Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo
| Autor: | Donald M. Miller, Charles Koller, Shelia D. Thomas, Ratna Ray, Scott W. Blume, Richard C. Snyder |
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| Jazyk: | angličtina |
| Rok vydání: | 1991 |
| Předmět: |
Transcription
Genetic Sp1 Transcription Factor Molecular Sequence Data Drug Resistance Biology Gene Expression Regulation Enzymologic chemistry.chemical_compound Transcription (biology) Dihydrofolate reductase parasitic diseases Consensus sequence Humans Binding site Promoter Regions Genetic Gene Regulation of gene expression Sp1 transcription factor Base Sequence General Medicine Plicamycin Molecular biology Tetrahydrofolate Dehydrogenase Methotrexate chemistry biology.protein DNA Research Article |
| Popis: | The promoter of the human dihydrofolate reductase (DHFR) gene contains two consensus binding sites for the DNA binding protein Sp1. DNAse protection and gel mobility shift assays demonstrate binding of recombinant Sp1 to both decanucleotide Sp1 binding sequences which are located 49 and 14 base pairs upstream of the transcription start site. The more distal of the two binding sites exhibits a somewhat higher affinity for Sp1. The G-C specific DNA binding drug, mithramycin, binds to both consensus sequences and prevents subsequent Sp1 binding. Promoter-dependent in vitro transcription of a DHFR template is selectively inhibited by mithramycin when compared to the human H2b histone gene. A similar effect is also noted in vivo. Mithramycin treatment of MCF-7 human breast carcinoma cells containing an amplified DHFR gene induces selective inhibition of DHFR transcription initiation, resulting in a decline in DHFR mRNA level and enzyme activity. This selective inhibition of DHFR expression suggests that it is possible to modulate the overexpression of the DHFR gene in methotrexate resistant cells. |
| Databáze: | OpenAIRE |
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