Platelet-derived growth factor (PDGF) is a disulfide-linked dimer consisting of two related polypeptide chains, designated PDGF A and PDGF B. The gene encoding the human PDGF B chain is the normal counterpart of the v-sis oncogene. Signaling molecules in growth factor/cytokine signaling pathways implicated in malignancies present potential targets for therapeutic intervention. We demonstrated that Stat6 and Jak1 are common elements in PDGF and IL-4 signaling pathways and that IL-4 potentiates PDGF-induced fibroblast proliferation. We have further cloned naturally occurring attenuated and dominant negative Stat6 variants that affect IL-4-mediated biologic responses through differential transcriptional regulation. Future studies will elucidate the role of these molecules in IL-4 and PDGF signaling pathways. Hepatocyte growth factor (HGF) is a multifunctional paracrine mediator of epithelial cell growth. An in vivo oncogenic role for HGF has not been demonstrated. Transgenic mice inappropriately overexpressing HGF developed a broad array of histologically distinct tumors of mesenchymal and epithelial origin. Hepatocellular carcinomas, melanomas, rhabdomyosarcomas, fibrosarcomas, and mammary tumors were identified that overexpressed both transgenic HGF and endogenous Met. Many neoplasms arose from tissues exhibiting abnormal development including mammary gland, skeletal muscle, and melanocytes suggesting a functional link between mechanisms regulating morphogenesis and those promoting tumorigenesis. Thus, subversion of normal mesenchymal epithelial paracrine regulation through the force misdirection of HGF expression induces aberrant morphogenesis and subsequent malignant transformation of cells of diverse origin. These HGF transgenic mice should provide excellent animal models for future studies of HGF-induced malignant processes. Title changed from Structural and Functional Characterization of v-sis Gene Product.
