Abstract 1768: The oncogene Mdmx promotes genomic instability independent of p53.

Abstract Mdmx is upregulated in many human cancers. As a member of the Mdm2 protein family, Mdmx functions similar to Mdm2 as a negative regulator of the tumor suppressor p53. With the ability to form heterodimers with Mdm2, p53 regulation by Mdmx predictably relies on Mdm2. However, while the p53- and Mdm2-dependent functions of Mdmx understandably contribute to cancer, Mdmx has also displayed p53- and Mdm2-independent functions in tumor development that are less well characterized. Therefore, we investigated novel avenues in which Mdmx contributes to tumorigenesis. We demonstrate increased expression of Mdmx results in an inhibition in double-strand DNA break repair and a delay in DNA damage signaling that was independent of p53 and surprisingly, independent of Mdm2. We identified a novel association between Mdmx and a key mediator of DNA repair, the Mre11-Rad50-Nbs1 complex. We also detected increased genomic instability and promotion of in vitro transformation as a result of Mdmx overexpression that was also independent of p53 and Mdm2. Our data show that Mdmx interacts with the Mre11-Rad50-Nbs1 complex and delays DNA break repair, which leads to genome instability and cellular transformation. This novel function of Mdmx provides insight into an alternative mechanism by which Mdmx contributes to tumor formation and possibly tumor progression independent of its interaction with Mdm2 or its negative regulation of p53. These data also highlight the potential for novel therapeutic intervention strategies that capitalize on this newly identified function of Mdmx. Citation Format: Alexia N. Melo, Alyssa Bouska, Maria P. Arrate, Christine M. Eischen. The oncogene Mdmx promotes genomic instability independent of p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2013-1768