A human aryl hydrocarbon receptor signaling pathway constructed in yeast displays additive responses to ligand mixtures.
An optimized signal transduction pathway that reproduces the response of human aryl hydrocarbon (Ah) receptor to ligands has been established in Saccharomyces cerevisiae. Ligand treatment induced a 50-fold increase in beta-galactosidase activity from a reporter plasmid in yeast engineered to express human Ah receptor and Ah nuclear translocator (Arnt) proteins. The archetypal Ah receptor ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, activated Ah receptor and induced lacZ reporter activity at concentrations of >/=0.3 nM. Mixtures of halogenated and nonhalogenated Ah receptor ligands produced additive signaling responses in this yeast bioassay. These results were consistent with the existence of a common binding site and mechanism of ligand-mediated Ah receptor activation. Although yeast have no natural counterpart to the Ah receptor pathway, expression of human Ah receptor and Arnt under the appropriate conditions provides a functional model system for studying Ah receptor activation and signal transduction.
Miller
C A
CA
Environmental Health Sciences Department, Tulane University School of Public Health and Tropical Medicine, Tulane-Xavier Center for Bioenvironmental Research, 1430 Tulane Avenue, New Orleans, Louisiana, 70112, USA.
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000633:toxicity; D001665:Binding Sites; D004268:DNA-Binding Proteins; D004357:Drug Synergism; D017930:Genes, Reporter; D005818:Genetic Engineering; D006581:Hexachlorobenzene / Q000633:toxicity; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010957:Plasmids; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D019324:beta-Naphthoflavone / Q000633:toxicity
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D006581:Hexachlorobenzene; D019324:beta-Naphthoflavone; D001616:beta-Galactosidase