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.
Original language | English (US) |
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Pages (from-to) | 1177-1182 |
Number of pages | 6 |
Journal | Genes and Development |
Volume | 23 |
Issue number | 10 |
DOIs | |
State | Published - May 15 2009 |
Keywords
- Histone methylation
- INK4a
- JmjC proteins
- Polycomb
- Senescence
ASJC Scopus subject areas
- Genetics
- Developmental Biology