Journal article
Stimulation of Dihydrofolate Reductase Promoter Activity by Antimetabolic Drugs
Proceedings of the National Academy of Sciences - PNAS, v 88(19), pp 8572-8576
01 Oct 1991
PMID: 1833762
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Dihydrofolate reductase (DHFR; EC 1.5.1.3) is required in folate metabolism for the synthesis of purines, thymidine, and glycine. Although there have been several reports of induction of DHFR enzyme by methotrexate (MTX), a drug that competitively inhibits DHFR, there are no studies reported that examine the effect of MTX on DHFR gene transcription. We have examined the effect of MTX and other inhibitors of DNA synthesis on DHFR transcription using a transient expression assay. MTX stimulates transient expression in a concentration-dependent manner from a hamster DHFR promoter construct containing 150 base pairs 5' to the start of transcription. Addition of either tetrahydrofolate or hypoxanthine plus thymidine prevents the promoter induction in response to MTX, suggesting that stimulation by MTX results from inhibition of these metabolites. Furthermore, two other antimetabolic drugs-fluorodeoxyuridine and hydroxyurea-also stimulate the DHFR promoter in a concentration-dependent manner. In contrast, aphidicolin, which blocks cell growth through inhibition of DNA polymerase α, has no effect on the DHFR promoter. The potential relevance of these results to cross-resistance to chemotherapeutic agents and to the process of gene amplification is discussed.
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Details
- Title
- Stimulation of Dihydrofolate Reductase Promoter Activity by Antimetabolic Drugs
- Creators
- Helen B. Eastman - University of North Carolina at Chapel HillAndrew G. SwickM. Christine SchmittJane Clifford Azizkhan
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 88(19), pp 8572-8576
- Publisher
- National Academy of Sciences of the United States of America
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:A1991GH80500060
- Scopus ID
- 2-s2.0-0026049582
- Other Identifier
- 991020200886604721
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- Web of Science research areas
- Biochemistry & Molecular Biology