The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements

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• 作者：Klinge ; Carolyn M. ; Bowers ; Jennifer L. ; Kulakosky ; Peter C. ; Kamboj ; Kulwant Kaur ; Swanson ; Hollie I.
• 关键词：Estrogen receptor ; Aryl hydrocarbon receptor ; Xenobiotic response element ; Dioxin ; Estrogen response element ; PAS ; per-ARNT-sim ; HAP ; hydroxylapatite ; LBD ; ligand binding domain ; CAT ; chloramphenicol acetyl transferase
• 刊名：Molecular and Cellular Endocrinology
• 出版年：1999
• 出版时间：November 25, 1999
• 年：1999
• 卷：157
• 期：1-2
• 页码：105-119
• 全文大小：400 K

文摘

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, β-naphthoflavone, or α-naphthoflavone, bound to ERα. We report the first examination of TCDD interaction with ERβ: TCDD did not displace E₂ from ERβ. We then examined a second possible mechanism, i.e. direct inhibition of ERα 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 ERα 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 ERα binding to imperfect ERE sites, adjacent to or overlapping XREs. Publisher: Elsevier Science Language of Publication: English Item Identifier: S0303-7207(99)00165-3 Publication Type: Article ISSN: 0303-7207 Cited by:

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Footnotes:

1. Part of the work communicated in this paper was presented in the 82nd (Toronto, Canada) Annual Meetings of the Endocrine Society. All cDNA clones used in the present experiments are available from the laboratory of Professor Hutz.