The neurotrophic activity of fibroblast growth factor 1 (FGF1) depends on endogenous FGF1 expression and is independent of the mitogen-activated protein kinase cascade pathway
The neurotrophic activity of fibroblast growth factor 1 (FGF1) depends on endogenous FGF1 expression and is independent of the mitogen-activated protein kinase cascade pathway
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DOI：
10.1074/jbc.271.5.2801
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发表时间：
1996-02-02
影响因子：
4.8
通讯作者：
Laurent, M
中科院分区：
文献类型：
--
作者：
Renaud, F;Desset, S;Laurent, M
成纤维细胞生长因子（FGF） 1是一种有效的神经营养因子，在分化过程中表达增加，并在成人神经元组织中保持高水平。为了检验这种表达对神经元表型的重要性，我们使用PC12细胞模型来研究fgf诱导的神经元分化。在证明了FGF1和FGF2是由PC12细胞合成后，我们研究了FGF1的表达是否可能是分化的关键因素。使用细胞信号通路来确定FGF1单独，FGF1加肝素或突变的FGF1的作用，我们发现有丝裂原活化蛋白（MAP）激酶和MAP激酶（细胞外调节激酶1）的激活程度相同。然而，只有FGF1 +肝素才能促进PC12细胞分化。因此，MAP激酶途径不足以促进分化。在加入FGF1 +肝素或FGF2后对PC12细胞进行的分析显示，FGF1表达水平显著增加，与神经炎延伸的出现时间相同。转染实验增强了地塞米松诱导前后FGF1的表达水平。细胞的分化程度与FGF1的表达量直接相关。MAP激酶途径似乎没有参与。有趣的是，组成型转染细胞中FGF1的5倍增加显著延长了它们在无血清培养基中的存活时间，这表明神经元分化过程中FGF1合成的增加可能与它们在成人中的存活能力有关。所有这些数据表明，与MAP激酶级联相反，FGF1的表达足以诱导PC12细胞分化和存活。研究还表明，FGF1表达的自动激活和反式激活参与了外源FGFs刺激的分化过程，这一途径仍有待研究。
The expression of fibroblast growth factor (FGF) 1, a potent neurotrophic factor, increases during differentiation and remains high in adult neuronal tissues. To examine the importance of this expression on the neuronal phenotype, we have used PC12 cells, a model to study FGF-induced neuronal differentiation. After demonstrating that FGF1 and FGF2 are synthesized by PC12 cells, we investigated if FGF1 expression could be a key element in differentiation. Using the cell signaling pathway to determine the effects of FGF1 alone, FGF1 plus heparin, or a mutated FGF1, we showed an activation to the same extent of mitogen-activated protein (MAP) kinase kinase and MAP kinase (extracellular regulated kinase 1). However, only FGF1 plus heparin could promote PC12 cell differentiation. Thus, the MAP kinase pathway is insufficient to promote differentiation. Analysis of the PC12 cells after the addition of FGF1 plus heparin or FGF2 demonstrated a significant increase in the level of FGF1 expression with the same time course as the appearance of the neuritic extensions. Transfection experiments were performed to enhance constitutivly or after dexamethasone induction the level of FGF1 expression. The degree of differentiation achieved by the cells correlated directly with the amount of FGF1 expressed. The MAP kinase pathway did not appear to be involved. Interestingly, a 5-fold increase in FGF1 in constitutive transfected cells extended dramatically their survival in serum-free medium, suggesting that the rise of FGF1 synthesis during neuronal differentiation is probably linked to their ability to survive in the adult. All of these data demonstrate that, in contrast to the MAP kinase cascade, FGF1 expression is sufficient to induce in PC12 cells both differentiation and survival. It also shows that auto- and trans-activation of FGF1 expression is involved in the differentiation process stimulated by exogenous FGFs through a new pathway which remains to be characterized.