Caspase-induced proteolysis of the cyclin-dependent kinase inhibitor p27Kip1 mediates its anti-apoptotic activity

Oncogene. 1999 Aug 26;18(34):4839-47. doi: 10.1038/sj.onc.1202860.

Abstract

The caspase-mediated cleavage of a limited number of cellular proteins is a common feature of apoptotic cell death. This cleavage usually inhibits the function of the target protein or generates peptides that actively contribute to the death process. In the present study, we demonstrate that the cyclin-dependent kinase inhibitor p27Kip1 is cleaved by caspases in human leukemic cells exposed to apoptotic stimuli. We have shown recently that p27Kip1 overexpression delayed leukemic cell death in response to cytotoxic drugs. In transient transfection experiments, the p23 and the p15 N-terminal peptides generated by p27Kip1 proteolysis demonstrate an anti-apoptotic effect similar to that induced by the wild-type protein, whereas cleavage-resistant mutants have lost their protective effect. Moreover, stable transfection of a cleavage-resistant mutant of p27Kip1 sensitizes leukemic cells to drug-induced cell death. Altogether, these results indicate that proteolysis of p27Kip1 triggered by caspases mediates the anti-apoptotic activity of the protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Base Sequence
  • CDC2-CDC28 Kinases*
  • Calpain / antagonists & inhibitors
  • Caspase 3
  • Caspase 6
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / drug effects
  • Caspases / metabolism*
  • Cell Cycle Proteins*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Etoposide / pharmacology
  • Humans
  • Leukemia / drug therapy
  • Leukemia / metabolism*
  • Leukemia / pathology
  • Leupeptins / pharmacology
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Oligopeptides / pharmacology
  • Protein-Serine-Threonine Kinases / metabolism
  • Thimerosal / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins*

Substances

  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cell Cycle Proteins
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Microtubule-Associated Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Oligopeptides
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • acetylleucyl-leucyl-norleucinal
  • calpain inhibitor 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Thimerosal
  • Etoposide
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • CASP3 protein, human
  • CASP6 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Calpain
  • Caspase 3
  • Caspase 6
  • Caspase 8
  • Caspase 9
  • Caspases