The missing link between proliferation and oxidative stress regulation in hematopoietic stem cells

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591216
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Miyagi University (2010-2011); Sendai University (2009)
• Principal Investigator: MINEGISHI Naoko 宮城大学, 看護学部, 教授 (40271895)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Takahumi 東北大学, 医学系研究科, 助教 (70508308)
• Project Period (FY): 2009 – 2011
• Keywords: 転写因子

Research Abstract

Long-term dormancy in proliferation and strong defense response against oxidative stresses, prevent the senescence and tumorigenesis of hematopoietic stem cells. Here, we show that GATA2, a transcription factor essential for the life-long maintenance of hematopoietic stem cells, directly activates the transcription of several genes regulating cell proliferation, as well as genes regulating oxidative status. Furthermore, mice deficient in transcription factor Nrf2, which inclusively regulates oxidative stress response genes, show the different kinetics of hematopoietic stem/progenitor cells from wild type mice. These results indicate that cell proliferation and defense against oxidative stresses have shared regulatory components in hematopoietic stem cells.

Research Products

• [Journal Article] Specific contribution of the erythropoietin gene 3' enhancer to hepatic erythropoiesis after late embryonic stages (2011)
  • Author(s): Suzuki N, Obara N, Pan X, Watanabe M, Jishage K, Minegishi N, Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 31 Pages: 3896-3905
  • DOI: DOI:10.1128/mcb.05463-11
  • Peer Reviewed
• [Journal Article] Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice (2011)
  • Author(s): Pan X, Suzuki N, Hirano I, Yamazaki S, Minegishi N, Yamamoto M.
  • Journal Title: PLoS ONE Volume: 6 Pages: 25839
  • DOI: DOI:10.1371/journal.pone.0025839
  • Peer Reviewed
• [Journal Article] Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice (2011)
  • Author(s): Asada N, Takase M, Nakamura J, Oguchi A, Asada A, Suzuki N, Yamamura K, Nagoshi N, Shibata S, Rao TN, Fehling HJ, Fukatsu A, Minegishi N, Kita T, KimuraT, Okano H, Yamamoto M, Yanagita M.
  • Journal Title: J Clin Invest Volume: 121 Pages: 3981-3990
  • DOI: DOI:10.1172/JCI57301
  • Peer Reviewed
• [Journal Article] Select Heterozygous Keap1 Mutations Have a Dominant-Negative Effect on Wild-Type Keap1 In Vivo (2011)
  • Author(s): Suzuki T, Maher J, Yamamoto M.
  • Journal Title: Cancer Res Volume: 71 Pages: 1700-1709
  • DOI: DOI:10.1158/0008-5472.Can-10-2939
  • Peer Reviewed
• [Journal Article] Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia (2011)
  • Author(s): Kawatani Y, Suzuki T, Shimizu R, Kelly VP, Yamamoto M.
  • Journal Title: Blood Volume: 117 Pages: 986-996
  • DOI: DOI:10.1182/blood-2010-05-285817
  • Peer Reviewed
• [Journal Article] Inducible disruption of autophagy in the lung causes airway hyper-responsivenes (2011)
  • Author(s): Inoue D, Kubo H, Taguchi K, Suzuki T, Komatsu M, Motohashi H, Yamamoto M.
  • Journal Title: Biochem Biophysi Res Commun Volume: 405 Pages: 13-18
  • DOI: DOI:10.1016/j.bbrc.2010.12.092
  • Peer Reviewed
• [Journal Article] Fractionation of mature eosinophils in GATA-reporter transgenic mice (2010)
  • Author(s): Kim K, Suzuki N, Ohneda K, Minegishi N, Yamamoto M.
  • Journal Title: Tohoku J Exp Med Volume: 220 Pages: 127-138
  • DOI: DOI:10.1620/tjem.220.127
  • Peer Reviewed
• [Journal Article] Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway (2010)
  • Author(s): Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S.
  • Journal Title: Cancer Res Volume: 70 Pages: 9095-9105
