Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “FGF”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2003

Peroxynitrite modulates acidic fibroblast growth factor (FGF-1) activity.

To establish peroxynitrite (ONOO(-)) as a mediator of acidic fibroblast growth factor (FGF-1) function, preparations of recombinant human FGF-1 were treated with the pro-oxidant in vitro and identified amino acid modifications were correlated with biologic activity. The sequence of FGF-1 amino acid modifications induced by increasing concentrations of ONOO(-) was from cysteine oxidation to dityrosine formation, and to tyrosine/tryptophan nitration. Low steady-state ONOO(-) concentrations (10-50 microM) induced formation of dityrosine, which involved less than 0.1% of the total tyrosines. Treatment of FGF-1 with ONOO(-) induced a dose-dependent (10-50 microM) loss of sulfhydryl groups that correlated with formation of reducible (dithiothreitol, arsenite) FGF-1 aggregates containing 50% latent biologic activity. Treatment with 0.1-0.5mM ONOO(-) induced increasing formation of non-reducible, inactivated FGF-1 structures. Combination of real-time spectral analysis and electrospray mass spectroscopy revealed that six residues (Y29, Y69, Y108, Y111, Y139, and W121) were nitrated by ONOO(-). ONOO(-) treatment (0.1mM) of an active FGF-1 mutant (cysteines converted to serines) induced dose-dependent, non-reversible inhibition of biologic activity that correlated with nitration of Y108 and Y111, both of which reside within a conserved domain encompassing the putative FGF-1 receptor binding site. Collectively, these observations predict a role for low levels of ONOO(-) during secretion of FGF-1 as an extracellular complex containing latent biologic activity. High steady-state levels of ONOO(-) may induce extensive cysteine oxidation, critical tyrosine nitration, and non-reversible inactivation of FGF-1, a potential inhibitory feedback mechanism restoring cellular homeostatis during the resolution of inflammation and repair.

3T3 Cells↗
PubMed2006

Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men.

INTRODUCTION: Fibroblast growth factor (FGF-23) is a novel phosphaturic factor. Current data suggest that serum phosphate, dietary phosphate and 1,25 dihydroxyvitamin D regulate circulating FGF-23 levels in vivo. We examined if hypogonadism-induced increases in serum phosphate are associated with increases in circulating FGF-23 in healthy men in the absence of dietary manipulation. MATERIALS AND METHODS: 25 healthy men were administered goserelin acetate (GnRH analog) 3.6 mg subcutaneously every 4 weeks for 12 weeks to induce acute testosterone and estrogen deficiency. Subjects consumed an ad libitum diet. Morning fasting blood and urine samples were collected to measure serum phosphate, serum intact FGF-23, PTH, and the maximum tubular reabsorption of phosphate (T(m)P/GFR) at baseline, weeks 4 and 12. The changes in serum FGF-23 and phosphate at weeks 4 and 12 were compared to baseline using paired t-tests. RESULTS: Goserelin therapy decreased mean serum testosterone levels from 543+/-160 ng/dL to 33+/-15 ng/dL at week 4 (p<0.001), and to 20+/-10 ng/dL at week 12 (p<0.001). Serum phosphate increased significantly from 3.4+/-0.6 mg/dL to 3.9+/-0.4 mg/dL at week 4 (p=0.002), and to 4.3+/-0.4 mg/dL at week 12 (p<0.001). T(m)P/GFR increased significantly from 3.2+/-0.6 mg/dL to 3.6+/-0.5 mg/dL at week 4 (p<0.004), and to 4.1+/-0.6 mg/dL at week 12 (p<0.001). FGF-23 levels, however, did not change during the 12-week study. CONCLUSIONS: Gonadal steroid deprivation increased serum phosphate levels in men but did not affect serum FGF-23 concentrations. The absence of any change in circulating FGF-23 suggests that supraphysiologic levels of serum phosphate may be required to stimulate circulating FGF-23 or that FGF-23 production is primarily sensitive to changes in dietary phosphate or 1,25 dihydroxyvitamin D within this physiologic serum phosphate range.

Adult↗
PubMed2004

Engineered FGF-2 expression induces glandular epithelial hyperplasia in the murine prostatic dorsal lobe.

