In previous studies (Housey et al.: Cell 52:343-354, 1988), our laboratory demonstrated that a cell line R6-PKC3 that stably overproduces high levels of the beta 1 isoform of PKC displayed several abnormalities in growth control, and these phenotypic changes were also markedly enhanced when the cells were exposed to TPA. The present studies indicate that these cells also display marked changes in their response to certain growth factors. A striking finding was that several agents when tested alone in serum-free medium, including EGF, PDGF, TPA, teleocidin, and OAG, stimulated DNA synthesis in quiescent R6-PKC3 cells but had a negligible effect in quiescent R6-C1 cells, a vector control cell line with normal levels of PKC. R6-PKC3 cells also show an exaggerated response to very low concentrations of serum, when compared to R6-C1 control cells. These studies provide direct genetic evidence that alterations in cellular levels of PKC can markedly influence the responses of cells to specific growth factors.