Cisplatin inhibits chromatin remodeling, transcription factor binding, and transcription from the mouse mammary tumor virus promoter in vivo.
The anticancer drug cis-diamminedichloro-platinum(II) (cisplatin) covalently modifies DNA, and these lesions are thought to lead to cell death by inhibiting DNA and RNA synthesis. By using in vivo analysis techniques, we have investigated the influence of cisplatin on hormone-induced transcription from the mouse mammary tumor virus (MMTV) promoter. Cisplatin substantially reduced glucocorticoid-induced expression from the MMTV promoter stably incorporated into mouse tumor cells. The glucocorticoid-receptor-dependent chromatin remodeling and loading of transcription factors that is a signature response of this promoter in the context of chromatin were significantly reduced by cisplatin but not by the clinically ineffective trans-isomer trans-diamminedichloroplatinum(II) (transplatin). Additional in vivo studies on transiently introduced nonchromatin MMTV templates demonstrated that cisplatin modification of DNA blocked binding of the transcription factor NF1. These results provide strong evidence that cisplatin influences transcription by interfering with the opening of repressive chromatin structures and by blocking transcription factor binding directly, each of which could contribute substantially to its toxicity.
Mymryk
J S
JS
Department of Obstetrics and Gynaecology, University of Western Ontario, London, Canada.
Zaniewski
E
E
Archer
T K
TK
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D002843:Chromatin / Q000187:drug effects* / Q000648:ultrastructure; D002945:Cisplatin / Q000494:pharmacology*; D004279:DNA, Viral / Q000302:isolation & purification / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis; D008324:Mammary Tumor Virus, Mouse / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D025542:Neurofibromin 1; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011506:Proteins / Q000302:isolation & purification / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D013698:Templates, Genetic; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D002843:Chromatin; D004279:DNA, Viral; D025542:Neurofibromin 1; D011506:Proteins; D014157:Transcription Factors; D003907:Dexamethasone; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D002945:Cisplatin