In this research project, we tried to clarify the molecular basis of cellular response to environmental signals, by collaborative study between research groups in University of Tsukuba and Tohoku University. Our attention is focused on how environmental signals are integrated into transcriptional activation of a series of responsive genes. We picked up three induction mechanisms of gene expression: 1) phase II xenobiotic enzymes, 2) phase I xenobiotic enzymes, 3) hypoxia response genes. Since it is important to understand the cellular response in a global perspective, we analyze not only cultured cell lines but also gene manipulated mouse and zebrafish.
As a result, following conclusions were drawn.
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Nrf2 is essential for ARE-mediated induction of phase II xenobiotic genes, and a newly identified factor Keap1 regulates the activity of Nrf2 by two actions, nuclear shuttling and protein degradation. |
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Analysis of zebrafish indicated that the Nrf2-Keap1 system is highly conserved among vertebrates. |
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The small Maf proteins are in vivo partner molecules for Nrf2 and Bach1, and quantitative balance of these factors is quite important for regulation of target genes. |
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Human AhR knock-in mouse showed quite weaker response to dioxin than wild-type mice. This humanized model mouse may supply better prediction of the biological effects of environmental toxicants. |
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HIF-1α and HLF are both important for hypoxia response, while their requirements vary among tissues and genes. We found that hypoxia-induce expression of erythropoietin gene in eye is HLF-dependent. |
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