Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication
Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication
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DOI：
10.1038/sj.onc.1210085
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发表时间：
2007-05-03
期刊：
影响因子：
8
通讯作者：
Fukasawa, K.
中科院分区：
文献类型：
--
作者：
Shinmura, K.;Bennett, R. A.;Fukasawa, K.
中心体的异常扩增是癌细胞有丝分裂缺陷和染色体不稳定的主要原因。中心体在每个细胞周期中复制一次，并且中心体复制的基础调节机制的废除导致中心体扩增。p53肿瘤抑制蛋白参与中心体复制的调节：p53的缺失以及某些p53突变体的表达导致中心体复制失调和中心体扩增。p53至少部分地依赖于其反式激活功能来控制中心体复制，主要通过上调p21细胞周期蛋白依赖性激酶（CDK）抑制剂，其防止CDK 2/细胞周期蛋白E的不合时宜的激活，CDK 2/细胞周期蛋白E是中心体复制的关键起始物。然而，许多研究表明p53存在于中心体，但中心体定位的p53在调节中心体复制中的作用一直是个谜。在这里，我们比较研究了野生型p53和p53突变体的反式激活（+）/中心体结合（-），反式激活（-）/中心体结合（+）和反式激活（-）/中心体结合（+）的控制中心体复制的能力。我们发现，反式激活（+）/中心体结合（-）和反式激活（-）/中心体结合（+）突变体抑制中心体复制相比，野生型p53只有部分。此外，反式激活（-）/中心体结合（-）突变体几乎完全失去了抑制中心体复制的能力。这些观察结果提供了直接的证据，中心体本地化的p53参与调节中心体复制的方式独立于其反式激活功能，除了其反式激活依赖的调节中心体复制。
Abnormal amplification of centrosomes is the major cause of mitotic defects and chromosome instability in cancer cells. Centrosomes duplicate once in each cell cycle, and abrogation of the regulatory mechanism underlying centrosome duplication leads to centrosome amplification. p53 tumor suppressor protein is involved in the regulation of centrosome duplication: loss of p53 as well as expression of certain p53 mutants result in deregulated centrosome duplication and centrosome amplification. p53 at least in part depends on its transactivation function to control centrosome duplication, primarily via upregulation of p21 cyclin-dependent kinase (CDK) inhibitor, which prevents untimely activation of CDK2/cyclin E, a key initiator of centrosome duplication. However, numerous studies have shown the presence of p53 at centrosomes, yet the role of the centrosomally localized p53 in the regulation of centrosome duplication had been enigmatic. Here, we comparatively examined wild-type p53 and p53 mutants that are transactivation(+)/centrosome-binding(-), transactivation(-)/centrosome-binding(+) and transactivation(-)/centrosome-binding(+) for their abilities to control centrosome duplication. We found that the transactivation(+)/centrosome-binding(-) and transactivation(-)/centrosome-binding(+) mutants suppress centrosome duplication only partially compared with wild-type p53. Moreover, the transactivation(-)/centrosome-binding(-) mutant almost completely lost the ability to suppress centrosome duplication. These observations provide direct evidence for the centrosomally localized p53 to participate in the regulation of centrosome duplication in a manner independent of its transactivation function in addition to its transactivation-dependent regulation of centrosome duplication.