Sage Journals: Discover world-class research

Abstract

Enhanced linear growth, hyperplasia, and tumorigenesis are well-known characteristics of “viable yellow” agouti A ^vy /- mice (Wolff GL, Roberts DW, Mountjoy KG. Physiol Genomics 1:151–163, 1999); however, the functional basis for this aspect of the phenotype is unknown. In the present study, we ascertained whether agouti signaling protein (ASIP) levels in A ^vy /a or a/a livers are associated with hepatocyte proliferation as a possible factor in promotion of hepatocellular tumor formation. Proliferating cell nuclear antigen (PCNA) assays and quantitative real-time reverse transcriptase polymerase chain reaction assays were performed on liver samples from mottled yellow A ^vy /a, pseudoagouti A ^vy /a, and black a/a VY mice to determine mitotic indices and expression levels of A ^vyand a in relation to the expression level of the housekeeping gene hprt. We found that ASIP levels were ~100-fold higher in yellow than in pseudoagouti or black mice and that the proportion of PCNA-positive hepatocytes was greater (P < 0.001) in yellow than in pseudoagouti or black mice.

Get full access to this article

View all access options for this article.

References

Duhl DMJ, Vrieling H, Miller KA, Wolff GL, Barsh GS. Neomorphic agouti mutations in obese yellow mice. Nat Genet 8:59–65, 1994.

Bultman SJ, Klebig ML, Michaud EJ, Sweet HO, Davisson MT, Woychik RP. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (a ^t) and white-bellied agouti (A ^w) reveals alternative forms of agouti transcripts. Genes Dev 8:481–490, 1994.

Frigeri LG, Wolff GL, Robel G. Impairment of glucose tolerance in yellow (A ^vy /A) (BALB/c x VY)F-1 hybrid mice by hyperglycemic peptides from human pituitary glands. Endocrinology 113:2097–2105, 1983.

Wolff GL, Greenman DL, Frigeri LG, Morrissey RL, Suber RL, Felton RP. Diabetogenic response to streptozotocin varies among obese yellow and among lean agouti (BALB/c x VY)F₁ hybrid mice. Proc Soc Exp Biol Med 193:155–163, 1990.

Wolff GL, Roberts DW, Mountjoy KG. Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome. Physiol Genomics 1:151–163, 1999.

Wolff GL. Growth of inbred yellow (A ^y a) and non-yellow (aa) mice in parabiosis. Genetics 48:1041–1058, 1963.

Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141, 1997.

Warbritton A, Gill AM, Yen TT, Bucci T, Wolff GL. Pancreatic islet cells in pre-obese yellow A ^vy /- mice: relation to adult hyperinsulinemia and obesity. Proc Soc Exp Biol Med 206:145–151, 1994.

Whittaker P, Dunkel VC, Bucci TJ, Kusewitt DF, Thurman JD, Warbritton A, Wolff GL. Genome-linked toxic responses to dietary iron overload. Toxicol Pathol 25:556–564, 1997.

10.

Mountjoy KG, Wu CSJ, Dumont LM, Wild JM. Melanocortin-4 receptor messenger ribonucleic acid expression in cardiorespiratory, musculoskeletal, and integumentary systems. Endocrinology 144: 5488–5496, 2003.

11.

Mynatt RL, Stephens JM. Agouti regulates adipocyte transcription factors. Am J Physiol Cell Physiol 280:C954–C961, 2001.

12.

Kuklin AI, Mynatt RL, Klebig ML, Kieffer LL, Wilkison WO, Woychik RP, Michaud EJ. Liver-specific expression of the agouti gene in transgenic mice promotes liver carcinogenesis in the absence of obesity and diabetes. Mol Cancer 3:17, 2004.

13.

Furumura M, Sakai C, Potterf SB, Vieira WD, Barsh GS, Hearing V. Characterization of genes modulated during pheomelanogenesis using differential display. Proc Natl Acad Sci U S A 95:7374–7378, 1998.

14.

Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132:2393S–2400S, 2002.

15.

Westfall PH, Tobias RD, Rom D, Wolfinger RD, Hochberg Y. Multiple Comparisons and Multiple Tests Using the SAS System. Cary, North Carolina: SAS Institute, pp30, 1999.

16.

Wolff GL, Medina D, Umholtz RL. Manifestation of hyperplastic alveolar nodules and mammary tumors in “viable yellow” and non-yellow mice. J Natl Cancer Inst 63:781–785, 1979.

17.

Wolff GL, Kodell RL, Cameron AM, Medina D. Accelerated appearance of chemically induced mammary carcinomas in obese yellow (A ^vy /A) (BALB/c x VY) F₁ hybrid mice. J Toxicol Environ Health 10:131–142, 1982.

18.

Wolff GL, Pitot HC. Variation of hepatic malic enzyme capacity with hepatoma susceptibility in mice of different genotypes. Cancer Res 32: 1861–1863, 1972.

19.

Wolff GL, Roberts DW, Morrissey RL, Greenman DL, Allen RR, Campbell WL, Bergman H, Nesnow S, Frith CH. Tumorigenic responses to lindane in mice: potentiation by a dominant mutation. Carcinogenesis 8:1889–1897, 1987.

20.

Furumura M, Potterf SB, Toyofuku K, Matsunaga J, Muller J, Hearing VJ. Involvement of ITF2 in the transcriptional regulation of melanogenic genes. J Biol Chem 276:28147–28154, 2001.

21.

Polakis P. Wnt signaling and cancer. Genes Dev 14:1837–1851, 2000.

A BRIEF COMMUNICATION

Abstract

Get full access to this article

References