Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression

Centrosome hyperamplification and the consequential mitotic defects contrib ute to chromosome instability in cancers. Loss or mutational inactivation o f p53 has been shown to induce chromosome instability through centrosome hy peramplification. It has recently been found that Cdk2-cyclin E is involved in the initiation of centrosome duplication, and that constitutive activat ion of Cdk2-cyclin E results in the uncoupling of the centrosome duplicatio n cycle and the DNA replication cycle. Cyclin E overexpression and p53 muta tions occur frequently in tumors. Here, we show that cyclin E overexpressio n and loss of p53 synergistically increase the frequency of centrosome hype ramplification in cultured cells as well as in tumors developed in p53-null , heterozygous, and wildtype mice, Through examination of cells derived fro m Waf1-null mice, we further found that Waf1, a potent inhibitor of Cdk2-cy clin E and a major target of p53's transactivation function, is involved in coordinating the initiation of centrosome duplication and DNA replication, suggesting that Waf1 may act as a molecular link between p53 and Cdk2-cycl in E in the control of the centrosome duplication cycle.