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Gene manipulation of hypoxia inducible gene regulation

Research Project

Project/Area Number 16590923
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionUniversity of Tsukuba

Principal Investigator

IMAGAWA Shigehiko  University of Tsukuba, GSCHS, Professor, 大学院・人間総合科学研究科, 教授 (60231164)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO Masayuki  University of Tsukuba, GSCHS, Professor, 大学院・人間総合科学研究科, 教授 (50166823)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordserythropoietin / HIF / GATA / VEGF / transcription factor / gene expression / promoter / enhancer / エリスロポエチン / 低酸素 / 酸素センサー / hypoxia inducible factor-1 / K-11706 / erythropoietin / vascular endothelial growth factor / 2-oxoglutarate / 血管形成
Research Abstract

Erythropoietin (Epo) gene expression is negatively regulated by GATA, which binds to the GATA site in the Epo promoter, and also positively regulated by hypoxia inducible factor-1 (HIF-1), which binds to the hypoxia responsive element (HRE) in the Epo enhancer. The disorders associated with anemia of chronic disease (ACD) are characterized by a deficiency of Epo, leading to Epo being considered as a treatment. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which increase the binding activity of GATA and inhibit Epo promoter activity, are increased in patients with ACD. In a previous study, we demonstrated the ability of K-7174 (a GATA-specific inhibitor) to improve Epo production that had been inhibited by IL-1β or TNF-α treatment in Hep3B cells in vitro and in an in vivo mouse assay (FASEB J 17:1742; 2003). However, K-7174 was injected intraperitoneally into the mice. We examined the ability of K-11706, a novel GATA-specific inhibitor that has a 1,000-fold higher affinity … More than K-7174, to improve Epo production following inhibition by IL-1β or TNF-α in Hep3B cells in vitro. Oral administration of K-11706 reversed the decreases of hemoglobin, serum Epo, reticulocyte counts and CFU-E induced by IL-1β or TNF-α. These results raise the possibility of using orally administered K-11706 as a novel drug for treating ACD (Blood 104:4300; 2004).
In oxygenated cells, hypoxia inducible factor-1 (HIF-1) α subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor E3 ligase complex using 2-oxoglutarate as a substrate. We examined the effect of 2-oxoglutarate on the production of Epo and vascular endothelial growth factor (VEGF). The expression of Epo and VEGF protein were dose-dependently downregulated in Hep3B cells by the addition of 2-oxoglutarate. The promoter activity of VEGF-luciferase was dose-dependently downregulated by the addition of 2-oxoglutarate. Gel mobility shift assays revealed that the addition of 2-oxoglutarate dose-dependently inhibited HIF-1 binding activity, but did not affect GATA binding activity. Western blot analysis revealed that 2-oxoglutarate dose-dependently inhibited the HIF-1α protein level in Hep3B cells in hypoxic conditions. However, MG132 (the proteasome inhibitor) rescued the inhibition of HIF-1α protein expression by 2-oxoglutarate. Furthermore, under hypoxic conditions, 2-oxoglutarate dose-dependently inhibited tube formation in in vitro angiogenesis assays. These results indicate that 2-oxoglutarate treatment may be useful for the inhibition of angiogenesis. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (18 results)

All 2005 2004

All Journal Article (17 results) Book (1 results)

  • [Journal Article] Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver; a new model for Kasabach-Merritt syndrome.2005

    • Author(s)
      Kitajima S, et al.
    • Journal Title

      Lab Invest 85

      Pages: 1517-1527

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Enhanced erythropoiesis mediated by activation of the rennin-angiotensin via angiotensin II type la receptor.2005

    • Author(s)
      Kato H, et al.
    • Journal Title

      FASEB J 19

      Pages: 2023-2025

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver : a new model for Kasabach-Merritt syndrome.2005

    • Author(s)
      Kitajima S, Liu E, Morimoto M, Koike T, Yu Y, Watanabe T, Imagawa S, Fan J.
    • Journal Title

