The stimulation of quiescent rat fibroblasts by v-src and v-fps oncogenic protein-tyrosine kinases leads to the induction of a subset of immediate early genes.

The stimulation of quiescent murine fibroblasts by growth factors and by phorbol esters results in a rapid and transient transcriptional activation of a large group of so-called immediate early genes. Several such genes were found to be induced in chicken embryo fibroblasts following activation of a temperature sensitive (ts) Rous sarcoma virus v-src mutant following temperature shift (Simmons et al., 1989). In contrast, the classical immediate early genes c-myc, c-fos and c-jun were essentially uninducible upon activation of a ts v-src mutant in rat-1 fibroblasts (Welham et al., 1990). We have cloned 9 cDNAs of genes that are rapidly and transiently inducible in rat fibroblasts by ts v-src mutants, and by a ts Fujinami sarcoma virus v-fps mutant. Six of these cDNAs are derived from the known immediate early genes NGFI-A, KC, c-fos, tissue factor, PC4 and ornithine decarboxylase; the other three cDNAs have not been described before. These 9 genes showed individual profiles of inducibility by fetal calf serum, epidermal growth factor (EGF) and by phorbol esters. Their response to the retroviral oncogenic protein-tyrosine kinases correlated best with the one to EGF, suggesting a common pathway of signal transduction. c-fos did not respond strongly to this pathway but was well induced by fetal calf serum. NGFI-A, however, was induced to a similar extent by all activators tested. Furthermore, we demonstrated that the induction of several of these genes by the retroviral oncogenic protein-tyrosine kinases is rapid, direct and occurs at the transcriptional level.