Document Detail


Regulation of p53 stabilization by DNA damage and protein kinase C.
MedLine Citation:
PMID:  12492119     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have demonstrated previously that the protein kinase C (PKC) signal transduction pathway acts upstream of caspases to regulate caspase activation and apoptosis induced by the DNA-damaging agent cisplatin (CP). In the present study, we have examined whether PKC influences p53 and, hence, cellular sensitivity/resistance to CP. The basal p53 level was low in HeLa cells but was elevated in CP-resistant HeLa (HeLa/CP) cells. CP had no effect on the p53 content in HeLa cells, but it caused p53 accumulation in HeLa/CP cells. Rottlerin, a PKCdelta inhibitor that prevents CP-induced proteolytic activation of PKCdelta, caused an accumulation of p53 in HeLa cells when treated in conjunction with CP, but it had no additional effect in HeLa/CP cells. The ability of rottlerin to prevent proteolytic activation of PKCdelta or to induce accumulation of p53 by CP was compromised in HeLa/CP cells. PKC activator phorbol 12, 13-dibutyrate attenuated constitutive p53 levels in both HeLa and HeLa/CP cells. Whereas the combination of rottlerin and CP increased the half-life of p53 in HeLa cells, CP alone was sufficient to stabilize p53 in HeLa/CP cells. These results suggest that both DNA damage and inhibition of proteolytic activation of PKCdelta by CP were necessary for the stabilization of p53 in HeLa cells. Furthermore, an increase in p53 was not associated with enhanced sensitivity of HeLa cells to CP.
Authors:
Cassie L Johnson; Dongmei Lu; Jie Huang; Alakananda Basu
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  1     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-12-20     Completed Date:  2003-04-07     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  861-7     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Institute for Cancer Research, Fort Worth, Texas 76107, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetophenones / pharmacology
Antineoplastic Agents / pharmacology
Benzopyrans / pharmacology
Cisplatin / pharmacology*
Cross-Linking Reagents / pharmacology
DNA Damage*
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Flow Cytometry
Gene Expression Regulation, Neoplastic*
HeLa Cells
Humans
Immunoblotting
Protein Kinase C / antagonists & inhibitors,  metabolism*
Protein Kinase C-delta
Time Factors
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
CA71727/CA/NCI NIH HHS; CA85682/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Acetophenones; 0/Antineoplastic Agents; 0/Benzopyrans; 0/Cross-Linking Reagents; 0/Enzyme Inhibitors; 0/Tumor Suppressor Protein p53; 15663-27-1/Cisplatin; 82-08-6/rottlerin; EC 2.7.11.13/PRKCD protein, human; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-delta

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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