Document Detail


Protein kinase C delta is required for survival of cells expressing activated p21RAS.
MedLine Citation:
PMID:  17350960     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-03-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-30     Completed Date:  2007-06-14     Revised Date:  2013-02-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13199-210     Citation Subset:  IM    
Affiliation:
Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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MeSH Terms
Descriptor/Qualifier:
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 / antagonists & inhibitors,  metabolism
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
Grant Support
ID/Acronym/Agency:
CA108100/CA/NCI NIH HHS; CA112102/CA/NCI NIH HHS; R01 CA112102/CA/NCI NIH HHS; R41 CA108100/CA/NCI NIH HHS; R41 CA141908/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.13/Protein Kinase C-delta; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras)
Comments/Corrections

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