| 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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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | G-CSF / Stat3 / C / EBP α / Granulopoiesis / ERK / SOCS3 / EBPα / 好中球 |
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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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