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p53 Transgenic mice are highly susceptible to 4-nitroquinoline-1-oxide-induced oral cancer. Mol Cancer Res 2006 Jun;4(6):401-10 PMID: 16778087

Pubmed ID

16778087

Abstract

In this study, we did a bioassay employing mice with a dominant-negative p53 mutation (p53(Val135/WT)) to assess whether a germ-line p53 mutation predisposed mice toward the development of squamous cell carcinomas (SCC) in the oral cavity. Treatment of the mouse oral cavity with 4-nitroquinoline-1-oxide produced a 66%, 91%, and 20% tumor incidence in the oral cavity, esophagus, and forestomach/stomach, respectively, in p53(Val135/WT) mice. In contrast, only a 25%, 58%, and 4% tumor incidence was observed in oral cavity, esophagus, and forestomach/stomach, respectively, in wild-type littermates (p53(WT/WT)). The most striking difference between p53(Val135/WT) and p53(WT/WT) mice following the carcinogen treatment was the higher prevalence and more rapid development of SSC in p53(Val135/WT) mice than in wild-type mice. To identify the precise genes or pathways involved in these differences during tumor development, we examined gene expression profiles of 4-nitroquinoline-1-oxide-treated normal tongues as well as tongue SCC in p53(Val135/WT) and p53(WT/WT) mice. Microarray and GenMAPP analysis revealed that dominant-negative p53 ((135)Valp53) affects several cellular processes involved in SCC development. Affected processes included apoptosis and cell cycle arrest pathways, which were modulated in both tumor and normal epithelium. These results showed that reduction of p53-dependent apoptosis and increases in cell proliferation might contribute to the observed increase in oral cavity and gastroesophageal malignancies in p53(Val135/WT) mice as well as to the more rapid growth and progression of tumors.

Author List

Zhang Z, Wang Y, Yao R, Li J, 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-s2.0-33745823859   17 Citations

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

4-Nitroquinoline-1-oxide
Animals
Apoptosis
Carcinogens
Carcinoma, Squamous Cell
Cell Cycle
Disease Models, Animal
Genes, p53
Genetic Predisposition to Disease
Germ-Line Mutation
Mice
Mice, Transgenic
Mouth Neoplasms
Mutation, Missense
Oligonucleotide Array Sequence Analysis
Tongue Neoplasms
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e