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The mechanism of granulopoiesis and leukemogenesis by the activation of Stat3

Research Project

Project/Area Number 15390302
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

SHIMODA Kazuya  Kyushu University, University Hospital, Associate professor, 大学病院, 助手 (90311844)

Co-Investigator(Kenkyū-buntansha) MATSUDA Tadashi  Hokkaidou University, Graduate school of Pharmacology, Professor, 大学院・薬学研究院, 教授 (20212219)
HARADA Mine  Kyushu University, Graduate school of Medicine, Professor, 大学院・医学研究院, 教授 (00019621)
NAGAFUJI Kouji  Kyushu University, University Hospital, Associate professor, 大学病院, 助手 (60343323)
MIYAMOTO Toshihiro  Kyushu University, University Hospital, Associate professor, 大学病院, 助手 (70343324)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2003: ¥6,500,000 (Direct Cost: ¥6,500,000)
KeywordsG-CSF / Stat3 / C / EBP α / Granulopoiesis / ERK / SOCS3 / EBPα / 好中球
Research Abstract

The Jak-Stat pathway plays an essential role in cytokine signaling. G-CSF promotes granulopoiesis, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the IL-3 dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile of G-CSF-stimulated cell lines revealed that the expression of C/EBP_α was up-regulated by the activation of Stat3. And activated Stat3 bound to C/EBP_α, leading to the enhancement of the transcription activity of C/EBP_α. Conditional expression of C/EBP_α in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF dependent cell proliferation and induces granulocytic differentiation. These results show that one of the major roles of Stat3 in G-CSF signaling pathway is to augment the function of C/EBP_α.
The function of Stat3 in vivo was examined using the Stat3 conditional deficient mice. Mice deficient for Stat3 in hematopoietic cells show neutrocytosis, and G-CSF-induced proliferation of progenitor cells was observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3 null bone marrow cells displayed a significant activation of ERK1/2 under basal conditions, and it was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. Stat3 functions in vivo as a negative regulator of G-CSF signaling by inducing SOCS3 expression, and ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (48 results)

All 2005 2004 2003 Other

All Journal Article (43 results) Publications (5 results)

  • [Journal Article] The roles of Stat3 and ERK in G-CSF signaling.2005

    • Author(s)
      Kamezaki K
    • Journal Title

      Stem Cells 23

      Pages: 252-263

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The roles of Stat3 and ERK in G-CSF signaling.2005

    • Author(s)
      Kamezaki K, Shimoda K, Numata A, Haro T, Kakumitsu H, Yoshie M, Yamamoto M, Takeda K, Matsuda T, Akira S, Ogawa K, Harada M
    • Journal Title

      Stem Cells 23

      Pages: 252-263

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The roles of Stat3 and ERK in G-CSF signaling.2005

    • Author(s)
      Kamezaki H
    • Journal Title

      Stem Cells 23

      Pages: 252-263

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Physical and functional interactions between Daxx and DNA methyltransferasel associated protein, DMAP.2004

    • Author(s)
      Muromoto R
    • Journal Title

      J Immunol 172

      Pages: 2985-2993

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tyk2 is essential for IFN-a-induced gene expression in mast cells.2004

    • Author(s)
      Mori Y
    • Journal Title

      International Archives of Allergy and Immunology 134

      Pages: 25-29

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Physical and Functional Interactions between Daxx and TSG101.2004

    • Author(s)
      Muromoto R
    • Journal Title

      Biochem.Biophys.Res.Commun. 316

      Pages: 827-833

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tyk2 interacts with and phosphorylates Rack-1, a WD motif containing protein.2004

    • Author(s)
      Haro T
    • Journal Title

      J Immunol 173

      Pages: 1151-1157

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Hapten-Induced Contact Hypersensitivity is enhanced in Tyk2-Deficient Mice.2004

    • Author(s)
      Hosogia M
    • Journal Title

      J Dermatol Sci 36

      Pages: 51-56

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Human Cord Blood- and Bone Marrow-derived CD34^+ Cells Regenerate Gastrointestinal Epithelial Cells.2004

    • Author(s)
      Ishikawa F
    • Journal Title

      FASEB Journal 18

      Pages: 1958-1960

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals.2004

    • Author(s)
      Kamezaki K
    • Journal Title

      Int Immunol 16

      Pages: 1173-1179

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Physical and functional interactions between Daxx and DNA methyltra nsferase1 associated protein, DMAP.2004

    • Author(s)
      Muromoto R, Sugiyama K, Takachi A, Imoto S, Sato N, Yamamoto T, Oritani K, Shimoda K, Matsuda T
    • Journal Title

      J Immunol 172

      Pages: 2985-2993

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tyk2 is essential for IFN-a-induced gene expression in mast cells.2004

    • Author(s)
      Mori Y, Hirose K, Suzuki K, Nakajima H, Seto Y, Ikeda K, Shimoda K, Nakayama K, Saito Y, Iwamoto I
    • Journal Title

