The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1.
The molecular mechanisms underlying the apparent "cross-talk" between estrogen receptor (ER)- and arylhydrocarbon receptor (AHR)-mediated activities are unknown. To determine how AHR ligand 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may inhibit ER action and, conversely, to examine how 17-beta-estradiol (E(2)) affects AHR activity, we examined discrete activities of each receptor, i.e., protein-protein interactions, DNA binding, and transcriptional activation. We report that AHR interacts directly with ERalpha, COUP-TF, and ERRalpha1, in a ligand-specific manner in vitro. Unoccupied or beta-napthoflavone (beta-NF)-occupied AHR showed stronger interaction with ERalpha, COUP-TF, and ERRalpha1 than when AHR was occupied by the partial antagonist alpha-naphthoflavone (alpha-NF), indicating a role for ligand in AHR interaction with these proteins. We also report that AHR interacts with COUP-TF in transfected CV-1 cells. In contrast, the AHR nuclear translocator protein (ARNT) did not interact with COUP-TF, ERRalpha1, or ERalpha. We next examined the interaction of either ERalpha or COUP-TF with a consensus xenobiotic response element (XRE). Purified ERalpha did not bind the consensus XRE, but COUP-TFI bound the consensus XRE, suggesting a role for COUP-TF as a AHR/ARNT competitor for XRE binding. In transiently transfected MCF-7 human breast cancer cells, overexpression of COUP-TFI inhibited TCDD- activated reporter gene activity from the CYP1A1 promoter. TCDD inhibited estradiol (E(2))-activated reporter gene activity from a consensus ERE and from the EREs in the pS2 and Fos genes, and COUP-TFI did not block the antiestrogenic activity of TCDD. The specific interaction of COUP-TF with XREs and AHR together with the inhibition of TCDD- induced gene expression by COUP-TF suggests that COUP-TF may regulate AHR action both by direct DNA binding competition and through protein-protein interactions.[1]References
- The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Klinge, C.M., Kaur, K., Swanson, H.I. Arch. Biochem. Biophys. (2000) [Pubmed]
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