2000 Fiscal Year Annual Research Report

遺伝子改変マウスを用いた環境異物モニタリングモデル動物の開発

Research Project

Project/Area Number	12794009
Research Institution	University of Tsukuba
Principal Investigator	山本雅之筑波大学, 基礎医学系, 教授 (50166823)
Co-Investigator(Kenkyū-buntansha)	原田孝則残留農薬研究所, 毒性第2部, 部長青木康展国立環境研究所, 環境研究部, 室長 (20159297) 高橋智筑波大学, 基礎医学系, 教授 (50271896)
Keywords	異物代謝 / 環境異物 / 転写制御 / モデル動物 / bZip型転写因子 / bHLH-PAS型転写因子
Research Abstract	今年度は以下の成果を得た. 1)Keapl欠失マウスの作製・AhR過剰発現マウスの作製培養細胞を用いた実験から,Keaplは,異物代謝系第2相の酵素群の発現誘導に重要であるNrf2の活性を負に制御する因子であると予想されていた.今回われわれはKeapl欠損マウスを作製したところ,このマウスの肝臓において,Nrf2の活性が増強していること,さらに,異物代謝系第2相の酵素の発現が誘導されていることが観察された.これにより,個体レベルでKeaplがNrf2の活性を負に制御する因子であることが証明された.また,AhRを皮膚特異的に過剰発現するマウスを作製したところ,皮膚の角化異常が観察された. 2)ヒト型AhRマウスの作製ヒト型AhRは,マウス型AhRに比べて,ダイオキシンに対する親和性が低い.マウス型AhRの替わりに,ヒトAhRを持つマウスを作製したところ,このマウスは3-メチルコラントレンに対する反応が減弱していることが明らかになった. 3)Nrf2欠損マウス・AhR欠損マウスの環境異物に対する反応の解析 3-メチルコラントレン投与により,AhR欠損マウスではCYP1A1及びCYP1A2の発現誘導が認められなくなるのに対し,Nrf2欠損マウスではその誘導は認められなかった.異物代謝系第1相酵素群であるCYP1A1及びCYP1A2の発現誘導にはNrf2は関与しないことが確認された. アセトアミノフェン投与により,Nrf2欠損マウスは効率に重症の肝障害をおこすことが観察された.Nrf2は,アセトアミノフェンの急性毒性の防御に重要であることが明らかになった. Nrf2::AhR2重欠損マウスにBHAを投与したところ,CYP1A2の誘導が観察された.BHAによるCYP1A2の誘導には,Nrf2・AhRのいずれも介さない誘導系が存在することが示唆された.

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] Nishimura,S.: "A GATA box in the GATA-l gene hematopoietic enhancer is critical element in the network of GATA factors and sites that regulate this gene."Mol.Cell.Biol.. 20. 713-723 (2000)
[Publications] Pan,X.: "Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions."J.Biochem.. 127. 105-112 (2000)
[Publications] Kobayashi,A.: "A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through BTB/POZ domain."Mol.Cell.Biol.. 20. 1733-1746 (2000)
[Publications] Onodera,K.: "Perinatal synthetic lethality and hematopoietic defects in compound mafG :: mafK mutant mice."EMBO J. 19. 1335-1345 (2000)
[Publications] Katsuoka,F.: "One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells."EMBO J.. 19. 2980-2991 (2000)
[Publications] Ishii,T.: "Induction of murine intestinal and hepatic peroxiredoxin MSP23 by dietary butylated hydroxyanisole."Carcinogenesis. 21. 1013-1016 (2000)
[Publications] Hoshino,H.: "Oxidative stress abolishes leptomycine B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element."J.Biol.Chem.. 275. 15370-15376 (2000)
[Publications] Ishii,T: "Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages."J.Biol.Chem.. 275. 16023-16029 (2000)
[Publications] Takahashi,S.: "GATA factor transgenes under GATA-1 locus control rescue germ line GATA-1 mutant deficiencies."Blood. 96. 910-916 (2000)
[Publications] Takahashi,S-I.: "Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein."Biochem.Biophys.Res.Commun.. 2732. 596-602 (2000)
[Publications] Hayes,J.D.: "The Nrf2 transcription factor contributes both to the basal expression of glutathion S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin."Biochem.Soc.Trans.. 28. 33-41 (2000)
[Publications] Zhou,Y.: "GATA2 is required for the generation of V2 interneurons."Development. 127. 3829-3838 (2000)
[Publications] Toki,T.: "Functional characterization of the two alternative promoters of human p45 NF-E2 gene."Exp.Hematol.. 28. 1113-1119 (2000)
[Publications] Wakabayashi,N.: "A novel cis-acting element regulates HES-1 gene expression in P19 embryonal carcinoma cells treated with retinoic acid."J.Biochem.. 128. 1087-1095 (2000)
[Publications] Motohashi,H.,: "Positive or negative MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins."Cell. 103. 865-875 (2000)

2000 Fiscal Year Annual Research Report

遺伝子改変マウスを用いた環境異物モニタリングモデル動物の開発

Principal Investigator

山本 雅之 筑波大学, 基礎医学系, 教授 (50166823)

Research Products

[Publications] Nishimura,S.: "A GATA box in the GATA-l gene hematopoietic enhancer is critical element in the network of GATA factors and sites that regulate this gene."Mol.Cell.Biol.. 20. 713-723 (2000)

[Publications] Pan,X.: "Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions."J.Biochem.. 127. 105-112 (2000)

[Publications] Kobayashi,A.: "A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through BTB/POZ domain."Mol.Cell.Biol.. 20. 1733-1746 (2000)

[Publications] Onodera,K.: "Perinatal synthetic lethality and hematopoietic defects in compound mafG :: mafK mutant mice."EMBO J. 19. 1335-1345 (2000)

[Publications] Katsuoka,F.: "One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells."EMBO J.. 19. 2980-2991 (2000)

[Publications] Ishii,T.: "Induction of murine intestinal and hepatic peroxiredoxin MSP23 by dietary butylated hydroxyanisole."Carcinogenesis. 21. 1013-1016 (2000)

[Publications] Hoshino,H.: "Oxidative stress abolishes leptomycine B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element."J.Biol.Chem.. 275. 15370-15376 (2000)

[Publications] Ishii,T: "Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages."J.Biol.Chem.. 275. 16023-16029 (2000)

[Publications] Takahashi,S.: "GATA factor transgenes under GATA-1 locus control rescue germ line GATA-1 mutant deficiencies."Blood. 96. 910-916 (2000)

[Publications] Takahashi,S-I.: "Cloning of a coproporphyrinogen oxidase promoter regulatory element binding protein."Biochem.Biophys.Res.Commun.. 2732. 596-602 (2000)

[Publications] Hayes,J.D.: "The Nrf2 transcription factor contributes both to the basal expression of glutathion S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin."Biochem.Soc.Trans.. 28. 33-41 (2000)

[Publications] Zhou,Y.: "GATA2 is required for the generation of V2 interneurons."Development. 127. 3829-3838 (2000)

[Publications] Toki,T.: "Functional characterization of the two alternative promoters of human p45 NF-E2 gene."Exp.Hematol.. 28. 1113-1119 (2000)

[Publications] Wakabayashi,N.: "A novel cis-acting element regulates HES-1 gene expression in P19 embryonal carcinoma cells treated with retinoic acid."J.Biochem.. 128. 1087-1095 (2000)

[Publications] Motohashi,H.,: "Positive or negative MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins."Cell. 103. 865-875 (2000)

山本雅之筑波大学, 基礎医学系, 教授 (50166823)