Mdm2 as a chromatin modifier.

Magdalena Wienken,Ute M Moll,Matthias Dobbelstein

doi:10.1093/jmcb/mjw046

Magdalena Wienken, Ute M Moll + Show 1 more

Open Access

https://doi.org/10.1093/jmcb/mjw046

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Abstract

Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure. We found that Mdm2 regulates a gene expression profile similar to that of PRC2 independent of p53. Moreover, Mdm2 promotes the stemness of murine induced pluripotent stem cells and human mesenchymal stem cells, and supports the survival of tumour cells. Mdm2 is recruited to target gene promoters by the PRC2 member and histone methyltransferase EZH2, and enhances PRC-dependent repressive chromatin modifications, specifically H3K27me3 and H2AK119ub1. Mdm2 also cooperates in gene repression with the PRC1 protein RING1B, a H2AK119 ubiquitin ligase. Here we discuss the possible implications of these p53-independent functions of Mdm2 in chromatin dynamics and in the stem cell phenotype. We propose that the p53-independent functions of Mdm2 should be taken into account for cancer drug design. So far, the majority of clinically tested Mdm2 inhibitors target its binding to p53 but do not affect the new functions of Mdm2 described here. However, when targeting the E3 ligase activity of Mdm2, a broader spectrum of its oncogenic activities might become druggable.

Highlights

20 years ago, Lozano and Bradley groups developed mice with targeted disruptions of both p53 and Mdm2 (Jones et al, 1995; Montes de Oca Luna et al, 1995)
It was concluded that the main function of Mdm2 consists in the regulation of p53 (Jones et al, 1995; Montes de Oca Luna et al, 1995)
Mammary gland-specific overexpression of Mdm2 in mice abrogated normal mammary gland development in a p53-independent manner and led to the formation of mammary tumours (Lundgren et al, 1997). These findings argued that Mdm2 is carrying out additional functions beyond the mere regulation of p53

Summary

Introduction

20 years ago, Lozano and Bradley groups developed mice with targeted disruptions of both p53 and Mdm2 (Jones et al, 1995; Montes de Oca Luna et al, 1995). Mdm2 acts on gene expression and chromatin modifications in a p53-dependent or p53-independent way Already in 1997, the Tjian laboratory showed that Mdm2, when associating with naked DNA, represses gene expression in a p53-independent way.

Results

Conclusion