Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion.
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.
Reddig
P J
PJ
Department of Human Oncology, Medical School, University of Wisconsin, Madison 53792, USA.
Dreckschmidt
N E
NE
Zou
J
J
Bourguignon
S E
SE
Oberley
T D
TD
Verma
A K
AK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D004817:Epidermis / Q000201:enzymology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D010641:Phenotype; D011493:Protein Kinase C / Q000502:physiology*; D012878:Skin Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D007527:Isoenzymes; D015127:9,10-Dimethyl-1,2-benzanthracene; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate