Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade

Mol Cell. 1998 Mar;1(4):553-63. doi: 10.1016/s1097-2765(00)80055-6.

Abstract

Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic up-regulation of cyclin A-associated cyclin-dependent kinase 2(cdk2) activity. In apoptotic cells, the C termini of the cdk inhibitors p21Cip1/Waf1 and p27Kip1 are truncated by specific cleavage. The enzyme involved in this cleavage is CPP32 and/or a CPP32-like caspase. After cleavage, p21Cip1/Waf1 loses its nuclear localization sequence and exits the nucleus. Cleavage of p21Cip1/Waf1 and p27Kip1 results in a substantial reduction in their association with nuclear cyclin-cdk2 complexes, leading to a dramatic induction of cdk2 activity. Dominant-negative cdk2, as well as a mutant of p21Cip1/Waf1 resistant to caspase cleavage, partially suppress apoptosis. These data suggest that cdk2 activation, through caspase-mediated cleavage of cdk inhibitors, may be instrumental in the execution of apoptosis following caspase activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / physiology*
  • CDC2-CDC28 Kinases*
  • Caspase 3
  • Caspases*
  • Cell Cycle Proteins*
  • Cell Nucleus / chemistry
  • Cell Nucleus / enzymology
  • Cells, Cultured
  • Cyclin A / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / chemistry
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Cysteine Endopeptidases / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / enzymology
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Precursors / metabolism
  • Humans
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mutagenesis / physiology
  • Peptide Fragments
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Suppressor Proteins*
  • Umbilical Veins / cytology

Substances

  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin A
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Enzyme Precursors
  • Microtubule-Associated Proteins
  • Peptide Fragments
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases