p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect

Increasing the complexity of their models, p53s are stabilized either in or der to function (wt p53) or due to the loss of function (mutant p53) with a cquiring a mysterious prion-like ability to drive the normal p53 into the a bnormal conformation to gain new functions. As already recognized, the loss of trans-activating function leads to a stabilization of mutant p53 becaus e of the disappearance of the p53-inducible proteins, which otherwise direc tly (Mdm-2) or indirectly (p21) target p53 for degradation. Simplifying fur ther, I will discuss that the loss of function results in a dominant-negati ve effect and gain-of-function (a dominant-positive effect). Thus, mutant p 53 lacking trans-activation function nevertheless may retain the ability to repress transcription due to its competition with numerous transcription f actors for their coactivators. When mutant p53 competes with wt p53, the in hibition of the wt p53-dependent transcription is perceived as a dominant-n egative effect. Just like trans-repression, a dominant-negative effect requ ires an excess of p53 and, therefore, a 'dominant'-negative effect is not d ominant. Furthermore, the stabilization of an endogenous mt p53 due to the loss of wt functions cannot occur in the presence of the wt p53 allele. Giv en the inability of mutant p53 to accumulate in the presence of wt p53, a d ominant-negative effect does not naturally occur and, not surprisingly, het erozygous mt/wt cells are rare. The detection of a dominant-negative effect simply indicates that mutant p53 indeed has lost its function. Last, since mutant p53 loses some or most but not all activities and accumulates in th e absence of wt allele, gain-of-function can be considered as an exaggerati on of the remaining functions. Applications to cancer therapy are discussed .