Overexpression of a constitutively active form of c-src in skin epidermis increases sensitivity to tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
Transgenic mice were developed to study the role of c-src in epithelial tumorigenesis through targeted expression of a constitutively active form of murine c-src (src(529)). Src(529) was targeted to the interfollicular epidermis with the human keratin 1 (HK1) promoter. The skin phenotype of these mice was characterized by exaggerated epidermal hyperplasia and hyperkeratosis within the first week after birth. The severity of this phenotype correlated with overall src kinase activity, both of which subsided with age. Treatment of adult HK1.src(529) transgenic mice with the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate resulted in an increase in epidermal hyperplasia and labeling index significantly greater than that seen in nontransgenic littermates. In addition, HK1.src(529) transgenic mice developed papillomas earlier and in significantly greater numbers compared with nontransgenic littermates in a standard initiation-promotion experiment. The data support the hypothesis that activation of c-src kinase plays a role in skin tumor promotion.
Matsumoto
Takashi
T
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Jiang
Jianghong
J
Kiguchi
Kaoru
K
Carbajal
Steve
S
Rho
Okkyung
O
Gimenez-Conti
Irma
I
Beltrán
Linda
L
DiGiovanni
John
J
D000818:Animals; D002273:Carcinogens; D004817:Epidermis / Q000201:enzymology / Q000473:pathology; D006965:Hyperplasia; D007633:Keratins / Q000235:genetics; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D007633:Keratins; D016392:Proto-Oncogene Proteins pp60(c-src); D013755:Tetradecanoylphorbol Acetate