细胞周期蛋白依赖性激酶通过磷酸化 EZH2 调节表观遗传基因沉默。
Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2.
机构信息
Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
出版信息
Nat Cell Biol. 2010 Nov;12(11):1108-14. doi: 10.1038/ncb2116. Epub 2010 Oct 10.
Abstract
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. This function of EZH2 is important for cell proliferation and inhibition of cell differentiation, and is implicated in cancer progression. 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.
摘要
多梳抑制复合物（PcG）蛋白，EZH2 同源物 2（EZH2），在促进组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）和表观遗传基因沉默方面具有重要作用。EZH2 的这种功能对于细胞增殖和抑制细胞分化很重要，并与癌症的进展有关。在这里，我们证明在生理条件下，细胞周期蛋白依赖性激酶 1（CDK1）和细胞周期蛋白依赖性激酶 2（CDK2）在进化上保守的基序中磷酸化 EZH2 的 Thr350。Thr350 的磷酸化对于 EZH2 的募集以及 EZH2 靶基因座处 H3K27me3 水平的维持很重要。阻断 Thr350 的磷酸化不仅会降低 EZH2 对基因沉默的整体影响，还会减轻 EZH2 介导的细胞增殖和迁移。这些结果表明，CDK 介导的磷酸化是调节 EZH2 功能的关键机制，细胞周期机制与表观遗传基因沉默之间存在联系。
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