  • DOI: DOI:10.1158/0008-5472.CAN-10-0384
  • Peer Reviewed
• [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 J, Suzuki T, Winnard PT, Raman V, Ebina M, Nukiwa T, Yamamoto M.
  • Journal Title: Carcinogenesis Volume: 31 Pages: 1833-1843
  • DOI: DOI:10.1093/carcin/bgq105
  • Peer Reviewed
• [Journal Article] Genetic analysis of cytoprotective functions supported by graded expression of Keap1 (2010)
  • Author(s): Taguchi K, Maher J, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 30 Pages: 3016-3026
  • DOI: DOI:10.1128/MCB.01591-09
  • Peer Reviewed
• [Journal Article] エリスロポエチン産生細胞 (2010)
  • Author(s): 峯岸直子, 山本雅之
  • Journal Title: 第72回日本血液学会学術集会教育口演要旨集 Volume: 51 Pages: 1607-1615
• [Journal Article] The analysis of the functions of human B and T cells in humanized NOD/shi-scid/γc^<null>(NOG) mice(hu-HSC NOG mice) (2009)
  • Author(s): Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N, Katano I, Ito R, Ito M, Minegishi M, Minegishi N, Tsuchiya S, Sugamura K.
  • Journal Title: Int Immunol Volume: 21 Pages: 843-858
  • DOI: DOI:10.1093/intimm/dxp050
  • Peer Reviewed
• [Presentation] GATA factors in tissue-specific erythropoietin gene regulation (2010)
  • Author(s): Minegishi N, Suzuki, N, Obara N, Pan X, Hirano I, Yamazaki S, Yamamoto M.
  • Organizer: 5th International Symposium on GATA factors
  • Place of Presentation: Sendai
  • Year and Date: 20100000
• [Presentation] Isolation and characterization of renal erythropoietin-producing cells : Contribution of HIF3α in vivo (2010)
  • Author(s): Pan X, Suzuki N, Hirano I, Yamazaki S, Yamashita T, Ohneda O, Minegishi N, Yamamoto M.
  • Organizer: 5th International Symposium on GATA factors
  • Place of Presentation: Sendai
  • Year and Date: 20100000
• [Presentation] Erythropoietin from neural and neural crest cells support primitive erythropoiesis (2010)
  • Author(s): Hirano I, Suzuki N, Pan X, Minegishi N, Yamamoto M.
  • Organizer: 5th International Symposium on GATA factors
  • Place of Presentation: Sendai
  • Year and Date: 20100000
• [Presentation] G1 Cyclin genes are direct target of GATA2 (2010)
  • Author(s): Minegishi N, Suzuki N, Suzuki M, Harigae H, Yamamoto M.
  • Organizer: 5th International Symposium on GATA factors
  • Place of Presentation: Sendai
  • Year and Date: 20100000
• [Presentation] Isolation and characterization of renal erythropoietin-producing cells : Contribution of HIF3 in vivo (2010)
  • Author(s): Pan X, Suzuki N, Hirano I, Yamazaki S, Obara N, Minegishi N, Yamamoto M.
  • Organizer: 52th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando
  • Year and Date: 20100000
• [Presentation] Deletion of selenocysteine tRNA gene results in compensatory gene induction of cytoprotective enzymes by Nrf2 (2010)
  • Author(s): Suzuki T, Kawatani Y, Ohkoshi A, Kelly V, Yamamoto M.
  • Organizer: 9^<th> International Sympoosium on Selenium in Biology and Medicine
  • Place of Presentation: Kyoto
  • Year and Date: 20100000
• [Presentation] Compound Deficiency of Nrf2 and Selenoproteins in hematopoietic cells leads to severe defects in erythroid and lymphoid lineage development (2010)
  • Author(s): Kawatani Y, Suzuki T, Shimizu R, Kelly V, Yamamoto M.
  • Organizer: 9^<th> International Sympoosium on Selenium in Biology and Medicine, Selenium 2010
  • Place of Presentation: Kyoto
  • Year and Date: 20100000
• [Presentation] Cytoprotective systems of skin by selenoproteins and Nrf2 (2010)
  • Author(s): Takayama M, Suzuki T, Takaya K, Okuyama R, Yamamoto M.
  • Organizer: 9^<th> International Sympoosium on Selenium in Biology and Medicine
  • Place of Presentation: Kyoto
  • Year and Date: 20100000
• [Presentation] 成獣における誘導的エリスロポエチン遺伝子破壊の造血に与える影響 (2010)
