Protein kinase C delta is required for survival of cells expressing activated p21RAS.

Abstract

Inhibition of protein kinase C (PKC) activity in transformed cells and tumor cells containing activated p21(RAS) results in apoptosis. To investigate the pro-apoptotic pathway induced by the p21(RAS) oncoprotein, we first identified the specific PKC isozyme necessary to prevent apoptosis in the presence of activated p21(RAS). Dominant-negative mutants of PKC, short interfering RNA vectors, and PKC isozyme-specific chemical inhibitors directed against the PKCdelta isozyme demonstrated that PKCdelta plays a critical role in p21(RAS)-mediated apoptosis. An activating p21(RAS) mutation, or activation of the phosphatidylinositol 3-kinase (PI3K) Ras effector pathway, increased the levels of PKCdelta protein and activity in cells, whereas inhibition of p21(RAS) activity decreased the expression of the PKCdelta protein. Activation of the Akt survival pathway by oncogenic Ras required PKCdelta activity. Akt activity was dramatically decreased after PKCdelta suppression in cells containing activated p21(RAS). Conversely, constitutively activated Akt rescued cells from apoptosis induced by PKCdelta inhibition. Collectively, these findings demonstrate that p21(RAS), through its downstream effector PI3K, induces PKCdelta expression and that this increase in PKCdelta activity, acting through Akt, is required for cell survival. The p21(RAS) effector molecule responsible for the initiation of the apoptotic signal after suppression of PKCdelta activity was also determined to be PI3K. PI3K (p110(C)(AAX), where AA is aliphatic amino acid) was sufficient for induction of apoptosis after PKCdelta inhibition. Thus, the same p21(RAS) effector, PI3K, is responsible for delivering both a pro-apoptotic signal and a survival signal, the latter being mediated by PKCdelta and Akt. Selective suppression of PKCdelta activity and consequent induction of apoptosis is a potential strategy for targeting of tumor cells containing an activated p21(RAS).

• Authors: Shuhua Xia, Lora W Forman, Douglas V Faller
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 18 Pg. 13199-210 (May 04 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17350960 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Proto-Oncogene Proteins c-akt
• Protein Kinase C-delta
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Apoptosis (genetics)
• BALB 3T3 Cells
• Cell Survival (genetics)
• Enzyme Activation (drug effects, genetics)
• Gene Expression
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Genes, Dominant
• Isoenzymes (biosynthesis, genetics)
• Mice
• Mutation
• NIH 3T3 Cells
• Neoplasms (enzymology, genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase C-delta (antagonists & inhibitors, biosynthesis, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects, genetics)