MDM2, MDMX and p53 in oncogenesis and cancer therapy

Abstract

The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.

Figure 1. Transcriptional and post-translational regulation of MDM2 an d MDMX

a | Transcriptional regulation of MDM2 and MDMX is shown. The first coding exon for both MDM2 and MDMX is exon 2. An ATG in an additional exon (1β) in MDMX can give rise to a longer MDMX-L protein. p53-induced transcription is mediated by the P2 promoter for both MDM2 and MDMX, whereas basal transcription initiates from the P1 promoter. Additional transcription factors (shown in blue) can positively modulate the expression of MDM2 and MDMX from both the P1 and the P2 promoters. Several microRNAs (miRNAs) have been proposed to block translation of either MDM2 or MDMX mRNA. In contrast to the situation with MDM2, one of the miRNAs that targets MDMX mRNA (miR-34a) binds to the coding sequence, rather than to the 3′ untranslated region (UTR). b | In addition to transcriptional regulation, both MDM2 and MDMX are subject to diverse post-translational modifications that affect their ability to bind to p53, to bind to each other and to interact with other cellular proteins that can dramatically affect their stability and that of p53. For simplicity, we focus on phosphorylation to show the diversity of the sites that are modified and the consequences of their modification. Shown in green are phosphorylation sites that are reported to increase MDM2- or MDMX-dependent inhibition of p53. Phosphorylation sites shown in orange are reported to inhibit MDM2- and MDMX-dependent p53 inhibition. In many cases, the precise mechanisms by which phosphorylation modulates the relationship between p53 and MDM2 or MDMX is unclear. Phosphorylation can disrupt the interaction with p53 (by inhibiting protein–protein interaction (PPI)), can modulate the stability of MDM2 or MDMX (S), change oligomerization status (O), modulate stability and oligomerization (O/S) or can alter subcellular localization (L). Residue numbering is for the human proteins, and it should be noted that not all kinase consensus sites are shared between humans and mice. AD, acidic domain; ATM, ataxia-telangiectasia mutated; CDK, cyclin-dependent kinase; CK, casein kinase; DNA-PK, DNA-dependent protein kinase; GSK3, glycogen synthase kinase 3; IRF8, interferon regulatory factor 8; NES, nuclear export signal; NF-κB, nuclear factor-κB; NLS, nuclear localization signal; Zn²⁺, zinc finger domain.