The human estrogen receptor structural gene contains a DNA sequence that binds activated mouse and human Ah receptors: a possible mechanism of estrogen receptor regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
TCDD decreases ER levels in vitro and in vivo, possibly through down-regulation of the ER structural gene, although the actual mechanism is unknown. We report the identification of six partial and two full length DREs in the 5' flanking and coding regions of the human ER gene. To test the ability of the coding region DRE (+102) to bind the activated AhR, two complementary oligonucleotides corresponding to the DRE-containing region of the human ER gene were synthesized, termed hERO, and used in a gel shift assay. TCDD-activated nuclear extracts from both mouse Hepa 1c1c7 cells and human MCF-7 cells specifically bound to the hERO with relative binding affinities of 15.5 nM and 5.6 nM, respectively. This binding was dependent upon a functional DRE. The hERO also specifically competed for AhR binding with a DRE-containing oligonucleotide from the mouse CYP1A1 gene. The results suggest a possible mechanism by which TCDD could be acting to modulate ER levels.
White
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Department of Environmental Medicine, University of Rochester Medical Center, New York 14642.
Gasiewicz
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D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005796:Genes; D006801:Humans; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D011960:Receptors, Estrogen; D004247:DNA; D003577:Cytochrome P-450 Enzyme System