Journal
NATURE CELL BIOLOGY
Volume 12, Issue 11, Pages 1108-U118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2116
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Funding
- National Institutes of Health [CA134514, CA130908, GM49850]
- Department of Defense [W81XWH-07-1-0137, W81XWH-09-1-622, W81XWH-07-1-0373]
- University of Minnesota Masonic Cancer Center
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The Polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), has an essential role in promoting histone H3 lysine 27 trimethylation (H3K27me3) and epigenetic gene silencing(1-4). This function of EZH2 is important for cell proliferation and inhibition of cell differentiation, and is implicated in cancer progression(5-10). Here, we demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2) phosphorylate EZH2 at Thr 350 in an evolutionarily conserved motif. Phosphorylation of Thr 350 is important for recruitment of EZH2 and maintenance of H3K27me3 levels at EZH2-target loci. Blockage of Thr 350 phosphorylation not only diminishes the global effect of EZH2 on gene silencing, it also mitigates EZH2-mediated cell proliferation and migration. These results demonstrate that CDK-mediated phosphorylation is a key mechanism governing EZH2 function and that there is a link between the cell-cycle machinery and epigenetic gene silencing.
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