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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29ES009055-04
Application #
6382234
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Heindel, Jerrold
Project Start
1998-07-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$91,084
Indirect Cost
Name
Tulane University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Cox, Marc B; Miller 3rd, Charles A (2004) Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling. Cell Stress Chaperones 9:4-20
Cox, Marc B; Miller 3rd, Charles A (2003) Pharmacological and genetic analysis of 90-kDa heat shock isoprotein-aryl hydrocarbon receptor complexes. Mol Pharmacol 64:1549-56
Cox, Marc B; Miller 3rd, Charles A (2002) The p23 co-chaperone facilitates dioxin receptor signaling in a yeast model system. Toxicol Lett 129:13-21
Miller, Charles A (2002) Two tetratricopeptide repeat proteins facilitate human aryl hydrocarbon receptor signalling in yeast. Cell Signal 14:615-23
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Miller 3rd, C A (1999) A human aryl hydrocarbon receptor signaling pathway constructed in yeast displays additive responses to ligand mixtures. Toxicol Appl Pharmacol 160:297-303
Miller 3rd, C A; Martinat, M A; Hyman, L E (1998) Assessment of aryl hydrocarbon receptor complex interactions using pBEVY plasmids: expressionvectors with bi-directional promoters for use in Saccharomyces cerevisiae. Nucleic Acids Res 26:3577-83