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Direct transactivation of c-Ha-Ras gene by p53: evidence for its involvement in p53 transactivation activity and p53-mediated apoptosis

Abstract

p53 protein is a sequence-specific transcriptional activator which induces the expression of a number of cellular genes involved in different metabolic pathways. We report that the computer-selected sequence in human and mouse C-Ha-Ras gene confers to a reporter gene the ability to be directly transactivated by wild-type p53 either overexpressed or activated in response to a cellular stress. By analysing human transformed cell lines, we showed, at both mRNA and protein level, that the endogenous c-Ha-Ras gene expression is positively regulated by wt p53 protein. The stimulation of c-Ha-Ras gene expression in Saos-2Ts cells by a temperature shift down to the permissive temperature for the p53-wt conformation is associated with a significant increase in the activated form of p21c-Ha-Ras protein. Furthermore, in human transformed cell lines, the transient expression of a dominant interfering mutant of c-Ha-Ras greatly reduced the ability of p53 to induce apoptosis and inhibited the p53-dependent transactivation. This is due, at least in part, to a decrease in the protein (but not mRNA) level of the transiently expressed p53, indicating that inactivation of p21c-Ha-Ras signalling pathways led to a specific degradation of p53 protein. We therefore suggest that, by inducing c-Ha-Ras, p53 activates a positive feedback loop that counteracts the negative feedback loop mediated by Mdm2.

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Acknowledgements

We are grateful to A Atfi, R Busca, M Levrero, M Oren, T Soussi and B Vogelstein for providing the plasmids used in this study, K Yamato for the Saos-2Ts and Saos-Neo cell lines, S Lain for SKNSH-DDp53 and SKNSH-CMVNeo cell lines and D Lane for providing DO7 hybridoma cells. We are very grateful to JC Lelong for providing us with baculovirus purified p53 protein. We wish to thank A Atfi for helpful discussions and many insightful comments and P May and V Bouvard for critical reading of the manuscript. This work was supported by a grant from the ‘Association pour la Recherche sur le Cancer’ (ARC), by grant CT94002 from European Commission and by a grant from EDF. V Deguin-Chambon was supported by a fellowship from the ‘Ligue contre le Cancer – comité régional de la Vendée’ and the ARC. JC Bourdon was supported by a fellowship from the ARC and the ‘Fondation pour la Recherche Medicale’.

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Deguin-Chambon, V., Vacher, M., Jullien, M. et al. Direct transactivation of c-Ha-Ras gene by p53: evidence for its involvement in p53 transactivation activity and p53-mediated apoptosis. Oncogene 19, 5831–5841 (2000). https://doi.org/10.1038/sj.onc.1203960

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Keywords

  • p53RE
  • c-Ha-Ras
  • transactivation
  • Ras.GTP
  • p53-stability

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