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Targeted disruption of Skp2 results in accumulation of cyclin E and p27 Kip1 , polyploidy and centrosome overduplication
Author(s) -
Nakayama Keiko,
Nagahama Hiroyasu,
Minamishima Yohji A.,
Matsumoto Masaki,
Nakamichi Ikuo,
Kitagawa Kyoko,
Shirane Michiko,
Tsunematsu Ryosuke,
Tsukiyama Tadasuke,
Ishida Noriko,
Kitagawa Masatoshi,
Nakayama Keiichi,
Hatakeyama Shigetsugu
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.9.2069
Subject(s) - biology , skp2 , skp1 , microbiology and biotechnology , f box protein , cyclin a2 , ubiquitin ligase , centrosome , cell cycle , cyclin b , cyclin a , cyclin e , cell division control protein 4 , cyclin d , cyclin , cullin , cyclin b1 , ubiquitin , cyclin dependent kinase 1 , biochemistry , cell , gene
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.