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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CDC2 Protein Kinase / genetics
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CDC2-CDC28 Kinases / genetics
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism*
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Cell Nucleus / genetics
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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DNA Replication / genetics
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G2 Phase / genetics
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Hepatocytes / metabolism
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Hyperplasia / genetics
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Hyperplasia / pathology
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Hyperplasia / physiopathology
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Mice
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Mice, Knockout
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Mitosis / genetics*
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Peptide Hydrolases / genetics
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Phenotype
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Protein Biosynthesis / genetics
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S-Phase Kinase-Associated Proteins / genetics*
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S-Phase Kinase-Associated Proteins / metabolism*
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism*
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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S-Phase Kinase-Associated Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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Cdk2 protein, mouse
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Cyclin-Dependent Kinase 2
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Peptide Hydrolases