Illuminating p53 function in cancer with genetically engineered mouse models

Abstract

The key role of the p53 protein in tumor suppression is highlighted by its frequent mutation in human cancers and by the completely penetrant cancer predisposition of p53 null mice. Beyond providing definitive evidence for the critical function of p53 in tumor suppression, genetically engineered mouse models have offered numerous additional insights into p53 function. p53 knock-in mice expressing tumor-derived p53 mutants have revealed that these mutants display gain-of-function activities that actively promote carcinogenesis. The generation of p53 knock-in mutants with alterations in different domains of p53 has helped further elucidate the cellular and biochemical activities of p53 that are most fundamental for tumor suppression. In addition, modulation of p53 post-translational modification (PTM) status by generating p53 knock-in mouse strains with mutations in p53 PTM sites has revealed a subtlety and complexity to p53 regulation. Analyses of mouse models perturbing upstream regulators of p53 have solidified the notion that the p53 pathway can be compromised by means other than direct p53 mutation. Finally, switchable p53 models that allow p53 reactivation in tumors have helped evaluate the potential of p53 restoration therapy for cancer treatment. Collectively, mouse models have greatly enhanced our understanding of physiological p53 function and will continue to provide new biological and clinical insights in future investigations.

Keywords: Mouse models; Tumor suppression; p53.

Fig. 1

p53 tumor-derived mutants examined in knock-in mouse models. The p53 tumor-derived mutants studied in mouse models and described in this review. Wild-type p53 is shown for reference. p53 functional domains: TAD1 = transactivation domain 1; TAD2 = transactivation domain 2; PRD = proline rich domain; DBD = DNA-binding domain; OD = oligomerization domain; CTD = C-terminal domain. Triangles denote mutated amino acid. Stippling indicates regions of p53 replaced with human sequences in the HUPKI mouse models.

Fig. 2

p53 domain mutants investigated in knock-in mouse models. The p53 domain mutants described in this review are categorized according to the functional domains targeted. Wild-type p53 is shown for reference. p53 functional domains: TAD1 = transactivation domain 1; TAD2 = transactivation domain 2; PRD = proline rich domain; DBD = DNA-binding domain; OD = oligomerization domain; CTD = C-terminal domain. Triangles denote mutated amino acids. ERTAM = tamoxifen-inducible estrogen receptor ligand-binding domain; VP16-herpes simplex viral protein 16 transactivation domain. RR is so-called because of the E180R mutation adjacent to the unmutated residue R181. Even though it is a tumor-derived mutant, p53^R172P is listed here again because it has been used for structure–function analysis of p53. Stippling indicates regions of p53 replaced with human sequences in the HUPKI mouse models.

Fig. 3

p53 post-translational modification site mutants investigated in knock-in mouse models. The p53 post-translational modification site mutants described in this review. Wild-type p53 is shown for reference. p53 functional domains: TAD1 = transactivation domain 1; TAD2 = transactivation domain 2; PRD = proline rich domain; DBD = DNA-binding domain; OD = oligomerization domain; CTD = C-terminal domain. Triangles denote mutated amino acids. Stippling indicates regions of p53 replaced with human sequences in the HUPKI mouse models.