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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / physiology*
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CDC2-CDC28 Kinases*
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Caspase 3
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Caspases*
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Cell Cycle Proteins*
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Cell Nucleus / chemistry
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Cell Nucleus / enzymology
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Cells, Cultured
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Cyclin A / metabolism
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / metabolism
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Cyclins / chemistry
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Cyclins / genetics
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Cyclins / metabolism*
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Cysteine Endopeptidases / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / enzymology
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Enzyme Activation / physiology
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism*
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Enzyme Precursors / metabolism
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Humans
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Microtubule-Associated Proteins / chemistry
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Mutagenesis / physiology
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Peptide Fragments
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Protein Serine-Threonine Kinases / metabolism
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Recombinant Proteins / metabolism
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Transfection
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Tumor Suppressor Proteins*
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Umbilical Veins / cytology
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin A
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Cyclin E
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Enzyme Precursors
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Microtubule-Associated Proteins
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Peptide Fragments
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Recombinant Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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Cysteine Endopeptidases