Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation

Takumi Kamura, Taichi Hara, Shuhei Kotoshiba, Masayoshi Yada, Noriko Ishida, Hiroyuki Imaki, Shigetsugu Hatakeyama, Keiko Nakayama, Keiichi Nakayama

Research output: Contribution to journalArticle

217 Citations (Scopus)

Abstract

The abundance of the cyclin-dependent kinase (CDK) inhibitor p57 Kip2, an important regulator of cell cycle progression, is thought to be controlled by the ubiquitin-proteasome pathway. The Skp1/Cul1/F-box (SCF)-type E3 ubiquitin ligase complex SCFSkp2 has now been shown to be responsible for regulating the cellular level of p57Kip2 by targeting it for ubiquitylation and proteolysis. The elimination of p57 Kip2 was impaired in Skp2-/- cells, resulting in abnormal accumulation of the protein. Coimmunoprecipitation analysis also revealed that Skp2 interacts with p57Kip2 in vivo. Overexpression of WT Skp2 promoted degradation of p57Kip2, whereas expression of a dominant negative mutant of Skp2 prolonged the half-life of p57Kip2. Mutation of the threonine residue (Thr-310) of human p57Kip2 that is conserved between the COOH-terminal QT domains of p57Kip2 and p27Kip1 prevented the effect of Skp2 on the stability of p57 Kip2, suggesting that phosphorylation at this site is required for SCFSkp2-mediated ubiquitylation. Finally, the purified recombinant SCFSkp2 complex mediated p57Kip2 ubiquitylation in vitro in a manner dependent on the presence of the cyclin E-CDK2 complex. These observations thus demonstrate that the SCFSkp2 complex plays an important role in cell-cycle progression by determining the abundance of p57Kip2 and that of the related CDK inhibitor p27Kip1.

Original languageEnglish
Pages (from-to)10231-10236
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number18
DOIs
Publication statusPublished - Sep 2 2003

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Ubiquitination
Cyclin-Dependent Kinase Inhibitor p57
Cell Cycle
Cyclin E
Ubiquitin-Protein Ligases
Cyclin-Dependent Kinases
Proteasome Endopeptidase Complex
Threonine
Ubiquitin
Proteolysis
Half-Life
Phosphorylation
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • General

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Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. / Kamura, Takumi; Hara, Taichi; Kotoshiba, Shuhei; Yada, Masayoshi; Ishida, Noriko; Imaki, Hiroyuki; Hatakeyama, Shigetsugu; Nakayama, Keiko; Nakayama, Keiichi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 18, 02.09.2003, p. 10231-10236.

Research output: Contribution to journalArticle

Kamura, T, Hara, T, Kotoshiba, S, Yada, M, Ishida, N, Imaki, H, Hatakeyama, S, Nakayama, K & Nakayama, K 2003, 'Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 18, pp. 10231-10236. https://doi.org/10.1073/pnas.1831009100
Kamura, Takumi ; Hara, Taichi ; Kotoshiba, Shuhei ; Yada, Masayoshi ; Ishida, Noriko ; Imaki, Hiroyuki ; Hatakeyama, Shigetsugu ; Nakayama, Keiko ; Nakayama, Keiichi. / Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 18. pp. 10231-10236.
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AU - Ishida, Noriko

AU - Imaki, Hiroyuki

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