p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements
Articolo
Data di Pubblicazione:
2001
Abstract:
The human p53 protein acts mainly as a stress inducible
transcription factor transactivating several genes involved
in cell cycle arrest (e.g. p21) or apoptosis (e.g. Bax,
PIG3). Roughly half of all human tumours contains p53
missense mutations. Virtually all tumour-derived p53
mutants are unable to activate Bax transcription but
some retain the ability to activate p21 transcription.
Identification of these mutants may have valuable clinical
implications. We have determined the transactivation
ability of 77 p53 mutants using reporter yeast strains
containing a p53-regulated ADE2 gene whose promoter
is regulated by p53 responsive elements derived from the
regulatory region of the p21, Bax and PIG3 genes. We
also assessed the in¯uence of temperature on transactiva-
tion. Our results indicate that a significant proportion of
mutants [16/77 (21%); 10/64 (16%) considering only
tumour-derived mutants] are transcriptionally active,
especially with the p21 promoter. Discriminant mutants
preferentially a ect less conserved (P50.04, Fisher's
exact test), more rarely mutated (P50.006, Fisher's
exact test) amino acids. Temperature sensitivity is
frequently observed, but is more common among
discriminant than non-discriminant mutants (P50.003,
Fisher's exact test). Finally, we extended the analysis to
a group of mutants isolated in BRCA-associated tumours
that surprisingly were indistinguishable from wild type in
standard transcription, growth suppression and apoptosis
assays in human cells, but showed gain of function in
transformation assays. The incidence of transcriptionally
active mutations among this group was significantly
higher than in the panel of mutants studied previously
(P50.001, Fisher's exact test). Since it is not possible to
predict the behaviour of a mutant from first principles,
we propose that the yeast assay be used to compile a
functional p53 database and fill the gap between the biophysical, pharmacological and clinical fields.
transcription factor transactivating several genes involved
in cell cycle arrest (e.g. p21) or apoptosis (e.g. Bax,
PIG3). Roughly half of all human tumours contains p53
missense mutations. Virtually all tumour-derived p53
mutants are unable to activate Bax transcription but
some retain the ability to activate p21 transcription.
Identification of these mutants may have valuable clinical
implications. We have determined the transactivation
ability of 77 p53 mutants using reporter yeast strains
containing a p53-regulated ADE2 gene whose promoter
is regulated by p53 responsive elements derived from the
regulatory region of the p21, Bax and PIG3 genes. We
also assessed the in¯uence of temperature on transactiva-
tion. Our results indicate that a significant proportion of
mutants [16/77 (21%); 10/64 (16%) considering only
tumour-derived mutants] are transcriptionally active,
especially with the p21 promoter. Discriminant mutants
preferentially a ect less conserved (P50.04, Fisher's
exact test), more rarely mutated (P50.006, Fisher's
exact test) amino acids. Temperature sensitivity is
frequently observed, but is more common among
discriminant than non-discriminant mutants (P50.003,
Fisher's exact test). Finally, we extended the analysis to
a group of mutants isolated in BRCA-associated tumours
that surprisingly were indistinguishable from wild type in
standard transcription, growth suppression and apoptosis
assays in human cells, but showed gain of function in
transformation assays. The incidence of transcriptionally
active mutations among this group was significantly
higher than in the panel of mutants studied previously
(P50.001, Fisher's exact test). Since it is not possible to
predict the behaviour of a mutant from first principles,
we propose that the yeast assay be used to compile a
functional p53 database and fill the gap between the biophysical, pharmacological and clinical fields.
Tipologia CRIS:
Articolo su Rivista
Elenco autori:
Campomenosi, Paola; Monti, P.; Aprile, A.; Abbondandolo, A.; Frebourg, T.; Gold, B.; Crook, T.; Inga, A.; Resnick, M. A.; Iggo, R.; Fronza, G.
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