転写因子Nrf1の神経細胞恒常性維持機構の解明

• Project/Area Number: 22659056
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: 山本 雅之 東北大学, 大学院・医学系研究科, 教授 (50166823)
• Co-Investigator(Kenkyū-buntansha): 勝岡 史城 東北大学, 大学院・医学系研究科, 准教授 (30447255)
• Project Period (FY): 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥2,900,000 (Direct Cost: ¥2,900,000); Fiscal Year 2010: ¥2,900,000 (Direct Cost: ¥2,900,000)
• Keywords: Nrf1 / 転写制御機構 / 神経変性疾患

Research Abstract

アルツハイマー病、パーキンソン氏病などに代表される神経変性疾患は、高齢化社会において、生活の質を脅かす疾患の一つである。そかし、その病態の発症・進行の機構は不明な点が多い。bZIP型転写因子のNrf1の欠失マウスは、異常タンパク質の蓄積を伴ったヒトの進行性神経変性疾患に極めて類似した症状を示す。本計画では、Nrf1欠失マウスの解析を通して、その破綻・異常タンパク質の蓄積に至る分子機構を理解することで、ヒトの神経変性疾患に対する新たな知見を得ることを目的とする。
Nrf1欠失マウス由来の神経初代培養細胞を用いたマイクロアレイ解析を実施した。その結果、Nrf1の欠失で発現に影響を受ける遺伝子は、これまでに報告されてきたNrf2が制御する生体防御関連の標的遺伝子とは異なる事が示された。また、Nrf1欠失マウス脳組織においての遺伝子発現解析を実施し、同様の結果を得ている。したがって、Nrf1は、Nrf2とは異なる標的遺伝子の発現制御を介して、神経細胞の恒常性の維持に寄与していると考えられた。Nrf1が直接制御する標的遺伝子の同定を試みるために、Nrf1のクロマチン免疫沈降解析(ChIP)を計画した。ChIP解析に用いる抗体の検討を行ったが特異性の高い抗体は得られなかったので、申請計画に記したように、Nrf1のパートナー因子である小Maf群因子に対する抗体を用いて、ChIPシークエンス解析を実施した。その結果、小Mafの結合部位は、Ataxin-1などの神経変性と関連した遺伝子の制御領域に結合していることが明らかなり、病態発症との関連が示唆された。上記の結果の一部は、学会発表として報告し、また、誌上発表の予定である。

