Dissociation of proto-oncogene induction from growth response in normal human fibroblasts.

Proto-oncogenes are cellular homologues of viral oncogenes that are known to be associated with regulation of growth and differentiation. The c-myc and c-fos proto-oncogenes have been extensively studied by using established cell lines but to a lesser extent by using normal cells. Using physiologic growth modulators, we have shown that mitotic stimulation of normal human dermal fibroblasts is associated with induction of c-myc and c-fos, but that growth inhibition of these cells is not necessarily accompanied by their down-regulation. When treated with both serum and interferon-alpha during quiescence, fibroblasts were delayed in their progress into the S-phase of the cell cycle as compared to cells treated with serum alone and displayed substantial growth inhibition as measured by cell number at the end of 1 week. However, this growth inhibition was not preceded by down-regulation or delay in induction of c-myc and c-fos mRNA. The above studies suggest that in normal fibroblasts growth inhibition is not necessarily dependent on down-regulation of transcription of either c-myc or c-fos and that interferon may act to inhibit cell growth either through a post-transcriptional effect on cellular proto-oncogenes necessary for cell proliferation or through induction of other, as yet unrecognized gene(s) associated with growth arrest.