The regulation of MDM2 oncogene and its impact on human cancers

Abstract

Tumor suppressor p53 plays a central role in preventing tumor formation. The levels and activity of p53 is under tight regulation to ensure its proper function. Murine double minute 2 (MDM2), a p53 target gene, is an E3 ubiquitin ligase. MDM2 is a key negative regulator of p53 protein, and forms an auto-regulatory feedback loop with p53. MDM2 is an oncogene with both p53-dependent and p53-independent oncogenic activities, and often has increased expression levels in a variety of human cancers. MDM2 is highly regulated; the levels and function of MDM2 are regulated at the transcriptional, translational and post-translational levels. This review provides an overview of the regulation of MDM2. Dysregulation of MDM2 impacts significantly upon the p53 functions, and in turn the tumorigenesis. Considering the key role that MDM2 plays in human cancers, a better understanding of the regulation of MDM2 will help us to develop novel and more effective cancer therapeutic strategies to target MDM2 and activate p53 in cells.

Keywords: E3 ubiquitin ligase; MDM2; gene regulation; p53.

Figure 1.

The regulation of MDM2 at the transcriptional and translational levels (A) The MDM2 gene has two promoters (P1 and P2). The P1 promoter controls the basal constitutive expression of MDM2, and the P2 promoter is highly regulated and responsible for the inducible expression of MDM2. p53 binds to MDM2 P2 promoter to induce the expression of MDM2. In addition to p53, MDM2 can be transcriptionally regulated by several oncogenic and tumor suppressive pathways. (B) Increased expression of alternatively and aberrantly spliced MDM2 variants have been detected in many types of human cancers. Among over 40 MDM2 spliced variants identified in human cancers, MDM2 isoforms A, B, and C are the isoforms that most frequently over-expressed in human cancers. (C) A group of microRNAs bind to the 3′-UTR of the MDM2 mRNA to inhibit its translation.

Figure 2.

The regulation of MDM2 protein levels and activity MDM2 protein levels and activity are highly regulated by many stress signals and factors. These stress signals regulate the ability of MDM2 to bind to p53, MDM2 E3 ubiquitin ligase activity, cellular localization of MDM2, and the stability of MDM2 protein. Genotoxic stress signals, such as IR and UV, negatively regulate MDM2 protein levels and activity mainly through post-translational modification (phosphorylation) of MDM2. Oncogenic activation negatively regulates MDM2 E3 ligase activity, and promotes MDM2 localization in nucleoli through ARF. Ribosomal stress signals negatively regulate MDM2 E3 ubiquitin ligase activity through interaction of RPs with MDM2. Some oncogenes, including AKT and Wip1, directly increase MDM2 activity. Chronic psychological stress signals increase the levels of neurohormones, including glucocorticoids and catecholamines, which can increase MDM2 activity through distinct pathways.