2004 Fiscal Year Final Research Report Summary
The mechanism of granulopoiesis and leukemogenesis by the activation of Stat3
| Project/Area Number |
15390302
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SHIMODA Kazuya Kyushu University, University Hospital, Associate professor, 大学病院, 助手 (90311844)
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| 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)
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| Project Period (FY) |
2003 – 2004
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| Keywords | G-CSF / Stat3 / C / EBP α / Granulopoiesis / ERK / SOCS3 |
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| 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.
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Research Products
(36 results)
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[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
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Journal Title
Stem Cells 23
Pages: 252-263
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
J Immunol 173
Pages: 1151-1157
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
FASEB Journal 18
Pages: 1958-1960
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Eur J Haematol 71
Pages: 412-417
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Br J Haemato 123
Pages: 528-535
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Bone Marrow Transplantaion 32
Pages: 505-510
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Exp Hematol. 31
Pages: 1317-1322
Description
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[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
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Description
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