The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1.

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Klinge CM, Kaur K, Swanson HI

The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1.

Arch Biochem Biophys. 2000 Jan 1;373(1):163-74.

PubMed ID

10620335 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
beta-Naphthoflavone	Aryl hydrocarbon receptor	Protein	Humans	Unknown	Agonist	Details
beta-Naphthoflavone	COUP transcription factor 1	Protein	Humans	Unknown	Not Available	Details
beta-Naphthoflavone	Estrogen receptor alpha	Protein	Humans	Unknown	Not Available	Details
beta-Naphthoflavone	Steroid hormone receptor ERR1	Protein	Humans	Unknown	Not Available	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Estradiol	Approved Investigational Vet Approved	FOS	2353	upregulated	Estradiol results in increased expression of FOS mRNA	14q24.3
Estradiol	Approved Investigational Vet Approved	TFF1	7031	upregulated	Estradiol results in increased expression of TFF1 mRNA	21q22.3