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Molecular Mechanism and physiological role of growth suppression by oncostatinM

制瘤素M抑制生长的分子机制及生理作用

基本信息

批准号：
08680760
负责人：
HARA Takahiko
金额：
$ 1.6万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08680760/
关键词：
oncostatinM cytokine cytokine receptor signal transduction LIF IL-6

项目摘要

OncostatinM (OSM) inhibits growth of melanoma cells, while it stimulates proliferation of Kaposi's sarcoma cells. Although this cell-type specific signal transduction has been revealed by using human OSM,its physiological role remained un known because there was no animal model. In this study, by using a recently cloned mouse OSM,we discovered following facts and established a novel animal system for OSM : 1) Unlike the case in human OSM,mouse OSM only utilizes the OSM-specific receptor complex but not the LIF receptor complex. 2) I cloned a cDNA encoding mouse OSM receptor beta chain (OSMRbeta). OSM binds to OSMRbeta and gp130 with low affinity, respectively, whereas combination of OSMRbeta and gp130 exhibits a high affinity binsing capacity to mOSM.Moreover, the high affinity OSMR complex is not activated bu human OSM or mouse LIF.3) OSM is expressed in gonadal region of embryos at midgestation and Sertoli cells at neonatal testes. In primary culture, OSM stimulates proliferation of gonad-derived cells and sertoli cells. 4) I established a novel endothelial cell line, LO,which strictly requires mouse OSM for its growth. 5) When I comparedOSM-***diated signaling pathways between growth-inhibitory NIH3T3 cells and growth stimulative LO cells, activation of JAK2/STAT and induction of immediate early response genes such as Myd118 and OIG31 were observed in both cell lines. However, disruption of adherens junction and accumulation of peripheral membrane proteins such as gamma-catenin in cytoplasm were only ovserved in LO cells. This result indicates that a molecular switch between growth supression and stimulation exsists not in the receptor level but in the cell type specific intracellular signal transduction pathways. By taking advantage of the progresses in this two-year study, we will be able to investigate the sritical molecules for the OSM-mediated trowth suppression.

OncostatinM（OSM）抑制黑色素瘤细胞的生长，同时刺激卡波西肉瘤细胞的增殖。虽然这种细胞类型特异性的信号转导已经通过使用人OSM被揭示，但由于没有动物模型，其生理作用仍然未知。本研究利用新近克隆的小鼠OSM，发现了以下事实并建立了一种新的OSM动物系统：1）与人OSM不同，小鼠OSM仅利用OSM特异性受体复合物，而不利用LIF受体复合物。2)我克隆了编码小鼠OSM受体β链（OSMR β）的cDNA。OSM分别与OSMR β和gp 130以低亲和力结合，而OSMR β和gp 130结合后对mOSM表现出高亲和力结合能力，而且这种高亲和力的OSMR复合物不被人OSM或小鼠LIF激活。3）OSM在妊娠中期胚胎的性腺区和新生睾丸的Sertoli细胞中表达。在原代培养中，OSM刺激性腺衍生细胞和支持细胞的增殖。4)我建立了一个新的内皮细胞系，LO，它严格需要小鼠OSM的生长。5)当我比较OSM-* 介导的生长抑制性NIH 3 T3细胞和生长刺激性LO细胞的信号通路时，在两种细胞系中均观察到JAK 2/STAT的激活和立即早期反应基因如Myd 118和OIG 31的诱导。然而，仅在LO细胞中观察到粘附连接的破坏和外周膜蛋白如γ-连环蛋白在细胞质中的积聚。这一结果表明，生长抑制和生长刺激之间的分子开关不存在于受体水平，而是存在于细胞类型特异性的细胞内信号转导途径。利用这两年的研究成果，我们将能够研究OSM介导的生长抑制的关键分子。