Skp2-Mediated Degradation of p27 Regulates Progression into Mitosis

Abstract

Although Skp2 has been thought to mediate the degradation of p27 at the G 1-S transition, Skp2 −/− cells exhibit accumulation of p27 in S-G 2 phase with overreplication. We demonstrate that Skp2 −/− p27 −/− mice do not exhibit the overreplication phenotype, suggesting that p27 accumulation is required for its development. Hepatocytes of Skp2 −/− mice entered the endoduplication cycle after mitogenic stimulation, whereas this phenotype was not apparent in Skp2 −/− p27 −/− mice. Cdc2-associated kinase activity was lower in Skp2 −/− cells than in wild-type cells, and a reduction in Cdc2 activity was sufficient to induce overreplication. The lack of p27 degradation in G 2 phase in Skp2 −/− cells may thus result in suppression of Cdc2 activity and consequent inhibition of entry into M phase. These data suggest that p27 proteolysis is necessary for the activation of not only Cdk2 but also Cdc2, and that Skp2 contributes to regulation of G 2-M progression by mediating the degradation of p27.