Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication.
The ubiquitin-proteasome pathway plays an important role in control of the abundance of cell cycle regulators. Mice lacking Skp2, an F-box protein and substrate recognition component of an Skp1-Cullin-F-box protein (SCF) ubiquitin ligase, were generated. Although Skp2(-/-) animals are viable, cells in the mutant mice contain markedly enlarged nuclei with ... polyploidy and multiple centrosomes, and show a reduced growth rate and increased apoptosis. Skp2(-/-) cells also exhibit increased accumulation of both cyclin E and p27(Kip1). The elimination of cyclin E during S and G(2) phases is impaired in Skp2(-/-) cells, resulting in loss of cyclin E periodicity. Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators.
Mesh Terms:
Animals, Apoptosis, CDC2-CDC28 Kinases, Cell Cycle Proteins, Cell Division, Cell Nucleus, Cell Size, Cells, Cultured, Centrosome, Cullin Proteins, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Fibroblasts, Gene Deletion, Helminth Proteins, Kinetics, Mice, Mice, Knockout, Microtubule-Associated Proteins, Molecular Sequence Data, Peptide Synthases, Periodicity, Polyploidy, Protein Binding, Protein-Serine-Threonine Kinases, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, T-Lymphocytes, Tumor Suppressor Proteins, Ubiquitins
Animals, Apoptosis, CDC2-CDC28 Kinases, Cell Cycle Proteins, Cell Division, Cell Nucleus, Cell Size, Cells, Cultured, Centrosome, Cullin Proteins, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Fibroblasts, Gene Deletion, Helminth Proteins, Kinetics, Mice, Mice, Knockout, Microtubule-Associated Proteins, Molecular Sequence Data, Peptide Synthases, Periodicity, Polyploidy, Protein Binding, Protein-Serine-Threonine Kinases, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, T-Lymphocytes, Tumor Suppressor Proteins, Ubiquitins
EMBO J.
Date: May. 02, 2000
PubMed ID: 10790373
View in: Pubmed Google Scholar
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