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

Research output: Contribution to journalArticle

582 Citations (Scopus)

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

Fingerprint

Cyclin E
Centrosome
Polyploidy
SKP Cullin F-Box Protein Ligases
Ubiquitin
Ligases
Cells
F-Box Proteins
Degradation
G2 Phase
Ubiquitination
Periodicity
Proteasome Endopeptidase Complex
Chromosomes
Cell Cycle Checkpoints
S Phase
Cell Cycle
Animals
Apoptosis
Substrates

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Nakayama, K., Nagahama, H., Minamishima, Y. A., Matsumoto, M., Nakamichi, I., Kitagawa, K., ... 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.

Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication. / Nakayama, Keiko; Nagahama, Hiroyasu; Minamishima, Yohji A.; Matsumoto, Masaki; Nakamichi, Ikuo; Kitagawa, Kyoko; Shirane, Michiko; Tsunematsu, Ryosuke; Tsukiyama, Tadasuke; Ishida, Noriko; Kitagawa, Masatoshi; Nakayama, Kei Ichi; Hatakeyama, Shigetsugu.

In: EMBO Journal, Vol. 19, No. 9, 02.05.2000, p. 2069-2081.

Research output: Contribution to journalArticle

Nakayama, K, Nagahama, H, Minamishima, YA, Matsumoto, M, Nakamichi, I, Kitagawa, K, Shirane, M, Tsunematsu, R, Tsukiyama, T, Ishida, N, Kitagawa, M, Nakayama, KI & Hatakeyama, S 2000, 'Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication', EMBO Journal, vol. 19, no. 9, pp. 2069-2081.
Nakayama K, Nagahama H, Minamishima YA, Matsumoto M, Nakamichi I, Kitagawa K et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication. EMBO Journal. 2000 May 2;19(9):2069-2081.
Nakayama, Keiko ; Nagahama, Hiroyasu ; Minamishima, Yohji A. ; Matsumoto, Masaki ; Nakamichi, Ikuo ; Kitagawa, Kyoko ; Shirane, Michiko ; Tsunematsu, Ryosuke ; Tsukiyama, Tadasuke ; Ishida, Noriko ; Kitagawa, Masatoshi ; Nakayama, Kei Ichi ; Hatakeyama, Shigetsugu. / Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication. In: EMBO Journal. 2000 ; Vol. 19, No. 9. pp. 2069-2081.
@article{d7da58786a1644eb83fbb7aa17394aa4,
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 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.",
keywords = "Cyclin E, F-box protein, SCF complex, Skp2, Ubiquitin ligase",
author = "Keiko Nakayama and Hiroyasu Nagahama and Minamishima, {Yohji A.} and Masaki Matsumoto and Ikuo Nakamichi and Kyoko Kitagawa and Michiko Shirane and Ryosuke Tsunematsu and Tadasuke Tsukiyama and Noriko Ishida and Masatoshi Kitagawa and Nakayama, {Kei Ichi} and Shigetsugu Hatakeyama",
year = "2000",
month = "5",
day = "2",
language = "English",
volume = "19",
pages = "2069--2081",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Targeted disruption of Skp2 results in accumulation of cyclin E and p27 (Kip1), polyploidy and centrosome overduplication

AU - Nakayama, Keiko

AU - Nagahama, Hiroyasu

AU - Minamishima, Yohji A.

AU - Matsumoto, Masaki

AU - Nakamichi, Ikuo

AU - Kitagawa, Kyoko

AU - Shirane, Michiko

AU - Tsunematsu, Ryosuke

AU - Tsukiyama, Tadasuke

AU - Ishida, Noriko

AU - Kitagawa, Masatoshi

AU - Nakayama, Kei Ichi

AU - Hatakeyama, Shigetsugu

PY - 2000/5/2

Y1 - 2000/5/2

N2 - 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.

AB - 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.

KW - Cyclin E

KW - F-box protein

KW - SCF complex

KW - Skp2

KW - Ubiquitin ligase

UR - http://www.scopus.com/inward/record.url?scp=0034595292&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034595292&partnerID=8YFLogxK

M3 - Article

VL - 19

SP - 2069

EP - 2081

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 9

ER -