OBJECTIVE: It is known that androgens and stromal-epithelial interactions are required for the formation and growth of the prostate. FGF-2 is overexpressed in prostatic stromal cells in benign prostatic hypertrophy (BPH)/prostate cancer. This supports the paracrine/autocrine growth of prostatic epithelial/stromal cells in the pathogenesis of BPH and invasive prostate cancer. METHODS: We established transgenic mice expressing FGF-2 under the control of a short rat probasin promotor. FGF-2 transgenic founder mice expressing FGF-2 in the prostate were infertile. Thus, male founder mice were sacrificed for histological analysis. RESULTS: FGF-2 was expressed in epithelial cells in glands of the dorsal, lateral, and ventral prostatic lobes of two FGF-2 transgenic founder mice, but not in the anterior lobe of transgenic mice or in any lobe of non-transgenic control littermates. Acinar epithelial glands in dorsal prostatic lobes of FGF-2 transgenic mice expressing FGF-2 were more dense and showed simple papillary hyperplasia of epithelial cells compared with those of control littermate mice. Glandular and luminal enlargement without epithelial growth was observed in the ventral lobe of FGF-2 transgenic mice compared with the controls. CONCLUSION: In conclusion, FGF-2 transgenic mice under the control of rat probasin promoter showed simple epithelial hyperplasia in glands of the prostatic dorsal lobe and glandular enlargement without epithelial growth in the prostatic ventral lobe.

Animals↗
PubMed2004

Enhanced survival, reinnervation, and functional recovery of intrastriatal dopamine grafts co-transplanted with Schwann cells overexpressing high molecular weight FGF-2 isoforms.

Dopaminergic (DA) micrografts were co-transplanted with Schwann cells (SC) overexpressing 18 kDa and 21/23 kDa FGF-2 into the caudate-putamen unit (CPu) of unilaterally 6-hydroxydopamine-lesioned rats. We report here that SC engineered to overexpress FGF-2 promoted DA-graft-induced restoration, whether co-transplanted at the same site or grafted at a second more distant site within the CPu. In addition, the 21/23 kDa FGF-2 isoforms resulted in a significantly better reinnervation and survival of dopaminergic micrografts when compared to the 18-kDa FGF-2 isoform. However, this effect was not that distinct on functional recovery due to, for example, ceiling effects. One main finding of this study was the influence of the gene promotor on DA survival, respectively, vector-mediated trophism. Therefore, comparisons in terms of survival between 18 kDa and higher molecular weight (HMW) FGF-2 are complicated in the mixed grafted experiments. Furthermore, the first demonstration of the presence of the 21/23 kDa FGF-2 isoforms in the nigrostriatal system and their potent neurotrophic in vivo activities, as shown in the present study, suggest (I) a physiological role of these proteins for dopaminergic neurons and (II) a restorative potential under normal as well as regenerative processes. However, FGF-2-mediated effects are more pronounced after co-transplantation with SC/DA cells mixed in one suspension at the same implantation side than in the side-by-side approach with a spatially and temporally separated transplantation of SC (day 1) and DA-cells (day 3). These findings indicate the necessity of direct contact between FGF-2 and DA-neurons, further elucidate the neurotrophic role of FGF-2 for DA-neurons and highlight the differential restorative potentials of its respective isoforms. We propose that administration of HMW FGF-2 may be used to improve function in the rat Parkinson's disease model.

Animals↗
PubMed2004

Heparin stabilizes FGF-2 and modulates striatal precursor cell behavior in response to EGF.

