title: PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence.
abstract: Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction.
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Paris cedex 10, France; INSERM U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Paris cedex 10, France; CNRS UMR 7212, Hôpital St. Louis 1, Paris cedex 10, France;
authors.forename: Lisa
authors.initials: L
authors.lastname: Ivanschitz
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Paris cedex 10, France; INSERM U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Paris cedex 10, France; CNRS UMR 7212, Hôpital St. Louis 1, Paris cedex 10, France;
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Paris cedex 10, France; INSERM U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Paris cedex 10, France; CNRS UMR 7212, Hôpital St. Louis 1, Paris cedex 10, France;
authors.forename: Florence
authors.initials: F
authors.lastname: Jollivet
authors.affiliation: CNRS UMR 3306, INSERM U1005, Équipe Avenir, Laboratoire Signalisation, Développement et Tumeurs Cérébrales, Institut Curie, Campus Universitaire d'Orsay, 91400 Orsay, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Paris cedex 10, France; INSERM U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Paris cedex 10, France; CNRS UMR 7212, Hôpital St. Louis 1, Paris cedex 10, France;
authors.forename: Morgane
authors.initials: M
authors.lastname: Le Bras
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Paris cedex 10, France; INSERM U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis 1, Paris cedex 10, France; CNRS UMR 7212, Hôpital St. Louis 1, Paris cedex 10, France; Assistance Publique-Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis 1, Paris cedex 10, France; Collège de France, Chaire d'Oncologie Cellulaire et Moléculaire, 75005 Paris, France hugues.dethe@inserm.fr.
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D055550:Protein Stability; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: UBC9; nuclear matrix; posttranslational modification; splicing; tumor suppression