To determine the role that
protein kinase C epsilon (PKCepsilon) may play in skin growth, differentiation, and
tumor promotion, transgenic mice were generated that overexpressed an
epitope-tagged
protein kinase C epsilon (T7-PKCepsilon) in their epidermis using the human
keratin 14 promoter. Three independent mouse lines that overexpressed the T7-PKCepsilon in their epidermis were produced. The three independent lines 206, 224, and 215 exhibited a 3-, 6-, and 18-fold elevation, respectively, in the level of PKCepsilon immunoreactive
protein. Line 215 exhibited a 19-fold greater
phosphatidylserine and 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated
kinase activity than line 224. Line 206 exhibited a low basal T7-PKCepsilon activity, which failed to be stimulated by
phosphatidylserine and TPA. All of the line 215 transgenic mice (F0 to the F2 generation) displayed phenotypic changes in the skin. The phenotypic changes progressed gradually, starting around 4-5 months of age, with mild dryness of the tail accompanied by
hair loss and
inflammation at the base of the tail. Hyperproliferation and ulceration of the affected regions were observed around 7-8 months of age. The hyperproliferative epidermis from the affected regions exhibited an expansion of the suprabasal epidermal cells.
Inflammation and/or ulceration were also observed in the dorsal skin, the ears, and around the eyes. The line 215 mice, which expressed the highest level of PKCepsilon, were evaluated for sensitivity to mouse skin
tumor promotion by TPA.
Tumors were elicited by the initiation (7,12-dimethylbenz[a]
anthracene, 100 nmol)-promotion (TPA, 5 nmol/twice weekly) protocol. The
papilloma burden was reduced by 95-96% for male and female T7-PKCepsilon mice compared to wild-type controls. However,
carcinomas developed rapidly in the T7-PKCepsilon mice treated with 7, 12-dimethylbenz[a]
anthracene and TPA. These
carcinomas appeared to form independently of prior
papilloma development. These results demonstrate that PKCepsilon is an important regulator of skin
tumor development.