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

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.
Mesh Terms:
Apoptosis, CDC2-CDC28 Kinases, Caspase 3, Caspases, Cell Cycle Proteins, Cell Nucleus, Cells, Cultured, Cyclin A, Cyclin E, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Cyclins, Cysteine Endopeptidases, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Enzyme Precursors, Humans, Microtubule-Associated Proteins, Mutagenesis, Peptide Fragments, Protein-Serine-Threonine Kinases, Recombinant Proteins, Transfection, Tumor Suppressor Proteins, Umbilical Veins
Mol. Cell
Date: Mar. 01, 1998
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