FGF1 nuclear translocation is required for both its neurotrophic activity and its p53-dependent apoptosis protection

Abstract

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.

A novel single‐chain variable fragment antibody against FGF‐1 inhibits the growth of breast carcinoma cells by blocking the intracrine pathway of FGF‐1

“…3E) and blocking of FGF-1 intracrine pathway. In view of the above, localization of FGF-1 in the nucleus is necessary for the activation of the intracrine pathway (19,21). These results not only demonstrate scFv1C9 as an effective inhibitor for cancer treatment but also substantiate the intracrine pathway of FGF-1.…”

“…Bouleau et al show that FGF-1 inhibits both p53-dependent apoptosis and cell growth arrest through an intracrine pathway by interacting with p53 in the nuclear compartment where it decreases the stability and the transcriptional activity of p53 (20). The p21, a target gene of p53, is not transactivated by p53 in physiological conditions (19,20). In this case, the cells will transit from G1 to S phase regulated by CDKs.…”

“…The p53 will activate the expression of p21 which arrests the cell cycle at G1 phase by inhibiting the CDK activities. Rodriguez-Enfedaque et al have demonstrated the stably overexpressed FGF-1 deleted NLS (FGF-1DNLS) is detained in the cytoplasm comparing with overexpression of intact FGF-1 (19), which blocks the intracrine pathway of FGF-1. In our study, the overexpressed scFv1C9 also induces the same phenomenon that FGF-1 cytoplasmic detainment (Fig.…”

“…Recent studies revealed the intracrine pathway of FGF-1 to be involved in the proliferation, differentiation, and survival of different cell-types (19,20). Localization of FGF-1 in the nucleus at the G1 phase is necessary for the activation of a downstream pathway (21).…”

FGF19 Protects Colonic Epithelial Cells against Hydrogen Peroxide

“…FGF8b is reported to protect breast cancer cells via activation of the PI3K/Akt pathway [15]. FGF1 is a differentiation and survival factor for neuronal cells, and protects neuronal cells from apoptosis induced by p53 activation [16]. FGF2, defined as a basic FGF, also protects human embryonic stem cells from apoptosis via activation of both mitogen-activated kinase and Akt kinase [17].…”