Aryl Hydrocarbon Receptor (AHR) is a ligand-activated component of a heterodimeric transcription factor called the Aryl Hydrocarbon Receptor Complex (AHRC). AHRC mediates transcription of many gene products that lay a role in carcinogenesis, teratogenesis, metabolism, endocrine regulation, and immune function. Many pollutants, drugs, and naturally occurring compounds with a planar aromatic structure bind to AHR and activate AHR- mediated transcription. Since considerable financial and human resources are directed towards protecting people and the environment from exposure to ligands of AHRC, understanding this receptor is central to the validity of determining the health risks of aromatic compounds. Yeast lack the genes encoding AHR and the AHR dimerization partner, ARNT, that comprise the AHRC. Expression of human AHR and ARNT in yeast allows the use of genetic approaches to study AHR regulation and structure. This proposal specifically addresses understanding how two groups of proteins, the cyclophilins and 90 kilodalton heat shock proteins, influence the initial stages of the AHR signal transduction. Yeast genetic methods will also be used to select for new HSP90 and AHR alleles with altered function. Characterization of these mutated derivatives will further elucidate the structural features of HSP90 and AHR. These studies will provide significant new information about the molecular biology of AHR-mediated signal transduction.
