Post-transcriptional destabilization of p21cip1 by protein kinase C in fibroblasts.
p21(cip1) inhibits S phase entry by binding to cyclin-cdk2 (cyclin-dependent kinase-2) complexes. The levels of p21(cip1) are rapidly induced after mitogenic stimulation of quiescent fibroblasts and then down-regulate as the cells reach late G(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 PKCdelta, or knockdown of PKCdelta with small interfering RNA elevates p21(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. PKCdelta inhibition results in a reduced entry into S phase, and this effect is not detected in p21(cip1)-null cells. Thus, post-transcriptional destabilization of p21(cip1) appears to be a major mitogenic effect of PKCdelta in fibroblasts.
Walker
Janice L
JL
Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Castagnino
Paola
P
Chung
Betty M
BM
Kazanietz
Marcelo G
MG
Assoian
Richard K
RK
D000818:Animals; D001483:Base Sequence; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D017931:DNA Primers; D005347:Fibroblasts / Q000201:enzymology; D016193:G1 Phase; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering
C493957:Cdkn1a protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D034741:RNA, Small Interfering; D011493:Protein Kinase C; D051357:Cyclin-Dependent Kinase 2