Journal
GENES & DEVELOPMENT
Volume 23, Issue 10, Pages 1177-1182Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.511109
Keywords
Polycomb; senescence; histone methylation; INK4a; JmjC proteins
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Funding
- NIDDK/NIH
- NIH
- CRUK
- MRC
- AICR
- EMBO Young Investigator Programme
- MRC [MC_U120085810] Funding Source: UKRI
- Medical Research Council [MC_U120085810] Funding Source: researchfish
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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.
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