Bouleau Sylvina, Grimal Hélène, Rincheval Vincent, Godefroy Nelly, Mignotte Bernard, Vayssière Jean-Luc, Renaud Flore
Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles/Saint Quentin-en Yvelines, CNRS FRE 2445, France.
Oncogene. 2005 Nov 24;24(53):7839-49. doi: 10.1038/sj.onc.1208932.
We analysed the relationships between p53-induced apoptosis and the acidic fibroblast growth factor 1 (FGF1) survival pathway. We found that p53 activation in rat embryonic fibroblasts induced the downregulation of FGF1 expression. These data suggest that the fgf1 gene is a repressed target of p53. Unlike extracellular FGF1, which has no effect on p53-dependent pathways, intracellular FGF1 inhibits both p53-dependent apoptosis and cell growth arrest via an intracrine pathway. FGF1 increases MDM2 expression at both mRNA and protein levels. This increase is associated with an acceleration of p53 degradation, which may partly account for the ability of endogenous FGF1 to counteract p53 pathways. In the presence of FGF1, p53 was unable to transactivate bax, but no modification of p21 gene transactivation was observed. As Bax is an essential component of the p53-dependent apoptosis pathway, this suggests that intracellular FGF1 inhibits p53 pathways not only by decreasing the stability of p53, but also by modifying some of its transactivation properties. In conclusion, we showed that p53 and FGF1 pathways may interact in the cell to determine cell fate. Deregulation of one of these pathways modifies the balance between cell proliferation and cell death and may lead to tumor progression.
我们分析了p53诱导的细胞凋亡与酸性成纤维细胞生长因子1（FGF1）生存途径之间的关系。我们发现，大鼠胚胎成纤维细胞中p53的激活导致FGF1表达下调。这些数据表明，fgf1基因是p53的一个受抑制靶点。与对p53依赖途径无影响的细胞外FGF1不同，细胞内FGF1通过自分泌途径抑制p53依赖的细胞凋亡和细胞生长停滞。FGF1在mRNA和蛋白质水平上均增加MDM2的表达。这种增加与p53降解加速有关，这可能部分解释了内源性FGF1对抗p53途径的能力。在FGF1存在的情况下，p53无法反式激活bax，但未观察到p21基因反式激活的改变。由于Bax是p53依赖的细胞凋亡途径的重要组成部分，这表明细胞内FGF1不仅通过降低p53的稳定性，还通过改变其一些反式激活特性来抑制p53途径。总之，我们表明p53和FGF1途径可能在细胞内相互作用以决定细胞命运。这些途径之一的失调会改变细胞增殖和细胞死亡之间的平衡，并可能导致肿瘤进展。
