NUCLEAR ACCUMULATION OF P21(CIP1) THE ONSET OF MITOSIS - A ROLE AT THE G(2) M-PHASE TRANSITION/

Cell cycle arrest in G(1) in response to ionizing radiation or senesce nce is believed to be provoked by inactivation of G(1) cyclin-cyclin-d ependent kinases (Cdks) by the Cdk inhibitor p21(Cip/Waf1/Sdi1). We pr ovide evidence that in addition to exerting negative control of the G( 1)/S phase transition, p21 may play a role at the onset of mitosis, In nontransformed fibroblasts, p21 transiently reaccumulates in the nucl eus near the G(2)/M-phase boundary, concomitant with cyclin B1 nuclear translocation, and associates with a fraction of cyclin A-Cdk and cyc lin B1-Cdk complexes, Premitotic nuclear accumulation of cyclin B1 is not detectable in cells with low p21 levels, such as fibroblasts expre ssing the viral human papillomavirus type 16 E6 oncoprotein, which fun ctionally inactivates p53, or in tumor-derived cells, Moreover, synchr onized E6-expressing fibroblasts show accelerated entry into mitosis c ompared to wild-type cells and exhibit higher cyclin A-and cyclin B1-a ssociated kinase activities, Finally, primary embryonic fibroblasts de rived from p21(-/-) mice have significantly reduced numbers of premito tic cells,vith nuclear cyclin B1, These data suggest that p21 promotes a transient pause late in G(2) that may contribute to the implementat ion of late cell cycle checkpoint controls.