Direct regulation of the centrosome duplication cycle by the p53-p21(Waf1/Cip1) pathway

The function of the centrosomes to direct mitotic spindles is critical for accurate chromosome transmission to daughter cells. Since each daughter cel l inherits one centrosome, each centrosome must duplicate prior to the next mitosis, and do so only once, Thus, there are control mechanism(s) that en sure the coordinated progression of centrosome duplication and other cell c ycle 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 inc reased chromosome transmission errors, This has been found to be the case f or cells lacking functional p53 tumor suppressor protein. However, it had r emained to be determined whether the deregulation of the centrosome duplica tion cycle is the direct or indirect effect of loss/mutational inactivation of p53, Here, we found that the normal centrosome duplication cycle is alm ost completely restored in p53(-/-) cells by re-introduction of wild-type p 53 at a physiologically relevant level, demonstrating that p,53 is directly involved in the regulation of centrosome duplication, Since cyclin depende nt kinase 2 (CDK2)/cyclin E triggers DNA synthesis as well as centrosome du plication, we tested whether Waf1, a CDK inhibitor and a major target of p5 3's transactivation function, is an effector of p,53-mediated regulation of centrosome duplication, We found that induced expression of Waf1 in p53(-/ -) cells only partially restored the centrosome duplication control, sugges ting that Waf1 comprises one of the multiple effector pathways of the p53-m ediated regulation of the centrosome duplication cycle.