title: The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, KY 40292, USA. carolyn.klinge@louisville.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Klinge
authors.forename: J L
authors.initials: JL
authors.lastname: Bowers
authors.forename: P C
authors.initials: PC
authors.lastname: Kulakosky
authors.forename: K K
authors.initials: KK
authors.lastname: Kamboj
authors.forename: H I
authors.initials: HI
authors.lastname: Swanson
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D016384:Consensus Sequence; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D009841:Oligonucleotides / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015262:Xenobiotics
chemical_list: C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009841:Oligonucleotides; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D014157:Transcription Factors; D015262:Xenobiotics; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D004958:Estradiol; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; C023035:3,4,5,3',4'-pentachlorobiphenyl