|Budget Amount *help
¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1997 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1996 : ¥1,300,000 (Direct Cost : ¥1,300,000)
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.