      Lab Invest 85

      Pages: 1517-1527

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type la receptor.2005

    • Author(s)
      Kato H, Ishida J, Imagawa S, Saito T, Suzuki N, Matsuoka T, Sugaya T, Tanimoto K, Yokoo T, Ohneda O, Sugiyama F, Yagami K, Fujita T, Yamamoto M, Nangaku M, Fukamizu A.
    • Journal Title

      FASEB J 19

      Pages: 2023-2025

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver ; a new model for Kasabach-Merritt syndrome.2005

    • Author(s)
      Kitajima S, et al.
    • Journal Title

      Lab Invest 85

      Pages: 1517-1527

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Enhanced erythropoiesis mediated by activation of the rennin-angiotensin via angiotensin II type 1a receptor.2005

    • Author(s)
      Kato H, et al.
    • Journal Title

      FASEB J 19

      Pages: 2023-2025

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Interleukin-6 and tumor necrosis factor α in patients with obstructive sleep apnea-hypopnea syndrome.2004

    • Author(s)
      Imagawa S, et al.
    • Journal Title

      Respiration 71

      Pages: 24-29

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] T-cell acute lymphoblastic leukemia with add (1)(p36) and del (12)(p11) following acute myelocytic leukemic with partial deletion of 9p.2004

    • Author(s)
      Yoshida ac, et al.
    • Journal Title

      Cancer Genet Cytogenet 150

      Pages: 62-65

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Do β-globin, GATA-1 or Epo R regulatory domains specifically mark erythroid progenitors in transgenic reporter mice?2004

    • Author(s)
      Suzuki Y, et al.
    • Journal Title

      Blood 104

      Pages: 2988-2989

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity and restores indicators in an in vivo mouse model of anemia of chromic disease.2004

    • Author(s)
      Nakano Y, et al.
    • Journal Title

      Blood 104

      Pages: 4300-4307

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Interleukin-6 and tumor necrosis factor a in patients with obstructive sleep apnea-hypopnea syndrome.2004

    • Author(s)
      Imagawa S, Yamaguchi Y, Ogawa K, Obara N, Suzuki N, Yamamoto Y, Nagasawa T.
    • Journal Title

      Respiration 71

      Pages: 24-29

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] T-cell acute lymphoblastic leukemia with add(1)(p36) and del(12)(p11) following acute myelocytic leukemia with partial deletion of 9p.2004

    • Author(s)
      Yoshida C, Suzukawa K, Katsura Y, Shimizu S, Mukai HY, Hasegawa Y, Imagawa S, Kojima H, Nagasawa T
    • Journal Title

      Cancer Genet Cytogenet. 150

      Pages: 62-65

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Do β-globin, GATA-1 or EpoR regulatory domains specifically mark erythroid progenitors in transgenic reporter mice?2004

    • Author(s)
      Suzuki N, Imagawa S, Noguchi CT, Yamamoto M, Klingmuller U.
    • Journal Title

      Blood 104

      Pages: 2988-2989

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity and restores indicators in an in vivo mouse model of anemia of chronic disease.2004

    • Author(s)
      Nakano Y, Imagawa S, Matsumoto K, Stockmann C, Obara N, Suzuki N, Doi T, Kodama T, Takahashi S, Nagasawa T, Yamamoto M.
    • Journal Title

      Blood 104

      Pages: 4300-4307

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity and restores indicators in an in vivo mouse model of anemia of chronic disease.2004

    • Author(s)
      Y.Nakano, S.Imagawa, et al.
    • Journal Title

      Blood 104

      Pages: 4300-4307

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 2-oxoglutarateによるvascular endotherial growth factorおよびerythropoietin産生抑制2004

    • Author(s)
      今川 重彦, 他
    • Journal Title

      医学のあゆみ 211巻4号

      Pages: 347-348

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 2-oxoflutarateによるhypoxia inducible factor-1結合活性および蛋白抑制2004

    • Author(s)
      松本 健, 今川 重彦, 他
    • Journal Title

      医学のあゆみ 211巻7号

      Pages: 785-786

    • Related Report
      2004 Annual Research Report
  • [Book] 科学大辞典2005

    • Author(s)
      今川 重彦
    • Total Pages
      4
    • Publisher
      丸善
    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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