Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1

Nature. 1999 Mar 11;398(6723):160-5. doi: 10.1038/18230.


The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo. Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation, for example as a result of phosphorylation by cyclinE/Cdk2 complexes, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27Kip1 by promoting its degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • COP9 Signalosome Complex
  • COS Cells
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Enzyme Inhibitors / metabolism
  • G1 Phase
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred BALB C
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mutagenesis
  • Peptide Hydrolases
  • Protein Binding
  • Recombinant Fusion Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins*


  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases
  • Peptide Hydrolases
  • COPS5 protein, human
  • Cops5 protein, mouse
  • COP9 Signalosome Complex