The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
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DOI：
10.1101/gad.415507
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发表时间：
2007-03-01
影响因子：
10.5
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
--
作者：
Bracken, Adrian P.;Kleine-Kohlbrecher, Daniela;Helin, Kristian
INK4A-ARF基因座编码的p16（INK4A）和p14（ARF）蛋白是细胞衰老的关键调控因子，但引发其上调的机制尚不清楚。在这里，我们表明癌基因BMI1抑制INK4A-ARF位点的能力需要其直接关联，并且依赖于含有ezh2的polycomb - repression Complex 2 （PRC2）复合物的持续存在。值得注意的是，EZH2在应激和衰老的细胞群体中下调，与相关的H3K27me3水平下降、BMI1位移和转录激活相一致。这些结果为INK4A-ARF基因座如何被激活以及polycomb如何促进癌症提供了一个模型。
The p16(INK4A) and p14(ARF) proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.