Document Detail

Phorbol ester exposure activates an AP-1-mediated increase in ERCC-1 messenger RNA expression in human ovarian tumor cells.
MedLine Citation:
PMID:  10228559     Owner:  NLM     Status:  MEDLINE    
ERCC-1 is an essential gene in the nucleotide excision repair pathway, and may be essential for life. However, the mechanism of transcriptional activation and regulation of ERCC-1 gene expression is unclear. We therefore investigated the effect of the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the expression of the ERCC-1 gene in A2780/CP70 human ovarian carcinoma cells. TPA induced a four- to sixfold increase in steady-state ERCC-1 messenger RNA (mRNA) levels that was time- and concentration-dependent. Nuclear run-on experiments demonstrated that the rate of transcription of ERCC-1 was approximately 2.8-fold higher in TPA-treated cells than in the controls. TPA stimulation of A2780/CP70 cells also resulted in a rapid but transient induction of c-jun and c-fos as determined by Northern and Western blot analyses, which peaked about 2 h before the peak in ERCC-1 expression. Electrophoretic mobility shift assays of nuclear extracts from TPA-treated cells revealed an increase in DNA-binding activity specific for the AP-1-like binding site in the 5'-flanking region of ERCC-1. c-Jun and c-Fos proteins were confirmed to be the components of the activated AP-1 complex by supershift analysis. The increase in AP-1 activity occurs immediately before the increase in ERCC-1 transcription. The increase in AP-1 DNA-binding activity and the increase in ERCC-1 mRNA expression were prevented by pretreatment with cycloheximide. These data suggest that AP-1 may contribute to the upregulation of ERCC-1 in response to TPA in human ovarian cancer cells.
Q Li; L Zhang; B Tsang; K Gardner; F Bostick-Bruton; E Reed
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cellular and molecular life sciences : CMLS     Volume:  55     ISSN:  1420-682X     ISO Abbreviation:  Cell. Mol. Life Sci.     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-05-19     Completed Date:  1999-05-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9705402     Medline TA:  Cell Mol Life Sci     Country:  SWITZERLAND    
Other Details:
Languages:  eng     Pagination:  456-66     Citation Subset:  IM    
Developmental Therapeutics Department, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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MeSH Terms
Amanitins / pharmacology
Binding Sites
Carcinogens / pharmacology*
Cycloheximide / pharmacology
DNA Repair / drug effects*
DNA-Binding Proteins*
Gene Expression Regulation, Neoplastic / drug effects*
Neoplasm Proteins / genetics*
Nucleic Acid Synthesis Inhibitors / pharmacology
Ovarian Neoplasms / metabolism,  pathology*
Protein Synthesis Inhibitors / pharmacology
Proteins / genetics*
RNA, Messenger / biosynthesis*,  genetics
RNA, Neoplasm / biosynthesis*,  genetics
Tetradecanoylphorbol Acetate / pharmacology*
Transcription Factor AP-1 / physiology*
Transcription, Genetic / drug effects*
Tumor Cells, Cultured
Reg. No./Substance:
0/Amanitins; 0/Carcinogens; 0/DNA-Binding Proteins; 0/Neoplasm Proteins; 0/Nucleic Acid Synthesis Inhibitors; 0/Protein Synthesis Inhibitors; 0/Proteins; 0/RNA, Messenger; 0/RNA, Neoplasm; 0/Transcription Factor AP-1; 16561-29-8/Tetradecanoylphorbol Acetate; 66-81-9/Cycloheximide; EC 3.1.-/ERCC1 protein, human; EC 3.1.-/Endonucleases

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