Tarapore P, Horn H F, Tokuyama Y, Fukasawa K
Department of Cell Biology, Neurobiology & Anatomy, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, PO Box 670521, Cincinnati, Ohio, OH 45267-0521, USA.
Oncogene. 2001 May 31;20(25):3173-84. doi: 10.1038/sj.onc.1204424.
The function of the centrosomes to direct mitotic spindles is critical for accurate chromosome transmission to daughter cells. Since each daughter cell inherits one centrosome, each centrosome must duplicate prior to the next mitosis, and do so only once. Thus, there are control mechanism(s) that ensure the coordinated progression of centrosome duplication and other cell cycle events (i.e. DNA synthesis), and limit centrosome duplication to once per cell cycle. Deregulation of the centrosome duplication cycle results in abnormal amplification of centrosomes, leading to aberrant mitoses and increased chromosome transmission errors. This has been found to be the case for cells lacking functional p53 tumor suppressor protein. However, it had remained to be determined whether the deregulation of the centrosome duplication cycle is the direct or indirect effect of loss/mutational inactivation of p53. Here, we found that the normal centrosome duplication cycle is almost completely restored in p53(-/-) cells by re-introduction of wild-type p53 at a physiologically relevant level, demonstrating that p53 is directly involved in the regulation of centrosome duplication. Since cyclin dependent kinase 2 (CDK2)/cyclin E triggers DNA synthesis as well as centrosome duplication, we tested whether Waf1, a CDK inhibitor and a major target of p53's transactivation function, is an effector of p53-mediated regulation of centrosome duplication. We found that induced expression of Waf1 in p53(-/-) cells only partially restored the centrosome duplication control, suggesting that Waf1 comprises one of the multiple effector pathways of the p53-mediated regulation of the centrosome duplication cycle.
中心体指导有丝分裂纺锤体的功能对于准确地将染色体传递给子细胞至关重要。由于每个子细胞继承一个中心体，每个中心体必须在下一次有丝分裂之前复制，并且只能复制一次。因此，存在控制机制来确保中心体复制与其他细胞周期事件（即DNA合成）的协调进行，并将中心体复制限制在每个细胞周期一次。中心体复制周期的失调会导致中心体异常扩增，从而导致有丝分裂异常和染色体传递错误增加。已发现缺乏功能性p53肿瘤抑制蛋白的细胞就是这种情况。然而，中心体复制周期的失调是p53缺失/突变失活的直接还是间接影响仍有待确定。在这里，我们发现通过在生理相关水平重新引入野生型p53，p53(-/-)细胞中的正常中心体复制周期几乎完全恢复，这表明p53直接参与中心体复制的调控。由于细胞周期蛋白依赖性激酶2（CDK2）/细胞周期蛋白E触发DNA合成以及中心体复制，我们测试了p53转录激活功能的主要靶点、CDK抑制剂Waf1是否是p53介导的中心体复制调控的效应器。我们发现p53(-/-)细胞中Waf1的诱导表达仅部分恢复了中心体复制控制，这表明Waf1是p53介导的中心体复制周期调控的多种效应器途径之一。
