Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation
| Autor: | Takumi Kamura, Keiko Nakayama, Masayoshi Yada, Hiroyuki Imaki, Shuhei Kotoshiba, Taichi Hara, Keiichi I. Nakayama, Shigetsugu Hatakeyama, Noriko Ishida |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases Cell Cycle Proteins Ligases Mice Ubiquitin Cyclin-dependent kinase Multienzyme Complexes TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY Skp1 Animals Humans Phosphorylation Cyclin-Dependent Kinase Inhibitor p57 Multidisciplinary biology Kinase Tumor Suppressor Proteins Nuclear Proteins Biological Sciences Cyclin-Dependent Kinases Ubiquitin ligase Cell biology Cysteine Endopeptidases Biochemistry biology.protein CUL1 Female CDK inhibitor Cyclin-Dependent Kinase Inhibitor p27 Half-Life HeLa Cells |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 100(18) |
| ISSN: | 0027-8424 |
| Popis: | 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 SCF Skp2 has now been shown to be responsible for regulating the cellular level of p57 Kip2 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 p57 Kip2 in vivo . Overexpression of WT Skp2 promoted degradation of p57 Kip2 , whereas expression of a dominant negative mutant of Skp2 prolonged the half-life of p57 Kip2 . Mutation of the threonine residue (Thr-310) of human p57 Kip2 that is conserved between the COOH-terminal QT domains of p57 Kip2 and p27 Kip1 prevented the effect of Skp2 on the stability of p57 Kip2 , suggesting that phosphorylation at this site is required for SCF Skp2 -mediated ubiquitylation. Finally, the purified recombinant SCF Skp2 complex mediated p57 Kip2 ubiquitylation in vitro in a manner dependent on the presence of the cyclin E-CDK2 complex. These observations thus demonstrate that the SCF Skp2 complex plays an important role in cell-cycle progression by determining the abundance of p57 Kip2 and that of the related CDK inhibitor p27 Kip1 . |
| Databáze: | OpenAIRE |
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