Mdm2-mediated ubiquitylation: p53 and beyond

Abstract

The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

“…In this way, MDM2 prevents p53‐mediated cell cycle arrest, cell senescence and premature death 42. We speculated that MDM2 may promote podocyte MC by mediating p53 expression.…”

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

“…2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.…”

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

“…38 MDM2 stimulates the nuclear export of p53 and targets p53 for proteasomal degradation. 9,40 Upon genotoxic cellular stress, p53 becomes stabilized by post-translational modifications, 41 is released from MDM2, and then migrates to the nucleus and binds the promoter region of target genes. 38,42 Although other Ub ligases are also involved in the control of p53 stability, 43 MDM2 is the most important Ub ligase that promotes p53 monoubiquitination and nuclear export as well as polyubiquitination and degradation.…”

“…8 By binding to a p53 transactivation domain, MDM2 interferes with p53-mediated transcription, promotes p53 nuclear export and induces Ub-mediated proteasomal p53 degradation. [9][10][11][12] This tightly controlled mechanism helps maintain physiological levels of p53 and restores these levels following stress responses.…”