In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models

Abstract

p53 is a crucial tumor suppressor, as evidenced by the high propensity for p53 mutation during human cancer development. Already more than a decade ago, p53 knockout mice confirmed that p53 is critical for preventing tumorigenesis. More recently, a host of p53 knock-in mouse strains has been generated, with the aim of either more precisely modeling p53 mutations in human cancer or better understanding p53's regulation and downstream activities. In the first category, several mouse strains expressing mutant p53 proteins corresponding to human-tumor-derived mutants have demonstrated that mutant p53 is not equivalent to loss of p53 but additionally exhibits gain-of-function properties, promoting invasive and metastatic phenotypes. The second class of p53 knock-in mouse models expressing engineered p53 mutants has also provided new insight into p53 function. For example, mice expressing p53 mutants lacking specific posttranslational modification sites have revealed that these modifications serve to modulate p53 responses in vivo in a cell-type- and stress-specific manner rather than being absolutely required for p53 stabilization and activation as suggested by in vitro experiments. Additionally, studies of p53 mouse models have established that both p53-driven cell-cycle arrest and apoptosis responses contribute to tumor suppression and that activation of p53 by oncogenic stress imposes an important barrier to tumorigenesis. Finally, the use of mouse strains expressing temporally regulatable p53 has demonstrated that p53 loss is not only required for tumor development but also required for tumor maintenance, suggesting that p53 restoration in human cancer patients may be a promising therapeutic strategy. These sophisticated p53 mouse models have taught us important lessons, and new mouse models will certainly continue to reveal interesting and perhaps surprising aspects of p53's complex biology.

Fig. 1.

Summary of the p53 mouse models described in this review, indicating the specific modification of the p53 locus and resulting phenotypes. Functional domains of p53: TAD = transactivation domain; PRD = proline-rich domain; DBD = DNA-binding domain; OD = oligomerization domain; CTD = C-terminal domain. Illustration of knockout, knockdown and knock-in alleles: 4-OHT = 4-hydroxytamoxifen; ERTAM = tamoxifen-regulatable estrogen receptor ligand-binding domain, HupKI = human p53 knock-in; LSL = lox-stop-lox transcriptional stop cassette; neo = neomycin cassette; TRE-CMV = tetracycline-inducible CMV promoter; VP16 = herpes simplex viral protein 16 transactivation domain. Asterisks indicate the location of point mutations, and hatching delineates the regions of p53 that are replaced by the human sequence in the HupKI mouse model.