Reactivation of p53 by Inhibiting Mdm2 E3 Ligase: A Novel Antitumor Approach

Abstract

The p53 tumor suppressor has been pursued as a cancer therapeutic target based on its ability to induce cell cycle arrest and apoptosis. Reactivation of p53 in the approximately 50% of tumors that retain a functional p53 has served as potential approach in the development of cancer drug therapy. Mdm2 is a major negative regulator of p53 and has long been thought to inhibit p53 in two ways: through ubiquitination of p53, signaling for its degradation by the proteasome, and through directly binding to p53, masking its transactivation domain. Research on Mdm2 E3 function and regulation has important implications for the feasibility of targeting Mdm2 in cancer treatment. By targeting Mdm2 in cancers, especially those harboring wild-type p53, it may be possible to restore p53 function to control tumor growth. Several inhibitors for Mdm2 have been developed and have shown promise in restoring p53 function. This review will summarize the current progress of targeting Mdm2 in cancer treatment with a focus on regulating Mdm2 E3 ubiquitin ligase activity via a number of small Mdm2 binding proteins and the post-translational modification of Mdm2 itself. The potential of inhibitors of Mdm2 E3 ligase as a new novel class of anticancer drugs will also be discussed.