genomic approaches to better understand p53 function. Using ChIP-sequencing and RNA-sequencing to analyze transcriptional programs in acute DNA damage-treated mouse embryo fibroblasts, our studies have revealed an extensive p53-regulated autophagy program that contributes to p53 responses. Together, these approaches will help better define the transcriptional networks important for p53 action in different settings. Citation Format: Colleen A. Brady, Daniela Kenzelmann Broz, Dadi Jiang, Stephano Spano Mello, Kathryn Bieging, Thomas M. Johnson, Leslie A. Jarvis, Margaret M. Kozak, Shashwati Basak, Laura D. Attardi. Deconstructing p53 pathways in vivo. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA4.