Mutant p53 oncogenicity: dominant-negative or gain-of-function?

The p53 protein is mutated in about 50% of human cancers. Aside from losing its tumor-suppressive activities, mutant p53 may acquire pro-oncogenic activity, which is facilitated by two underlying mechanisms. The first mechanism is the inhibition of co-expressed wild-type p53 (WTp53) activity, dubbed the dominant-negative effect (DNE). The second mechanism is a neomorphic pro-oncogenic activity that does not involve the inhibition of WTp53, termed gain-of-function (GOF). Throughout the years, both mechanisms were demonstrated in a plethora of in vitro and in vivo models. However, whether both account for protumorigenic activities of mutant p53 and in which contexts is still a matter of ongoing debate. Here, we discuss evidence for both DNE and GOF in a variety of models. These models suggest that both GOF and DNE can be relevant, but are highly dependent on the specific mutation type, genetic and cellular context and even the phenotype that is being assessed. In addition, we discuss how mutant and WTp53 might not exist as two separate entities, but rather as a continuum that may involve a balance between the two forms in the same cells, which could be tilted by various factors and drugs. Further elucidation of the factors that dictate the balance between the WT and mutant p53 states, as well as the factors that govern the impact of DNE and GOF in different cancer types, may lead to the development of more effective treatment regimens for cancer patients.