Tumour-suppressor super models

Point mutations in the tumour-suppressor gene TP53 cause Li–Fraumeni syndrome, which predisposes patients to a broad spectrum of malignancies, particularly sarcomas and carcinomas. However, the range of tumours seen in these patients cannot be explained simply by the loss of wild-type p53 function. Now, two research groups have generated mouse models that closely resemble Li–Fraumeni syndrome and have used these models to investigate why the TP53 mutations seen in a wide range of human cancers are so oncogenic.

Mice that lack p53 develop lymphomas and sarcomas but not carcinomas, and these tumours tend not to metastasize. Furthermore, p53 is an unusual tumour suppressor because it is commonly altered through missense mutation rather than deletion. So, Kenneth Olive and co-workers produced mice with missense point mutations in two of the most commonly mutated p53 codons in human cancer: Trp53^R172H affects the overall structure of the p53 DNA-binding domain, whereas Trp53^R270H affects a residue that makes direct contact with DNA. Although Trp53^R270H/− and Trp53^R172H/− mice developed distinct tumour spectra, both developed different tumour phenotypes compared with Trp53-knockout mice, indicating that missense Trp53 mutants have pro-tumorigenic or oncogenic functions that cannot be explained simply by the loss of wild-type p53. In particular, strains carrying these two mutant alleles developed metastatic carcinomas and are therefore more accurate models of Li–Fraumeni syndrome.

The possibility that mice carrying Trp53 missense mutations are useful models of Li–Fraumeni syndrome was further supported by work carried out by Gene Lang and colleagues, who also generated mice that possess the Trp53^R172H structural mutation. The results from the two laboratories show that the same Trp53 mutation causes different tumour spectra in different mouse strains; whereas Olive and co-workers found that Trp53^R172H/+ mice developed more carcinomas than Trp53^+/− mice, the Trp53^R172H/+ mice generated by Lang et al. developed metastatic tumours.

Lang and colleagues also found that Trp53^R172H/R172H and Trp53^R172H/+ mouse embryonic fibroblasts grow faster, have more DNA synthesis and have greater transformation potential than Trp53^+/+, Trp53^+/− or Trp53^−/− cells, again supporting the idea that mutant p53 proteins function differently to wild-type p53. So, how do missense mutant p53 proteins exert their oncogenic effects?

p53 interacts with its family members p63 and p73, which themselves activate several p53 target genes in response to DNA damage. Both groups found evidence that p53^R172H interacts with and inhibits endogenous p63 and p73 in cell lines that are derived from mouse tumours expressing this protein. Lang and colleagues also found that the disruption of p63 and p73 causes increased transformation of Trp53^−/− cells and augments DNA synthesis to levels seen in Trp53^R172H/R172H cells. The researchers conclude that the ability of mutant p53 to bind and inhibit p63 and p73 could explain why mutant p53 is more detrimental than the lack of p53, and why TP53 missense mutations — rather than deletions of TP53 — are so commonly found in human tumours.