転写因子の発現量依存的な細胞運命決定機構の解明

• Project/Area Number: 18659082
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University (2007); University of Tsukuba (2006)
• Principal Investigator: 山本 雅之 Tohoku University, 大学院・医学系研究科, 教授 (50166823)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: 発生・分化 / 転写因子 / 遺伝子発現 / 血液学

Research Abstract

申請者らは,GATA-1と構造的に高い相同性を有する転写因子であるGATA-2が,GATA-1との機能的相補性を有することを鑑み,GATA-1とGATA-2の機能分担、ネットワーク制御、さらに、それらの合計発現量が血球細胞の運命決定に与える影響を解析する必要があると考える。そこで、これら両者の発現量を個体レベルで明らかにするために、申請書らが既に樹立した、Gata1遺伝子発現制御領域下で赤色蛍光蛋白質(dsRed2)を発現するトランスジェニックマウスとGata2遺伝子座に相同組換え法で緑色蛍光蛋白質(GFP)をノックインしたマウス、及びそれらを交配した複合改変マウスを用いて、以下の解析をおこなった。これらのマウスの造血細胞における蛍光蛋白質発現を、フローサイトメーター(FACS)を用いて定量的かつ定性的に測定し、FACSにより分取した後に、コロニー法などでin vitro分化誘導することにより、その分化能を調べた。また、GATA-1とGATA-2を共発現する細胞の同定と解析を行い、細胞の増殖・分化・アポトーシスにおける2つのGATA因子の発現量を単一細胞レベルで明らかにすることを試みた。さらに、既に樹立されているGata1およびGata2遺伝子の部分破壊マウスや条件付き遺伝子破壊マウス、及びそれらを交配した複合改変マウスをの血液細胞の解析を行い、2つの転写因子の発現量変化が細胞運命に与える影響を調べた。また、レトロウイルス遺伝子導入系を用いて、GATA-1とGATA-2を高中低の様々な発現量で未分化前駆細胞に導入することにより、細胞運命決定に与える影響を検討した。これらの結果、GATA-1、GATA-2の発現量がその機能に大きく影響することが示唆された。

