p53 directs conformational change and translation initiation blockade of human fibroblast growth factor 2 mRNA

被引:44
作者
Galy, B [1 ]
Créancier, L [1 ]
Prado-Lourenço, L [1 ]
Prats, AC [1 ]
Prats, H [1 ]
机构
[1] CHU Rangueil, INSERM, U397, Inst Fed Rech Louis Bugnard, F-31403 Toulouse 04, France
关键词
FGF; p53; translational control; RNA-protein interactions; RNA structure;
D O I
10.1038/sj.onc.1204630
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Ala(143) 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.
引用
收藏
页码:4613 / 4620
页数:8
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