title: Lack of ligand-selective binding of the aryl hydrocarbon receptor to putative DNA binding sites regulating expression of Bax and paraoxonase 1 genes.
abstract: The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxicological effects of structurally diverse chemicals through its ability to bind specific DNA recognition sites (dioxin responsive elements (DREs)), and activate transcription of adjacent genes. While the DRE has a highly conserved consensus sequence, it has been suggested that the nucleotide specificity of AhR DNA binding may be ligand-dependent. The upstream regulatory regions of the murine Bax and human paraoxonase 1 (PON1) genes reportedly contain unique DRE-like sequences that respond to AhRs activated by some ligands but not others. Given the significant implications of this observation to understanding the diversity in AhR responses and that of other ligand-dependent nuclear receptors, a combination of DNA binding, nuclear translocation and gene expression analysis was used to investigate the molecular mechanisms underlying these ligand-selective responses. Although known AhR agonists stimulated AhR nuclear translocation, DRE binding and gene expression, the ligand-selective DRE-like DNA elements identified in the Bax and PON1 upstream regulatory regions failed to bind ligand-activated AhR or confer AhR-responsiveness upon a reporter gene. These results argue against the reported ligand-selectivity of AhR DNA binding and suggest DNA binding by ligand activated AhR involves DRE-containing DNA.
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, CA 95616, United States.
authors.forename: Danica E
authors.initials: DE
authors.lastname: DeGroot
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, CA 95616, United States.
authors.forename: Ai
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, CA 95616, United States. Electronic address: msdenison@ucdavis.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013379:Substrate Specificity; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D051028:bcl-2-Associated X Protein; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004247:DNA; D043303:Aryldialkylphosphatase
keywords: Aryl hydrocarbon receptor; Bax; DNA binding; Paraoxonase 1