Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication

• Published in: The EMBO journal 2000-05, Vol.19 (9), p.2069-2081
• Main Authors: Nakayama, K, Nagahama, H, Minamishima, Y A, Matsumoto, M, Nakamichi, I, Kitagawa, K, Shirane, M, Tsunematsu, R, Tsukiyama, T, Ishida, N, Kitagawa, M, Hatakeyama, S
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; CDC2-CDC28 Kinases; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Division; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Size; Cells, Cultured; Centrosome - metabolism; Cullin Proteins; Cyclin E - antagonists & inhibitors; Cyclin E - metabolism; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases - metabolism; Fibroblasts - cytology; Gene Deletion; Helminth Proteins - metabolism; Kinetics; Mice; Mice, Knockout; Microtubule-Associated Proteins - metabolism; Molecular Sequence Data; Peptide Synthases - chemistry; Peptide Synthases - genetics; Peptide Synthases - metabolism; Periodicity; Polyploidy; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; S-Phase Kinase-Associated Proteins; SKP Cullin F-Box Protein Ligases; T-Lymphocytes - cytology; Tumor Suppressor Proteins; Ubiquitins - metabolism
• ISSN: 0261-4189
• DOI: 10.1093/emboj/19.9.2069

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.