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Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism

Oncogene volume 20, pages 1669–1677 (2001)Cite this article

Abstract

Fibroblast growth factor-2 (FGF-2) is a powerful mitogen and angiogenic factor whose expression is strongly regulated at the translational level. The constitutive upregulation of FGF-2 isoforms in transformed cells prompted us to investigate the post-transcriptional effects of a tumour suppressor, p53, on FGF-2 expression. We show here in human primary skin fibroblasts that the cell density-dependent variation of FGF-2 mRNA translatability was inversely correlated with endogenous p53 expression. Transient cell transfection revealed an inhibitory effect of wild-type p53 on the expression of chimeric FGF–CAT proteins. RNAse mapping experiments ruled out any effect of p53 on FGF–CAT mRNA accumulation, suggesting a translational inhibition. This inhibition was mediated by the FGF-2 mRNA leader, but not by vascular endothelial growth factor or platelet derived growth factor mRNA leaders. Neither p53-like protein p73, nor p21/waf had any inhibitory activity. Furthermore a set of hot spot mutants of p53 bearing mutations in the DNA binding domain had no post-transcriptional inhibitory effect. In contrast a p53 mutant of the transactivating domain was still able to block FGF–CAT expression, indicating that the post-transcriptional activity of p53 described here was independent of the trans-activation of target genes. Such data reveal a novel mechanism by which p53 efficiently blocks the expression of a major proliferating, anti-apoptotic and angiogenic gene.

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Abbreviations

FGF:

fibroblast growth factor

bFGF:

basic fibroblast growth factor

IRES:

internal ribosome entry site

TGFβ1:

transforming growth factor β1

VEGF:

vascular endothelial growth factor

PDGF:

platelet differentiating growth factor

CAT:

chloramphenicol acetyl-transferase

ORF:

open reading frame

CMV:

cytomegalovirus

RT–PCR:

reverse transcription and polymerase chain reaction

UTR:

untranslated region.

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Acknowledgements

We thank Stephan Vagner for helpful discussions, D Warwick for English proofreading, R Couret for the pictures and C Touriol for his help to finish the manuscript. We are grateful to D Caput and M Kaghad (Sanofi Recherche, France) for the anti-p73 antibody and for the p73α and p21/waf cDNAs, to Dr E Elroy-Stein (Tel Aviv University, Israel) for the pPD1 plasmid, and to Bert Vogelstein (John Hopkins Oncology Center, Baltimore, MD, USA) for the gift of pc53-SN3 and pc53-SCX3 plasmids. This work was supported by grants from the Association pour la Recherche contre le Cancer, the Ligue Nationale contre le Cancer. B Galy had a fellowship from the Ligue Nationale contre le Cancer and then from Retina France. L Creancier was financed by Aventis and Retina France.

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  1. Bruno Galy

    Present address: Gene Expression Programme, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U397, Endocrinologie et Communication Cellulaire, Institut Fédératif de Recherche Louis Bugnard, CHU Rangueil, 31403 Toulouse Cedex 04, France

    Bruno Galy, Laurent Créancier, Catherine Zanibellato, Anne-Catherine Prats & Hervé Prats

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Galy, B., Créancier, L., Zanibellato, C. et al. Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism. Oncogene 20, 1669–1677 (2001). https://doi.org/10.1038/sj.onc.1204271

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