The long-term objective is to understand the mechanisms by which mammalian cells adapt to environmental exposures and the mechanisms by which environmental exposures produce toxicity. The focus is on responses that involve alterations in gene expression. Environmental exposures of particular interest are to the halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and to low oxygen tension (hypoxia), because the responses to dioxin and to hypoxia share an interesting transcriptional regulatory protein. The exposure to dioxin is associated with cancer, birth defects, and immunotoxicity in animals. Hypoxia occurs under physiological conditions (high altitude) and in disease states (cancer, ischemia, anemia). Exposure to dioxin or to hypoxia induces the expression of a distant set of genes. The aromatic hydrocarbon receptor nuclear translocator (Arnt) protein participates in both induction mechanisms, by heterodimerizing with the aromatic hydrocarbon receptor in the response to dioxin, and by heterodimerizing with hypoxia-inducible factor 1a (HIF1a) in the response to hypoxia. The proposed experiments involve the use of mouse hepatoma cells and biochemical and genetic techniques to study the mechanism by which HIF1 and Arnt induce gene transcription in response to hypoxia, with an emphasis on analyses of protein-DNA interactions, chromatin structure, and enhancer-promoter communication in intact cells. The experiments involve analyses of the response of the phosphoglycerate kinase 1 and aldolase A genes to hypoxia, genetic analyses of wild-type and mutant forms of HIF1a, and functional studies of cross talk between the hypoxia-responsive and dioxin-mechanisms of environmental toxicity, control of mammalian gene transcription, and maintenance of cellular homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008655-04
Application #
6178508
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Packenham, Joan P
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$238,307
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Okino, S T; Whitlock Jr, J P (2000) The aromatic hydrocarbon receptor, transcription, and endocrine aspects of dioxin action. Vitam Horm 59:241-64
Barthel, A; Okino, S T; Liao, J et al. (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274:20281-6
Whitlock Jr, J P (1999) Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol 39:103-25
Okino, S T; Chichester, C H; Whitlock Jr, J P (1998) Hypoxia-inducible mammalian gene expression analyzed in vivo at a TATA-driven promoter and at an initiator-driven promoter. J Biol Chem 273:23837-43