Transient accumulation of c-fos RNA following serum stimulation requires both a conserved 5' regulatory element and sequences at the 3' end of the gene. Here we show that mutations at the C terminus of Fos protein, of the type found in a virally-transduced actively transforming Fos variant, prevent the rapid down-regulation of c-fos transcription that occurs following serum-induced activation. Fos mutants that prevent down-regulation are dominant, acting in trans to prevent down-regulation of a co-transfected c-fos gene. Co-transfection experiments suggest that this effect is mediated by multiple sequence elements in the 5'-flanking region. Analysis of different Fos mutants showed that replacement of Fos sequences C-terminal to amino acid 337 with heterologous polypeptide, rather than simple truncation of the protein, is required to produce mutants defective in down-regulation. The results are discussed with reference to transformation by Fos.