title: Epstein-Barr virus nuclear antigen 3A protein regulates CDKN2B transcription via interaction with MIZ-1.
abstract: The Epstein-Barr virus (EBV) nuclear antigen 3 family of protein is critical for the EBV-induced primary B-cell growth transformation process. Using a yeast two-hybrid screen we identified 22 novel cellular partners of the EBNA3s. Most importantly, among the newly identified partners, five are known to play direct and important roles in transcriptional regulation. Of these, the Myc-interacting zinc finger protein-1 (MIZ-1) is a transcription factor initially characterized as a binding partner of MYC. MIZ-1 activates the transcription of a number of target genes including the cell cycle inhibitor CDKN2B. Focusing on the EBNA3A/MIZ-1 interaction we demonstrate that binding occurs in EBV-infected cells expressing both proteins at endogenous physiological levels and that in the presence of EBNA3A, a significant fraction of MIZ-1 translocates from the cytoplasm to the nucleus. Moreover, we show that a trimeric complex composed of a MIZ-1 recognition DNA element, MIZ-1 and EBNA3A can be formed, and that interaction of MIZ-1 with nucleophosmin (NPM), one of its coactivator, is prevented by EBNA3A. Finally, we show that, in the presence of EBNA3A, expression of the MIZ-1 target gene, CDKN2B, is downregulated and repressive H3K27 marks are established on its promoter region suggesting that EBNA3A directly counteracts the growth inhibitory action of MIZ-1.
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses team, Université de Lyon, Lyon 69364, France Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Bazot
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses team, Université de Lyon, Lyon 69364, France Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Deschamps
authors.affiliation: Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France Ecole Normale Supérieure de Lyon, Lyon 69364, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Tafforeau
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
authors.forename: Maha
authors.initials: M
authors.lastname: Siouda
authors.affiliation: CNRS, UMR5308, Lyon 69364, France CNRS UMR5239, Laboratoire de Biologie de la Cellule, Lyon 69364, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leblanc
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Harth-Hertle
authors.affiliation: Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France Ecole Normale Supérieure de Lyon, Lyon 69364, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Rabourdin-Combe
authors.affiliation: Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France Ecole Normale Supérieure de Lyon, Lyon 69364, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses team, Université de Lyon, Lyon 69364, France Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Gruffat
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses team, Université de Lyon, Lyon 69364, France Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69364, France CIRI, International Center for Infectiology Research, Cell Biology of Viral Infections team, Université de Lyon, Lyon 69364, France INSERM, U1111, Lyon 69364, France CNRS, UMR5308, Lyon 69364, France evelyne.manet@ens-lyon.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Manet
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D004268:DNA-Binding Proteins; C508151:EBNA-3A antigen; C422762:EBNA-3B antigen; D019309:Epstein-Barr Virus Nuclear Antigens; D006657:Histones; D051741:Kruppel-Like Transcription Factors; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C107961:ZBTB17 protein, human; D000090243:Nucleophosmin; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein
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