To determine the role of protein kinase Cδ in mouse skin carcinogenesis, we have developed transgenic FVB/N mouse lines expressing in the epidermis an epitope-tagged protein kinase Cδ (T7-PKCδ) regulated by the human keratin 14 promoter. The untreated T7-PKCδ mice displayed excessive dryness in the skin of the tail with a variable penetrance over time. Histologically, the tail skin showed hyperplasia with evidence of hyperkeratosis. The epidermis of the rest of the T7-PKCδ mouse was unremarkable. Despite this mild phenotype, the effects of PKCδ overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7-PKCδ mice (16 and 37) expressing the T7-PKCδ transgene were examined for responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA. By immunoblot analysis, the T7-PKCδ-16 and T7-PKCδ-37 mice showed an 8- and 2-fold increase of PKCδ protein. The T7-PKCδ-16 mice averaged 300% more T7-PKCδ activity than the T7-PKCδ-37 mice did. The T7-PKCδ-37 mice did not manifest any difference in tumor burden or incidence. However, the reduction in papilloma burden at 25 weeks of promotion for the T7-PKCδ-16 mice relative to wild-type mice averaged 72 and 74% for males and females, respectively. The T7-PKCδ-16 mice reached 50% papilloma incidence between 12 and 13 weeks of promotion compared with 8 weeks for wild-type mice. Furthermore, the carcinoma incidence was also reduced in T7-PKCδ-16 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7-PKCδ-16 females, 37%; wild-type males, 45%; and T7-PKCδ-16 males, 7%. Thus, PKCδ when expressed at sufficient levels can suppress skin tumor promotion by TPA.