  • Author(s): 山奇瞬, 峯岸直子, 鈴木教郎, 小原直, 潘小青, 平野育生, 寺社下浩一, 本田紅里穂, 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合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20100000
• [Presentation] 単離腎臓Erythropoietin産生細胞を用いたErythropoietin遺伝子制御機構の解明 (2010)
  • Author(s): 平野育生, 潘小青, 鈴木教郎, 山奇瞬, 小原直, 峯岸直子, 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合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20100000
• [Presentation] 転写因子GATA2によるG1サイクリン遺伝子発現の制御 (2010)
  • Author(s): 峯岸直子, 鈴木教郎, 鈴木未来子, 張替秀郎, 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合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20100000
• [Presentation] エリスロポエチン欠損マウスの部分レスキューによる遺伝性超貧血マウスの樹立 (2010)
  • Author(s): 山奇瞬, 峯岸直子, 鈴木教郎, 山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20100000
• [Presentation] 胎仔期神経細胞,神経堤細胞によるエリスロポエチン産生 (2010)
  • Author(s): 平野育生, 鈴木教郎, 潘小青, 山奇瞬, 峯岸直子, 山本雅之
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20100000
• [Presentation] 慢性腎臓病における線維化と腎性貧血を担う細胞の同定およびその制御法の開発 (2010)
  • Author(s): 高瀬昌幸, 浅田礼光, 中村仁, 小口綾貴子, 浅田三咲子, 鈴木教郎, 山村研一, 名越慈人, 芝田晋介, Tata Rao Nageswara, Hans Fehling Joerg, 深津敦司, 峯岸直子, 北徹, 木村剛, 岡野栄之, 山本雅之, 柳田素子
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20100000
• [Presentation] Rescue of erythropoietin-deficient mice from anemia by complementation with BAC transgene (2009)
  • Author(s): Yamazaki, S, Suzuki N, Obara N, Pan X, Hirano I, Jishage K, Honda C, Minegishi N, Yamamoto, M.
  • Organizer: 51th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: New Orleans
  • Year and Date: 20090000
• [Presentation] Compound deficiency of Nrf2 and selenoproteins in hematopoietic cells leads to severe defects in erythroid and lymphoid development (2009)
  • Author(s): Kawatani Y, Suzuki T, Shimizu R, Kelly V, Yamamoto M.
  • Organizer: 51th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: New Orleans
  • Year and Date: 20090000
• [Presentation] Select heterogenous Keap1 mutations have a dominant-negative effect on wild type Keap1 in vivo (2009)
  • Author(s): Suzuki T, Maher J, Kawatani Y, Yamamoto M.
  • Organizer: JST International Symposium on Molecular Mechanism of Environmental Response to Food and Oxyge III
  • Place of Presentation: Sendai
  • Year and Date: 20090000
• [Presentation] Deletion of selenocysteine tRNA gene results in compensatory gene induction of cytopeotective enzymes by Nrf2 (2009)
  • Author(s): Kawatani Y, Suzuki T, Kelly V, Yamamoto M.
  • Organizer: JST International Symposium on Molecular Mechanism of Environmental Response to Food and Oxygeniii
  • Place of Presentation: Sendai
  • Year and Date: 20090000
• [Presentation] Select heterogenous Keap1 mutations have a dominant-negative effect on wild type Keap1 in vivo. (2009)
  • Author(s): Suzuki T, Maher J, Kawatani Y, Yamamoto M.
  • Organizer: International Symposium 2009 on Signaling Function of Reactive Oxygen Species
  • Place of Presentation: Aso
  • Year and Date: 20090000
• [Presentation] 含セレン蛋白質とNrf2による2段階生体防御機構 (2009)
  • Author(s): 鈴木隆史, 川谷幸恵, Vincent Kelly, 山本雅之
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 20090000
• [Presentation] 遺伝子欠失マウスのレスキューと条件付きEpo遺伝子破壊マウスの樹立 (2009)
  • Author(s): 山奇瞬, 鈴木教郎, 小原直, 潘小青, 平野育生, 峯岸直子, 山本雅之
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 20090000
• [Presentation] 転写因子GATA2によるG1サイクリン遺伝子発現の制御 (2009)
  • Author(s): 峯岸直子, 張替秀郎, 山本雅之
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 20090000
• [Patent(Industrial Property Rights)] Epo欠損GFPtg貧血マウス (2011)
  • Inventor(s): 山本雅之,峯岸直子,山嵜瞬
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Industrial Property Number: 特許願、特願2011-83664
  • Filing Date: 2011-04-05
  • Overseas