BioProject

The specific roles of mutant p53’s dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. More...

The specific roles of mutant p53’s dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using “knock-in” mouse strains expressing varying R246S mutant levels, we show that DN effect on transactivation is universally observed after acute p53 activation whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53’s DN effect protected against radiation-induced death, but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53-/- mice in various models, even in the absence of MDM2, unlike the R172H mutant. Together, these data demonstrate that mutant p53’s DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific. Overall design: Transcriptomes of 10 normal thymi harvested from 4-5 weeks old mice of different p53 and mdm2 genotype were profiled. Data was analysed by mixed model ANOVA using Partek. Less...