Disease relevance of Fgf2

• Fgf2 knockout mice are morphologically normal and display decreased vascular smooth muscle contractility, low blood pressure and thrombocytosis [1].
• AC Fgf2(-/-) mice develop significantly less hypertrophy (4-24% increase) compared with AC Fgf2(+/+) mice (41-52% increase) [2].
• Mice with or without FGF2 (Fgf2(+/+) and Fgf2(-/-), respectively) were subjected to transverse aortic coarctation (AC) [2].
• Injection of PTH caused hypercalcemia in Fgf2+/+ but not Fgf2-/mice [3].
• Given the equivalent responses observed in Fgf2(+/+) and Fgf2(-/-) mice, we demonstrate that endogenous FGF-2 is not required for revascularization in the setting of peripheral ischemia [4].
• Analysis of gene expression and protein analysis demonstrated the expression of FGF2 and VEGF by the breast cancer cells, and the presence of VEGF (FLK1) and FGF2 receptors on the MSCs [5].

Psychiatry related information on Fgf2

• The experimental animals were divided among four groups: negative control, positive control (topical basic fibroblast growth factor [bFGF] on wound), laser therapy group; and a combination group of laser therapy and topical bFGF [6].
• These results suggest that bFGF ameliorates the memory deficit without affecting the cortical ChAT activity [7].

High impact information on Fgf2

• Heparan sulfate-deficient mutants transfected to express a cloned mouse FGF receptor cDNA are not able to bind bFGF [8].
• Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor [8].
• The role of low affinity, heparin-like binding sites for basic fibroblast growth factor (bFGF) was investigated in CHO cells mutant in their metabolism of glycosaminoglycans [8].
• Analysis of cell cultures derived from biopsies of these lesions has revealed that basic fibroblast growth factor (bFGF) is synthesized in all three stages and in normal dermal fibroblasts derived from the same mice [9].
• Unexpectedly, there is a change in the localization of bFGF from its normal cell-associated state to extracellular release in the latter two stages, which is concomitant both with the neovascularization seen in vivo and with the tumorigenicity of these cell lines [9].

Chemical compound and disease context of Fgf2

• We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein [10].
• Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis [11].
• Furthermore, we have examined the effects of 18-mer phosphorothioate oligodeoxynucleotides of different sequences on 125I-bFGF binding to low and high affinity sites on both NIH 3T3 fibroblasts and DU-145 prostate cancer cells [12].
• The altered balance between bFGF and IFN-beta was associated with increased endothelial cell proliferation (bromodeoxyuridine + CD31 + cells) within existing blood vessels, leading to telangiectasia and new blood vessels [13].
• We now show in the mouse that thalidomide given intraperitoneally but not orally significantly inhibits bFGF-induced and vascular endothelial growth factor (VEGF)-induced corneal neovascularization [14].

Biological context of Fgf2

• To examine the potential role of fibroblast growth factor (FGF) signalling during cell differentiation, we used conditionally immortalised podocyte cells isolated from kidneys of Fgf2 mutant and wild-type mice [15].
• We found that FGF2 treatment of developing bone fronts stimulated Bmp2 gene expression but that BMP2 treatment could not induce Fgf2 expression [16].
• We show that the absence of Fgf2 gene products reduces by 50% the dividing progenitor population of the anterior SVZ (SVZa) without changing their cell cycle time [17].
• Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation [18].
• Basic fibroblast growth factor (FGF-2), an important modulator of cartilage and bone growth and differentiation, is expressed and regulated in osteoblastic cells [18].

Anatomical context of Fgf2

• In addition, there was a profound decreased mineralization of bone marrow stromal cultures from Fgf2(-/-) mice [18].
• After 6 days of treatment, osteoprotegerin protein in cell supernatants was 40-fold higher in vehicle-treated and 30-fold higher in PTH-treated co-cultures of osteoblast and spleen cells from Fgf2-/mice compared with Fgf2+/+ mice [3].
• Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone [3].
• Bone marrow stromal cells (BMOp) isolated from Fgf2(-/-) and Fgf2(+/+) mice were used to study the importance of FGF-2 in MS-induced proliferation [19].
• In contrast to vascular endothelial growth factor, which is required for proliferation and survival of endothelial cells, FGF2 does not seem to be essential since the Fgf2 knockout is not lethal [20].

