2000 Fiscal Year Final Research Report Summary
Control of Hematopoiesis by AP-1 and Bcl6
| Project/Area Number |
11670978
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Chiba University |
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Principal Investigator |
OKADA Seiji Chiba University Dept.of Developmental Genetics, Associate Professor, 大学院・医学研究科, 助教授 (50282455)
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| Co-Investigator(Kenkyū-buntansha) |
HATANO Masahiko Chiba University Dept.of Developmental Genetics, Associate Professor, 大学院・医学研究科, 助教授 (20208523)
TOKUHISA Takeshi Chiba University Dept.of Developmental Genetics, Professor, 大学院・医学研究科, 教授 (20134364)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Hematopoietic stem cells / c-fos / Bcl6 / Transcriptional factor |
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| Research Abstract |
Proliferation and differentiation of hematopoietic stem cells are regulated by transcriptional factors. In this study, we have analyzed role of two immediated early gene families, AP-1 and Bcl6 using transgenic mice and knock out mice.
c-Fos forms AP-1 complex with Jun family and regulates the expression of AP-1 binding genes. c-fos is transiently upregulated in primitive hematopoietic stem cells stimulated with cytokines. To investigate the role of c-fos in hematopoiesis, we used transgenic mice carrying the c-fos gene under the control of the interferon-inducible Mx-promoter (Mx-c-fos) and c-fos deficient mice. Prolonged expression of c-fos in hematopoietic stem cells inhibited factor dependent colony formation and stroma dependent hematopoiesis by keeping them at G0/G1 phase of the cell cycle. These result suggest that the c-fos induced i hematopoietic stem cells negatively control s cell cycle progression and maintains them in a dormant state.
The Bcl6 gene has been identified from t
… More
he chromosomal translocation breakpoint in B-cell lymphoma and its product functions as a sequence-specific transcriptional repressor. Bcl6 is critical for the differentiation of germinal center B cell. To analyze the function of Bcl6 in B cell development, we used an efficient retroviral transduction system to murine hematopoietic stem cells. We constructed a bicistronic retrovirus expressing the murine Bcl6 and the enhanced green fluorescent protein (EGFP). Lin-Sca-1^+ BM cells (hematopoietic stem cell fraction) were infected with this virus in the presence of SCF and IL-6, and EGFP^+ cells were sorted and injected into the 2.5 Gy irradiated SCID mice or co-cultured on OP-9 stromal cells with or without IL-7. BM cells infected with a control virus (MSCV-EGFP) proliferated and differentiated into B cells and myeloid cells both in vivo and in vitro. BM cells infected with the Bcl6 virus (MSCV-EGFP-Bcl6) differentiated into myeloid cells, but B cell differentiation was impaired. Although myeloid cells expressed high level of EGFP were developed, B cells developed were low or lack in EGFP.On the other hand, hematopoietic stem cells lacking Bcl6 could differentiate into both myeloid and B lymhoid cells. These results suggest that expression of Bcl6 can be used to specify distinct cell fates in the hematopoietic system. Less
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[Publications] Shimizu C, Kawamoto H, Yamashita M, Kimura M, Kondou E, Kaneko Y, Okada S, Tokuhisa T, Yokoyama M, Taniguchi M, Katsura Y, and Nakayama T: "Progression of T cell lineage restriction in the earliest subpopulation of murine adult thymus visualized by the expression of lck proximal promoter activity."Int Immunol. 13(1). 95-103 (2001)
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