Lessons on p53 from Mouse Models

Abstract

Mutations in the p53 gene are implicated in the development of at least half of all human cancers, of a wide variety of types.1,2 This high incidence of mutations suggests that there exists a strong selection pressure for p53 inactivation during tumorigenesis. The idea that p53 mutations are important for tumor development in humans has also been supported by the finding that in the Li-Fraumeni syndrome, individuals inherit a mutant p53 allele and show a predisposition to developing a wide variety of cancers.3 An unambiguous cause and effect relationship, however, between p53 mutation and tumorigenesis has been clearly provided through the generation and analysis of p53 knockout mice.4–6 p53 null mice are subject to tumorigenesis at 100% frequency, indicating that the presence of p53 is crucial for preventing cancer development. In addition to this initial observation, significant understanding of the role of p53 as a tumor suppressor has come through further analysis of the p53 knockout mouse as well as other versions of mice with altered p53 genes. In this chapter, we will summarize various p53 knockout and knock-in models and how these models have helped us to understand p53 function in vivo.