THE ROLE OF Tp53 IN THE FORMATION OF Ras INDUCED SQUAMOUS CELL CARCINOMAS

Abstract

To increase our understanding of the nature of the genetic events leading to cancer formation, we have investigated the role of the Tp53 tumor suppressor gene in the progression of Ras-induced squamous cell carcinomas (SCC) by the use of complementary chemically-induced and genetically-defined mouse models. These models include the classic 2-hit chemical carcinogenesis model, and the targeted expression in stratified epithelium of a mutated form of K-Ras using a tetracycline- inducible system or a tamoxifen-inducible Cre-recombinase system in Tp53 wild-type, heterozygous, and conditional double knockout mice. Overall, we conclude that Ras activation and Tp53 inactivation are sufficient to initiate SCC in the oral epithelium, but that additional events are necessary to promote skin SCC. We also provide evidence that Ras activation and overexpression, such as by gene amplification, in a cell population that includes the epithelial stem cells is sufficient to initiate SCC progression, thus overriding the requirement for Tp53 inactivation.