Modulation of oestrogen receptor signalling by association with the activated dioxin receptor.
Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects. Although their anti-oestrogenic actions are well described, dioxins can also induce endometriosis and oestrogen-dependent tumours, implying possible oestrogenic effects. However, the molecular mechanism underlying oestrogen-related actions of dioxins remains largely unknown. A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins. Here we show that the agonist-activated AhR/Arnt heterodimer directly associates with oestrogen receptors ER-alpha and ER-beta. This association results in the recruitment of unliganded ER and the co-activator p300 to oestrogen-responsive gene promoters, leading to activation of transcription and oestrogenic effects. The function of liganded ER is attenuated. Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-alpha-/- ovariectomized mice. Our findings suggest a novel mechanism by which ER-mediated oestrogen signalling is modulated by a co-regulatory-like function of activated AhR/Arnt, giving rise to adverse oestrogen-related actions of dioxin-type environmental contaminants.
Ohtake
Fumiaki
F
The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Takeyama
Ken-ichi
K
Matsumoto
Takahiro
T
Kitagawa
Hirochika
H
Yamamoto
Yasuji
Y
Nohara
Keiko
K
Tohyama
Chiharu
C
Krust
Andree
A
Mimura
Junsei
J
Chambon
Pierre
P
Yanagisawa
Junn
J
Fujii-Kuriyama
Yoshiaki
Y
Kato
Shigeaki
S
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001665:Binding Sites; D019556:COS Cells; D004268:DNA-Binding Proteins; D004147:Dioxins / Q000494:pharmacology; D004785:Environmental Pollutants / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects
C497396:ARNT protein, human; C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D004147:Dioxins; D004785:Environmental Pollutants; D004967:Estrogens; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D008748:Methylcholanthrene