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PMID: 26748827 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.

Molecular cell ·Vol. 61 ·No. 1 ·2016-01-07 ·Pages 68-83

Wienken M, Dickmanns A, Nemajerova A, Kramer D, Najafova Z, Weiss M, Karpiuk O, Kassem M, Zhang Y, Lozano G, Johnsen SA, Moll UM, Zhang X, Dobbelstein M

Abstract

The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53.

MeSH Terms
Animals Cell Differentiation Cell Lineage Cell Proliferation Cell Survival Chromatin Assembly and Disassembly Gene Expression Regulation, Neoplastic HCT116 Cells Histones/metabolism Humans Induced Pluripotent Stem Cells/metabolism MCF-7 Cells Mesenchymal Stem Cells/metabolism Methylation Mice Neoplastic Stem Cells/metabolism Osteogenesis Phenotype Polycomb Repressive Complex 1/metabolism Polycomb Repressive Complex 2/genetics,metabolism Proto-Oncogene Proteins c-mdm2/genetics,metabolism RNA Interference Signal Transduction Time Factors Transfection Tumor Suppressor Protein p53/genetics,metabolism Ubiquitin-Protein Ligases/metabolism Ubiquitination
Chemicals
Histones TP53 protein, human Tumor Suppressor Protein p53 Polycomb Repressive Complex 2 MDM2 protein, human Mdm2 protein, mouse Polycomb Repressive Complex 1 Proto-Oncogene Proteins c-mdm2 RNF2 protein, human Rnf2 protein, mouse Ubiquitin-Protein Ligases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Wienken Magdalena
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
Dickmanns Antje
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
Nemajerova Alice
Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Kramer Daniela
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
Najafova Zeynab
Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen 37077, Germany.
Weiss Miriam
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
Karpiuk Oleksandra
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
Kassem Moustapha
Molecular Endocrinology and Stem Cell Research Unit (KMEB), University Hospital of Odense and University of Southern Denmark, Odense 5000, Denmark.
Zhang Yanping
Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Lozano Guillermina
Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Johnsen Steven A
Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen 37077, Germany.
Moll Ute M
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.
Zhang Xin
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany. Electronic address: xzhang1@gwdg.de.
Dobbelstein Matthias
Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany. Electronic address: mdobbel@gwdg.de.
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2015.12.008
Email
xzhang1@gwdg.de
mdobbel@gwdg.de
Published
2016-01-07
Epub
2015-00-31
Pages
68-83
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC6284523
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA100302 · United States
NCI NIH HHS · R01 CA167637 · United States
NCI NIH HHS · R01 CA212407 · United States
Corrections
CommentIn
PMID: 27315554
External Links
PubMed source DOI: 10.1016/j.molcel.2015.12.008 PMC Full Text View journal details
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