Manipulating the p53 Gene in the Mouse: Organismal Functions of a Prototype Tumor Suppressor

The early discoveries elucidating p53 function were based on cell culture experiments. Most of our fundamental knowledge of the role of p53 in cell signaling, stress response, cell cycle control, and apoptosis are a result of these in vitro studies (Giaccia and Kastan, 1998; Ko and Prives, 1996; Levine, 1997; Vogelstein et al., 2000). However, a greater depth of understanding was facilitated by the advent first of transgenic mouse methodologies and then by embryonic stem (ES) cell-based genetic manipulations. The sequencing of the mouse genome (www.ensembl.org and www.myscience.appliedbiosystems.com) has greatly simplified and accelerated the generation of null alleles. Methods have been developed to generate single nucleotide substitutions in the germline of mice, and importantly, to generate somatic mutations in genes to study somatic inactivation as occurs in most human cancers. The availability of whole genome analysis at the RNA expression level (arrays) and at the genomic level (array CGH) provides another level of analysis that is sure to provide insights into the molecular changes that lead to the initiation, progression, and maintenance of the tumor phenotype.