Research Products

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• [Journal Article] Differential Modulation of Keratin Expression by Sulforaphane Occurs via Nrf2-dependent and -independent Pathways in Skin Epithelia. (2011)
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• [Journal Article] Possible Involvement of Oxidative Stress in 5-Fluorouracil-Mediated Myelosuppression in Mice. (2011)
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• [Journal Article] Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keapl-Nrf2 system : study using GFP transgenic zebrafish. (2011)
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• [Journal Article] Nrf2 degron-fused reporter system ; a new tool for specific evaluation of Nrf2 inducers. (2011)
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• [Journal Article] Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction. (2011)
  • Author(s): Akira Kobayashi, Takako Tsukide, Tomohiro Miyasaka, Tomoko Morita, Tatsuya Mizoroki, Yoshiro Saito, Yasuo Ihara, Akihiko Takashima, Noriko Noguchi, Akiyoshi Fukamizu, Yosuke Hirotsu, Makiko Ohtsuji, Fumiki Katsuoka, Masayuki Yamamoto.
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• [Journal Article] Molecular mechanisms of the Keapl-Nrf2 pathway in stress response and cancer evolution. (2011)
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  • Journal Title: Genes Cells Volume: 16 Pages: 123-140
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• [Journal Article] Discovery of the negative regulator of Nrf2, Keapl: A historical overview. (2011)
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• [Journal Article] Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. (2010)
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• [Journal Article] Regulation of Notchl signaling by Nrf2 : Implications for tissue regeneration. (2010)
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• [Journal Article] Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene. (2010)
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  • Journal Title: BMC Cancer Volume: 10 Pages: 540-556
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• [Journal Article] Nrf2 is closely related to allergic airway inflammatory responses induced bylow-dose diesel exhaust particles in mice. (2010)
  • Author(s): Li YJ, Takizawa H, Azuma A, Kohyama T, Yamauchi Y, Takahashi S, Yamamoto M, Kawada T, Kudoh S, Sugawara I.
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• [Journal Article] Suppression of SLCIIA2 Expression is essential to maintain duodenal integrity during dietary iron overload. (2010)
  • Author(s): Shirase T, Mori K, Okazaki Y, Itoh K, Yamamoto M, Tabuchi M, Kishi F, Jiang L, Akatsuka S, Nakao K, Toyokuni S.
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• [Journal Article] Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. (2010)
  • Author(s): Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT Jr, Raman V, Ebina M, Nukiwa T, Yamamoto M.
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• [Journal Article] The critical role of nitric oxide signaling, via protein S-guanylation and nitratedcyclic GMP,in the antioxidant adaptive response. (2010)
  • Author(s): Fujii S, Sawa T, Ihara H, Tong KI, Ida T, Okamoto T, Ahtesham AK, Ishima Y, Motohashi H, Yamamoto M, Akaike T.
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• [Journal Article] The anemia of the newborn induces erythropoietin expression in the developing mouse retina. (2010)
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• [Journal Article] Ischemia-Induced Neovascularization by Enhancing the Inflammatory Response. (2010)
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• [Journal Article] The flavanol(-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. (2010)
  • Author(s): Shah ZA, Li RC, Ahmad AS, Kensler TW, Yamamoto M, Biswal S, Dore S.
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• [Journal Article] Genetic analysis of cytoprotective functions supported by graded expression of Keapl. (2010)
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• [Journal Article] Cytochrome P450 2A5 constitutive expression and induction by heavy metalsH, is dependent on redox-sensitive transcription factor Nrf2 in liver. (2010)
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• [Journal Article] Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defense and lipid metabolism as primary Nrf2-dependent pathways in the liver. (2010)
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• [Journal Article] Genetic analysis of hierarchical regulation for Gatal and NF-E2 p45 gene expression in megakaryopoiesis. (2010)
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• [Journal Article] Increased susceptibility of Nrf2 null mice to 1-bromopropane-induced hepatotoxicity. (2010)
  • Author(s): Liu F, Ichihara S, Valentine WM, Itch K, Yamamoto M, Mohideen SS, Kitoh J, Ichihara G.
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• [Journal Article] Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy. (2010)
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• [Journal Article] Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance. (2010)
  • Author(s): Kikuchi N, Ishii Y, Morishima Y, Yageta Y, Haraguchi N, Itch K, Yamamoto M, Hizawa N.
