PKCδ modulates p21WAF1/CIP1 ability to bind to Cdk2 during TNFα-induced apoptosis

Cyclin-dependent kinase 2 (Cdk2) activity is thought to be involved in cell death-associated chromatin condensation and other manifestations of apoptotic death. Here we show that during TNFα-induced apoptosis, PKCδ is activated in a caspase-3-dependent manner and phosphorylates p21WAF1/CIP1, a specific cyclin-dependent kinase inhibitor, on 146Ser. This residue is located near a cyclin-binding motif (Cy2) that plays an important role in the interaction between p21WAF1/CIP1 and Cdk2, and its phosphorylation modulates the ability of p21WAF1/CIP1 to associate with Cdk2. The phosphorylation of p21WAF1/CIP1 is temporally related to the activation kinetics of Cdk2 activity during the apoptosis. We propose that during TNFα-induced apoptosis, PKCδ-mediated phosphorylation of p21WAF1/CIP1 at 146Ser attenuates the Cdk2 binding of p21WAF1/CIP1 and thereby upregulates Cdk2 activity.