The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements.
To determine the molecular mechanisms underlying the "cross talk" between the activity of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), which binds to arylhydrocarbon receptor (AHR) and estradiol (E2)-liganded estrogen receptor (ER), we first examined the initial step of estrogen action, ligand binding to ER. None of the AHR ligands tested, i.e. TCDD, benzo[a]pyrene, 3,3',4,4',5-pentachlorobiphenyl, ... beta-naphthoflavone, or alpha-naphthoflavone, bound to ER alpha. We report the first examination of TCDD interaction with ER beta: TCDD did not displace E2 from ER beta. We then examined a second possible mechanism, i.e. direct inhibition of ER alpha binding to estrogen response elements (EREs) by the AHR/AHR nuclear translocator (ARNT) complex. The AHR/ARNT heterodimer did not bind either a full or half-site ERE. However, AHR/ARNT bound specifically to oligomers containing naturally occurring EREs derived from the human c-fos, pS2, and progesterone receptor (PR) gene promoters that include xenobiotic response element (XRE)-like sequences. In contrast, neither purified E2-liganded-ER from calf uterus or recombinant human ER alpha bound a consensus XRE. TCDD inhibited E2-activated reporter gene activity from a consensus ERE and from EREs in the pS2, PR, and Fos genes in transiently transfected MCF-7 human breast cancer cells. However, this inhibition was not reciprocal since E2 did not inhibit TCDD-stimulated luciferase activity from the CYP1A1 promoter in transiently transfected MCF-7 or human endometrial carcinoma HEC-1A cells. We propose that at least part of the mechanism by which the AHR/ARNT complex inhibits estrogen action is by competitively inhibiting ER alpha binding to imperfect ERE sites, adjacent to or overlapping XREs.
Mesh Terms:
Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, Base Sequence, Benzo(a)pyrene, Binding, Competitive, Cattle, Consensus Sequence, Cytochrome P-450 CYP1A1, DNA-Binding Proteins, Dimerization, Drug Interactions, Environmental Pollutants, Estradiol, Estrogen Antagonists, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Gene Expression, Genes, Reporter, Humans, Oligonucleotides, Polychlorinated Biphenyls, Polychlorinated Dibenzodioxins, Promoter Regions, Genetic, Protein Binding, Receptors, Aryl Hydrocarbon, Receptors, Estrogen, Response Elements, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured, Xenobiotics
Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, Base Sequence, Benzo(a)pyrene, Binding, Competitive, Cattle, Consensus Sequence, Cytochrome P-450 CYP1A1, DNA-Binding Proteins, Dimerization, Drug Interactions, Environmental Pollutants, Estradiol, Estrogen Antagonists, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Gene Expression, Genes, Reporter, Humans, Oligonucleotides, Polychlorinated Biphenyls, Polychlorinated Dibenzodioxins, Promoter Regions, Genetic, Protein Binding, Receptors, Aryl Hydrocarbon, Receptors, Estrogen, Response Elements, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured, Xenobiotics
Mol. Cell. Endocrinol.
Date: Nov. 25, 1999
PubMed ID: 10619402
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