Skp2-Mediated degradation of p27 regulates progression into mitosis

Keiko Nakayama, Hiroyasu Nagahama, Yohji A. Minamishima, Satoshi Miyake, Noriko Ishida, Shigetsugu Hatakeyama, Masatoshi Kitagawa, Shun ichiro Iemura, Tohru Natsume, Keiichi I. Nakayama

Research output: Contribution to journalArticlepeer-review

321 Citations (Scopus)


Although Skp2 has been thought to mediate the degradation of p27 at the G1-S transition, Skp2 -/- cells exhibit accumulation of p27 in S-G2 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 G2 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 G2-M progression by mediating the degradation of p27.

Original languageEnglish
Pages (from-to)661-672
Number of pages12
JournalDevelopmental Cell
Issue number5
Publication statusPublished - 2004 May


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