The tumor suppressor function of the wild-type
p53 protein is transdominantly inhibited by tumor-derived
mutant p53 proteins. Such transdominant inhibition limits
the prospects for gene therapy approaches that aim to introduce
wild-type p53 into cancer cells. The molecular mechanism
for transdominant inhibition involves sequestration of
wild-type p53 subunits into inactive wild-type/mutant hetero-tetramers.
Thus, p53 proteins, whose oligomerization specificity is
altered so they cannot interact with tumor-derived mutant
p53, would escape transdominant inhibition. Aided by the
known three-dimensional structure of the p53 tetramerization
domain and by trial and error we designed a novel domain
with seven amino acid substitutions in the hydrophobic
core. A full-length p53 protein bearing this novel domain
formed homo-tetramers and had tumor suppressor function,
but did not hetero-oligomerize with tumor-derived mutant
p53 and resisted transdominant inhibition. Thus, hydrophobic
core residues influence the oligomerization specificity
of the p53 tetramerization domain.