Research Products

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• [Journal Article] Inchinkoto, an herbal medicine, and its ingredients dually exertMrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in ratlivers. (2007)
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• [Journal Article] Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. (2007)
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• [Journal Article] Does K-11706 enhance performance and why? (2007)
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• [Journal Article] Functional polymorphisms in the transcription factor NRF2 increase the risk of acute lung injury. (2007)
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• [Journal Article] Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t (8;21) (q24;q22) acute myeloid leukemia. (2007)
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• [Journal Article] Cell cycle-dependent oscillation of GATA2 expression in hematopoietic cells. (2007)
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• [Journal Article] Dynamic regulation of Gata factor levels is more important than their identity. (2007)
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• [Journal Article] Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. (2007)
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• [Journal Article] A Gata2 intronic enhancer confers its pan-endothelia-specific regulation. (2007)
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• [Journal Article] Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. (2007)
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• [Journal Article] GATA-1 self-association controls erythroid development in vivo. (2007)
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• [Journal Article] Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants. (2007)
  • Author(s): Reddy NM, Kleeberger SR, Cho H-Y, Yamamoto M, Kensler TW, Biswal S, and Reddy SP.
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• [Journal Article] Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. (2007)
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  • Journal Title: Neuroscience. 147 Pages: 53-59
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• [Journal Article] Enhanced spontaneous and benzo [α] pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice. (2007)
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• [Journal Article] Oxidative and electrophilic stress induces Mrp transporters via the Nrf2 transcriptional pathway. (2007)
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  • Journal Title: Hepatology. 46 Pages: 1597-1610
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• [Journal Article] Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. (2007)
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  • Journal Title: Free Rad Biol Med. 43 Pages: 408-414
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• [Journal Article] Nrf2 and p53 cooperatively protect agahlst BBN-induced urinary bladder carcinogensis. (2007)
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• [Journal Article] NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. (2007)
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• [Journal Article] Different Electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. (2007)
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• [Journal Article] Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. (2007)
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• [Journal Article] Subcellul localization and cytoplasmic complex status of endogenous Keapl. (2007)
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• [Journal Article] In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-lc expression. (2007)
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• [Journal Article] Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity. (2007)
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• [Journal Article] Potential involvement of pathophysiologically formed 8-nitroguanosine 3',5'-cyclic monophosphate in nitric oxide-induced signal transduction. (2007)
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• [Journal Article] The N-terminal homology box 1(NHB1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its Asn-glycosylation. (2007)
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• [Journal Article] The TR2 and TR4 orphan nuclear receptors repress Gatal transcription. (2007)
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  • Journal Title: Genes Dev. 21 Pages: 2832-2844
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• [Journal Article] Loss of p62/SQSTM1 suppresses cytoplasmic inclusion body formation and liver injury in autophagy-deficient mouse. K (2007)
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• [Journal Article] Molecular basis distinguishing the DNA binding profile of NRF2-MAF heterodimer from that of MAF homodimer. (2007)
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• [Journal Article] A novel class of proly1 hydroxylase inhibitors induces angiogenesis and exerts or gan protection against ischemia. (2007)
  • Author(s): Nangaku M, Izuhara Y, Takizawa S, Yamashita T, Fujii-Kuriyama Y, Ohneda O, Yamamoto M, van Ypersele de Strihou C, Hirayama N, and Miyata T.
  • Journal Title: Arterioscler Thromb Vas Biol. 27 Pages: 2548-2554
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• [Journal Article] Molecular mechanism of transcriptional repression of AhR repressor in volving ANKRA2, HDAC4, and HDAC5. (2007)
  • Author(s): Oshima M, Mimura J, Yamamoto M, and Fujii-Kuriyama Y.
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• [Journal Article] Regulation of adipocyte differentiation of bone marrow stromal cells by transcription factor GATA-2. (2007)
  • Author(s): Okitsu Y, Takahashi S, Minegishi N, Kameoka J, Kaku M, Yamamoto M, Sasaki T, and Harigae H
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• [Journal Article] Dysfunction of Nrf2 decreases KBrO_3-induced oxidative DNA damage in Oggl-null mice. (2007)
