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Analysis on the mechanisms of NF-κB/Reactive Oxigen Species-mediated survival of hematopoietic cells and its clinical application

Research Project

Project/Area Number 16390278
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

MATSUMURA Itaru  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294083)

Co-Investigator(Kenkyū-buntansha) KANAKURA Yuzuru  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20177489)
MIZUKI Masao  Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (80283761)
SHIBAYAMA Hirohiko  Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (60346202)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
KeywordsNF-κB / apoptosis / reactive oxygen species / cytokine / mitochondrial membrane potential / H2O2 / OP9システム
Research Abstract

To examine the roles for NF-κB family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-κB (IκBSR), which can inhibit the function of all NF-κB family proteins, in a factor-dependent cell line, Ba/F3, in an inducible manner. Although the induced IκBSR neither affected thrombopoietin-dependent nor gp130-mediated growth of Ba/F3 cells, it suppressed interleukin-3- and erythropoietin-dependent growth at low concentrations. In addition, IκBSR enhanced factor-deprived apoptosis, which was associated with the reduction of the mitochondrial membrane potential and accumulation of reactive oxygen species (ROS). Since IκBSR-enhanced apoptosis was cancelled by ROS scavenger enzymes such as MnSOD and thioredoxin X (TRX) almost completely, ROS were supposed be involved in the IκBSR-enhanced apoptosis. When IκBSR was expressed in normal hematopoietic stem/progenitor cells, IκBSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS, which was also r … More elieved by ROS scavenger enzymes, MCI-186, N-acetyl-cysteine (NAC), and TRX. As for the mechanism of the IκBSR-induced ROS accumulation and apoptosis, semiquantitative reverse transcriptese-PCR analyses showed that the expression of ROS scavenger enzymes (MnSOD, glutathione peroxidase, and TRX) was suppressed by IκBSR. In addition, the expression of anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-XL and A1) was also suppressed. Next, we expressed IκBSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from embryonic stem cells. When IκBSR was expressed at the stage of Flk-1^+ cells (putative hemangioblasts), IκBSR inhibited the development of primitive hematopoietic progenitor cells by inducing apoptosis through the ROS accumulation. Furthermore, when IκBSR was expressed affer the development of hematopoietic progenitor cells, it inhibited their terminal differentiation toward erythrocytes, megakaryocytes, and granulocytes by inducing apoptosis through the ROS accumulation. These results indicate that NF-κB is required for preventing apoptosis at multiple steps of hematopoiesis by eliminating ROS. Less

Report

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

    (19 results)

All 2005 2004 Other

All Journal Article (19 results)

  • [Journal Article] Roles of tyrosine residues 845,892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.2005

    • Author(s)
      Ishiko J, et al.
    • Journal Title

      Oncogene 24・55

      Pages: 8144-8153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopoietic cell line through the inhibition of STAT3 activity.2005

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

      J Biol Chem 280・13

      Pages: 13163-13170

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1.2005

    • Author(s)
      Ishiko J, et al.
    • Journal Title

      J Biol Chem 280・6

      Pages: 4929-4939

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell cycle regulation in hematopoietic stem/progenitor cells.2005

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

      T Biol Sci 5・1

      Pages: 50-60

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1.2005

    • Author(s)
      Ishiko E, et al.
    • Journal Title

      J Biol Chem 280

      Pages: 4929-4939

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Roles of tyrosine residues 845, 892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.2005

    • Author(s)
      Ishiko J, et al.
    • Journal Title

      Oncogene 24

      Pages: 8144-8153

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopietic cell line through the inhibition of STAT3 activity.2005

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

      J Biol Chem 280

      Pages: 13163-13170

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell cycle regulation in hematopoietic stem/progenitor cells.2005

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

      J Biol Sci 5

      Pages: 50-60

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Notch signals inhibit the development of erythroid/megakaryocytiv cells by suppressing GATA-1 activity through the induction of HES1.2005

    • Author(s)
      Ishiko E, et al.
    • Journal Title

      J Biol Chem 280・6

      Pages: 4929-4939

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Cell cycle regulation in hematopoietic stem/progenitor cells.2005

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

      J Biol Sci 5・1

      Pages: 50-60

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Notch signals inhibit the development of erythroid/megakaryocytic cells by suppressing GATA-1 activity through the induction of HES1.2005

    • Author(s)
      Ishiko E, et al.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 4929-4939

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cell cycle regulation in hematopoietic stem/progenitor cells.2005

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

      J.Biol.Sciences 5

      Pages: 50-60

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of a cytokine-induced antiapoptotic molecule anamorsin essential for definitive hematopoiesis.2004

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

      J.Exp.Med. 199

      Pages: 581-592

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Roles for c-Myc in self-renewal of hematopoietic stem cells.2004

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

      J.Biol.Chem. 279

      Pages: 24986-24993

    • Related Report
      2004 Annual Research Report
  • [Journal Article] NF-κB family proteins participates in multiple steps of hematopoiesis through elimination of reactive oxygen species.2004

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

      J.Biol.Chem. 279

      Pages: 55578-55586

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Suppressor of cytokine signalling-1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines.2004

    • Author(s)
      Watanabe D, et al.
    • Journal Title

      Br.J.Haematol. 126

      Pages: 726-735

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cell cycle regulation in hematopoietic stem/progenitor cells.2004

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

      Cell Cycle 3

      Pages: 314-318

    • Related Report
      2004 Annual Research Report
  • [Journal Article] GATA transcription factors inhibit cytokine-dependent growth and survival of a hematopoietic cell line through the inhibition of STAT3 activity.

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

      J.Biol.Chem. (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cell cycle regulation in hematopoietic stem cells.

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

      Trends in Cell & Mol.Biol. (印刷中)

    • Related Report
      2004 Annual Research Report

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

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