2001 Fiscal Year Annual Research Report

高次生命現象の基盤となるbZip型転写制御ネットワークの包括的解析

Research Project

Project/Area Number	12308036
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)	本橋ほづみ筑波大学, 基礎医学系, 講師 (00282351)
Keywords	bZip型転写因子 / 遺伝子破壊マウス / 転写制御 / 巨核球 / 神経変性 / 遺伝子制御ネットワーク
Research Abstract	今年度は以下の成果を得た. (1)bZipネットワークの標的遺伝子の探索 mafG-/-::mafK+/-マウスの巨核球は,血小板形成の主たる過程である胞体突起形成が著名に障害されている.小Maf群因子の下流で機能する因子で,血小板の放出に重要な因子を明らかにするために,mafG-/-::mafK+/-マウスの巨核球のmRNAと野生型マウス巨核球のmRNAとのあいだでサブトラクションを行った.その結果,アクチン,チュブリンなどの細胞骨格系の遺伝子が得られた.また,新規の因子clone325を得ることができた.Clone325は,赤血球系細胞で発現が低いのに対して,巨核球系細胞において発現量が多いことが明らかになった.この発現プロファイルから,同因子は,巨核球の分化・成熟,血小板の放出過程において重要な機能を果たしている可能性が大きいと考えられる. (2)神経細胞におけるbZipネットワークの機能解析 mafG-/-::mafK+/-マウスは,生後8週目あたりから重度の運動障害を発症する.この症状はヒトのHereditary Hyperekplexiaに類似していることから,その原因遺伝子として報告されているグリシンレセプターmRNAの発現を,同マウスの神経組織において調べたところ,その発現は約3分の1程度に減少していた.これにより,神経細胞において,bZip制御ネットワークの下流にグリシンレセプター遺伝子が存在することが明らかになった. (3)Bach因子の核局在に対する,小Maf群因子の機能 mafG-/-::mafK+/-マウスの神経細胞のMARE結合活性を検討したところ,Bach/小Mafヘテロ2量体が顕著に減少していた.これは,興味深いことに,Bach因子の核局在が阻害された結果であることが明らかになった.小Maf群因子には,Bach因子の核内移行を促進する作用があり,それは小Maf群因子のbZip構造に依存していることがわかった.

Research Products
(31 results)

All Other

All Publications (31 results)

