title: Evaluation of the effectiveness of DNA-binding drugs to inhibit transcription using the c-fos serum response element as a target.
abstract: Previous work has demonstrated that sequence-selective DNA-binding drugs can inhibit transcription factors from binding to their target sites on gene promoters. In this study, the potency and effectiveness of DNA-binding drugs to inhibit transcription were assessed using the c-fos promoter's serum response element (SRE) as a target. The drugs chosen for analysis included the minor groove binding agents chromomycin A(3) and Hoechst 33342, which bind to G/C-rich and A/T-rich regions, respectively, and the intercalating agent nogalamycin, which binds G/C-rich sequences in the major groove. The transcription factors targeted, Elk-1 and serum response factor (SRF), form a ternary complex (TC) on the SRE that is necessary and sufficient for induction of c-fos by serum. The drugs' abilities to prevent TC formation on the SRE in vitro were nogalamycin > Hoechst 33342 > chromomycin. Their potencies in inhibiting cell-free transcription and endogenous c-fos expression in NIH3T3 cells, however, were chromomycin > nogalamycin > Hoechst 33342. The latter order of potency was also obtained for the drugs' cytotoxicity and inhibition of general transcription as measured by [(3)H]uridine incorporation. These systematic analyses provide insight into how drug and transcription factor binding characteristics are related to drugs' effectiveness in inhibiting gene expression.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: White
authors.forename: O
authors.initials: O
authors.lastname: Heidenreich
authors.forename: A
authors.initials: A
authors.lastname: Nordheim
authors.forename: T A
authors.initials: TA
authors.lastname: Beerman
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000235:genetics; D015152:Blotting, Northern; D002474:Cell-Free System / Q000187:drug effects / Q000378:metabolism; D014128:Chromomycin A3 / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D009621:Nogalamycin / Q000378:metabolism / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements / Q000187:drug effects*; D026362:Serum Response Factor; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004364:Pharmaceutical Preparations; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D026362:Serum Response Factor; D014157:Transcription Factors; D004247:DNA; D014128:Chromomycin A3; D009621:Nogalamycin; C017807:bisbenzimide ethoxide trihydrochloride