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，而刺激Kaposi肉瘤细胞的增殖。尽管通过使用人OSM揭示了这种细胞类型的特异性信号转导，但由于没有动物模型，因此其生理作用尚不清楚。在这项研究中，通过使用最近克隆的小鼠OSM，我们发现了以下事实，并为OSM建立了一种新型的动物系统：1）与人类OSM中的情况不同，小鼠OSM仅利用OSM特异性受体复合物，但不使用LIF受体复合物。 2）我克隆了一个编码小鼠OSM受体β链（OSMRBETA）的cDNA。 OSM分别与OSMRBETA和GP130结合，分别具有低亲和力，而OSMRBETA和GP130的组合表现出对MOSM.MOMM的高亲和力均值能力，高亲和力OSMR复合物未激活BU人类OSM或小鼠LIF.3）OSM在MISTAL和SERTAL的GONADAL区域中表达了OSM。在原发性培养中，OSM刺激性腺衍生细胞和Sertoli细胞的增殖。 4）我建立了一种新型的内皮细胞系LO，严格要求小鼠OSM的生长。 5）当我比较了抑制生长的NIH3T3细胞和生长刺激性LO细胞之间的SOISM- ***时，在两个细胞系中都观察到了JAK2/STAT的激活以及诱导诸如MYD118和OIG31之类的直接早期响应基因的激活。然而，在LO细胞中仅卵形蛋白（如伽马 - 钙蛋白）的外周膜蛋白（如伽马 - 钙蛋白）的破坏和在LO细胞中仅卵形。该结果表明，生长抑制和刺激之间的分子切换不在受体水平，而是在细胞类型特定的细胞内信号转导途径中。通过利用这项为期两年的研究中的进展，我们将能够研究OSM介导的Trowth抑制作用的智力分子。