Transgenic mice overexpressing protein kinase C delta in the epidermis areresistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate

To determine the role of protein kinase C delta in mouse skin carcinogenesi s, we have developed transgenic FVB/N mouse lines expressing in the epiderm is an epitope-tagged protein kinase CS (T7-PKC delta) regulated by the huma n keratin 14 promoter. The untreated T7-PKC delta mice displayed excessive dryness in the skin of the tail with a variable penetrance over time. Histo logically, the tail skin showed hyperplasia with evidence of hyperkeratosis . The epidermis of the rest of the T7-PKC delta mouse was unremarkable. Des pite this mild phenotype, the effects of PKC delta overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dra matic. Two independent lines of T7-PKC delta mice (16 and 37) expressing th e T7-PKC delta transgene were examined for responsiveness to skin tumor pro motion by 7,12-dimethylbenz[a]anthracene and TPA. Ey immunoblot analysis, t he T7-PKC delta-16 and T7-PKC delta-37 mice showed an 8- and 2-fold increas e of PKC delta protein. The T7-PKC delta-16 mice averaged 300% more T7-PKC delta activity than the T7-PKC delta-37 mice did. The T7-PKC delta-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-PKC delta -16 mice relative to wild-type mice averaged 72 and 74% for males and femal es, respectively. The T7-PKC delta-16 mice reached 50% papilloma incidence between 12 and 13 weeks of promotion compared with 8 weeks for wild-type mi ce. Furthermore, the carcinoma incidence was also reduced in T7-PKC delta-1 6 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-ty pe females, 78%; T7-PKC delta-16 females, 37%; mild-type males, 45%; and T7 - PKC delta-16 males, 7%. Thus, PKC delta when expressed at sufficient leve ls can suppress skin tumor promotion by TPA.