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  • NAID: 120007138178
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• [Journal Article] The transcriptome of Nrf2^-/- Mice provides evidence for impaired cell cycle progression in the development of cigarette-smoke-induced emphysematous changes. (2010)
  • Author(s): Gebel S, Diehl S, Pype J, Friedrichs B, Weiler H, Schuller J, Xu H, Taguchi K, Yamamoto M, Muller T.
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• [Journal Article] Select heterozygous Keapl mutations have a dominant-negative effect on wild-type Keapl in vivo. (2010)
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• [Journal Article] The rise of antioxidant signaling-the evolution and hormetic actions of Nrf2. (2010)
  • Author(s): Maher J, Yamamoto M.
  • Journal Title: Antioxidant Redox Biol Volume: 244 Pages: 4-15
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• [Presentation] Embryonic lethality and fetal liver hypoplasia in mice lacking all three small Maf proteins. (2011)
  • Author(s): Fumiki Katsuoka, Hiromi Yamazaki, Hozumi Motohashi, James Douglas Engel, Masayuki Yamamoto.
  • Organizer: 9th Japanese Biochemical Society(JBS)Bio-Frontier Symposium2010/5th International Symposium on GATA factors.
  • Place of Presentation: 仙台
  • Year and Date: 2011-11-17
• [Presentation] Functional Roles of NF-E2 p45 in the Regulation of Platelet Activity. (2011)
  • Author(s): Rie Fujita, Mariko Takayama-Tsujimoto, Hozumi Motohashi, Masayuki Yamamoto.
  • Organizer: 9th Japanese Biochemical Society Bio-Frontier Symposium2010/5th International Symposium on GATA factors.
  • Place of Presentation: 仙台
  • Year and Date: 2011-11-17
• [Presentation] Analysis of the Role of Nrf2-Keapl System in Hematopoietic Stem Cell. (2011)
  • Author(s): Shohei Murakami, Hozumi Motohashi, Masayuki Yamamoto.
  • Organizer: 9th Japanese Biochemical Society Bio-Frontier Symposium2010/5th International Symposium on GATA factors.
  • Place of Presentation: 仙台
  • Year and Date: 2011-11-17
• [Presentation] Stress response of megakaryocytes alters inherent reactivity of platelets. (2010)
  • Author(s): Hozumi Motohashi, Rie Fujita, Hironori Satoh, Hiroyuki Aburatani, Masayuki Yamamoto.
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] ニトロ化環状ヌクレオチドによるタンパク質S-グアニル化を介する酸化ストレス適応応答の分子機序 (2010)
  • Author(s): 藤井重元、澤智裕、居原秀、Kit ITong、井田智章、岡本竜哉、Ahmed Khandaker Ahtesham、本橋ほづみ、山本雅之、赤池孝章
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Regulation of platelet reactivity by transcription factor NF-E2 p45 in megakaryocytes (2010)
  • Author(s): 藤田理恵、高山昌理子、本橋ほづみ、山本雅之
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Cytoplasmic and nuclear degradation mechanisms regulate biological function of the transcription factor Nrf1 (2010)
  • Author(s): 森田智子, 土谷佳樹, 金美姫, 家村俊一郎, 突出貴子, 夏目徹, 山本雅之, 小林聡
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] 転写因子Nrf1とNrf2の中枢神経系における機能的差異の検証 (2010)
  • Author(s): 弘津陽介, 勝岡史城, 小林聡, 山本雅之
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] 生体のストレス応答の分子基盤 (2010)
  • Author(s): 山本雅之
  • Organizer: 日本抗加齢医学会研修便新用講習会
  • Place of Presentation: 東京
  • Year and Date: 2010-12-05
• [Presentation] 酸素と医学 (2010)
  • Author(s): 山本雅之
  • Organizer: 創生応用医学研究会
  • Place of Presentation: 仙台
  • Year and Date: 2010-11-27
• [Presentation] エリスロポエチン産生細胞(Erythropoietin Producing Cells) (2010)
  • Author(s): 山本雅之
  • Organizer: 第74回日本皮膚科学会学術大会
  • Place of Presentation: 仙台
  • Year and Date: 2010-11-21
• [Presentation] 発癌性物質や酸化ストレスに応答する生体防御系センサーの構造基盤 (2010)
  • Author(s): 黒河博文、本橋ほづみ、佐藤主税、山本雅之
  • Organizer: ターゲットタンパク研究プログラム平成22年度成果発表会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-20
• [Presentation] Molecular basis of CNC and small Mafdimer function in neural tissues. (2010)
  • Author(s): Fumiki Katsuoka.
  • Organizer: Jomada Cientifica-Regulatory mechanisms in inflammatory processes.
  • Place of Presentation: スペイン、バレンシア
  • Year and Date: 2010-10-15
• [Presentation] 酸化ストレス応答の分子基盤 (2010)
  • Author(s): 山本雅之
  • Organizer: 日本分子脳神経外科学会ランチョンセミナー
  • Place of Presentation: 仙台
  • Year and Date: 2010-09-22
• [Presentation] 宿主におけるNrf2欠損はMDSCs細胞に著明な酸化ストレスの蓄積を誘導し、肺癌転移に対して有利な微小環境を創造する (2010)
  • Author(s): 佐藤大希、森口尚、田口恵子、海老名雅仁、貫和敏博、山本雅之
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 転写因子Nrf2はヒト肺線癌細胞株A549でosteopontinの発現を増加させる (2010)
  • Author(s): 光石陽一郎、本橋ほづみ、貫和敏博、山本雅之
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 環境応答の分子基盤 (2010)
  • Author(s): 山本雅之
  • Organizer: 平成22年度ターゲットタンパクプロジェクト産学懇談会
  • Place of Presentation: 東京
  • Year and Date: 2010-07-07
• [Presentation] Nrf2-Keapl System and Respiratory Diseases. (2010)
  • Author(s): Masayuki Yamamoto.
  • Organizer: The 6th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide.
  • Place of Presentation: 京都
  • Year and Date: 2010-06-14
• [Presentation] 環境応答の分子基盤 (2010)
  • Author(s): 山本雅之
  • Organizer: 分子生物学会第10回春季シンポジウム
  • Place of Presentation: 松島
  • Year and Date: 2010-06-08
• [Presentation] Keapl-Nrf2 system and cancer. (2010)
  • Author(s): Masayuki Yamamoto
  • Organizer: Tuesday Special Seminar, Cancer Research Institute of seonl National University
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2010-06-01
• [Book] Diabetes Frontier (2010)
  • Author(s): 宇留野晃、森口尚、山本雅之
  • Publisher: メディカルレビュー社