Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication

被引:73
作者
Shinmura, K. [1 ]
Bennett, R. A. [1 ]
Tarapore, P. [1 ]
Fukasawa, K. [1 ]
机构
[1] Univ Cincinnati, Coll Med, Dept Cell Biol, Cincinnati, OH 45267 USA
关键词
p53; centrosome; centrosome duplication;
D O I
10.1038/sj.onc.1210085
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2939 / 2944
页数:6
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