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Genes Dev. 2009 May 15;23(10):1177-82. doi: 10.1101/gad.511109.

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

Author information

1
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College, London W12 0NN, United Kingdom.

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.

PMID:
19451218
PMCID:
PMC2685533
DOI:
10.1101/gad.511109
[Indexed for MEDLINE]
Free PMC Article

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