[Publications] Enomoto, A., et al.: "High sensitivity of Nrf2 knockout mice to acetoaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzyme and antioxidant genes."Toxicol.Sci. 59. 169-177 (2001)
[Publications] Tabata, M. et al.: "Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression."J.Cell.Physiol.. 186. 260-267 (2001)
[Publications] Ramos-Gomez, M.: "Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice."Proc.Natl.Acad.Sci.USA. 98. 3410-3415 (2001)
[Publications] Kwak, M-K, et al.: "Role of Transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemopreventive agent, 3H-1, 2-dithiole-3-thione."Mol.Med.. 7. 135-145 (2001)
[Publications] Kanezaki, R, et al.: "Transcription factor BACH1 is recruited to nucleus by its novel alternative spliced isoform expressed in testis."J.Biol.Chem.. 276. 7278-7284 (2001)
[Publications] Kobayashi, M, et al.: "The homeobox protein Six3 interacts with the Groucho corepressor and acts as a transcriptional repressor in eye and forebrain formation."Dev.Biol.. 232. 315-326 (2001)
[Publications] Hosoya, T. et al.: "Defective development of secretary neurons in the hypothalamus of Arnt2-knockout mice."Genes Cells. 6. 361-374 (2001)
[Publications] Umetani, M.: "Function of GATA transcription factors in the induction of endothelial VCAM-1 by TNF-α."Arterioscler.Thromb.Vasc.Biol.. 21. 917-922 (2001)
[Publications] Kobayashi, M. et al.: "Positive regulation by GATA-1 of GATA-1 gene hematopoietic regulatory domain in zebrafish embryos in vivo."Development. 128. 2341-2350 (2001)
[Publications] Kim, Y-C. et al.: "Hemin-induced activation of the Thioredoxin gene by Nrf2:a differential regulation of the antioxidant responsive element(ARE)by switch of its binding factors."J.Biol.Chem.. 276. 18399-18406 (2001)
[Publications] Ogawa, K.: "Heme mediates de-repression of Maf recognition element through direct binding to transcription factor Bach1."EMBO J.. 20. 2835-2843 (2001)
[Publications] Yoh, K.: "Nrf2 deficient mouse:a novel model for lupus nephritis."Kidney Int.. 60. 1343-1353 (2001)
[Publications] Katoh, Y. et al.: "Two domains of Nrf2 cooperatively bind CBP(CREB binding protein) and synergistically activate transcription."Genes Cells. 6. 857-868 (2001)
[Publications] Shimizu, R. et al.: "In vivo requirements for functional GATA-1 domains during primitive and definitive erythropoiesis."EMBO J.. 20. 5250-5260 (2001)
[Publications] Sun, J. et al.: "The promoter of mouse transcription repressor bach1 is regulated by Sp1 and transactivated by Bach1."J.Biochem.. 130. 385-392 (2001)
[Publications] McMahon, M. et al.: "The Cap'n' Collar basic leucine zipper transcription factor Nrt2 controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes."Cancer Res.. 61. 3299-3307 (2001)
[Publications] Imagawa, S. et al.: "Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea-hypopnea syndrome."Blood. 98. 1255-1257 (2001)
[Publications] Kwak, M.K. et al.: "Role of phase 2 enzyme induction in chemoprotection by dithiolethiones."Mutat Res.. 481. 305-315 (2001)
[Publications] Yoh, K. et al.: "Transgenic overexpression of MafK suppresses T cell proliferation and function in vivo."Genes Cells. 6. 1055-1066 (2001)
[Publications] Fujimoto, T. et al.: "Stepwise divergence of primitive and definitive hematopoietic and endothelial cell lineages."Genes Cells. 6. 1113-1127 (2001)
[Publications] Aoki, Y. et al.: "Accelerated DNA adducts formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust."Toxicol.Appl.Pharmacol. 173. 154-160 (2001)
[Publications] Cho, H.Y. et al.: "Linkage analysis of susceptibility to hyperoxic lung injury:role of Nrf2 as a candidate gene."Am.J.Res.Cell Mol.Biol.. (in press).
[Publications] Morimitsu, Y.: "A sulforaphane analogue that potentially activates the Nrf2-dependent detoxification pathway."J.Biol.Chem.. (in press).
[Publications] Kirito, K. et al.: "A functional role of Stat3 in in vivo megakaryopoiesis."Blood. (in press).
[Publications] Kusunoki, H. et al.: "Solution structure of the DNA-binding domain of MafG."Nature Str.Biol.. (in press).
[Publications] Kwak, M.K. et al.: "Regulation of the expression of Nrf2 transcription factor by cancer chemopreventive agents through antioxidant response element (ARE)-like sequences in its proximal promoter region."Mol.Cell.Biol.. (in press).
[Publications] Ueno, Y. et al.: "Elimination of Pasteurella pneumotropica from a Contaminated Mouse Colony by Oral Administration of Enrofloxacin."Exp.Animals. (in press).
[Publications] 山本雅之編: "「遺伝子の構造と機能」シリーズ・バイオサイエンスの新世紀,(日本生化学会編集)"共立出版. 178 (2001)
[Publications] 勝岡史城, 山本雅之: "新臨床医のための分子医学シリーズ/造血幹細胞研究のいまと臨床応用「遺伝子操作マウスを用いた血液疾患モデルの作製」"羊土社. (2001)
[Publications] 中島修, 山本雅之: "Annual Review 血液 2002 「X 染色体連鎖型鉄芽球性貧血モデルおよび鉄代謝異常関連遺伝子改変動物の分子生物学的解析」"中外医学社(印刷中).
[Publications] 鈴木教郎, 山本雅之: "造血幹細胞:基礎から遺伝子治療・再生医療へ「造血幹細胞の転写調節機構」"中外医学社(印刷中).

2001 Fiscal Year Annual Research Report

高次生命現象の基盤となるbZip型転写制御ネットワークの包括的解析

Principal Investigator

山本 雅之 筑波大学, 基礎医学系, 教授 (50166823)

Research Products

[Publications] Enomoto, A., et al.: "High sensitivity of Nrf2 knockout mice to acetoaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzyme and antioxidant genes."Toxicol.Sci. 59. 169-177 (2001)

[Publications] Tabata, M. et al.: "Stimulation of GATA-2 as a mechanism of hydrogen peroxide suppression in hypoxia-induced erythropoietin gene expression."J.Cell.Physiol.. 186. 260-267 (2001)

[Publications] Ramos-Gomez, M.: "Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice."Proc.Natl.Acad.Sci.USA. 98. 3410-3415 (2001)

[Publications] Kwak, M-K, et al.: "Role of Transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemopreventive agent, 3H-1, 2-dithiole-3-thione."Mol.Med.. 7. 135-145 (2001)

[Publications] Kanezaki, R, et al.: "Transcription factor BACH1 is recruited to nucleus by its novel alternative spliced isoform expressed in testis."J.Biol.Chem.. 276. 7278-7284 (2001)

[Publications] Kobayashi, M, et al.: "The homeobox protein Six3 interacts with the Groucho corepressor and acts as a transcriptional repressor in eye and forebrain formation."Dev.Biol.. 232. 315-326 (2001)

[Publications] Hosoya, T. et al.: "Defective development of secretary neurons in the hypothalamus of Arnt2-knockout mice."Genes Cells. 6. 361-374 (2001)

