Abstract
Tumour suppressor p53 has been shown to inhibit fibroblast growth factor 2 expression post-transcriptionally in cultured cells. Here we have investigated the mechanism responsible for this post-transcriptional blockade. Deletion mutagenesis of the FGF-2 mRNA leader revealed the requirement of at least four RNA cis-acting elements to mediate the inhibitory effect of p53 in SK-Hep-1 transfected cells, suggesting the involvement of RNA secondary or tertiary structures. Recombinant wild-type, but not Ala143 mutant p53, was able to specifically repress FGF-2 mRNA translation in rabbit reticulocyte lysate, in a dose dependent manner. Sucrose gradient experiments showed that p53 blocks translation initiation by preventing 80S ribosome formation on an mRNA bearing the FGF-2 mRNA leader sequence. Interaction of wild-type and mutant p53 with different RNAs showed no significant correlation between p53 RNA binding activity and its translational inhibiting effect. However, by checking the accessibility of the FGF-2 mRNA leader to complementary oligonucleotide probes, we showed that the binding to RNA of wild-type, but not mutant p53, induced RNA conformational changes that might be responsible for the translational blockade. This strongly suggests that p53 represses FGF-2 mRNA translation by a direct mechanism involving its nucleic acid unwinding–annealing activity.
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Acknowledgements
We thank Stephan Vagner and F Bayard for helpful discussions, and D Warwick for English proofreading. We are grateful to W Deppert and J Mosner (University of Hamburg, Germany) for the murine p53 exon 1. This work was supported by grants from the Association pour la Recherche sur le Cancer, the Ligue Nationale contre le Cancer, the Conseil Régional Midi-Pyrénées, the European Commission Biotechnology program (subprogram Cell Factory, Actions de Recherches Concertées, contract 94/99-181) and Aventis. B Galy had a fellowship from the Ligue Nationale contre le Cancer and then from Retina France. L Creancier was financed by the EC BIOTECH Program and then by Retina France.
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Galy, B., Créancier, L., Prado-Lourenço, L. et al. p53 directs conformational change and translation initiation blockade of human fibroblast growth factor 2 mRNA. Oncogene 20, 4613–4620 (2001). https://doi.org/10.1038/sj.onc.1204630
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DOI: https://doi.org/10.1038/sj.onc.1204630
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