Cabin1 restrains p53 activity on chromatin
Cabin1 restrains p53 activity on chromatin
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DOI：
10.1038/nsmb.1657
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发表时间：
2009-09-01
影响因子：
16.8
通讯作者：
Youn, Hong-Duk
中科院分区：
文献类型：
--
作者：
Jang, Hyonchol;Choi, Soo-Youn;Youn, Hong-Duk
已经提出肿瘤抑制因子p53在基因毒性应激时结合靶启动子。然而，最近的证据表明，p53占据了一些目标启动子没有这样的压力，这表明负调控可能使p53在这些启动子上转录失活。在这里，我们表明，钙调神经磷酸酶结合蛋白1（Cabin1）是p53的负调节。Cabin1的下调诱导p53靶基因亚组的活化。Cabin1与这些靶启动子上的p53发生物理相互作用，并通过调节组蛋白修饰和p53乙酰化标记，在不存在遗传毒性应激的情况下抑制p53转录活性。Cabin1的敲除以p53依赖性方式延缓细胞生长并促进DNA损伤后的细胞死亡。因此，Cabin1在静止状态下抑制染色质上的p53功能;在一些启动子上存在无活性的p53可能允许在DNA损伤时迅速响应。
The tumor suppressor p53 has been proposed to bind target promoters upon genotoxic stress. However, recent evidence shows that p53 occupies some target promoters without such stress, suggesting that a negative regulator might render p53 transcriptionally inactive on these promoters. Here we show that calcineurin binding protein 1 (Cabin1) is a negative regulator of p53. Downregulation of Cabin1 induces activation of a subset of p53 target genes. Cabin1 physically interacts with p53 on these target promoters and represses p53 transcriptional activity in the absence of genotoxic stress, by regulating histone modification and p53 acetylation marks. Knockdown of Cabin1 retards cell growth and promotes cell death after DNA damage in a p53-dependent manner. Thus, Cabin1 inhibits p53 function on chromatin in the quiescent state; the presence of inactive p53 on some promoters might allow a prompt response upon DNA damage.