NuMA Is Required for the Selective Induction of p53 Target Genes
NuMA Is Required for the Selective Induction of p53 Target Genes
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DOI：
10.1128/mcb.01221-12
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发表时间：
2013-06-01
影响因子：
5.3
通讯作者：
Enari, Masato
中科院分区：
文献类型：
--
作者：
Ohata, Hirokazu;Miyazaki, Makoto;Enari, Masato
p53 肿瘤抑制蛋白是一种转录因子，通过调节不同组的靶基因来控制各种结果，例如生长停滞和细胞凋亡。核有丝分裂器蛋白 (NuMA) 在有丝分裂期间的纺锤体极组织和间期细胞核染色质调节中发挥重要作用。尽管 NuMA 已被证明与多种核蛋白共定位，包括高迁移率蛋白 I、Y 和 GAS41，但 NuMA 在间期的作用仍不清楚。在这里，我们报告 NuMA 与 p53 结合来调节 p53 介导的转录。 NuMA 的急性和部分消融会减弱 DNA 损伤后 p21 基因的诱导，随后导致细胞周期停滞受损。有趣的是，NuMA 敲低对 p53 依赖性促凋亡 PUMA 基因的诱导几乎没有影响。此外，NuMA 是招募细胞周期蛋白依赖性激酶 8 (Cdk8) 所必需的，Cdk8 是介导复合物的一个组成部分，也是 p53 介导的 p21 基因功能的启动子。这些数据表明 NuMA 对于 p53 介导的转录的靶点选择性至关重要。
The p53 tumor suppressor protein is a transcription factor controlling various outcomes, such as growth arrest and apoptosis, through the regulation of different sets of target genes. The nuclear mitotic apparatus protein (NuMA) plays important roles in spindle pole organization during mitosis and in chromatin regulation in the nucleus during interphase. Although NuMA has been shown to colocalize with several nuclear proteins, including high-mobility-group proteins I and Y and GAS41, the role of NuMA during interphase remains unclear. Here we report that NuMA binds to p53 to modulate p53-mediated transcription. Acute and partial ablation of NuMA attenuates the induction of the proarrested p21 gene following DNA damage, subsequently causing impaired cell cycle arrest. Interestingly, NuMA knockdown had little effect on the induction of the p53-dependent proapoptotic PUMA gene. Furthermore, NuMA is required for the recruitment of cyclin-dependent kinase 8 (Cdk8), a component of the Mediator complex and a promoter of p53-mediated p21 gene function. These data demonstrate that NuMA is critical for the target selectivity of p53-mediated transcription.