Differential ligand-dependent activation and a role for Y322 in aryl hydrocarbon receptor-mediated regulation of gene expression.

Abstract

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF). Non-traditional activators, including omeprazole (Omp), are thought to regulate AHR action through phosphorylation rather than binding to the receptor. In this study, we examined the ability of these compounds to induce AHR-dependent regulation of cytochrome P450 1A1 (CYP1A1) and CYP1B1 in T-47D human breast cancer cells. The role of Y322, a residue implicated in Omp-dependent activation of AHR was also investigated. All four compounds induced CYP1A1 and CYP1B1 mRNA expression, with Omp differing from the HAHs. Chromatin immunoprecipitation assays revealed ligand- and gene-selectivity in the recruitment patterns of AHR coactivators. We also found that residue Y322 of human AHR was important for maximum activation of AHR by 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF, but required for 2,3,7,8-TCDF and Omp in an AHR-deficient MCF-7 human breast cancer cell line. In summary, this study provides evidence for context- and ligand-selective differences in coactivator recruitment in AHR-regulated gene expression and reveal an important role of Y322 in AHR activation.

• Authors: Melanie Powis, Trine Celius, Jason Matthews
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 410 Issue 4 Pg. 859-65 (Jul 15 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21703235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• AHR protein, human
• Basic Helix-Loop-Helix Transcription Factors
• Benzofurans
• Ligands
• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon
• Tyrosine
• Aryl Hydrocarbon Hydroxylases
• CYP1B1 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1B1
• Omeprazole
• 2,3,4,7,8-pentachlorodibenzofuran
• 2,3,7,8-tetrachlorodibenzofuran

Topics

• Aryl Hydrocarbon Hydroxylases (genetics)
• Basic Helix-Loop-Helix Transcription Factors (agonists, chemistry, genetics)
• Benzofurans (pharmacology)
• Cell Line, Tumor
• Cytochrome P-450 CYP1A1 (genetics)
• Cytochrome P-450 CYP1B1
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Ligands
• Omeprazole (pharmacology)
• Polychlorinated Dibenzodioxins (pharmacology)
• Receptors, Aryl Hydrocarbon (agonists, chemistry, genetics)
• Tyrosine (chemistry, genetics)