The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence
The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence
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DOI：
10.1101/gad.510809
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发表时间：
2009-05-15
影响因子：
10.5
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
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作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
由INK 4A-ARF基因座编码的肿瘤抑制蛋白p16（INK 4A）和p14（ARF）是细胞衰老的关键调节因子。该基因座在正常生长的细胞中被抑制性H3 K27 me 3标记表观遗传沉默，但在致癌应激反应中被激活。在这里，我们表明，组蛋白H3赖氨酸27（H3 K27）去甲基化酶JMJD 3的表达诱导后激活的RAS-RAF信号通路。JMJD 3被募集到INK 4A-ARF基因座，并有助于人二倍体成纤维细胞中p16（INK 4A）的转录激活。此外，抑制小鼠胚胎成纤维细胞中的Jmjd 3表达导致p16（Ink 4a）和p19（Arf）表达的抑制及其永生化。
The tumor suppressor proteins p16(INK4A) and p14(ARF), encoded by the INK4A-ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS-RAF signaling pathway. JMJD3 is recruited to the INK4A-ARF locus and contributes to the transcriptional activation of p16(INK4A) in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16(Ink4a) and p19(Arf) expression and in their immortalization.