Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase

Nat Cell Biol. 2004 Dec;6(12):1229-35. doi: 10.1038/ncb1194. Epub 2004 Nov 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amino Acid Sequence / genetics
  • Animals
  • Base Sequence / genetics
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cytoplasm / genetics
  • Cytoplasm / metabolism*
  • DNA, Complementary / analysis
  • DNA, Complementary / genetics
  • Down-Regulation / genetics
  • G1 Phase / genetics*
  • Humans
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Macromolecular Substances / isolation & purification
  • Macromolecular Substances / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics
  • NIH 3T3 Cells
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / isolation & purification
  • Peptide Hydrolases / metabolism
  • Protein Structure, Tertiary / genetics
  • Protein Subunits / genetics
  • Protein Subunits / isolation & purification
  • Protein Subunits / metabolism*
  • RNA Interference
  • Rabbits
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / isolation & purification
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA, Complementary
  • Karyopherins
  • Macromolecular Substances
  • Protein Subunits
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Suppressor Proteins
  • Ubiquitin
  • exportin 1 protein
  • Cyclin-Dependent Kinase Inhibitor p27
  • RNF123 protein, human
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases

Associated data

  • GENBANK/AY744152
  • GENBANK/AY744153