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• [Journal Article] Carcinogenesis and transcriptional regulation through Maf recognition elements. (2007)
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• [Journal Article] Regulation of GATAI gene expression. (2007)
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• [Journal Article] Use of gene manipulated mice in the study of erythropoietin gene expression. (2007)
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• [Journal Article] 酸素センシングと赤血球造血シグナル (2007)
  • Author(s): 今川重彦、小原 直、鈴木教郎、山本雅之
  • Journal Title: 細胞 39 Pages: 537-540
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• [Journal Article] GATA因子スイッチングとGATA-1白血病 (2007)
  • Author(s): 清水律子、山本雅之
  • Journal Title: 生化学 79 Pages: 941-952
  • Peer Reviewed
• [Journal Article] 酸化ストレス防御のための生体内センサー:Keap1-Nrf2制御システム (2007)
  • Author(s): 田口恵子、山本雅之
  • Journal Title: 化学と生物 45 Pages: 857-862
  • NAID: 10019973647
  • Peer Reviewed
• [Journal Article] 食物と酸素由来の環境ストレスを感知するセンサー系 (2007)
  • Author(s): 大辻摩希子、山本雅之
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• [Presentation] The environmental response to food and oxygen. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: JST-ERATO Environmental Response Project International Symposium on "The Environmental Response".
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  • Year and Date: 2007-12-21
• [Presentation] Molecular Mechanisms of Adaptive Responses to Food and Oxygen. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: The International Conference on Food Factors for Health Promotion(ICOFF2007)
  • Place of Presentation: Kyoto
  • Year and Date: 2007-11-29
• [Presentation] 酸化ストレス応答の分子基盤と疾患 (2007)
  • Author(s): 山本雅之
  • Organizer: CKDと心血管イベントExpert Meeting特別講演
  • Place of Presentation: 東京會舘
  • Year and Date: 2007-11-27
• [Presentation] 親電子性物質・酸化ストレス応答の分子機構 (2007)
  • Author(s): 山本雅之
  • Organizer: 第7回システム生物医学研究会
  • Place of Presentation: 東京大学先端科学技術研究センターシステム生物医学ラボラトリー主催、箱根湯本
  • Year and Date: 2007-11-21
• [Presentation] 親電子性物質・活性酸素応答の分子メカニズム (2007)
  • Author(s): 山本 雅之
  • Organizer: 東海医学会講演会
  • Place of Presentation: 東海大学
  • Year and Date: 2007-11-13
• [Presentation] The Nrf2-Keapl Stress Response System. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: The 23rd Kumamoto Medical Bioscience Symposium on New Insights into Metabolic Disorders and Vascular Disease.
  • Place of Presentation: Kumamoto
  • Year and Date: 2007-11-12
• [Presentation] GATA因子と白血病 (2007)
  • Author(s): 山本雅之
  • Organizer: 第2回つくば医科学研究交流会 ランチョンセミナー
  • Place of Presentation: 三菱化学つくばクリエーションセンター
  • Year and Date: 2007-11-10
• [Presentation] Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: Distinguished Professor's Seminar.
  • Place of Presentation: University of Arizone, Tucson, USA
  • Year and Date: 2007-11-02
• [Presentation] Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: Adjunct Professor Lecture at Johns Hopkins University Blumberg School of Public Health, Baltimore
  • Place of Presentation: Johns Hopkins University Blumberg School of Public Health, Baltimore, USA
  • Year and Date: 2007-10-31
• [Presentation] Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. (2007)
  • Author(s): Masavuki Yamamoto.
  • Organizer: NIEHS Seminar.
  • Place of Presentation: Research Triangle Park (RTP), USA
  • Year and Date: 2007-10-30
• [Presentation] Two-site substrate recognition model for the Keapl-Nrf2 system: a hinge and latch mechanism. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: National University of Singapore - Tohoku University/Centre of Excellence Joint Symposium "Basic and Clinical Research on Signal Transduction Diseases".
  • Place of Presentation: Centre for Life Sciences, National University of Singapore, Singapore, Singapore
  • Year and Date: 2007-09-05
• [Presentation] 親電子性物質・活性酸素応答の分子メカニズム (2007)
  • Author(s): 山本雅之
  • Organizer: 臨床研セミナー
  • Place of Presentation: (財)東京都医学研究機構 東京都臨床医学総合研究所
  • Year and Date: 2007-08-10
• [Presentation] Two-site substrate recognition model for the Keapl-Nrt2 system:a hinge and latch mechanism (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: The 3rd DECODE for Biological Responses Intemational Meeting.
  • Place of Presentation: Odaiba, Tokyo
  • Year and Date: 2007-08-04
• [Presentation] 親電子性物質・活性酸素応答の分子メカニズム (2007)
  • Author(s): 山本雅之
  • Organizer: 第5回フリーラジカルと脳疾患 東日本研究会特別講演
  • Place of Presentation: 経団連会館、大手町
  • Year and Date: 2007-07-28
• [Presentation] 環境応答の分子機構 (2007)
  • Author(s): 山本雅之
  • Organizer: 第5回RCGMフロンティアシンポジウム「ゲノム医学一基礎から未来医療へ」
  • Place of Presentation: 埼玉医科大学日高キャンパス創立30周年記念講堂、日高市
  • Year and Date: 2007-07-27
• [Presentation] GATA転写因子群の機能異常と白血病 (2007)
  • Author(s): 山本雅之
  • Organizer: 第17回 日本産婦人科・新生児血液学会シンポジウム「ダウン症候群と一過性骨髄造血(TAM)」
  • Place of Presentation: 富山国際会議場
  • Year and Date: 2007-06-30
• [Presentation] 細胞の癌化とその抑制における転写因子の役割 (2007)
  • Author(s): 山本雅之
  • Organizer: 文部科学省がん特定領域研究「遺伝情報システム異常と発がん」
  • Place of Presentation: 癌研究会吉田富三記念講堂、有明
  • Year and Date: 2007-06-30
• [Presentation] 親電子性物質・酸化ストレス応答の分子メカニズム (2007)
  • Author(s): 山本雅之
  • Organizer: 循環器内科リサーチセミナー
  • Place of Presentation: 東北大学
  • Year and Date: 2007-05-30
• [Presentation] 親電子性物質・活性酸素応答の分子メカニズム (2007)
  • Author(s): 山本雅之
  • Organizer: 日本生化学会東北支会シンポジウム
  • Place of Presentation: 艮陵会館、仙台
  • Year and Date: 2007-05-12
• [Presentation] 酸化ストレス応答と呼吸器疾患 (2007)
  • Author(s): 山本雅之
  • Organizer: 第47回日本呼吸器学会学術講演会
  • Place of Presentation: 東京フォーラム
  • Year and Date: 2007-05-11
• [Presentation] GATA転写因子群の機能異常と白血病 (2007)
  • Author(s): 山本雅之
  • Organizer: 第50回 東北小児白血病研究会
  • Place of Presentation: かんぽヘルスプラザ仙台
  • Year and Date: 2007-04-28
• [Presentation] Functional analyses of GATA-2 with knockdown and conditional knockout mice. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: EMBO WORKSHOP ON The Role and Control of GATA Factors in Tissue Development and Disease.
  • Place of Presentation: Capri, Italy
• [Presentation] Genetic Analysis of Mouse GATA-related Leukemia and Leukemic Stem Cells. (2007)
  • Author(s): Masayuki Yamamoto.
  • Organizer: Gordon Research Conference on Red Cells, Centre Paul Langevin in Aussois.
  • Place of Presentation: Aussois, France