Mutant p53: Gain-of-function oncoproteins and wild-type p53 inactivators

Cancers frequently express mutant forms of the p53 transcription factor and tumor suppressor. Early observations indicated that mutant p53 can enhance the malignancy of tumor cells and immortalize primary cells, Immortalizati on is also frequently observed in primary cell cultures upon loss of wild-t ype (wt) p53, and since p53 acts as a tetramer and mutant p53 can hetero-ol igomerize with the wild type, a significant number of effects are assigned to mutant p53 acting as a dominant-negative protein. Dominance depends on t he ratio of the proteins as well as on the position of the mutated amino ac id residue. Mutations that alter the tertiary structure can give rise to pr oteins capable of forcing upon wt p53 a non-wild-type conformation, and het ero-tetrameric complexes with altered conformation are impaired for DNA bin ding. Mutations that affect DNA contact sites compromise DNA binding in dep endence on the affinity of the hetero-tetrameric complex for a p53 recognit ion motif, In addition to dominance, mutant p53 can exert oncogenic functio ns independently of the inactivation of wt p53. Such gain-of-function manif ests itself in the enhancement of tumorigenicity, of metastatic potential, and of survival and therapy resistance of wt p53-null tumor cells, The sign ificance of dominant-negative function and gain-of-function for the various cancer phenotypes, for prognosis and for the success of therapy are curren tly unclear and subject of study.