title: Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication.
abstract: 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.
authors.affiliation: Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakayama
authors.forename: H
authors.initials: H
authors.lastname: Nagahama
authors.forename: Y A
authors.initials: YA
authors.lastname: Minamishima
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: I
authors.initials: I
authors.lastname: Nakamichi
authors.forename: K
authors.initials: K
authors.lastname: Kitagawa
authors.forename: M
authors.initials: M
authors.lastname: Shirane
authors.forename: R
authors.initials: R
authors.lastname: Tsunematsu
authors.forename: T
authors.initials: T
authors.lastname: Tsukiyama
authors.forename: N
authors.initials: N
authors.lastname: Ishida
authors.forename: M
authors.initials: M
authors.lastname: Kitagawa
authors.forename: K
authors.initials: K
authors.lastname: Nakayama
authors.forename: S
authors.initials: S
authors.lastname: Hatakeyama
mesh_terms: D000818:Animals; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D044842:Cullin Proteins; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D015801:Helminth Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010507:Periodicity; D011123:Polyploidy; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases; D013601:T-Lymphocytes / Q000166:cytology; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; C503646:Cul3 protein, mouse; C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; D015801:Helminth Proteins; D008869:Microtubule-Associated Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044843:SKP Cullin F-Box Protein Ligases; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D010453:Peptide Synthases