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Evaluation of the effectiveness of DNA-binding drugs to inhibit transcription using the c-fos serum response element as a target

Lookup NU author(s): Professor Olaf Heidenreich


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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.

Publication metadata

Author(s): White CM, Heidenreich O, Nordheim A, Beerman TA

Publication type: Article

Publication status: Published

Journal: Biochemistry

Year: 2000

Volume: 39

Issue: 40

Pages: 12262-73

ISSN (print): 0006-2960

ISSN (electronic): 1943-295X


DOI: 10.1021/bi001427l


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