Direct regulation of the centrosome duplication cycle by the p53-p21Waf1/Cip1 pathway.

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.