      International Archives of Allergy and Immunology 134

      Pages: 25-29

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Physical and Functional Interactions between Daxx and TSG1012004

    • Author(s)
      Muromoto R, Sugiyama K, Yamamoto T, Oritani K, Shimoda K, Matsuda T
    • Journal Title

      Biochem.Biophys.Res.Commun. 316

      Pages: 827-833

    • NAID

      120000966782

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tyk2 interacts with and phosphorylates Rack-1, a WD motif containing protein.2004

    • Author(s)
      Haro T, Shimoda K, Kakumitsu H, Kamezaki K, Numata A, Ishikawa F, Sekine Y, Muromoto R, Matsuda T, Harada M
    • Journal Title

      J Immunol 173

      Pages: 1151-1157

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hapten-Induced Contact Hypersensitivity is enhanced in Tyk2-Deficient Mice.2004

    • Author(s)
      Hosogia M, Tonogaito H, Aioi A, Hamada K, Shimoda K, Muromoto R, Matsuda T, Miyachi Y
    • Journal Title

      J Dermatol Sci 36

      Pages: 51-56

    • NAID

      10016185143

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Human Cord Blood- and Bone Marrow-derived CD34^+ Cells Regenerate Gastrointestinal Epithelial Cells.2004

    • Author(s)
      Ishikawa F, Yasukawa M, Yoshida S, Nakamura K, Nagatoshi Y, Kanemaru T, Shimoda K, Shimoda S, Miyamoto T, Okamura J, Shultz L.D, Harada M
    • Journal Title

      FASEB Journal 18

      Pages: 1958-1960

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals.2004

    • Author(s)
      Kamezaki K, Shimoda K, Numata A, Matsuda T, Nakayama K, Harada M
    • Journal Title

      Int Immunol 16

      Pages: 1173-1179

    • NAID

      10013425510

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Physical and functional interactions between Daxx and DNA methyltransferase1 associated protein, DMAP.2004

    • Author(s)
      Muromoto R
    • Journal Title

      J Immunol 172

      Pages: 2985-2993

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Physical and Functional Interactions between Daxx and TSG101.2004

    • Author(s)
      Muromoto R
    • Journal Title

      Biochem.Biophys.Res.Commun, 316

      Pages: 827-833

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The role of Tyk2, Stat1 and Stat 4 in LPS-induced endotoxin signals.2004

    • Author(s)
      Kamezaki K
    • Journal Title

      Int Immunol 16

      Pages: 1173-1179

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice.2003

    • Author(s)
      Seto Y
    • Journal Title

      J Immunol 170

      Pages: 1077-1083

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Daxx enhances Fas-mediated apoptosis in a murine pro-B cell line, BAF3.2003

    • Author(s)
      Muromoto R
    • Journal Title

      FEBS Letters 540

      Pages: 223-228

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The lipocalin 24p3, which is an essential molecule in IL-3 withdrawal-induced apoptosis, is not required in the G-CSF withdrawal-induced apoptosis.2003

    • Author(s)
      Kamezaki K
    • Journal Title

      Eur J Haematol 71

      Pages: 412-417

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth.2003

    • Author(s)
      Kato K
    • Journal Title

      Br J Haematol 123

      Pages: 528-535

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Influence of transplanted dose of GD56+cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized perip heral blood progenitor cells from HLA-identical sibling donors.2003

    • Author(s)
      Yamasaki S
    • Journal Title

      Bone Marrow Transplantaion 32

      Pages: 505-510

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Statl, followed by the induction and nuclear translocation of Daxx.2003

    • Author(s)
      Aoki K
    • Journal Title

      Exp Hematol 31

      Pages: 1317-1322

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] G-CSF does not stimulate leukemic stem cells in vivo.2003

    • Author(s)
      Asano Y
    • Journal Title

      J Clin Exp Hematopathology 43

      Pages: 49-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice.2003

    • Author(s)
      Seto Y, Nakajima H, Suto A, Shimoda K, Saito Y, Nakayama KI, Iwamoto I
    • Journal Title

      J Immunol 170

      Pages: 1077-1083

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Daxx enhances Fas-mediated apoptosis in a murine pro-B cell line, BAF3.2003

    • Author(s)
      Muromoto R, Yamamoto T, Yumioka T, Sekine Y, Sugiyama K, Shimoda K, Oritani K, Matsuda T
    • Journal Title

      FEBS Letters. 540

      Pages: 223-228

    • NAID

      120000973629

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The lipocalin 24p3, which is an essential molecule in IL-3, withdrawal-induced apoptosis, is not required in the G-CSF withdrawal-induced apoptosis.2003

    • Author(s)
      Kamezaki K, Shimoda K, Numata A, Aoki K, Kato K, Takase K, Nakajima H, Ihara K, Haro T, Ishikawa F, Imamura R, Miyamoto T, Nagafuji K, Gondo H, Hara T, Harada M
    • Journal Title

