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.
Li
Q
Q
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.
Gardner
K
K
Zhang
L
L
Tsang
B
B
Bostick-Bruton
F
F
Reed
E
E
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