This study was undertaken to assess the effects of a single, or two sequential, topical applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of c-fos, c-jun, jun-B, c-myc, and ornithine decarboxylase (ODC) in promotion-sensitive SSIN mice and the relatively promotion-resistant C57BL/6 strain. Northern blot analysis demonstrated that a single promoting dose of TPA induced ODC mRNA 10-15 fold in either strain. Treatment of each strain with a second dose of TPA, 48 h (C57Bl/6) or 72 h (SSIN) after the first, leads to hyperinduction of ODC activity. Although this involved transcription of new ODC mRNA, the hyperinduction of ODC enzyme activity was primarily post-transcriptional. Induction of c-fos mRNA or protein was maximal about 3 h after a single treatment of either strain but was sustained for at least 6 h in C57BL/6 mice. In contrast, two treatments of SSIN with TPA caused a rapid, strong c-fos induction 1-2 h after treatment, while the C57BL/6 responded no more strongly than after a single treatment. c-jun mRNA and protein were induced only slightly in either strain, but jun-B was induced about 5-fold in SSIN and 10-fold in C57BL/6. Although c-myc was induced to comparable levels in both strains, the response was more prolonged in C57BL/6. Compared with SSIN mice, C57BL/6 mice responded to TPA treatment, in general, with changes in proto-oncogene mRNA either to a higher level, for a longer duration, or both. Thus, although small differences in expression of these genes were observed, they were not positively correlated with the differential sensitivity of SSIN and C57BL/6 mice towards tumor promotion by phorbol esters, with the possible exception of c-fos.