[Publications] Umetani, M.: "Function of GATA transcription factors in the induction of endothelial VCAM-1 by TNF-α."Arterioscler.Thromb.Vasc.Biol.. 21. 917-922 (2001)

[Publications] Kobayashi, M. et al.: "Positive regulation by GATA-1 of GATA-1 gene hematopoietic regulatory domain in zebrafish embryos in vivo."Development. 128. 2341-2350 (2001)

[Publications] Kim, Y-C. et al.: "Hemin-induced activation of the Thioredoxin gene by Nrf2:a differential regulation of the antioxidant responsive element(ARE)by switch of its binding factors."J.Biol.Chem.. 276. 18399-18406 (2001)

[Publications] Ogawa, K.: "Heme mediates de-repression of Maf recognition element through direct binding to transcription factor Bach1."EMBO J.. 20. 2835-2843 (2001)

[Publications] Yoh, K.: "Nrf2 deficient mouse:a novel model for lupus nephritis."Kidney Int.. 60. 1343-1353 (2001)

[Publications] Katoh, Y. et al.: "Two domains of Nrf2 cooperatively bind CBP(CREB binding protein) and synergistically activate transcription."Genes Cells. 6. 857-868 (2001)

[Publications] Shimizu, R. et al.: "In vivo requirements for functional GATA-1 domains during primitive and definitive erythropoiesis."EMBO J.. 20. 5250-5260 (2001)

[Publications] Sun, J. et al.: "The promoter of mouse transcription repressor bach1 is regulated by Sp1 and transactivated by Bach1."J.Biochem.. 130. 385-392 (2001)

[Publications] McMahon, M. et al.: "The Cap'n' Collar basic leucine zipper transcription factor Nrt2 controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes."Cancer Res.. 61. 3299-3307 (2001)

[Publications] Imagawa, S. et al.: "Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea-hypopnea syndrome."Blood. 98. 1255-1257 (2001)

[Publications] Kwak, M.K. et al.: "Role of phase 2 enzyme induction in chemoprotection by dithiolethiones."Mutat Res.. 481. 305-315 (2001)

[Publications] Yoh, K. et al.: "Transgenic overexpression of MafK suppresses T cell proliferation and function in vivo."Genes Cells. 6. 1055-1066 (2001)

[Publications] Fujimoto, T. et al.: "Stepwise divergence of primitive and definitive hematopoietic and endothelial cell lineages."Genes Cells. 6. 1113-1127 (2001)

[Publications] Aoki, Y. et al.: "Accelerated DNA adducts formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust."Toxicol.Appl.Pharmacol. 173. 154-160 (2001)

[Publications] Cho, H.Y. et al.: "Linkage analysis of susceptibility to hyperoxic lung injury:role of Nrf2 as a candidate gene."Am.J.Res.Cell Mol.Biol.. (in press).

[Publications] Morimitsu, Y.: "A sulforaphane analogue that potentially activates the Nrf2-dependent detoxification pathway."J.Biol.Chem.. (in press).

[Publications] Kirito, K. et al.: "A functional role of Stat3 in in vivo megakaryopoiesis."Blood. (in press).

[Publications] Kusunoki, H. et al.: "Solution structure of the DNA-binding domain of MafG."Nature Str.Biol.. (in press).

[Publications] Kwak, M.K. et al.: "Regulation of the expression of Nrf2 transcription factor by cancer chemopreventive agents through antioxidant response element (ARE)-like sequences in its proximal promoter region."Mol.Cell.Biol.. (in press).

[Publications] Ueno, Y. et al.: "Elimination of Pasteurella pneumotropica from a Contaminated Mouse Colony by Oral Administration of Enrofloxacin."Exp.Animals. (in press).

[Publications] 山本雅之 編: "「遺伝子の構造と機能」シリーズ・バイオサイエンスの新世紀,(日本生化学会編集)"共立出版. 178 (2001)

[Publications] 勝岡史城, 山本雅之: "新臨床医のための分子医学シリーズ/造血幹細胞研究のいまと臨床応用「遺伝子操作マウスを用いた血液疾患モデルの作製」"羊土社. (2001)

[Publications] 中島修, 山本雅之: "Annual Review 血液 2002 「X 染色体連鎖型鉄芽球性貧血モデルおよび鉄代謝異常関連遺伝子改変動物の分子生物学的解析」"中外医学社(印刷中).

[Publications] 鈴木教郎, 山本雅之: "造血幹細胞:基礎から遺伝子治療・再生医療へ「造血幹細胞の転写調節機構」"中外医学社(印刷中).

山本雅之筑波大学, 基礎医学系, 教授 (50166823)

[Publications] 山本雅之編: "「遺伝子の構造と機能」シリーズ・バイオサイエンスの新世紀,(日本生化学会編集)"共立出版. 178 (2001)