Journal of Biological Chemistry
Volume 286, Issue 32, 12 August 2011, Pages 28511-28519
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Gene Regulation
Cyclin-dependent Kinase 1 (CDK1)-mediated Phosphorylation of Enhancer of Zeste 2 (Ezh2) Regulates Its Stability*

https://doi.org/10.1074/jbc.M111.240515Get rights and content
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The H3K27 histone methyltransferase, Ezh2 (enhancer of zeste 2), is a Polycomb group protein that plays important roles in many biological processes including cellular differentiation, stem cell biology, and cancer development. Up-regulation of Ezh2 is observed in various human cancers consistent with its role in cell proliferation. Thus, understanding the regulation of Ezh2 may reveal how it contributes to the cellular proliferation process. Here, we demonstrate that Ezh2 can be regulated by the cyclin-dependent kinase, CDK1, which phosphorylates Ezh2 at threonines 345 and 487. Consistent with the cell cycle phase during which CDK1 exhibits peak activity, Ezh2 phosphorylation is enriched in cells arrested in mitosis when compared with S-phase. Phosphorylation of Thr-345 and Thr-487 promotes Ezh2 ubiquitination and subsequent degradation by the proteasome. Furthermore, expression of T345A/T487A confers a proliferative disadvantage when compared with cells expressing wild-type Ezh2, which suggests that phosphorylation of Ezh2 is important for cell proliferation. Collectively, these results establish a novel function for CDK1-mediated Ezh2 phosphorylation and provide a mechanism by which Ezh2 protein levels can be regulated in cells.

Cell Cycle
Epigenetics
Mitosis
Protein Stability
Ubiquitin
CDK1
Ezh2
Phosphorylation
Polycomb

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*

This work was supported, in whole or in part, by National Institutes of Health Grant GM68804 (to Y. Z.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental methods and Figs. S1–S3.