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

SummaryThe 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 “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 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 when MDM2 is absent, 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.

► DN effect of mutant p53 is cell-type specific, apparent upon acute p53 activation
► Hypomorphic expression of mutant p53 abrogates DN effects
► DN effect on acute cell death does not promote long-term tumorigenesis
► Mutant p53's gain-of-function property is mutation-type specific