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

Valerie Deguin-Chambon, Monique Vacher, Martial Jullien, Evelyne May, Jean-Christophe Bourdon

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    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 ovrespressed 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 p21(e-11a-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 p21(e-11a-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.

    Original languageEnglish
    Pages (from-to)5831-5841
    Number of pages11
    JournalOncogene
    Volume19
    Issue number51
    Publication statusPublished - 30 Nov 2000

    Keywords

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

    Cite this