Cell-type, Dose, and Mutation-type Specificity Dictate Mutant p53 Functions In Vivo

Summary ecific roles of mutant p53ʹs dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using “knockin” mouse strains expressing varying R246S mutant levels, we show that the 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 p53ʹs 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 when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53ʹs DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.