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.