サイトカインによるシグナル伝達機構の解析

细胞因子诱导的信号转导机制分析

• 批准号: 07409001
• 负责人: MIYAJIMA Atsushi
• 金额: $ 23.36万
• 依托单位: Institute of Molecular and Cellular Biosciencesa, The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07409001/
• 关键词: cytokine; cytokine receptors; signal transduction; hematopoiesis; differentiation; apoptosis; RAS; STAT; サイトカイン; サイトカイン受容体; 血管内皮; 発生; 誘導遺伝子; 細胞分化; 造血因子; JAK; Ras; 幹細胞; 造血細胞; 増殖; 細胞死; キナーゼ; 細胞増殖

As studies on signaling by using the mutant IL-3/GM-CSF/IL-5 receptors revealed two major signaling pathways, RAS and STAT5, we have focused our efforts to elucidate the role of these pathways in cytokine functions. Hematopoietic cells require cytokines for their growth and also for their survival. We found that activation of RAS is important for suppression of cell death. RAS activates both RAF/MAP kinase and P13 kinase and both pathways were found to be involved in suppression of cell death. We also showed that caspase-3 is involved in cell death induced by cytokine depletion in hematopoietic cells. To find the role of STAT5 in cytokine functions, we isolated STAT5 target genes. Among them, ClS encodes a novel SH2 protein that negatively regulates cytokine signaling. Expression of a dominant negative form of STAT5 blocked proliferation induced by IL-3 and erythroid differentiation induced by EPO, indicating that STAT5 plays a distinct role depending on the cell tynes. Cross talk between STAT5 and RAS was also demonstrated. In addition, we studied the function of Oncostatin M(OSM), another STAT5 target gene, and found that OSM plays an important role in development of hematopoietic cells and germ cells. The OSM receptor cDNA was cloned and the molecular structure of the functional receptor was elucidated.

由于使用突变型 IL-3/GM-CSF/IL-5 受体进行的信号传导研究揭示了两种主要的信号传导途径：RAS 和 STAT5，因此我们集中精力阐明这些途径在细胞因子功能中的作用。造血细胞的生长和生存需要细胞因子。我们发现 RAS 的激活对于抑制细胞死亡很重要。 RAS 激活 RAF/MAP 激酶和 P13 激酶，并且发现这两种途径都参与抑制细胞死亡。我们还表明 caspase-3 参与造血细胞中细胞因子耗竭诱导的细胞死亡。为了找出 STAT5 在细胞因子功能中的作用，我们分离了 STAT5 靶基因。其中，ClS 编码一种新型 SH2 蛋白，可负向调节细胞因子信号传导。 STAT5 显性失活形式的表达阻断了 IL-3 诱导的增殖和 EPO 诱导的红细胞分化，表明 STAT5 根据细胞类型发挥不同的作用。 STAT5 和 RAS 之间的串扰也得到了证明。此外，我们研究了STAT5的另一个靶基因Oncostatin M(OSM)的功能，发现OSM在造血细胞和生殖细胞的发育中发挥着重要作用。克隆了OSM受体cDNA并阐明了功能受体的分子结构。

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