Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity

Abstract

MDM2 oncogenic protein is the principal cellular antagonist of the p53 tumor suppresser gene. p53 activity needs exquisite control to elicit appropriate responses to differential cellular stress conditions. p53 becomes stabilized and active upon various types of stresses. However, too much p53 is not beneficial to cells and causes lethality. At the steady state, p53 activity needs to be leashed for cell survival. Early studies suggested that the MDM2 oncoprotein negatively regulates p53 activity through the induction of p53 protein degradation. MDM2 serves as an E3 ubiquitin ligase of p53; it catalyzes polyubiquitination and subsequently induces proteasome degradation to downregulate p53 protein level. However, the mechanism by which MDM2 represses p53 is not a single mode. Emerging evidence reveals another cellular location of MDM2-p53 interaction. MDM2 is recruited to chromatin, specifically the p53 responsive promoter regions, in a p53 dependent manner. MDM2 is proposed to directly inhibit p53 transactivity at chromatin. This article provides an overview of the mechanism by which p53 is repressed by MDM2 in both ubiquitination dependent and ubiquitination independent pathways.

Keywords: MDM2; antirepression model; ubiquitination dependent; ubiquitination independent.

Figure 1.

Ubiquitination dependent function of MDM2: the classic model of MDM2 as a repressor of p53. In the nucleus, MDM2 associates with p53 and conjugates monoubiquitin onto p53. MDM2 facilitates p53 translocation from nucleus into cytoplasm, where MDM2, together with other co-factor, presumably E4 ubiquitin ligase of p53, catalyzes polyubiquitin chains onto p53 to induce proteasome degradation. Simultaneously, p53 ubiquitination and degradation take place in the nucleus. Upon cellular stresses, a series of post-translational modifications occur on MDM2. The modified MDM2 dissociates from p53, and p53 is prevented from MDM2 mediated ubiquitination and degradation. p53 therefore becomes stabilized. P = phosphorylation; Ub = ubiquitin; Poly-Ub = polyubiquitination.

Figure 2.

Ubiquitination independent function of MDM2: the antirepression model of p53 activation. Under homeostasis, p53 is kept in a preset repressed state when staying in the same complex with MDM2 and MDMX on chromatin. When p53 acetylation is fully activated, the recruitments of MDM2 and MDMX on those p53 target promoters will be abrogated due to the decreased association between the acetylated form of p53 and MDM2/MDMX. p53 is then released from the originally repressed status, and this step is designated as antirepression step in this modified p53 activation model. Ac = acetylation.