P53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements

Paola Campomenosi, Paola Monti, Anna Aprile, Angelo Abbondandolo, Thierry Frebourg, Barry Gold, Tim Crook, Alberto Inga, Michael A. Resnick, Richard Iggo, Gilberto Fronza

Research output: Contribution to journalArticle

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, P1G3). 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 influence of temperature on transactivation. 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 affect less conserved (P <0.04, Fisher's exact test), more rarely mutated (P <0.006, Fisher's exact test) amino acids. Temperature sensitivity is frequently observed, but is more common among discriminant than non-discriminant mutants (P <0.003, 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 (P <0.001, 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.

Original languageEnglish
Pages (from-to)3573-3579
Number of pages7
JournalOncogene
Volume20
Issue number27
DOIs
Publication statusPublished - Jun 14 2001

Keywords

  • P53
  • P53 responsive elements
  • Yeast functional assay

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Fingerprint Dive into the research topics of 'P53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements'. Together they form a unique fingerprint.

  • Cite this

    Campomenosi, P., Monti, P., Aprile, A., Abbondandolo, A., Frebourg, T., Gold, B., Crook, T., Inga, A., Resnick, M. A., Iggo, R., & Fronza, G. (2001). P53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements. Oncogene, 20(27), 3573-3579. https://doi.org/10.1038/sj.onc.1204468