High impact information on FGF1

• Brain-derived acidic fibroblast growth factor: complete amino acid sequence and homologies [1].
• Acidic and basic fibroblast growth factors (aFGF and bFGF) have been isolated and purified from rod outer segments (ROS). aFGF is tightly bound to ROS membranes and can be specifically released by ATP [2].
• This demonstrates that aFGF release from ROS membranes is dependent on its phosphorylation by endogenous kinase C. In addition specific binding sites for exogenous FGFs have been identified on ROS and disc membranes [2].
• We show that this mechanism is dependent on the phosphorylation of aFGF itself [2].
• The presence of specific receptors for FGFs and the kinase C dependent release of endogenous membrane bound aFGF suggest an autocrine mechanism which may be involved in photoreceptor cell biology [2].

Biological context of FGF1

• Experiments with cells lacking active HS indicated that extended >/=14-mer heparin domains were needed to enhance cell proliferation and Erk phosphorylation by FGF8b, whereas in cells stimulated with FGF1 or FGF2 the corresponding responses were achieved by much shorter, 6-8-mer, oligosaccharides [3].
• Both inhibition of endogenous fibroblast growth factor (FGF) synthesis on nondividing lens epithelial cells and inhibition of secreted FGF1 in confluent quiescent retinal pigmented epithelial (RPE) cells induce rapid cell apoptosis (Renaud et al., 1996, J. Biol. Chem., 271, 2801-2811) [4].
• To determine the possible relationship between exogenous FGF2, endogenous FGF1, and cell survival, we examined the protective effect of a single dose of exogenous FGF2 on long-term culture of quiescent RPE cells after serum withdrawal [4].
• After 4 days of culture, a dramatic and sustained upregulation of FGF1 protein expression occurs specifically in response to exogenous FGF2 [4].
• Secreted FGF1 from RPE cells, purified from culture medium and added to either Go-arrested RPE or RMG cells at low plating density induced cell proliferation, whereas when it is added once to serum-depleted confluent RPE and RMG cells it prevented apoptosis [5].

Anatomical context of FGF1

• The role of heparin and heparan sulfate in the binding and signaling of fibroblast growth factors (FGFs) has been subject to intense investigation, but the studies have largely been confined to two species (FGF1 and FGF2) of the family with approximately 20 members [3].
• FGF2-stimulated release of endogenous FGF1 is associated with reduced apoptosis in retinal pigmented epithelial cells [4].
• Fibroblast growth factor 1 (FGF1) and 2 (FGF2) bind to two classes of receptors: the high affinity receptors, a family of four known transmembrane tyrosine kinases (FGF R1-R4), and the low affinity receptors, cell surface and basement membrane heparan sulfate proteoglycan (HSPG) [6].
• The FGF1 protein could be predominantly localized in the cytoplasm of GC, in smooth muscle cells of blood vessels, in the rete ovarii, and at a lesser degree in theca cells [7].
• We show that this secreted form of phosphorylated FGF1 binds to the high affinity tyrosine kinase receptors of RPE and RMG cells on retinal sections and to heparan sulfate proteoglycan in RPE cell extracellular matrix [5].

Associations of FGF1 with chemical compounds

• Degradation of bFGF appeared to occur in the lysosomal compartment since it was inhibited by chloroquine, an inhibitor of lysosomal proteases; aFGF internalization and degradation followed the same kinetics as bFGF with the appearance of 7 kDa and 5 kDa fragments [8].
• The number of steroidogenic (3beta HSD positive) cells per unit area was counted for control cultures (no treatment) and cultures treated with the most effective doses of FGF-1, FGF-2, LH, OR FBS in proliferation and (or) progesterone assays [9].
• Importance of 6-O-sulfate groups of glucosamine residues in heparin for activation of FGF-1 and FGF-2 [10].
• Anti-aFGF antibody inhibited thymidine incorporation by more than 32% in the cells exposed to 0.05 mM Ca2+ shortly before adding [3H]thymidine, whereas the incorporation was not significantly affected by the antibody at 0.7 mM Ca2+ [11].
• Poly-L-arginine, an inhibitor for aFGF binding to the receptor, appeared to stimulate the mitogenesis or cell growth of responsive cells by mimicking aFGF activity [12].

Regulatory relationships of FGF1

• Secreted FGF1 induced long-term activation of FGFR1 and ERK2, which was necessary to induce a constant and high level of Bcl-x production, and to induce cell survival in FGFI cells [13].
• FGF-1 stimulated DNA synthesis while FGF-2 in concentrations above 10 ng/ml inhibited DNA synthesis [14].
• Endogenous FGF1-induced activation and synthesis of extracellular signal-regulated kinase 2 reduce cell apoptosis in retinal-pigmented epithelial cells [15].
• Overexpression of a secretory form of FGF-1 promotes MMP-1-mediated endothelial cell migration [16].

Other interactions of FGF1

• By contrast, the saccharide structures required for the biological activity of FGF8b differed significantly from those characteristic for FGF1 and FGF2 [3].
• In aged RPE cells, FGFR1 was rapidly activated, and its autophosphorylation followed the kinetics of endogenous FGF1 secretion, before the onset of apoptosis [15].
• In the NBT-II system in vivo FGF-1 and FGF-2 are highly and comparatively angiogenic in the resultant carcinoma and this occurs in the absence of production of significant amounts of VEGF by the carcinoma cells [17].
• Furthermore, TGF beta potentiates the effects of bFGF and aFGF on the proliferation of bone cells [18].
• These experiments examined several aspects of FGF signaling and the contribution of endogenous FGF1 to activation of the extracellular signal-regulated kinase 2 (ERK2) [15].

Analytical, diagnostic and therapeutic context of FGF1

• Acidic fibroblast growth factor (FGF) from bovine brain has been isolated by a combination of salt precipitation, ion-exchange chromatography, heparin-Sepharose affinity chromatography and reverse phase h.p.l.c. The amino acid composition of the mitogen is indistinguishable from that of acidic FGF previously purified [19].
• We now show that a major mitogenic fraction, isolated from heparin-Sepharose-purified material by Mono-S cation-exchange chromatography and reverse-phase high-performance liquid chromatography, is related to acidic fibroblast growth factor (aFGF) [20].
• Northern blot analysis of bovine brain and retina poly(A+) RNAs showed the existence of four aFGF mRNA species [21].
• Cloning of two different 5' untranslated exons of bovine acidic fibroblast growth factor by the single strand ligation to single-stranded cDNA methodology [22].
• Thus, the proliferation and survival activities of FGF1 depend on the secretion of FGF1 which is determined by the cell culture conditions [13].

References