Associations of Fgf2 with chemical compounds

• Treatment of the transformed transfected NIH 3T3 cells with suramin, which blocks the interaction of bFGF with its receptor, reversed the morphological transformation and restored receptors almost to normal numbers [21].
• Protection by bFGF or aFGF plus heparin is not associated with cell-cycle traverse into S phase [22].
• In vitro, short hairpin RNA-mediated down-regulation of HSulf-1 in human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation mediated by heparan sulfate-dependent FGF-2, hepatocyte growth factor, and vascular endothelial growth factor 165 (VEGF165) but not by heparan sulfate-independent VEGF121 [23].
• Finally, the most potent phosphorothioate oligodeoxynucleotides used in these experiments (e.g. SdC28) were inhibitors of bFGF-induced DNA synthesis in NIH 3T3 cells [12].
• The increase in inositol phosphates induced by bFGF, EGF, or bombesin was significantly enhanced by Ro-31-8220, an inhibitor of protein kinase C (PKC), suggesting that PtdIns(4,5)P2-hydrolyzing phospholipase is coupled to the receptors for these agonists but that the response is down-regulated by PKC [24].

Physical interactions of Fgf2

• These results demonstrate that in these cells bFGF transforms cells by interacting with its receptor and that bFGF and hst/K-fgf may use the same receptor [21].
• Despite the fact that we have observed inhibition of bFGF binding by the 18-mer phosphorothioate oligodeoxynucleotides for both the high and low affinity classes of bFGF receptor, the inhibition was sequence-selective only for the high affinity receptors [12].
• By using purified proteins, FGF-2 is shown to directly interact through two separate domains with two RSK2 domains on both sides of the hydrophobic motif, namely the NH2-terminal kinase domain (residues 360-381) by amino acid Ser-117 and the COOH-terminal kinase domain (residues 388-400) by amino acids Leu-127 and Lys-128 [25].
• We have also demonstrated that phosphorothioate homopolymers of cytidine and thymidine release bFGF bound to low affinity receptors in extracellular matrix (ECM) [12].
• Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment [26].
• Mbd1 bound to the Fgf-2 promoter and regulates its expression in adult NSPCs [27].

Regulatory relationships of Fgf2

• The acquisition of EGF responsiveness is promoted by FGF-2 [28].
• Low dose fibroblast growth factor-2 (FGF-2) enhances bone morphogenetic protein-2 (BMP-2)-induced ectopic bone formation in mice [29].
• Interestingly, IL-1 beta stimulated a greater induction in bFGF mRNA levels in the middle-aged mice compared to young mice [30].
• Simultaneous addition of cycloheximide blocked bFGF-induced accumulation of FGF receptor mRNA, although exposure of SC-3 cells to cycloheximide alone caused marginal increase in its basal level [31].
• Here we provide evidence that both the mitogenic effect of bFGF and the differentiation-promoting effect of NT3 are linked with modifications of cell cycle kinetics in mouse cortical precursor cells [32].

Other interactions of Fgf2

• Exogenous provision of visceral endoderm-derived factors (VEGF-A, IHH, and bFGF) failed to rescue endothelial cell proliferative control but collectively promoted vascular remodeling, suggesting that these processes are independently regulated via a signaling hierarchy downstream of RA [33].
• Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo [34].
• To determine whether the FGF signal is mediated via the MAPK cascade in myoblasts, MM14 cells were stimulated with basic FGF (bFGF) and activities of the various kinases were measured [35].
• Differential activation of mitogen-activated protein kinase in response to basic fibroblast growth factor in skeletal muscle cells [35].
• We have investigated the mechanism of inhibition by examining the interaction of PF-4 and the fibroblast growth factor-2 (FGF-2)/fibroblast growth factor receptor (FGFR) system [36].
• Increased disease in Fgf2(-/-) mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase [37].

Analytical, diagnostic and therapeutic context of Fgf2

• Femoral ligation increased capillary and arteriole density in the ischemic calf in both Fgf2(+/+) and Fgf2(-/-) mice [4].
• Cell cultures from subcutaneous Matrigel plugs demonstrated that E2 increased both migration and proliferation in endothelial cells from Fgf2+/+ mice, but not from in Fgf2-/- mice [38].
• Both NDP and LTP cells expressed bFGF-like and TGF beta-like polypeptides as detected by Western blot analysis [39].
• In addition, using a radioreceptor assay, we have shown that phosphorothioate homopolymers of cytidine and thymidine blocked binding of not only 125I-bFGF, but also of 125I-PDGF to NIH 3T3 cells, whereas phosphodiester oligodeoxynucleotides were ineffective [12].
• By means of a gel mobility shift assay, we demonstrated that phosphodiester and phosphorothioate homopolymers bound to basic fibroblast growth factor (bFGF) [12].

References