The group made mice with a p53 point mutation that leaves the protein with the ability to delay cell cycle but not induce apoptosis. This mutation causes a much less severe phenotype than p53 deletions, with a long delay in tumor onset and only rare cases of lymphoma. They then showed that the decreased tumorigenesis is a result of the p53 cell cycle activity's ability to maintain genome stability. Most of the tumor cells from p53 null mice were aneuploid, but those from mice with the point mutation remained diploid. The point mutation cells also had two centrosomes during division, whereas the null cells had multiple centrosomes that led to large chromosomal breaks and missegregations.
“If you look at the literature, it is almost dogma that the apoptosis function of p53 is the crucial activity for preventing tumorigenesis,” says Lozano. “Our data says that the cell cycle arrest function of p53 is as pivotal.” The tumors that do develop, however, tend to be aggressive, which supports the idea that apoptosis is critical for controlling tumor progression. ▪