Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Induction of invasive mouse skin carcinomas in transgenic mice with mutations in both H-ras and p53. Mol Cancer Res 2005 Oct;3(10):563-74 PMID: 16254190

Pubmed ID

16254190

Abstract

Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53(Val135/wt) mice with TG.AC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced approximately 26% skin tumor incidence, whereas BaP treatment of p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53(wt/wt)Hras(wt/wt)) mice, whereas approximately 1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53(wt/wt)Hras(wt/wt)) in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. Histopathologically, all tumors from p53(wt/wt)Hras(wt/wt) mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53(Val135/wt)Hras(TG.AC/wt) mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val135) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression.

Author List

Zhang Z, Yao R, Li J, Wang Y, Boone CW, Lubet RA, You M

Author

Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-27644506100   13 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Benzo(a)pyrene
Carcinogens
Carcinoma, Squamous Cell
Cocarcinogenesis
Female
Genes, p53
Genes, ras
Germ-Line Mutation
Mice
Mice, Inbred BALB C
Mice, Transgenic
Papilloma
Skin Neoplasms
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e