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

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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 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.

Original languageEnglish
Pages (from-to)2069-2081
Number of pages13
JournalEMBO Journal
Volume19
Issue number9
Publication statusPublished - 2000 May 2

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Keywords

  • Cyclin E
  • F-box protein
  • SCF complex
  • Skp2
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Nakayama, K., Nagahama, H., Minamishima, Y. A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K. I., & Hatakeyama, S. (2000). Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication. EMBO Journal, 19(9), 2069-2081.