Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TG.AC mice

Laura A. Hansen, David E. Malarkey, J. Erby Wilkinson, Michael Rosenberg, Richard E. Woychik, Raymond W. Tennant

Research output: Contribution to journalArticle

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Abstract

We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TG.AC 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 TG.AC 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 TG.AC 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 TG.AC mouse line results in an ~ 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 μg 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 TG.AC mice.

Original languageEnglish
Pages (from-to)1837-1845
Number of pages9
JournalCarcinogenesis
Volume19
Issue number10
DOIs
StatePublished - Oct 1998
Externally publishedYes

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Hypercalcemia
Carcinogenesis
Alleles
Skin
Papilloma
Tetradecanoylphorbol Acetate
Parathyroid Hormone-Related Protein
Hair Follicle
Agouti Signaling Protein
Epithelium
Hypophosphatemia
Dasyproctidae
Pigmentation
Carcinogens
Hair
Weight Loss
Color
Mutation
Liver
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TG.AC mice. / Hansen, Laura A.; Malarkey, David E.; Wilkinson, J. Erby; Rosenberg, Michael; Woychik, Richard E.; Tennant, Raymond W.

In: Carcinogenesis, Vol. 19, No. 10, 10.1998, p. 1837-1845.

Research output: Contribution to journalArticle

Hansen, Laura A. ; Malarkey, David E. ; Wilkinson, J. Erby ; Rosenberg, Michael ; Woychik, Richard E. ; Tennant, Raymond W. / Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TG.AC mice. In: Carcinogenesis. 1998 ; Vol. 19, No. 10. pp. 1837-1845.
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abstract = "We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TG.AC 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 TG.AC 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 TG.AC 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 TG.AC mouse line results in an ~ 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 μg 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 TG.AC mice.",
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