We have examined the role of raf and myc family oncogenes in naturally occurring human tumors and in the mouse, and have determined their transforming properties and likely mechanisms of action. In the mouse, raf tumor induction was studied using a series of recombinant murine retroviruses. Viruses carrying only raf family oncogenes, including constructs with the cellular homolog of v-raf, c-raf-l, and a raf-related gene, A-raf-1, induce predominantly fibrosarcoma and erythroid hyperplasia. The J-2 virus, which contains both v-raf and v-myc, demonstrated a synergism of these two oncogenes in inducing hemopoietic and epithelial neoplasias in newborn mice with a greatly reduced latency period compared to disease induction by raf or myc viruses. Murine retroviruses containing only v-myc (J-3 and J-5) predominantly induce lymphomas (of both T and B lineage) but transform other hemopoietic and epithelial lineage cells as well, with a latency period which depends upon the replication efficiency of the pseudotyping MuLV. raf-induced neoplasias require specific interleukins (IL) for culturing in vitro, whereas cell lines established from J-2, J-3, or J-5 neoplasias grow in culture without specific growth factor supplements. A function for v-myc in synergism with v-raf has been established by experiments demonstrating that v-myc can abrogate growth factor requirements of IL-3- and IL-2-dependent cells and v-myc-infected fibroblasts grow in medium depleted of PDGF. A function for raf in the signal transmission pathway of growth factors has been established in studies involving raf transformation of Ki-ras-resistant cells and in microinjection analyses of ras and raf antibodies into normal, ras- and raf-transformed mouse fibroblasts. These studies suggest that raf is located downstream of ras in signal transmission. Finally, even tumors induced by the dual oncogene virus J-2 are clonal, suggesting that additional events may be required in the maintenance of the transformed phenotype. In an in vitro-derived J-2-infected myeloid cell line, we have identified a likely alteration in the c-myb proto-oncogene, a proviral insertion common to an in vivo-derived tumor.
