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The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents

Oncogene volume 19, pages 3498–3507 (2000)Cite this article

Abstract

To analyse the effect of p53 on liver tumor development, we generated transgenic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) induces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibited anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplastic cells. Moreover, whereas expression of p53 did not affect hepatic development, its constitutive expression in tumorigenic livers resulted in a significantly enhanced apoptosis once nodules had appeared. In contrast, p53 overexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no effect on hepatocarcinoma progression. In vitro analysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAg-transformed hepatocytes to apoptosis, except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results confirmed that the hepatocyte cell type is very resistant to genotoxic agents and showed that constitutive expression of p53 failed to improve their responsiveness. In addition, our results showed that suppression of dysplastic cells, probably by restoring normal cytokinesis and karyokinesis, and enhancement of apoptosis by means of p53 overexpression were insufficient to counteract or delay the TAg-induced liver tumoral progression.

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Abbreviations

SV40:

Simian Virus 40

TAg:

SV40 large T antigen

BrdU:

bromodeoxyuridine

TUNEL:

TdT-mediated dUTP-biotin nick end labeling

AT3:

antithrombin III

UV:

ultraviolet

wt:

wild-type

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Acknowledgements

We would like to thank Dr E May for kindly providing the wt p53 transgenic construct. We also thank Dr K Huppi and Dr B Vogelstein for p21/Waf-1/Cip-1 and mdm2 cDNA probes, respectively, Pr T Soussi for the generous gift of HR231 monoclonal antibody and Dominique Couton for technical expertise in liver sections. We thank Dr J Richardson for editing the text. All animals' procedures reported in this paper were carried out in accordance with French government regulations. (Services Vétérinaires de la Santé et de la Production Animale, Ministère de l'Agriculture). R Gillet was supported by the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche and Association pour la Recherche sur le Cancer (ARC). This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), ARC and Ligue contre le cancer.

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  1. INSERM U380, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, Paris, 75014, France

    R Gillet, G Grimber, M Bennoun, C Caron de Fromentel, P Briand & V Joulin

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Gillet, R., Grimber, G., Bennoun, M. et al. The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents. Oncogene 19, 3498–3507 (2000). https://doi.org/10.1038/sj.onc.1203671

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