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  • Original Paper
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Adenovirus-mediated transfer of wild-type p53 gene sensitizes TNF resistant MCF7 derivatives to the cytotoxic effect of this cytokine: relationship with c-myc and Rb

Oncogene volume 18, pages 5464–5472 (1999)Cite this article

Abstract

Tumor suppressor p53 is a nuclear transcription factor that blocks cell cycle progression and induces apoptosis. We have previously shown that the MCF7 resistance to the cytotoxic action of TNF correlates with p53 mutations. In the present study, we used a recombinant adenovirus carrying a wild-type p53 gene (Adwtp53) in order to investigate the effect of wt p53 transfer on modulation of cell resistance to the cytotoxic action of TNF. Our data indicate that infection of TNF resistant MCF7 cells (1001 and MCF7/Adr) with Adwtp53 resulted in the restoration of wt p53 expression and function as respectively revealed by the yeast assay and the induction of p53 inducible genes MDM2 and p21. Furthermore, the restoration of p53 function significantly sensitized TNF resistant cells to TNF cytotoxic action. This correlated with a significant down-regulation of c-myc in both TNF-resistant cell lines and a decrease of Retinoblastoma protein (Rb) in 1001 clone. In contrast, the effect of p53 seems to be independent from Bcl-2 and Bax protein level regulation. The present study suggests that the combination of TNF and Adwtp53 may be a potential strategy to sensitize mutant p53 TNF-resistant tumors to the cytotoxic action of this cytokine.

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Abbreviations

Rb:

retinoblastoma

TNF:

tumor necrosis factor

Adwtp53:

adenovirus wild type p53

MDM2:

murine double minute 2

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Acknowledgements

We thank A Vervish (IRSC, Villejuif, France) and Yann Lécluse (IGR, Villejuif, France) for FACS analysis, Dr O Brison (IGR, France) for providing c-myc antibody and for helpful discussion, and Dr E May (CEA, Saclay) for recombinant virus and plasmid constructions. This work was supported in part by grants from the INSERM, the Association pour la Recherche sur le Cancer (S Chouaib and H Haddada), La Ligue Nationale contre le Cancer and the Institut Gustave Roussy.

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Authors and Affiliations

  1. INSERM U487 ‘Cytokines et Immunologie des Tumeurs Humaines’, Institut Gustave Roussy, Villejuif, 94805, France

    Maya Ameyar, Vladimir Shatrov, Zhenzi Cai, Rodica Stancou & Salem Chouaib

  2. INSERM U362, Institut Gustave Roussy, Villejuif, 94805, France

    Céline Bouquet & Hedi Haddada

  3. UMR 1598, Institut Gustave Roussy, Villejuif, 94805, France

    Corinne Capoulade

  4. UMR CNRS 1772, Institut Gustave Roussy, Villejuif, 94805, France

    Christophe Badie

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Ameyar, M., Shatrov, V., Bouquet, C. et al. Adenovirus-mediated transfer of wild-type p53 gene sensitizes TNF resistant MCF7 derivatives to the cytotoxic effect of this cytokine: relationship with c-myc and Rb. Oncogene 18, 5464–5472 (1999). https://doi.org/10.1038/sj.onc.1202919

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