Abstract 1234: Impact of cancer-associated mutations on MDM2 function

Abstract

Abstract MDM2 is an E3 ubiquitin ligase that functions as a negative regulator of the tumor suppressor p53. MDM2 can promote the ubiquitination and proteasomal degradation through 26S proteasome. In addition to p53, MDM2 can ubiquitinate and promote the degradation of other proteins including SLUG, PCNA, and TERT. Although MDM2 has a well accepted role as an oncogene in human cancer, it also exhibits the ability to suppress the SLUG-driven epithelial mesenchymal transition (EMT) that is a key component of the metastasis process. The fact that MDM2 is required to suppress the SLUG-driven epithelial mesenchymal transition (EMT) led us to speculate that mutations in the MDM2 gene might impair the proteasomal degradation of key regulatory proteins that control biological events and thereby contribute to tumorogenesis. Here, we studied twenty-one somatic point mutants in MDM2 that occur in human cancer. We find that seven of these MDM2 mutants have lost the capacity to degrade p53. Of these mutants, three have lost the capacity to polyubiquitinate and two do not interact with p53. Additionally, we found that two of the mutants exhibit enhanced ability to degrade p53. We also assessed whether these mutants impacted the ability of mdm2 to degrade SLUG. Although previous studies have shown that MDM2 needs to form a trimeric complex with p53 and SLUG in order for degradation of the latter, we find that MDM2 efficiently degraded SLUG in the absence of p53. Furthermore, MDM2 mutants that do not interact with p53 still retain the ability to degrade SLUG. Our study indicates that mutations in MDM2 can yield mutant proteins that exhibit distinct capacities to degrade its substrates. Further, in vitro and in vivo studies will address the impact of these mutations on the oncogenic properties of MDM2. Citation Format: Krishna M. Chauhan, Luis A. Martinez. Impact of cancer-associated mutations on MDM2 function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1234. doi:10.1158/1538-7445.AM2015-1234