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Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay

Oncogene volume 20, pages 3533–3540 (2001)Cite this article

Abstract

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 conformation 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, Ethyol®) activates wild-type p53 in cultured mammalian cells. In the present study, we have used a yeast functional assay to investigate the effect 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 flexible p53 mutants. The results indicate that the yeast functional assay may be used to identify compounds that modulate p53 activity, with potential therapeutic implications.

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Acknowledgements

The authors thank Dr Janet Hall and Dr Kris Mann for critical reading of the manuscript, Anne Marie Camus-Randon for technical assistance, Jean Michel Flaman for advice on yeast strains and helpful suggestions and George Mollon for photographic assistance. Daniela Maurici is recipient of a Special Training Award of the International Agency for Research on Cancer. Paola Monti was supported by a fellowship from the Fondazione Italiana per la Ricerca sul Cancro (FIRC). Sophie North was recipient of a postdoctoral fellowship from the Ligue Nationale de Recherche sur le Cancer. This work was supported in part by a pre-clinical research grant from USB Pharma Biosciences, and by EC contract No17225-2000-12F1ED ISP IT.

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Authors and Affiliations

  1. Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon, 69372, France

    Daniela Maurici, Sophie North & Pierre Hainaut

  2. Mutagenesis Laboratory, National Cancer Institute (IST), largo Rosanna Benzi 10, Genova, 16132, Italy

    Paola Monti, Paola Campomenosi & Gilberto Fronza

  3. INSERM EPI 9906, Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, Rouen, 76183, France

    Thierry Frebourg

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  1. Daniela Maurici
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Maurici, D., Monti, P., Campomenosi, P. et al. Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay. Oncogene 20, 3533–3540 (2001). https://doi.org/10.1038/sj.onc.1204428

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