Skp2-mediated degradation of p27 regulates progression into mitosis

Dev Cell. 2004 May;6(5):661-72. doi: 10.1016/s1534-5807(04)00131-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDC2 Protein Kinase / genetics
  • CDC2-CDC28 Kinases / genetics
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA Replication / genetics
  • G2 Phase / genetics
  • Hepatocytes / metabolism
  • Hyperplasia / genetics
  • Hyperplasia / pathology
  • Hyperplasia / physiopathology
  • Mice
  • Mice, Knockout
  • Mitosis / genetics*
  • Peptide Hydrolases / genetics
  • Phenotype
  • Protein Biosynthesis / genetics
  • S-Phase Kinase-Associated Proteins / genetics*
  • S-Phase Kinase-Associated Proteins / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*


  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • S-Phase Kinase-Associated Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Peptide Hydrolases