Abstract 2459: The oncogenic activity of MDMx is associated with physical interaction and suppression of retinoblastoma protein

Abstract

Abstract The aim of this study is to investigate the role of MDMx (or MDM4) on the regulation of retinoblastoma protein (Rb). Inactivation of Rb plays a critical role in the development of human malignancies. We have previously shown that MDM2, an ubiquitin E3 ligase and a major negative regulator of p53, binds to and promotes proteasome-mediated degradation of Rb independent of p53. MDMX, a homolog of MDM2, also binds to and inhibits p53 transactivation activity, yet it does not possess an ubiquitin E3 ligase activity. In this study, we show that MDMX binds to and promotes proteasome-mediated degradation of Rb in a MDM2-dependent manner. The C-terminal Ring domain of MDMX binds to the Rb C-pocket and enhances MDM2-Rb interaction. Knockdown of MDMX induces Rb protein accumulation, cell cycle G1 arrest, and premature cellular senescence, which can be reverted by simultaneous knockdown of Rb. Furthermore, ablation of MDMX significantly suppresses tumor growth, concomitant with Rb accumulation, in an animal xenograft model. Together, these results demonstrate that MDMX possesses oncogenic activity associated with suppression of Rb and suggest that both MDM2 and MDMX can be targets for cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Zhi-Xiong Xiao, Haibo Zhang, Yujun Zhang. The oncogenic activity of MDMx is associated with physical interaction and suppression of retinoblastoma protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2459. doi:10.1158/1538-7445.AM2014-2459