The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRα1

Carolyn M. Klinge, Kulwant Kaur, Hollie I. Swanson

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


The molecular mechanisms underlying the apparent 'cross-talk' between estrogen receptor (ER)- and aryl-hydrocarbon 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-β-estradiol (E2) 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 ERα, COUP-TF, and ERRα1, in a ligand-specific manner in vitro. Unoccupied or β-napthoflavone (β-NF)-occupied AHR showed stronger interaction with ERα, COUP-TF, and ERRα1 than when AHR was occupied by the partial antagonist α-naphthoflavone (α-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 COUPTF, ERRα1, or ERα. We next examined the interaction of either ERα or COUP-TF with a consensus xenobiotic response element (XRE). Purified ERα 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 (E2)-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.

Original languageEnglish
Pages (from-to)163-174
Number of pages12
JournalArchives of Biochemistry and Biophysics
Issue number1
StatePublished - Jan 1 2000

Bibliographical note

Funding Information:
We thank Dr. Peter C. Kulakosky for preparing rhERα and for his comments on the manuscript. We thank Sheetal J. Mehta for preparation of some of the plasmids used in transient transfection assays and for her assistance in β-gal and luciferase assays. We thank the following investigators for sharing plasmids and antisera with us: Drs. C. A. Bradfield, R. M. Evans, J. E. Mertz, R. A. Prough, and R. S. Pollenz. We thank Drs. B. J. Clark and R. A. Prough and Sarah C. Jernigan for their comments on the manuscript. This work was supported by NIEHS 1P20 ES06832-12, NIH R01 DK 53220, a University of Louisville School of Medicine Research Grant, and Veterans Administration Center for the Study of Environmental Hazards to Reproductive Health Grant 0006 (Department of Veterans Affairs Medical Center, Louisville, Kentucky) to C.M.K. and in part by University of Kentucky Medical Center Research Fund Grant 847 and NIEHS R29 ES08088 to H.I.S.


  • Antiestrogens
  • Aryl hydrocarbon receptor
  • COUP- TF
  • Dioxin
  • ERRα1
  • Estrogen receptor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology


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