title: MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.
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.
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.
authors.forename: Antje
authors.initials: A
authors.lastname: Dickmanns
authors.affiliation: Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Nemajerova
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kramer
authors.affiliation: Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Najafova
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Karpiuk
authors.affiliation: Molecular Endocrinology and Stem Cell Research Unit (KMEB), University Hospital of Odense and University of Southern Denmark, Odense 5000, Denmark.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen 37077, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
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. Electronic address: xzhang1@gwdg.de.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Oncology, Göttingen Center for Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen 37077, Germany. Electronic address: mdobbel@gwdg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D042002:Chromatin Assembly and Disassembly; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010012:Osteogenesis; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D063151:Polycomb Repressive Complex 2; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D063150:Polycomb Repressive Complex 1; D051736:Proto-Oncogene Proteins c-mdm2; C489841:RNF2 protein, human; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases