Amifostine (WR2721) restores transcriptional activity of speci®c p53mutant proteins in a yeast functional assay

Many p53 mutants found in human cancer have an altered ability to bind DNA and transactivate gene expression. Re-expression of functional p53 in cells in which the endogenous TP53 gene is inactivated has been demonstrated to restore a non-tumorigenic phenotype. Pharmacological modulation of p53 mutant conforma- tion may therefore represent a mechanism to reactivate p53 function and consequently improve response to radio- and chemotherapy. We have recently reported that the radio- and chemoprotector Amifostine (WR2721, Ethyol1) activates wild-type p53 in cultured mammalian cells. In the present study, we have used a yeast functional assay to investigate the e ect of WR2721 on the transcriptional activity of p53. WR2721 restored this activity in a temperature-sensitive mutant V272M (valine to methionine at codon 272) expressed at the non- permissive temperature and it also partially restored the transcriptional activity of several other conformationally ¯exible p53 mutants. The results indicate that the yeast functional assay may be used to identify compounds that modulate p53 activity, with potential therapeutic im- plications.