Treatment of serum-deprived fibroblasts with serum or growth factors results in an immediate induction of the c-fos and c-myc proto-oncogenes. Maximal levels of c-fos mRNA are detected 30 minutes after treatment and maximal levels of c-myc mRNA are detected 60 minutes after treatment. The c-fos protein is expressed at high levels for about two hours following induction, yet the cell morphology remains normal. Thus, either an extended period of c-fos expression is required for cellular transformation, or the highly modified form of the fos protein, present in stimulated cells, is biochemically different from the transforming protein and is therefore not capable of inducing transformation. In this system, growth factor treatment results in mitogenesis. However, c-fos and c-myc are also induced in A431 cells, and in subclones derived from A431 cells, treated with epidermal growth factor (EGF). No correlation was found between the effects of EGF on A431 cell proliferation and the induction of c-fos and c-myc. Interestingly, the strongest inducer of c-fos in A431 cells was the calcium ionophore A23187. Induction occurred in almost 100% of the treated cells without prior serum deprivation or growth arrest. Treatment of HL60 cells with 12-0 tetra decanoylphorbol-13-acetate (TPA), which promotes macrophage-like differentiation, also induced c-fos with a time course similar to that observed in mitogen-treated fibroblasts. Thus, in HL60 cells, c-fos induction is associated with differentiation. In normal macrophages c-fos and c-myc can also be induced by CSF-1. However, the kinetics of induction are entirely different from those in growth factor-stimulated fibroblasts. Taken together, the data suggest a more general role for c-fos and c-myc in the transduction of growth factor signals received at the cell membrane, within the nucleus.