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

Keiko Nakayama, Hiroyasu Nagahama, Yohji A. Minamishima, Masaki Matsumoto, Ikuo Nakamichi, Kyoko Kitagawa, Michiko Shirane, Ryosuke Tsunematsu, Tadasuke Tsukiyama, Noriko Ishida, Masatoshi Kitagawa, Kei Ichi Nakayama, Shigetsugu Hatakeyama

研究成果: Article査読

622 被引用数 (Scopus)

抄録

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 G2 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.

本文言語English
ページ(範囲)2069-2081
ページ数13
ジャーナルEMBO Journal
19
9
DOI
出版ステータスPublished - 2000 5 2
外部発表はい

ASJC Scopus subject areas

  • 神経科学(全般)
  • 分子生物学
  • 生化学、遺伝学、分子生物学(全般)
  • 免疫学および微生物学(全般)

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