Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

Marta Barradas, Emma Anderton, Juan Carlos Acosta, Side Li, Ana Banito, Marc Rodriguez-Niedenführ, Goedele Maertens, Michaela Banck, Ming-Ming Zhou, Martin J Walsh, Gordon Peters, Jesús Gil

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1177-1182
Number of pages6
JournalGenes & Development
Volume23
Issue number10
DOIs
Publication statusPublished - 15 May 2009

Keywords

  • Cyclin-Dependent Kinase Inhibitor p16
  • Animals
  • ras Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Cell Aging
  • Humans
  • Oxidoreductases, N-Demethylating
  • Mice
  • Gene Expression Regulation
  • Epigenesis, Genetic
  • Signal Transduction
  • Fibroblasts

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