      Eur J Haematol 71

      Pages: 412-417

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth.2003

    • Author(s)
      Kato K, Kamezaki K, Shimoda K, Numata A, Haro T, Aoki K, Ishikawa F, Takase K, Ariyama H, Matsuda T, Miyamoto T, Nagafuji K, Gondo H, Nakayama KI, Harada M
    • Journal Title

      Br J Haemato 123

      Pages: 528-535

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Influence of transplanted dose of CD56+cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors.2003

    • Author(s)
      Yamasaki S, Henzan H, Ohno Y, Yamanaka T, Iino T, Itou Y, Kuroiwa M, Maeda M, Kawano N, Kinukawa N, Miyamoto T, Nagafuji K, Shimoda K, Inada S, Hayashi S, Taniguchi S, Shibuya T, Gondo H, Otsuka T, Harada M
    • Journal Title

      Bone Marrow Transplantaion 32

      Pages: 505-510

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by the induction and nuclear translocation of Daxx.2003

    • Author(s)
      Aoki K, Shimoda K, Oritani K, Matsuda T, Kamezaki K, Muromoto R, Numata A, Tamiya S, Haro T, Ishikawa F, Takase K, Yamamoto T, Yumioka T, Miyamoto T, Nagafuji K, Gondo H, Nagafuchi S, Nakayama KI, Harada M
    • Journal Title

      Exp Hematol. 31

      Pages: 1317-1322

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] G-CSF does not stimulate leukemic stem cells in vivo.2003

    • Author(s)
      Asano Y, Numata A, Takase K, Shimoda K, Gondo H, Okamura T, Kinukawa N, Niho Y
    • Journal Title

      J Clin Exp Hematopathology 43

      Pages: 49-51

    • NAID

      50000357842

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer binding protein a in G-CSF signaling pathway.

    • Author(s)
      Numata A
    • Journal Title

      Journal of Biological Chemistry (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Physical and functional interactions between STAP-2/BKS and STAT5.

    • Author(s)
      Sekine Y
    • Journal Title

      Journal of Biological Chemistry (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transgenic Mice Overexpressing Murine Thrombopoietin Develop Myelofibosis and Osteosclerosis.

    • Author(s)
      Kakumitsu H
    • Journal Title

      Leukemia Research (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer binding protein a in G-CSF signaling pathway.

    • Author(s)
      Numata A, Shimoda K, Kamezaki K,.Haro T, Kakumitsu H, Shide K, Kato K, Miyamoto T, Yamashita Y, Oshima Y, Nakajima H, Iwama A, Aoki K, Takase K, Gondo H, Mano H, Harada M
    • Journal Title

      JBC (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Physical and functional interactions between STAP-2/BKS and STAT5.

    • Author(s)
      Sekine Y, Yamamoto T, Yumioka T, Sugiyama K, Tsuji S, Oritani K, Shimoda K, Minoguchi M, Yoshimura A, Matsuda T
    • Journal Title

      JBC (in press)

    • NAID

      120000962160

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transgenic Mice Overexpressing Murine Thrombopoietin Develop Myelofibrosis and Osteosclerosis.

    • Author(s)
      Kakumitsu H, Kamezaki K, Shimoda K, Karube K, Haro T, Numata A, Shide K, Matsuda T, Oshima K, Harada M
    • Journal Title

      Leuk Res (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signal transducers are activators of transcription 3 augments the transcriptional activity of CCAAT/enhancer binding protein a in G-CSF signaling pathway.

    • Author(s)
      Numata A
    • Journal Title

      Journal of Biological Chemistry (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Physical and functional interactions between STAP-2/BKS and STAT5.

    • Author(s)
      Sekine Y
    • Journal Title

      Journal of Biological Chemistry (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transgenic Mice Overexpressing Murine Thrombopoietin Develop Myelofibrosis and Osteosclerosis.

    • Author(s)
      Kakumitsu H
    • Journal Title

      Leukemia Research (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Publications] Aoki K, Shimoda K et al.: "Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Statl, followed by the induction and nuclear translocation of Daxx."Experimaental Hematology. 31. 1317-1322 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kato K, Kamezaki K, Shimoda K et al.: "Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth."British Journal of Haematology. 123. 528-535 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kamezaki K, Shimoda K et al.: "The lipocalin 24p3, which is an essential molecule in IL-3 withdrawal-induced apoptosis, is not required in the G-CSF withdrawal-induced apoptosis."European Journal of Haematology. 71. 412-417 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Seto Y, Nakajima H, Suto A, Shimoda K, et al.: "Enhanced Th2 Cell-mediated Allergic Inflammation in Tyk2-deficient Mice."Journal of Immunology. 170. 1077-1083 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Muromoto R, Shimoda K et al.: "Physical and functional interactions between Daxx and DNA methyltransferasel associated protein, DMAP."Journal of Immunology. 印刷中. (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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