Abstract

The aromatic hydrocarbon (Ah) receptor is an intracellular protein that binds and mediates the biological effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The liganded Ah receptor heterodimerizes with a second protein (known as Arnt) in activating CYP1A1 gene transcription in mouse hepatoma cells. The proposed studies involve: (1) analyses of the functional domains of the Ah receptor, (2) identification of additional protein partners for the receptor, and (3) characterization of receptor function in the absence of TCDD. The experiments utilize a variety of techniques in molecular biology, cellular biology, and genetics. The studies are designed to generate new insights into the mechanism of TCDD action; the findings may help in assessing the risk that dioxin poses to human health.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003719-11
Application #
2153396
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1985-06-15
Project End
1998-05-31
Budget Start
1995-06-10
Budget End
1996-05-31
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Gao, L; Whitlock Jr, J P (2001) Accessibility and activity of the promoter for a dioxin-inducible ecto-ATPase gene. Arch Biochem Biophys 392:270-8
Okino, S T; Whitlock Jr, J P (2000) The aromatic hydrocarbon receptor, transcription, and endocrine aspects of dioxin action. Vitam Horm 59:241-64
Whitlock Jr, J P (1999) Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol 39:103-25
Gao, L; Dong, L; Whitlock Jr, J P (1998) A novel response to dioxin. Induction of ecto-ATPase gene expression. J Biol Chem 273:15358-65
Whitlock Jr, J P; Chichester, C H; Bedgood, R M et al. (1997) Induction of drug-metabolizing enzymes by dioxin. Drug Metab Rev 29:1107-27
Ma, Q; Whitlock Jr, J P (1997) A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 272:8878-84
Whitlock Jr, J P; Okino, S T; Dong, L et al. (1996) Cytochromes P450 5: induction of cytochrome P4501A1: a model for analyzing mammalian gene transcription. FASEB J 10:809-18
Ma, Q; Whitlock Jr, J P (1996) The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Mol Cell Biol 16:2144-50
Dong, L; Ma, Q; Whitlock Jr, J P (1996) DNA binding by the heterodimeric Ah receptor. Relationship to dioxin-induced CYP1A1 transcription in vivo. J Biol Chem 271:7942-8
Ma, Q; Dong, L; Whitlock Jr, J P (1995) Transcriptional activation by the mouse Ah receptor. Interplay between multiple stimulatory and inhibitory functions. J Biol Chem 270:12697-703

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