Transgenic overexpression of transforming growth factor alpha bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis.
The induction of skin papillomas in mice can be divided into two different stages. Chemical initiation frequently elicits mutations in the Ha-ras gene, leading to the constitutive activation of ras. The second step, promotion, involves repetitive topical application of phorbol esters or wounding, leading to epidermal hyperproliferation and papilloma formation. We have found that overexpression of transforming growth factor alpha (TGF-alpha) in the basal epidermal layer of transgenic mice yielded papillomas directly upon wounding or 12-O-tetradecanoylphorbol-13-acetate treatment without the need for an initiator. Moreover, papillomas from TGF-alpha mice did not exhibit mutations in the Ha-ras gene. Interestingly, TGF-alpha acted synergistically with 12-O-tetradecanoylphorbol-13-acetate to enhance epidermal hyperproliferation. Our results demonstrate a central role for TGF-alpha overexpression in tumorigenesis and provide an important animal model for the study of skin tumorigenesis.
Vassar
R
R
Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, Illinois 60637.
Hutton
M E
ME
Fuchs
E
E
D000818:Animals; D001483:Base Sequence; D004273:DNA, Neoplasm; D004195:Disease Models, Animal; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010212:Papilloma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications
D004273:DNA, Neoplasm; D016211:Transforming Growth Factor alpha; D013755:Tetradecanoylphorbol Acetate