Post-transcriptional Destabilization of p21 super(cip1) by Protein Kinase C in Fibroblasts

p21 super(cip1) inhibits S phase entry by binding to cyclin-cdk2 (cyclin-dependent kinase-2) complexes. The levels of p21 super(cip1) are rapidly induced after mitogenic stimulation of quiescent fibroblasts and then down-regulate as the cells reach late G sub(1) phase and activate cyclin E-cdk2. In this study, we have shown that pharmacological inhibition of protein kinase C (PKC), expression of dominant negative PKC delta , or knockdown of PKC delta with small interfering RNA elevates p21 super(cip1) protein levels in mouse embryo fibroblasts. This effect is selective, post-transcriptional, and proteasome-dependent but distinct from previously identified post-transcriptional control mechanisms involving cyclin D1 and Skp2. PKC delta inhibition results in a reduced entry into S phase, and this effect is not detected in p21 super(cip1)-null cells. Thus, post-transcriptional destabilization of p21 super(cip1) appears to be a major mitogenic effect of PKC delta in fibroblasts.