Sci. STKE, 3 June 2003
DIOXINS Bypassing Estrogen
Ohtake et al. discovered an unexpected mechanism whereby dioxins can modulate estrogen signaling through the arylhydrocarbon receptor (AhR). Dioxins are widespread environmental contaminants that act as endocrine disrupters with both estrogenic and antiestrogenic activity. They have been implicated in the pathogenesis of endometriosis and possibly certain cancers. Both estrogens and dioxins bind to and activate nuclear receptors that function as transcription factors; estrogens act through the estrogen receptors ERα and ERβ, and dioxins act through the AhR-arylhydrocarbon nuclear translocator complex (AhR-Arnt, see Brosens and Parker). Ohtake et al. expressed reporter genes containing either ER or AhR-Arnt binding elements (ERE and XRE, respectively) in breast and uterine cancer cell lines and showed that AhR agonists stimulated transcription through the ERE in the absence of estrogens but inhibited 17β-estradiol (E2)-induced transcription. Transcriptional activation through the ERE by AhR agonists required ER, AhR, and Arnt. The authors used coimmunoprecipitation, glutathione-S-transferase pull-down assays, and chromatin immunoprecipitation analysis to demonstrate that ligand-activated AhR-Arnt associates with unliganded ER, recruits an ER coactivator, and promotes binding of the unliganded ER to the ERE. Dioxins stimulated estrogen-responsive genes and increased uterine weight and cell proliferation in the uterine glandular epithelium in ovariectomized mice, but had antiestrogenic effects in the presence of high doses of E2. These estrogenic effects were not observed in ovariectomized mutant mice lacking AhR or ERα. These data indicate that the estrogenic effects of dioxin may be mediated through ligand-independent activation of the ER through the dioxin-AhR-Arnt complex.
F. Ohtake, K.-I. Takeyama, T. Matsumoto, H. Kitagawa, Y. Yamamoto, K. Nohara, C. Tohyama, A. Krust, J. Mimura, P. Chambon, J. Yanagisawa, Y. Fujii-Kuriyama, S. Kato, Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423, 545-550 (2003). [Online Journal]
J. J. Brosens, M. G. Parker, Oestrogen receptor hijacked. Nature 423, 487-488 (2003). [Online Journal]
Citation: Bypassing Estrogen. Sci. STKE 2003, tw207 (2003).
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