Transgenic mice overexpressing protein kinase Cδ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate

To determine the role of protein kinase C delta in mouse skin carcinogenesis, we have developed transgenic FVB/N mouse lines expressing in the epidermis an epitope-tagged protein kinase C delta (T7-PKC delta ) regulated by the human keratin 14 promoter. The untreated T7-PKC delta 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-PKC delta mouse was unremarkable. Despite this mild phenotype, the effects of PKC delta overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7-PKC delta mice (16 and 37) expressing the T7-PKC delta transgene were examined for responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA. By immunoblot analysis, the T7-PKC delta -16 and T7-PKC delta -37 mice showed an 8- and 2-fold increase 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 females, 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 mice. Furthermore, the carcinoma incidence was also reduced in T7-PKC delta -16 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7-PKC delta -16 females, 37%; wild-type males, 45%; and T7- PKC delta -16 males, 7%. Thus, PKC delta when expressed at sufficient levels can suppress skin tumor promotion by TPA.