title: Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.
abstract: We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow mutation (A(vy)) of the mouse agouti gene which regulates coat color pigmentation by acting within the micro-environment of the hair follicle has been shown to function as a tumor promoter in the liver, we hypothesized that it may also play a role in TGxAC skin tumorigenesis. Endogenous agouti protein product was detected in the outer root sheath of anagen hair follicles following plucking of the hair shaft, but not in the interfollicular epithelium, in TGxAC mice on an FVB/N genetic background. It was also detected in papillomas from these mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking. Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line results in an approximately 2-fold increase in papilloma development compared with controls which did not carry the A(vy) allele following twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition, TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of humoral hypercalcemia mediated by parathyroid hormone-related protein (PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus, we conclude that the A(vy) allele can influence the development of skin tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.
authors.affiliation: Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute for Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Hansen
authors.forename: D E
authors.initials: DE
authors.lastname: Malarkey
authors.forename: J E
authors.initials: JE
authors.lastname: Wilkinson
authors.forename: M
authors.initials: M
authors.lastname: Rosenberg
authors.forename: R E
authors.initials: RE
authors.lastname: Woychik
authors.forename: R W
authors.initials: RW
authors.lastname: Tennant
mesh_terms: D054366:Agouti Signaling Protein; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D017931:DNA Primers; D011905:Genes, ras; D006934:Hypercalcemia / Q000150:complications / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D054366:Agouti Signaling Protein; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C515183:a protein, mouse; D013755:Tetradecanoylphorbol Acetate