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

Fibroblast growth factor-2 (FGF-2) is a powerful mitogen and angiogenic fac tor whose expression is strongly regulated at the translational level. The constitutive upregulation of FGF-2 isoforms in transformed cells prompted u s to investigate the posttranscriptional effects of a tumour suppressor, p5 3, on FGF-2 expression. We show here in human primary skin fibroblasts that the cell density-dependent variation of FGF-2 mRNA translatability was inv ersely correlated with endogenous p53 expression. Transient cell transfecti on revealed an inhibitory effect of wild-type p53 on the expression of chim eric FGF-CAT proteins. RNAse mapping experiments ruled out any effect of p5 3 on FGF-CAT mRNA accumulation, suggesting a translational inhibition. This inhibition was mediated by the FGF-2 mRNA leader, but not by vascular endo thelial growth factor or platelet derived growth factor mRNA leaders. Neith er p53-like protein p73, nor p21/waf had any inhibitory activity. Furthermo re a set of hot spot mutants of p53 bearing mutations in the DNA binding do main had no post-transcriptional inhibitory effect. In contrast a p53 mutan t of the transactivating domain was still able to block FGF - CAT expressio n, 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.