title: Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis.
abstract: To directly evaluate the role of increased ornithine decarboxylase (ODC) and polyamines in mouse skin carcinogenesis, we used bovine keratin 5 (K5) and keratin 6 (K6) promoter elements to direct the expression of antizyme (AZ) to specific skin cell populations. AZ is a multifunctional regulator of polyamine metabolism that inhibits ODC activity, stimulates ODC degradation, and suppresses polyamine uptake. K5-AZ mice treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0 and 24 h exhibit increases in epidermal and dermal ODC activity that are reduced in magnitude. K6-AZ mice treated similarly do not show any increased ODC activity or protein after a second application due to TPA-induced expression of AZ protein. Epidermal and dermal polyamine content, particularly spermidine, is reduced in untreated K5-AZ mice and TPA-treated K5-AZ and K6-AZ mice. Susceptibility to 7,12-dimethylbenz(a)anthracene/TPA carcinogenesis was also investigated for two K6-AZ transgenic lines [K6-AZ(52) and K6-AZ(18)] and a single K5-AZ line. K6-AZ(52) mice had a substantial delay in tumor onset and a >80% reduction in tumor multiplicity compared with normal littermates. K6-AZ(18) and K5-AZ mice also developed fewer papillomas than littermate controls (35% and 50%, respectively), and the combination of these lines to produce double transgenic animals yielded an additive decrease (70%) in tumor multiplicity. These mice demonstrate for the first time that AZ suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Feith
authors.forename: L M
authors.initials: LM
authors.lastname: Shantz
authors.forename: A E
authors.initials: AE
authors.lastname: Pegg
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002417:Cattle; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D053569:Keratin-15; D053555:Keratin-5; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D015317:Biogenic Polyamines; D002273:Carcinogens; D004791:Enzyme Inhibitors; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate