The roles and regulation of MDM2 and MDMX: it is not just about p53

Abstract

Most well studied as proteins that restrain the p53 tumor suppressor protein, MDM2 and MDMX have rich lives outside of their relationship to p53. There is much to learn about how these two proteins are regulated and how they can function in cells that lack p53. Regulation of MDM2 and MDMX, which takes place at the level of transcription, post-transcription, and protein modification, can be very intricate and is context-dependent. Equally complex are the myriad roles that these two proteins play in cells that lack wild-type p53; while many of these independent outcomes are consistent with oncogenic transformation, in some settings their functions could also be tumor suppressive. Since numerous small molecules that affect MDM2 and MDMX have been developed for therapeutic outcomes, most if not all designed to prevent their restraint of p53, it will be essential to understand how these diverse molecules might affect the p53-independent activities of MDM2 and MDMX.

Keywords: MDM2; MDM2 and MDMX inhibitors; MDMX; cancer; p53; pathologies; roles; upstream regulation.

Figure 1.

Structural landmarks of MDM2 and MDMX proteins. Schematic representation of the key domains found in MDM2 and MDMX proteins from N terminus (left) to C terminus (right). Shown are their conserved p53 binding domains, acidic domains, and zinc finger regions, as well as their RING domains, which contain an NoLS; MDM2 alone has NLS and NES signal sequences. (NLS) Nuclear localization signal, (NES) nuclear export signal, (NoLS) nucleolar localization signal.

Figure 2.

Regulation of MDM2. Different factors are involved in the regulation of MDM2 at the DNA, RNA, and protein levels in eukaryotic cells. Listed are the most important or most recently described processes and biomolecules regulating MDM2. (Top) Polymorphisms (SNPs) in the MDM2 gene that have been characterized, as well as transcription factors reported to regulate transcription from the two well-studied MDM2 promoters 1 and 2 and regulation of P2 by P1. (Middle) Factors, including numerous listed microRNAs, that interact with and regulate MDM2 mRNA levels, splicing, and translation. (Bottom) MDM2 protein is extensively modified by ubiquitination (Ub), acetylation (A), phosphorylation (P), SUMOylation (S), and NEDDylation (N).

Figure 3.

Regulation of MDMX. Different factors are involved in the regulation of MDMX at the DNA, RNA, and protein levels in eukaryotic cells. Listed are the most important or most recently described processes and biomolecules regulating MDMX. (Top) Polymorphisms in the MDMX gene that have been characterized, as well as factors reported to regulate transcription from the MDMX promoters 1 and 2. (Middle) Factors, including numerous listed microRNAs, that interact with and regulate MDMX mRNA levels, splicing, and translation. (Bottom) MDM2 protein is modified by ubiquitination (Ub) and phosphorylation (P).

Figure 4.

Clinically relevant functions of MDM2 and MDMX. MDM2 and MDMX affect several clinical pathologies in a p53-independent fashion, including nonmalignant disease and cancer-related functions. p53-independent activities of MDM2 and MDMX that have been studied in a clinical context are summarized in this figure. Nonmalignant physiological processes and pathologies are separated by organ system at the left. Cancer-related activities mediated by MDM2 and MDMX are represented graphically at the right.

Figure 5.

A look at MDM2 and MDMX with p53-blind glasses. Several proteins other than p53 regulate MDM2 and MDMX at the transcriptional, translational, and post-translational levels through distinct mechanisms. These mechanisms are summarized at the top. The bottom depicts some of the most prominent p53-independent functions of MDM2 and MDMX, both individually and together as a complex. In red are the different inhibitors of these two proteins that are capable of modifying the ability of MDM2 and MDMX to undertake these p53-independent roles. The figure also briefly indicates the mechanism of action of these drugs; while some of them impair the regulation of MDM2 and/or MDMX (e.g., SQ, SP141, NSC 207895, and FL-118), others can directly affect their functionality (e.g., HLI, MEL23, and Nutlin-3).