Nature Cell Biology
6, 1229 - 1235 (2004)
Published online: 7 November 2004; | doi:10.1038/ncb1194
Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27Kip1 at G1 phaseTakumi Kamura1, 2, Taichi Hara1, 2, Masaki Matsumoto1, 2, Noriko Ishida2, 3, Fumihiko Okumura1, 2, Shigetsugu Hatakeyama1, 2, Minoru Yoshida4, Keiko Nakayama2, 3
& Keiichi I. Nakayama1, 21
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. 2
CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. 3
Department of Developmental Biology, Center for Translational and Advanced Animal Research on Human Disease, Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. 4
Chemical Genetics Laboratory, Discovery Research Institute, RIKEN, Hirosawa 2-1, Wako, Saitama 351-0198, Japan.
Correspondence should be addressed to Keiichi I. Nakayama nakayak1@bioreg.kyushu-u.ac.jpThe cyclin-dependent kinase inhibitor p27Kip1 is degraded at the G0−G1 transition of the cell cycle by the ubiquitin−proteasome pathway1,
2. Although the nuclear ubiquitin ligase (E3) SCFSkp2 is implicated in p27Kip1 degradation3,
4,
5,
6, proteolysis of p27Kip1 at the G0−G1 transition proceeds normally in Skp2-/- cells7,
8. Moreover, p27Kip1 is exported from the nucleus to the cytoplasm at G0−G1 (refs 9−11). These data suggest the existence of a Skp2-independent pathway for the degradation of p27Kip1 at G1 phase. We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27Kip1 and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27Kip1, whereas a dominant-negative mutant of KPC1 delayed p27Kip1 degradation. The nuclear export of p27Kip1 by CRM1 seems to be necessary for KPC-mediated proteolysis. Depletion of KPC1 by RNA interference also inhibited p27Kip1 degradation. KPC thus probably controls degradation of p27Kip1 in G1 phase after export of the latter from the nucleus.
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