We have established rat PC12 pheochromocytoma cell lines stably expressing the estrogen-activatable transcription factor FosER to identify genes that can be regulated by c-Fos in this neuronal cell type. Induction of ectopic c-Fos activity in PC12 cells increased the mRNA levels of the ornithine decarboxylase (ODC) and tyrosine hydroxylase genes with similar kinetics and to the same maximal level as nerve growth factor treatment. In both cases the rate of transcription initiation was increased. Induction of the ODC gene occurred even in the absence of protein synthesis, indicating direct regulation by FosER. ODC expression, however, was not induced by a mutant FosER protein containing a proline insertion in the basic region of the c-Fos moiety, demonstrating the requirement for a functional DNA-binding domain. These data show that FosER, and by extrapolation c-Fos, can directly activate transcription of the endogenous ODC gene in PC12 cells by binding to cis-regulatory sequences. Activation of the ODC gene was unexpectedly transient, as transcripts returned to the basal level after prolonged exposure of PC12 cells to FosER activity. Furthermore, ODC transcription was not at all induced by FosER in rat fibroblasts. To account for this cell-specific action of FosER, we propose that stimulation of the ODC gene by FosER requires either (i) cooperation with another transcription factor(s) or (ii) a specific pattern of modification which is present in PC12 cells but not in otherwise unstimulated fibroblasts. One or both of these mechanisms may be employed by cells to achieve selective gene activation in response to apparently stereotyped induction of c-fos.