FGF1 nuclear translocation is required for both its neurotrophic activity and its p53-dependent apoptosis protection.
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.
Rodriguez-Enfedaque
Aida
A
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.
Bouleau
Sylvina
S
Laurent
Maryvonne
M
Courtois
Yves
Y
Mignotte
Bernard
B
Vayssière
Jean-Luc
JL
Renaud
Flore
F
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019898:Autocrine Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016716:PC12 Cells; D019899:Paracrine Communication / Q000502:physiology; D051381:Rats; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D016220:Fibroblast Growth Factor 1