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Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms

Mayumi Nakashima1, Hiroshi Hamajima, Jinghe Xia

  • 1Department of Internal Medicine, Saga Medical School, Saga, Saga 849-8501, Japan.

Biochimica Et Biophysica Acta
|May 18, 2010
PubMed

Insights

Protein kinase C (PKC) regulates programmed cell death protein 4 (PDCD4) protein levels by promoting its degradation. Tumor promoter TPA inhibits apoptosis by reducing PDCD4 protein, but not mRNA, via PKC signaling and proteasomal pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transforming growth factor-beta1 (TGF-beta1) induces apoptosis in liver cells, involving programmed cell death protein 4 (PDCD4) via the Smad pathway.
  • The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C (PKC) stimulator, inhibits TGF-beta1-induced apoptosis, but its effect on PDCD4 is unclear.

Purpose of the Study:

  • To elucidate the regulatory mechanism of PDCD4 expression by protein kinase C (PKC).
  • To investigate the role of PKC isoforms in PDCD4 regulation and TGF-beta1-induced apoptosis.

Main Methods:

  • Human hepatoma Huh7 cells were treated with TPA, PKC inhibitors (Ro-31-8425, bisindolylmaleimide-1-hydrocholoride, rottlerin, Go6976), and TGF-beta1.
  • siRNA-mediated knockdown of PKC isoforms (PKCalpha, PKCdelta, PKCepsilon) was performed.
  • PDCD4 protein and mRNA expression levels were analyzed, along with the effect of proteasome inhibitor MG132.

Main Results:

  • TPA treatment suppressed PDCD4 protein expression and blocked TGF-beta1's effect.
  • PKC inhibitors targeting PKCdelta/epsilon, but not PKCalpha, enhanced TGF-beta1-induced PDCD4 protein.
  • Knockdown of PKCdelta/epsilon, but not PKCalpha, augmented TGF-beta1-stimulated PDCD4 protein; TPA's effect on PDCD4 protein was reversed by MG132, indicating proteasomal degradation.

Conclusions:

  • PKC isoforms, specifically PKCdelta and PKCepsilon, regulate PDCD4 protein stability through proteasomal degradation.
  • TPA inhibits TGF-beta1-induced apoptosis by promoting PDCD4 protein degradation via PKC signaling.

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