サイトカインによるシグナル伝達機構の解析

由于利用突变型IL-3/GM-CSF/IL-5受体对信号转导的研究揭示了两条主要的信号转导途径，即RAS和STAT5，我们致力于阐明这些信号转导途径在细胞因子功能中的作用。造血细胞的生长和生存都需要细胞因子。我们发现RAS的激活对于抑制细胞死亡是重要的。RAS激活RAF/MAP和P13两条通路，这两条通路都参与了细胞死亡的抑制。我们还发现caspase-3参与了细胞因子耗竭所致的造血细胞死亡。为了发现STAT5在细胞因子功能中的作用，我们分离了STAT5的靶基因。其中，CLS编码一种新的负调控细胞因子信号转导的SH2蛋白。STAT5的表达阻断了IL-3诱导的增殖和EPO诱导的红系分化，表明STAT5的作用依赖于Tynes细胞。STAT5和RAS之间的串扰也被证明。此外，我们还研究了另一个STAT5靶基因OSM的功能，发现OSM在造血细胞和生殖细胞的发育中起着重要的作用。克隆了OSM受体基因，并阐明了该功能性受体的分子结构。

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.