Summary of Research Project Results under JSPS FY2002
"Research for the Future Program"

1.Research Institution University of Tsukuba
2.Research Area Life Sciences
3.Research Field Regulation Networks of Eukaryotic Gene Expression
4.Term of Project FY 1998 - FY 2002
5.Project Number 98L01102
6.Title of Project Regulatory Mechanisms of Gene Expression for Environment Adaptation

7.Project Leader
Name Institution,Department Title of Position
Masayuki, Yamamoto University of Tsukuba, Institute of Basic Medical Sciences Professor

8.Core Members

Name Institution,Department Title of Position
Kazuhiro, Sogawa Tohoku University, Graduate School of Life Sciences Professor

9.Summary of Research Results

  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.
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.
Analysis of zebrafish indicated that the Nrf2-Keap1 system is highly conserved among vertebrates.
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.
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.
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.

10.Key Words
(1)Gene Expression   (2)Transcription Factor   (3)Xenobiotic Enzyme
(4)Hypoxia Response   (5)Knockout Mice   (6)Transgenic Mice
(7)Zebrafish   (8)Oxidative Stress Response