title: Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.
abstract: The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2. In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest. In mouse embryo fibroblasts, Jmjd3 activates both Ink4a and Arf and elicits a p53-dependent arrest, echoing the effects of RAS in this system. Our findings directly implicate JMJD3 in the regulation of INK4a/ARF during oncogene-induced senescence and suggest that JMJD3 has the capacity to act as a tumor suppressor.
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Barradas
authors.forename: Emma
authors.initials: E
authors.lastname: Anderton
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Acosta
authors.forename: Side
authors.initials: S
authors.lastname: Li
authors.forename: Ana
authors.initials: A
authors.lastname: Banito
authors.forename: Marc
authors.initials: M
authors.lastname: Rodriguez-Niedenführ
authors.forename: Goedele
authors.initials: G
authors.lastname: Maertens
authors.forename: Michaela
authors.initials: M
authors.lastname: Banck
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating; D018631:ras Proteins