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 TNF alpha-induced apoptosis, PKC delta is activated in a caspase-3-dependent manner and phosphorylates p21(WAF1/CIP1), a specific cyclin-dependent kinase inhibitor, on (146)Ser. This residue is located near a cyclin-binding motif (Cy2) that plays an important role in the interaction between p21(WAF1/CIP1) and Cdk2, and its phosphorylation modulates the ability of p21(WAF1/CIP1) to associate with Cdk2. The phosphorylation of p21(WAF1/CIP1) temporally related to the activation kinetics of Cdk2 activity during the apoptosis. We propose that during TNF alpha-induced apoptosis, PKC delta-mediated phosphorylation of p21(WAF1/CIP1) at (146)Ser, attenuates the Cdk2 binding of p21(WAF1/CIP1) and thereby upregulates Cdk2 activity. (c) 2005 Elsevier Inc. All rights reserved.