Caspase-dependent Cdk activity is a requisite effector of apoptotic death events

The caspase-dependent activation of cyclin-dependent kinases (Cdks) in vari ed cell types in response to disparate suicidal stimuli has prompted our ex amination of the role of Cdks in cell death. We have tested the functional role of Cdk activity in cell death genetically, with the expression of domi nant negative Cdk mutants (DN-Cdks) and Cdk inhibitory genes, Here we demon strate that Cdk2 activity is necessary for death-associated chromatin conde nsation and other manifestations of apoptotic death, including cell shrinka ge and the loss of adhesion to substrate. Susceptibility to the induction o f the cell death pathway? including the activation of the caspase cascade, is unimpaired in cells in which Cdk2 activity is inhibited. The direct visu alization of active caspase activity in these cells confirms that death-ass ociated Cdk2 acts downstream of the caspase cascade. Cdk inhibition also do es not prevent the loss of mitochondrial membrane potential and membrane ph ospholipid asymmetry, which may be direct consequences of caspase activity, and dissociates these events from apoptotic condensation. Our data suggest that caspase activity is necessary, but not sufficient, for the full physi ological cell death program and that a requisite function of the proteolyti c caspase cascade is the activation of effector Cdks.