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.
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| 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 |
