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.