Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of cdk2: Role of a caspase cascade

Bodo Levkau, Hidenori Koyama, Elaine W. Raines, Bruce E. Clurman, Barbara Herren, Kim Orth, James M. Roberts, Russell Ross

Research output: Contribution to journalArticlepeer-review

406 Scopus citations


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 P21Clp1/Waf1 and p27Klp1 are truncated by specific cleavage. The enzyme involved in this cleavage is CPP32 and/or a CPP32-like caspase. After cleavage, p21Clp1/Waf1 loses its nuclear localization sequence and exits the nucleus. Cleavage of p21Clp1/Waf1 and p27Klp1 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 P2Clp1/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.

Original languageEnglish (US)
Pages (from-to)553-563
Number of pages11
JournalMolecular cell
Issue number4
StatePublished - Mar 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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