Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism.
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.
Galy
B
B
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.
Créancier
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L
Zanibellato
C
C
Prats
A C
AC
Prats
H
H
D017209:Apoptosis; D016228:Endothelial Growth Factors / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D008222:Lymphokines / Q000235:genetics; D009369:Neoplasms / Q000209:etiology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000502:physiology; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2