DDB1-CUL4 and MLL1 mediate oncogene-induced p16INK4a activation.
DDB1-CUL4 and MLL1 mediate oncogene-induced p16INK4a activation.
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DOI：
10.1158/0008-5472.can-08-2739
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Kotake Y;Zeng Y;Xiong Y
由致癌信号诱导的细胞衰老作为细胞转化的屏障，并且部分地通过p16 INK 4a肿瘤抑制基因的升高来实现。p16的表达在表观遗传学上被Polycomb抑制，但p16是如何被诱导的尚不清楚。我们在这里报告，p16基因座是H3 K4-甲基化的高表达细胞。H3 K4甲基转移酶MLL 1直接结合到其核心组分RbBP 5上，并与其核心组分RbBP 5一起沿着是致癌Ras诱导p16所必需的。我们进一步表明，受损的DNA结合蛋白DDB 1和CUL 4，组装不同的E3泛素连接酶通过招募各种WD 40蛋白，MLL 1介导的H3 K4甲基化的上游行动。我们发现CUL 4A直接与p16结合，DDB 1沉默阻断Ras诱导的p16活化。Ras表达使BMI 1与p16位点分离，而CUL 4和MLL 1在正常和致癌刺激的细胞中类似地结合到p16位点。这些结果表明，DDB 1-CUL 4和MLL 1复合物构成了一种新的途径，介导致癌检查点反应过程中的p16激活，并在年轻细胞的正常生长过程中被多梳阻遏复合物阻遏。
The induction of cellular senescence by oncogenic signals acts as a barrier to cellular transformation and is attained, in part, by the elevation of the p16INK4a tumor suppressor gene. p16 expression is repressed epigenetically by Polycomb, but how p16 is induced is not known. We report here that the p16 locus is H3K4-methylated in highly expressing cells. H3K4 methyltransferase MLL1 directly binds to and is required, along with its core component RbBP5, for the induction of p16 by oncogenic Ras. We further show that damaged DNA binding protein DDB1 and CUL4, which assemble distinct E3 ubiquitin ligases by recruiting various WD40 proteins, act upstream of MLL1-mediated H3K4 methylation. We showed that CUL4A directly binds to p16 and that silencing DDB1 blocks Ras-induced p16 activation. Ras expression dissociates BMI1 from the p16 locus, while both CUL4 and MLL1 bind to the p16 locus similarly in both normal and oncogenic stimulated cells. These results suggest that DDB1-CUL4 and MLL1 complexes constitute a novel pathway that mediates p16 activation during oncogenic checkpoint response and is repressed by the polycomb repression complexes during normal growth of young cells.