Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells.
ERCC-1 is a critical gene within the nucleotide excision repair pathway, and cells without a functional ERCC-1 do not perform cisplatin-DNA adduct repair. We therefore investigated the cisplatin effect on ERCC-1 mRNA expression in vitro. In response to a 1-h cisplatin exposure, A2780/CP70 human ovarian cancer cells showed a 6-fold increase in steady-state level of ERCC-1 mRNA. This rise was attributable to increased transcription as measured by nuclear run-on assays and a 60% increase in ERCC-1 mRNA half-life. The increase in ERCC-1 mRNA was preceded by a 4-5-fold rise in mRNA expressions of c-fos and c-jun, a 14-fold increase in c-Jun protein phosphorylation, and an increase in in vitro nuclear extract binding activity to the AP-1-like site of ERCC-1. These data suggest that the induction of ERCC-1 expression in A2780/CP70 cells exposed to cisplatin results from two major factors: (a) an increase in the expression of transactivating factors that bind the AP-1-like site in the 5'-flanking region of ERCC-1 and (b) an increase in the level of c-Jun phosphorylation that enhances its transactivation property.
Medical Ovarian Cancer Section, Department of Developmental Therapeutics, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Q
Li
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K
Gardner
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L
Zhang
B
B
Tsang
F
F
Bostick-Bruton
E
E
Reed
D000546:Amanitins / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D011485:Protein Binding; D014176:Protein Biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000493:pharmacokinetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000546:Amanitins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C057270:cisplatin-DNA adduct; D003513:Cycloheximide; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin