Abstract 5069: c-Abl contributes to Mdm2-Mdmx complex formation protecting p53 levels

Abstract

Abstract This study was designed to better understand the signaling events through c-Abl kinase that impact p53 activity. The p53 tumor suppressor protein is a key protein in maintaining the integrity of the genome by inducing either cell cycle arrest or apoptosis following cellular stress signals. Two human family members, Mdm2 and Mdmx, are primarily responsible for inactivating transcription initiation of p53 or destabilizing p53 through ubiquitination. In response to genotoxic stress, post-translational modifications to Mdm2 and Mdmx relieve inhibition on p53, which is in part mediated through the c-Abl kinase. c-Abl is necessary for maintaining p53 expression levels and for maximal accumulation of p53 following DNA damage. While p53 is not a direct substrate of c-Abl there are c-Abl phosphorylation sites present in Mdm2 and Mdmx. Considering that c-Abl regulates both Mdm2 and Mdmx, we designed this study to understand the role of c-Abl phosphorylation of Mdm2 in protecting p53 activity. We hypothesized that protection of p53 would be linked to Mdm2-Mdmx complex formation and modulated by c-Abl phosphorylation. Here we present a mechanism of p53 stabilization whereby c-Abl promotes Mdm2-Mdmx heterodimer complex formation. For this study we used multiple complementary approaches including: recombinant in vitro protein assays, therapeutic drug treatments of cells and targeted mutagenesis of Mdm2 phosphorylation sites to show the role of c-Abl in protecting p53. Additionally, blocking c-Abl phosphorylation has therapeutic implications in treatment of disease through modulation of p53 activity. There are several small molecule inhibitors that affect c-Abl activity, such as imatinib, and a better understanding of the mechanistic role of c-Abl in the stoichiometric balance between Mdm2 and Mdmx may lead to better approaches for engaging p53 activity. This could lead to improvements in current disease treatment and the development of novel therapeutics for cancers harboring wild-type p53. 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 5069.