Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
To determine the role of protein kinase Cdelta in mouse skin carcinogenesis, we have developed transgenic FVB/N mouse lines expressing in the epidermis an epitope-tagged protein kinase Cdelta (T7-PKCdelta) regulated by the human keratin 14 promoter. The untreated T7-PKCdelta 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-PKCdelta mouse was unremarkable. Despite this mild phenotype, the effects of PKCdelta overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7-PKCdelta mice (16 and 37) expressing the T7-PKCdelta transgene were examined for responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA. By immunoblot analysis, the T7-PKCdelta-16 and T7-PKCdelta-37 mice showed an 8- and 2-fold increase of PKCdelta protein. The T7-PKCdelta-16 mice averaged 300% more T7-PKCdelta activity than the T7-PKCdelta-37 mice did. The T7-PKCdelta-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-PKCdelta-16 mice relative to wild-type mice averaged 72 and 74% for males and females, respectively. The T7-PKCdelta-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-PKCdelta-16 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7-PKCdelta16 females, 37%; wild-type males, 45%; and T7- PKCdelta-16 males, 7%. Thus, PKCdelta when expressed at sufficient levels can suppress skin tumor promotion by TPA.
Reddig
P J
PJ
Department of Human Oncology, Medical School, University of Wisconsin, Madison 53792, USA.
Dreckschmidt
N E
NE
Ahrens
H
H
Simsiman
R
R
Tseng
C P
CP
Zou
J
J
Oberley
T D
TD
Verma
A K
AK
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D053547:Keratin-14; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D007642:Keratosis / Q000139:chemically induced; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D010212:Papilloma / Q000139:chemically induced* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D012737:Sex Factors; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects* / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D007527:Isoenzymes; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D009363:Neoplasm Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate