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PMID: 10790373 Published · ppublish English Journal Article

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

The EMBO journal ·Vol. 19 ·No. 9 ·2000-05-02 ·Pages 2069-81

Nakayama K, Nagahama H, Minamishima YA, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M, Tsunematsu R, Tsukiyama T, Ishida N, Kitagawa M, Nakayama K, Hatakeyama S

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.

MeSH Terms
Animals Apoptosis CDC2-CDC28 Kinases Cell Cycle Proteins/antagonists & inhibitors,genetics,metabolism Cell Division Cell Nucleus/genetics,metabolism Cell Size Cells, Cultured Centrosome/metabolism Cullin Proteins Cyclin E/antagonists & inhibitors,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,genetics,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
Chemicals
Cdkn1b protein, mouse Cell Cycle Proteins Cul3 protein, mouse Cullin 1 Cullin Proteins Cyclin E Helminth Proteins Microtubule-Associated Proteins S-Phase Kinase-Associated Proteins Tumor Suppressor Proteins Ubiquitins Cyclin-Dependent Kinase Inhibitor p27 SKP Cullin F-Box Protein Ligases Protein Serine-Threonine Kinases CDC2-CDC28 Kinases Cdk2 protein, mouse Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Peptide Synthases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Nakayama K
Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nagahama H
Minamishima Y A
Matsumoto M
Nakamichi I
Kitagawa K
Shirane M
Tsunematsu R
Tsukiyama T
Ishida N
Kitagawa M
Nakayama K
Hatakeyama S
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.9.2069
Published
2000-05-02
Pages
2069-81
Language
English
Region
England
NLM ID
8208664
PMCID
PMC305685
Subset
IM
Databases
GENBANK
AF083215
External Links
PubMed source DOI: 10.1093/emboj/19.9.2069 PMC Full Text View journal details
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