Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase.
The cyclin-dependent kinase inhibitor p27(Kip1) is degraded at the G0-G1 transition of the cell cycle by the ubiquitin-proteasome pathway. Although the nuclear ubiquitin ligase (E3) SCF(Skp2) is implicated in p27(Kip1) degradation, proteolysis of p27(Kip1) at the G0-G1 transition proceeds normally in Skp2(-/-) cells. Moreover, p27(Kip1) 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 p27(Kip1) 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 p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation. The nuclear export of p27(Kip1) by CRM1 seems to be necessary for KPC-mediated proteolysis. Depletion of KPC1 by RNA interference also inhibited p27(Kip1) degradation. KPC thus probably controls degradation of p27(Kip1) in G1 phase after export of the latter from the nucleus.
Kamura
Takumi
T
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Hara
Taichi
T
Matsumoto
Masaki
M
Ishida
Noriko
N
Okumura
Fumihiko
F
Hatakeyama
Shigetsugu
S
Yoshida
Minoru
M
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D016193:G1 Phase / Q000235:genetics*; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D046911:Macromolecular Substances / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D010447:Peptide Hydrolases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D034622:RNA Interference; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000097606:Exportin 1 Protein
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018076:DNA, Complementary; D028884:Karyopherins; D046911:Macromolecular Substances; D010447:Peptide Hydrolases; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000097606:Exportin 1 Protein; C493961:Cdkn1b protein, mouse; C574376:RNF123 protein, human