Abstract B12: Deciphering mechanisms of p53-mediated pancreatic cancer suppression.

The essential role of p53 in tumor suppression is highlighted by the observations that p53 is mutated in over half of human cancers and that p53-null mice are highly predisposed to developing cancer. Although p53 is thought to suppress cancer by inducing growth arrest or apoptosis in response to cellular stress signals, its molecular mechanism of action in tumor suppression has remained unclear. p53 is a transcriptional activator that can induce numerous target genes, but it also displays other biochemical activities. To define the mechanism of p53 action in vivo, we previously sought to establish the contribution of transcriptional activation to p53 function by generating p53 knock-in mouse strains expressing mutants altered in the first (p5325,26, with L25Q;W26S mutations), second (p5353,54, with F53Q;F54S mutations), or both transcriptional activation domains (p5325,26,53,54, with L25Q;W26S;F53Q;F54S mutations) from the endogenous p53 promoter1. Upon analysis of these p53 mutants in fibroblasts, we found that p5325,26 is greatly impaired for transactivation of most known p53 target genes, but retains the capacity to activate a small set of p53 target genes. In contrast, p5353,54 retains wild-type transactivation potential, while p5325,26,53,54 completely lacks transactivation activity. To assess the biological function of these mutants, we analyzed their activities in acute DNA damage-induced responses and tumor suppression. Analysis of p5325,26 demonstrated that although it cannot induce growth arrest or apoptosis in response to acute DNA damage, it is active in tumor suppression. Specifically, it can suppress the development of mouse cancers driven by different oncogenic lesions and derived from a wide variety of cell types of origin. Recently, using a well-established model for pancreatic ductal adenocarcinoma (PDA) driven by activated KRasG12D expression in the pancreas, we showed that p5325,26 is also active as a tumor suppressor in this context. In contrast, the transcriptionally dead p5325,26,53,54 mutant is completely defective for the suppression of pancreatic and other tumors. These findings highlight the importance of transcriptional activation for p53 tumor suppressor function, but without robust induction of most classical p53 target genes. Interestingly, p5325,26-driven tumor suppression is associated with the activation of a small cohort of new direct p53-inducible genes, whose analysis is in progress. Detailed analyses of these genes will provide a powerful strategy for better elucidating the networks downstream of p53 in tumor suppression. Reference: 1. Brady CA, Jiang D, Mello SS, Johnson TM, Jarvis LA, Kozak MM, Broz DK, Basak S, Park EJ, McLaughlin ME, Karnezis AN, Attardi LD. Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression. Cell. 2011 May 13;145(4):571-83. Citation Format: Stephano Spano Mello, Colleen A. Brady, Dadi Jiang, Daniela Kenzelmann Broz, Eunice J. Park, Hannes Vogel, Laura D. Attardi. Deciphering mechanisms of p53-mediated pancreatic cancer suppression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B12.