Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
- 15 May 2009
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 23 (10), 1177-1182
- https://doi.org/10.1101/gad.511109
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 p16INK4a-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.Keywords
This publication has 36 references indexed in Scilit:
- The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene SilencingCell, 2007
- Cellular senescence: when bad things happen to good cellsNature Reviews Molecular Cell Biology, 2007
- Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cellsGenes & Development, 2007
- Knockdown of ALR (MLL2) Reveals ALR Target Genes and Leads to Alterations in Cell Adhesion and GrowthMolecular and Cellular Biology, 2007
- The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cellsGenes & Development, 2007
- Polycomb silencers control cell fate, development and cancerNature Reviews Cancer, 2006
- Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for allNature Reviews Molecular Cell Biology, 2006
- Cellular senescence in naevi and immortalisation in melanoma: a role for p16?British Journal of Cancer, 2006
- Novel Genes Associated with Malignant Melanoma but not Benign Melanocytic LesionsClinical Cancer Research, 2005
- BRAFE600-associated senescence-like cell cycle arrest of human naeviNature, 2005