title: Mdm2 as a chromatin modifier.
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.
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Wienken
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.|Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Ute M
authors.initials: UM
authors.lastname: Moll
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002843:Chromatin / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002843:Chromatin; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: EZH2; Mdm2; histone methylation; histone ubiquitination; polycomb repressor complex