Skp2-Mediated Degradation of p27 Regulates Progression into Mitosis

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 requir...

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Published in:	Developmental cell Vol. 6; no. 5; pp. 661 - 672
Main Authors:	Nakayama, Keiko, Nagahama, Hiroyasu, Minamishima, Yohji A, Miyake, Satoshi, Ishida, Noriko, Hatakeyama, Shigetsugu, Kitagawa, Masatoshi, Iemura, Shun-ichiro, Natsume, Tohru, Nakayama, Keiichi I
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-05-2004
Subjects:	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
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1534-5807 1878-1551
DOI:	10.1016/S1534-5807(04)00131-5