Signaling molecules activated by growth factors or cytokines implicated in malignancy present potential targets for therapeutic intervention. One such factor, platelet-derived growth factor (PDGF) B, is a homolog of the v-sis oncogene product. We have recently demonstrated that Stat6 is a common element in both PDGF and IL-4 signaling pathways, and that IL-4 enhances PDGF-induced proliferation. These findings suggest that IL-4 may potentiate certain PDGF related responses including malignant transformation. 1)Further investigations of the relationship between PDGF and IL-4 signaling led to the cloning of two naturally occurring human Stat6 isoforms, Stat6b and Stat6c that inhibited some IL-4- related effects including proliferation. To understand the regulation and genesis of the human Stat6 variant mRNAs, we cloned the human Stat6 gene, characterized its genomic structure, and identified putative regulatory elements within the basal promoter. Stat6 variant transcripts were best explained by selective exon deletion and utilization of alternative donor/acceptor splice sites. The human Stat6 gene was mapped to chromosome 12q13.3-14.1, a breakpoint region implicated in a wide variety of solid tumors.2)We investigated the consequences of deleting Stat6 on PDGF and IL-4 signaling, proliferation, and transcriptional activation by establishing wild-type and Stat6 null early passage fibroblasts. PDGFR and IL-4R expression/activation, substrate activation, and Stat1, Stat3 and Stat5 DNA binding activity remained unchanged. Although PDGF-mediated proliferation was not significantly altered, IL-4-enhancement of PDGF- induced proliferation was markedly diminished. Strikingly, IL-4, but not PDGF induction of the proinflammatory gene products, IL-6 and MCP-1 was markedly reduced in null fibroblasts. Rescue of Stat6 DNA binding activity by transfection of a Stat6 expression construct attributed these effects directly to the Stat6 lesion. Therefore, Stat6 appears to play a unique role in PDGF proliferative events enhanced by IL-4, as well as IL-4s induction of IL-6 and MCP-1 in murine fibroblasts. Regulation of stromal fibroblast IL-6 and MCP-1 induction provides further evidence for Stat6s contribution to inflammatory disease.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 including hepatocellular carcinomas, melanomas, rhabdomyosarcomas, fibrosarcomas, and mammary tumors. Natural splice variants of HGF, NK1 and NK2, have been proposed to be therapeutic antagonists of HGF and their biologic roles have been controversial. NK1 transgenic mice possess the phenotypic characteristics of HGF transgenic mice including tumor development. Apparently, NK1 acts as a partial agonist in vivo and its therapeutic value as a HGF antagonist must be seriously questioned. NK2, however, possesses none of the HGF or NK1 tumor phenotypes. Preliminary results suggest that NK2 transgenic mice do have increased metastatic potential when challenged with tumor cells. HGF, NK1 and NK2 transgenic mice should provide excellent animal models for future studies of HGF-induced malignant processes. - Cancer cell growth regulation, growth factor, receptor signaling, transcription factor, Transgenic Mice,
