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p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements

Oncogene volume 20, pages 3573–3579 (2001)Cite this article

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 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.

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Acknowledgements

P Monti is supported by a ‘Fondazione Italiana per la Ricerca sul Cancro’ (FIRC) fellowship. This work was partially supported by the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST), by Associazione Italiana per la Ricerca sul Cancro (AIRC), by EC contract No. 17225-2000-12 F1ED ISP IT, and by National Institute of Health (grant R01 CA29088).

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Author notes

  1. Paola Campomenosi and Paola Monti: P Campomenosi and P Monti contributed equally to this work.

Authors and Affiliations

  1. Mutagenesis-Laboratory, National Cancer Research Institute (IST), Largo R. Benzi, 10, 16132-, Genova, Italy

    Paola Campomenosi, Paola Monti, Anna Aprile, Angelo Abbondandolo, Alberto Inga & Gilberto Fronza

  2. Department of Oncology, Biology and Genetics, University of Genova, Italy

    Angelo Abbondandolo

  3. INSERM EP19906, IFRMP, Faculté de Medicine et de Pharmecie, Rouen Cedex, 76183, France

    Thierry Frebourg

  4. Eppley Institute for Research in Cancer and Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, 69198-6805, Nebraska, NE, USA

    Barry Gold

  5. Section of Cell Biology and Experimental Pathology, Ludwig Institute for Cancer Research, St. Mary's Hospital Medical School, Norfolk Place, London, W2 1PG, UK

    Tim Crook

  6. Chromosome Stability Group, National Institute of Environmental Health Sciences (NIEHS), NIH, 27709 , Research Triangle Park, North Caroline, USA

    Alberto Inga & Michael A Resnick

  7. Swiss Institute for Experimental Cancer Research (ISREC), 1066 , Epalinges, Switzerland

    Richard Iggo

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  1. Paola Campomenosi
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Campomenosi, P., Monti, P., Aprile, A. et al. p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements. Oncogene 20, 3573–3579 (2001). https://doi.org/10.1038/sj.onc.1204468

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