p53-dependent repression of polo-like kinase-1 (PLK1)
p53-dependent repression of polo-like kinase-1 (PLK1)
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DOI：
10.4161/cc.9.20.13532
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发表时间：
2010-10-15
期刊：
影响因子：
4.3
通讯作者：
Meek, David W.
中科院分区：
文献类型：
--
作者：
McKenzie, Lynsey;King, Sharon;Meek, David W.
PLK 1是G（2）/M细胞周期转换的关键介质，其作为DNA损伤诱导的G（2）/M检查点的一部分被失活和耗尽。在这里，我们表明，下调PLK 1的表达发生通过转录抑制机制和p53是必要的，足以介导这种效果。p53对PLK 1的抑制不依赖于p21，也不依赖于G（1）/S的阻滞，在G（1）/S，PLK 1水平通常通过CDE/ERK元件以细胞周期依赖性方式被抑制。染色质免疫沉淀分析表明，p53存在于PLK 1启动子上的两个不同位点，称为p53 RE 1和p53 RE 2。募集p53到p53 RE 2，而不是p53 RE 1，是刺激响应DNA损伤和/或p53激活，并与抑制相关的染色质的变化是一致的。组蛋白去乙酰化酶抑制剂，抑制素A，减轻了p53对PLK 1表达的下调，并涉及组蛋白去乙酰化酶募集到p53 RE 2附近，进一步支持转录抑制机制。此外，野生型p53，而不是突变体，抑制PLK 1启动子的表达时，融合上游的报告基因。通过RNAi沉默PLK 1表达干扰细胞周期进程，这与p53介导的检查点中的作用一致。这些数据确定PLK 1作为p53的直接转录靶点，独立于p21，这是有效的G（2）/M阻滞所必需的。
PLK1 is a critical mediator of G(2)/M cell cycle transition that is inactivated and depleted as part of the DNA damage-induced G(2)/M checkpoint. Here we show that downregulation of PLK1 expression occurs through a transcriptional repression mechanism and that p53 is both necessary and sufficient to mediate this effect. Repression of PLK1 by p53 occurs independently of p21 and of arrest at G(1)/S where PLK1 levels are normally repressed in a cell cycle-dependent manner through a CDE/CHR element. Chromatin immunoprecipitation analysis indicates that p53 is present on the PLK1 promoter at two distinct sites termed p53RE1 and p53RE2. Recruitment of p53 to p53RE2, but not to p53RE1, is stimulated in response to DNA damage and/or p53 activation and is coincident with repression-associated changes in the chromatin. Downregulation of PLK1 expression by p53 is relieved by the histone deacetylase inhibitor, trichostatin A, and involves recruitment of histone deacetylase to the vicinity of p53RE2, further supporting a transcriptional repression mechanism. Additionally, wild type, but not mutant, p53 represses expression of the PLK1 promoter when fused upstream of a reporter gene. Silencing of PLK1 expression by RNAi interferes with cell cycle progression consistent with a role in the p53-mediated checkpoint. These data establish PLK1 as a direct transcriptional target of p53, independently of p21, that is required for efficient G(2)/M arrest.