ROLE OF KINASE ONCOGENES IN GROWTH FACTOR ABROGATION AND C-MYC REGULATION

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We have investigated the functional significance of various oncogenes in interleukin-3 (IL-3) signal transduction in two myeloid-dependent cell lines, FCD-Pl and 32DC13, by testing their potential to abrogate IL-3 requirements and to induce the expression of genes which are normally regulated by IL-3. In these cells, IL-3 tightly regulates expression of c-myc, c-fos, and junB. We and others have demonstrated conditional abrogation of IL-3 dependence by introduction of temperature-sensitive (ts) v-abl retroviral constructs and nonconditional abrogation by several other intracellular tyrosine kinase oncogenes including src and trk. Furthermore, this tyrosine kinase mimics IL-3 in its ability to regulate c-myc transcription, yet differs from IL-3 signal transduction in that ts v-abl fails to induce c-fos and junB, suggesting that IL-3 induction of these two genes requires distinct signaling pathways. In comparison to abrogation by tyrosine kinase oncogenes, we have demonstrated that exogenous v-myc or c-myc can either completely or partially abrogate IL-3 requirements, respectively. v-raf is comparable to c-myc in abrogating IL-3 requirements. However, when constructs carrying both raf plus myc oncogenes are introduced into IL-3-dependent lines or if raf or myc viruses are used to superinfect raf- or myc-containing factor-dependent clones, factor-independent lines are generated with frequencies comparable to tyrosine kinase oncogene constructs. Abrogation was not due to induction of autocrine loops involving IL-3 or GM-CSF. The mechanism for this synergism appears to be the result of combination of two jointly required pathways which function in IL-3 signal transduction. This hypothesis is based upon the finding that introduction of exogenous, activated v-raf has no effect upon c-myc, c-fos, and junB expression. To examine other potential downstream intermediates in IL-3 signal transduction, the effects of protein kinase C constructs upon the regulation of cell growth and gene expression, and its potential to synergize with other oncogenes is being examined.