2000 Fiscal Year Annual Research Report

Nrf2による新しい酸化ストレス応答機構の解析

Research Project

Project/Area Number	11877025
Research Institution	University of Tsukuba
Principal Investigator	山本雅之筑波大学, 基礎医学系, 教授 (50166823)
Keywords	異物代謝 / 環境異物 / 転写制御 / モデル動物 / bZip型転写因子
Research Abstract	今年度は以下の成果を得た. 1)親電子性物質・活性酸素種によるNrf2蛋白質蓄積の分子機構の解析 Nrf2が親電子性物質により蓄積するメカニズムを腹腔マクロファージを用いて調べた。親電子性物質とプロテオソーム阻害剤にはNrf2蓄積に対する協調効果が認められなかったことより、新電子性物質は、プロテオソーム阻害剤と同じ経路でNrf2を蓄積することが示唆された。さらに、Nrf2の半減期が親電子性物質により延長することより、新電子性物質がNrf2を安定化することが明らかになった。Keaplとの相互作用に重要であるNeh2ドメインを用いたNeh2-GFP融合蛋白質の半減期は,GFP蛋白質やNeh5-GFP蛋白質に比較して著明に短縮していることより,Neh2ドメインが,Nrf2蛋白質の分解に寄与することが示唆された。 2)Keapl遺伝子破壊実験によるKeaplの生体機能の解析 Keapl遺伝子破壊マウスを作製して,肝臓におけるNrf2の蓄積を調べたところ,同因子が著明に蓄積していることが明らかになった.また,Nrf2の標的遺伝子である異物代謝系第2相の酵素群の発現が上昇していることも明らかになった.さらに,Keapl :: Nrf22重欠損マウスでは,これらの酵素の誘導が認められず,Keapl遺伝子欠損マウスの表現型は,Nrf2の過剰状態を反映していることが示された.以上により,Nrf2の活性は,Keaplにより負に制御されていることが個体レベルで証明された.

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] Nishimura,S.: "A GATA box in the GATA-1 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 B ach2 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 B ach2 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-L: "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 intemeurons."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

Nrf2による新しい酸化ストレス応答機構の解析

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-1 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 B ach2 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 B ach2 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-L: "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 intemeurons."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)