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, Immortalization is also frequently observed in primary cell cultures upon loss of wild-type (wt) p53, and since p53 acts as a tetramer and mutant p53 can hetero-oligomerize with the wild type, a significant number of effects are assigned to mutant p53 acting as a dominant-negative protein. Dominance depends on the ratio of the proteins as well as on the position of the mutated amino acid residue. Mutations that alter the tertiary structure can give rise to proteins capable of forcing upon wt p53 a non-wild-type conformation, and hetero-tetrameric complexes with altered conformation are impaired for DNA binding. Mutations that affect DNA contact sites compromise DNA binding in dependence on the affinity of the hetero-tetrameric complex for a p53 recognition motif, In addition to dominance, mutant p53 can exert oncogenic functions independently of the inactivation of wt p53. Such gain-of-function manifests itself in the enhancement of tumorigenicity, of metastatic potential, and of survival and therapy resistance of wt p53-null tumor cells, The significance of dominant-negative function and gain-of-function for the various cancer phenotypes, for prognosis and for the success of therapy are currently unclear and subject of study.