Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
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DOI：
10.1101/gad.511109
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发表时间：
2009-05-15
影响因子：
10.5
通讯作者：
Gil, Jesus
中科院分区：
文献类型：
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作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
INK 4a/ARF肿瘤抑制基因座是细胞衰老的关键执行者，受多梳组（Polycomb group，PcG）转录抑制因子的成员调节。在这里，我们表明，来自致癌RAS的信号通过激活H3 K27去甲基化酶JMJD 3和下调甲基转移酶EZH 2来推翻PcG介导的INK 4a抑制。在人成纤维细胞中，JMJD 3激活INK 4a，但不激活ARF，并导致p16（INK 4a）依赖性停滞。在小鼠胚胎成纤维细胞中，Jmjd 3激活Ink 4a和Arf，并激活p53依赖性阻滞，与RAS在该系统中的作用相呼应。我们的研究结果直接暗示JMJD 3在癌基因诱导的衰老过程中参与INK 4a/ARF的调节，并表明JMJD 3具有作为肿瘤抑制因子的能力。
The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors. Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2. In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest. In mouse embryo fibroblasts, Jmjd3 activates both Ink4a and Arf and elicits a p53-dependent arrest, echoing the effects of RAS in this system. Our findings directly implicate JMJD3 in the regulation of INK4a/ARF during oncogene-induced senescence and suggest that JMJD3 has the capacity to act as a tumor suppressor.