Rodriguez-Enfedaque Aida, Bouleau Sylvina, Laurent Maryvonne, Courtois Yves, Mignotte Bernard, Vayssière Jean-Luc, Renaud Flore
Laboratoire de Génétique et Biologie Cellulaire, UMR 8159 CNRS, Université de Versailles-Saint-Quentin-en-Yvelines, Ecole Pratique des Hautes Etudes, 78035 Versailles Cedex, France.
Biochim Biophys Acta. 2009 Nov;1793(11):1719-27. doi: 10.1016/j.bbamcr.2009.09.010. Epub 2009 Sep 16.
Fibroblast growth factor 1 (FGF1) is a differentiation and survival factor for neuronal cells both in vitro and in vivo. FGF1 activities can be mediated not only by paracrine and autocrine pathways involving FGF receptors but also by an intracrine pathway, which is an underestimated mode of action. Indeed, FGF1 lacks a secretion signal peptide and contains a nuclear localization sequence (NLS), which is consistent with its usual intracellular and nuclear localization. To progress in the comprehension of the FGF1 intracrine pathway in neuronal cells, we examined the role of the nuclear translocation of FGF1 for its neurotrophic activity as well as for its protective activity against p53-dependent apoptosis. Thus, we have transfected PC12 cells with different FGF1 expression vectors encoding wild type or mutant (Delta NLS) FGF1. This deletion inhibited both FGF1 nuclear translocation and FGF1 neurotrophic activity (including differentiation and serum-free cell survival). We also show that endogenous FGF1 protection of PC12 cells against p53-dependent cell death requires FGF1 nuclear translocation. Strikingly, wild type FGF1 is found interacting with p53, in contrast to the mutant FGF1 deleted of its NLS, suggesting the presence of direct and/or indirect interactions between FGF1 and p53 pathways. Thus, we present evidences that FGF1 may act by a nuclear pathway to induce neuronal differentiation and to protect the cells from apoptosis whether cell death is induced by serum depletion or p53 activation.
成纤维细胞生长因子1（FGF1）在体外和体内均是神经元细胞的分化和存活因子。FGF1的活性不仅可通过涉及FGF受体的旁分泌和自分泌途径介导，还可通过一种内分泌途径介导，而这种途径是一种未被充分认识的作用方式。实际上，FGF1缺乏分泌信号肽且含有核定位序列（NLS），这与其通常的细胞内和细胞核定位一致。为了深入理解神经元细胞中FGF1的内分泌途径，我们研究了FGF1核转位对其神经营养活性以及对其抵抗p53依赖性凋亡的保护活性的作用。因此，我们用编码野生型或突变型（缺失NLS）FGF1的不同FGF1表达载体转染了PC12细胞。这种缺失抑制了FGF1的核转位和FGF1的神经营养活性（包括分化和无血清细胞存活）。我们还表明，内源性FGF1对PC12细胞抵抗p53依赖性细胞死亡的保护作用需要FGF1的核转位。令人惊讶的是，与缺失NLS的突变型FGF1相反，发现野生型FGF1与p53相互作用，这表明FGF1和p53途径之间存在直接和/或间接相互作用。因此，我们提供的证据表明，无论细胞死亡是由血清剥夺还是p53激活诱导，FGF1都可能通过核途径发挥作用，以诱导神经元分化并保护细胞免于凋亡。
