1997 Fiscal Year Final Research Report Summary
Control of cytokine function by modified signaling molecules
| Project/Area Number |
07559018
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
広領域
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| Research Institution | Institute of Molecular and Cellular Biosciences, The University of Tokyo |
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Principal Investigator |
MIYAJIMA Atsushi Institute of Molecular and Cellular Biosciences, The University of Tokyo, PROFESSOR, 分子細胞生物学研究所, 教授 (50135232)
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| Co-Investigator(Kenkyū-buntansha) |
KINOSHITA Taisei Institute of Molecular and Cellular Biosciences, The University of Tokyo, ASSIST, 分子細胞生物学研究所, 助手
HARA Takahiko Institute of Molecular and Cellular Biosciences, The University of Tokyo, ASSOCI, 分子細胞生物学研究所, 助教授 (80280949)
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| Project Period (FY) |
1995 – 1997
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| Keywords | cytokines / signal transduction / hematopoietic growth factors / RAS / STAT / cell proliferation / cell differentiation / cell death |
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| Research Abstract |
We investigated the signaling mechanisms of RAS and STAT5, which are major signaling molecules activated by hematopoietic cytokines such as IL-3/GM-CSF.We also attempted to develop means to regulate these pathways by modification of signaling molecules.
RAS is required for prevention of apoptosis by cytokines in hematopoietic cells. By using partially active RAS mutants, we found that RAS prevents apoptosis through both activation of the RAF/MAP kinase cascade as well as the P13 kinase pathway. As'the mechanism of apoptosis induced by cytokine depletion has remained uncovered, we tested if Caspases are involved in the apoptotic process. We found that Caspase-3 is activated in the absence of a cytokine in hematopoietic cells and the activation of Caspase-3 is required for the apoptosis.
While STAT5 is activated by various cytokines including IL-3/GM-CSF,the role of STAT5 in cytokine functions was unknown. To uncover the role of STAT5, we attempted to isolate STAT5 target genes. Among such genes we obtained a novel SH-2 protein CIS Oncostatin M,a member of IL-6 family cytokines. CIS is induced by cytokines through STAT5 and inhibits signaling by binding to a tyrosine phosphorylated signaling moleculea. OSM is expressed in the aorta/gonad/mesonephros (AGM) region where the definitive hematopoiesis is believed to emerge. OSM stimulates the development of hematopoietic cells as well as endothelial cells in the in vitro culture of AGM cells. This raised a possibility that the putative common precursor of hematopoietic cells and endothelial cells may be a target of OSM.
We generated a dominant negative (dn) form of STAT5 and demonstrated that expression of dnSTAT5 blocks IL-3-induced proliferation of BaF3, suggesting that STAT5 may be involved in proliferation. We also showed that STAT5 is involved in erythropoietininduced maturation of the erythroid cell line, SKT6.
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[Publications] Yoshimura, A., Ohkubo, T., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hara, T., and Miyajima, A: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tyrosine phosphorylated interleukin-3 and erythropoietin receptors." EMBO J.14. 2816-2826 (1995)
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