Carcinogenesis, Vol. 22, No. 4, 651-659,
April 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Age-dependent skin tumorigenesis and transgene expression in the Tg.AC (v-Ha-ras) transgenic mouse
1 Laboratory of Environmental Carcinogenesis and Mutagenesis and
2 Laboratory of Signal Transduction, National Institutes of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709,
3 Lankenau Medical Research Center, 100 Lancaster Avenue West of City Line, Wynnewood, PA, 19096, USA and
4 BASF Aktiengesellschaft, Department of Toxicology Z470, 67056, Ludwigshafen, Germany and
5 College of Pharmacy, Sung Kyun Kwan University, Suwon, Kyunggi-Do 440-746, South Korea
Transgenic Tg.AC (v-Ha-ras ) mice develop skin tumors in response to specific carcinogens and tumor promoters. The Tg.AC mouse carries the coding sequence of v-Ha ras, linked to a 
-globin promoter and an SV40 polyadenylation signal sequence. The transgene confers on these mice the property of genetically initiated skin. This study examines the age-dependent sensitivity of the incidence of skin papillomas in Tg.AC mice exposed to topically applied 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, full thickness skin wounding or UV radiation. Skin tumor incidence and multiplicity were strongly age-dependent, increasing with increasing age of the animal when first treated at 5, 10, 21 or 32 weeks of age. Furthermore, the temporal induction of transgene expression in keratinocytes isolated from TPA-treated mouse skin was also influenced by the age of the mice. Transgene expression was seen as early as 14 days after the start of TPA treatment in mice that were 10–32 weeks of age, but was not detected in similarly treated 5-week old mice. When isolated keratinocytes were fractionated by density gradient centrifugation the highest transgene expression was found in the denser basal keratinocytes. Transgene expression could be detected in the denser keratinocyte fraction as early as 9 days from start of TPA treatment in 32-week old mice. Using flow cytometry, a positive correlation was observed between expression of the v-Ha-ras transgene and enriched expression of the cell surface protein ß1-integrin, a putative marker of epidermal stem cells. This result suggests that, in the Tg.AC mouse, an age-dependent sensitivity to tumor promotion and the correlated induction of transgene expression are related to changes in cellular development in the follicular compartment of the skin.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Lynch, J. Svoboda, S. Putta, H. E. J. Hofland, W. H. Chern, and L. A. Hansen Mouse Skin Models for Carcinogenic Hazard Identification: Utilities and Challenges Toxicol Pathol, December 1, 2007; 35(7): 853 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ridd, S.-D. Zhang, R. E. Edwards, R. Davies, P. Greaves, A. Wolfreys, A. G. Smith, and T. W. Gant Association of gene expression with sequential proliferation, differentiation and tumor formation in murine skin Carcinogenesis, August 1, 2006; 27(8): 1556 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fuhrman, L. Shafer, S. Repertinger, T. Chan, and L. A. Hansen Mechanisms of SEPA 0009-Induced Tumorigenesis in v-rasHa Transgenic Tg.AC Mice Toxicol Pathol, October 1, 2005; 33(6): 623 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Regier, J. Higbee, K. M. Lund, F. Sakane, S. M. Prescott, and M. K. Topham Diacylglycerol kinase {iota} regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling PNAS, May 24, 2005; 102(21): 7595 - 7600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lozano, R. Xing, Z. Cai, H. L. Jensen, C. Trempus, W. Mark, R. Cannon, and R. Kolesnick Deficiency of Kinase Suppressor of Ras1 Prevents Oncogenic Ras Signaling in Mice Cancer Res., July 15, 2003; 63(14): 4232 - 4238. [Abstract] [Full Text] [PDF]
|
|