Platelet-derived growth factor (PDGF) exerts its mitogenic effect on fibroblasts by inducing the expression of a family genes. The proto- oncogenes c-myc and c-fos are members of this family, but there are an additional 10-30 members, including the first PDGF-inducible genes to be described as such, JE and KC. Recent data suggest that JE and KC, unlike c-myc an dc-fos, are not intracellular mediators of the growth response to PDGF. Rather, they encode secreted glycoproteins, and the JE protein, in particular, has the characteristics of a cytokine. Thus, like T lymphocytes, fibroblasts appear to secrete cytokines as part of their program of mitogenic activation. The products of these PDGF-inducible genes may be members of a new class of fibroblast cytokines. The physiologic function of the JE gene is not known. However, its possible importance is reflected in the fact that its nucleic acid sequence is conserved in D. melanogaster DNA. Multiple criteria suggest that the JE protein is a cytokine, but no cellular target has been identified. Preliminary data suggest that Chinese hamster ovary (CHO) cells may respond to nanomolar concentrations of the JE protein by adopting a less transformed phenotype. This grant application proposes to determine the function and systemic targets of the JE protein. To this end, the work has three broad objectives: The first objective is to complete the structural analysis of the JE protein. A stable source of recombinant JE protein will be developed in both mammalian and insect expression systems. The JE protein will be purified and antibodies raised against it. The second objective is to characterize the effect of the JE protein on target cells in vitro and to search for organ-specific target in vivo. The effect of the JE protein on the phenotype of CHO cells will be defined. It will be determined whether this effect is receptor mediated and, if so, the receptor will be affinity labelled. Target cells for the JE protein will be determined by radioreceptor assay in vitro, and by organ-specific binding in vivo. The third objective is to analyze the expression of the JE homologue in Drosophilia. The gene and cDNA for the JE homologue will be cloned. Its spatial and temporal pattern of expression will then be determined by Northern analysis and in situ hybridization.
| Taubman, M B; Rollins, B J; Poon, M et al. (1992) JE mRNA accumulates rapidly in aortic injury and in platelet-derived growth factor-stimulated vascular smooth muscle cells. Circ Res 70:314-25 |
| Rollins, B J; Walz, A; Baggiolini, M (1991) Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood 78:1112-6 |
| Rollins, B J; Yoshimura, T; Leonard, E J et al. (1990) Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant, MCP-1/JE. Am J Pathol 136:1229-33 |
| Rollins, B J; Stier, P; Ernst, T et al. (1989) The human homolog of the JE gene encodes a monocyte secretory protein. Mol Cell Biol 9:4687-95 |
