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Post-transcriptional destabilization of p21cip1 by protein kinase C in fibroblasts

Janice L Walker1, Paola Castagnino, Betty M Chung

  • 1Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.

The Journal of Biological Chemistry
|October 18, 2006
PubMed

Insights

Protein kinase C delta (PKCdelta) regulates cell cycle progression. Inhibiting PKCdelta increases p21(cip1) protein levels, preventing fibroblasts from entering S phase. This highlights PKCdelta

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • p21(cip1) is a key inhibitor of S phase entry, binding to cyclin-dependent kinase-2 (CDK2) complexes.
  • p21(cip1) levels rise after mitogenic stimulation but decrease as cells progress through G1.
  • Understanding p21(cip1) regulation is crucial for comprehending cell cycle control.

Purpose of the Study:

  • To investigate the role of Protein Kinase C delta (PKCdelta) in regulating p21(cip1) protein levels.
  • To determine the mechanism by which PKCdelta influences p21(cip1) stability and cell cycle progression.

Main Methods:

  • Pharmacological inhibition of PKC.
  • Expression of dominant-negative PKCdelta.
  • Knockdown of PKCdelta using small interfering RNA (siRNA) in mouse embryo fibroblasts.
  • Analysis of p21(cip1) protein levels and S phase entry.

Main Results:

  • Inhibition or knockdown of PKCdelta led to elevated p21(cip1) protein levels in fibroblasts.
  • This effect was post-transcriptional, proteasome-dependent, and independent of cyclin D1/Skp2 pathways.
  • PKCdelta inhibition reduced fibroblast entry into S phase, an effect absent in p21(cip1)-null cells.

Conclusions:

  • PKCdelta plays a significant role in the post-transcriptional destabilization of p21(cip1).
  • This destabilization is a key mitogenic function of PKCdelta in fibroblasts.
  • Targeting PKCdelta could offer a strategy to modulate cell cycle progression via p21(cip1) regulation.

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