Fibroblast and epidermal growth factors (FGF-2 and EGF) are powerful mitogens for neural precursor cells isolated from the developing striatum and grown as neurospheres. However, questions remain as to the exact role of each of these molecules, and how the proteoglycan heparin may modify their behavior. Here, we show that FGF-2 is remarkably unstable in culture media, but that heparin could completely prevent its degradation, which led to faster cell growth rates. In addition, heparin significantly increased the number of cells within the E14 striatum responding to a brief pulse of FGF-2. In contrast, EGF was unable to stimulate the growth of E14 striatal precursors. However, EGF could induce the division of E18 striatal precursors as neurospheres and acted synergistically with FGF-2. FGF-2/heparin neurospheres generated significantly more neurons than EGF neurospheres. Interestingly, the addition of heparin to EGF neurospheres, which had no effects on EGF stability or growth rates, increased the numbers of neurons generated to that seen for FGF-2/heparin neurospheres. EGF neurospheres were found to produce FGF-2, but addition of heparin did not affect its concentration within cells or in the medium suggesting this released FGF-2 may already be bound to a proteoglycan. In addition, expanding cells with EGF plus heparin in the presence of an FGF-2 blocker did not have a significant effect on the number of neurons generated confirming that the increase in neuronal number is through a mechanism which is independent of FGF-2.

Animals↗
PubMed2006

Activation of phosphatidylinositol 3-kinase/Akt limits FGF-2-induced VEGF release in osteoblasts.

We previously reported that basic fibroblast growth factor (FGF-2) activates stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p44/p42 mitogen-activated protein (MAP) kinase, resulting in the release of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the role of Akt/protein kinase B in the FGF-2-stimulated VEGF release in these cells. FGF-2 time-dependently induced the phosphorylation of Akt and GSK-3beta, a downstream element of Akt. The Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, significantly amplified the FGF-2-induced VEGF release, in a dose-dependent manner between 1 and 70microM, while it suppressed the FGF-2-induced phosphorylation of GSK-3beta. The phosphorylation of Akt induced by FGF-2 was markedly attenuated by wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) in osteoblast-like MC3T3-E1 cells. Both wortmannin and LY294002 enhanced the FGF-2-induced VEGF release. In addition, Akt inhibitor had no significant effect on the FGF-2-induced phosphorylation of p44/p42 MAP kinase and SAPK/JNK. Furthermore, the FGF-2-induced Akt phosphorylation was not affected by PD98059, a MEK inhibitor, or SP600125, a SAPK/JNK inhibitor. Taken together, our findings strongly suggest that PI3-kinase/Akt plays an inhibitory role in FGF-2-induced VEGF release in osteoblasts.

Androstadienes↗
PubMed2003

FGF-10 plays an essential role in the growth of the fetal prostate.

Induction and branching morphogenesis of the prostate are dependent on androgens, which act via the mesenchyme to induce prostatic epithelial development. One mechanism by which the mesenchyme may regulate the epithelium is through secreted growth factors such as FGF-10. We have examined the male reproductive tract of FGF-10(-/-) mice, and at birth, most of the male secondary sex organs were absent or atrophic, including the prostate, seminal vesicle, bulbourethral gland, and caudal ductus deferens. Rudimentary prostatic buds were occasionally observed in the prostatic anlagen, the urogenital sinus (UGS) of FGF-10(-/-) mice. FGF-10(-/-) testes produced sufficient androgens to induce prostatic development in control UGS organ cultures. Prostatic rudiments from FGF-10(-/-) mice transplanted into intact male hosts grew very little, but showed some signs of prostatic differentiation. In cultures of UGS, the FGF-10 null phenotype was partially reversed by the addition of FGF-10 and testosterone, resulting in the formation of prostatic buds. FGF-10 alone did not stimulate prostatic bud formation in control or FGF-10(-/-) UGS. Thus, FGF-10 appears to act as a growth factor which is required for development of the prostate and several other accessory sex organs.

Androgens↗
PubMed1996

Cloning and characterization of a novel upstream untranslated exon of the mouse Fgf-1 gene.

Fibroblast growth factor 1 (FGF-1 or aFGF), is the prototype member of the heparin-binding growth factors which are capable of angiogenesis in vivo. FGF-1 has been implicated in atherosclerosis, cancer, wound repair and inflammatory autoimmune diseases. As part of an effort to understand the role of FGF-1 in the etiopathogenesis of inflammation and cancer, we have undertaken steps to isolate and characterize the mouse Fgf-1 gene. Southern blotting and sequence analysis displayed considerable conservation within the coding and upstream untranslated regions of Fgf-1 in human, mouse, hamster, rat and bovine. By using primers derived from the 5'-untranslated exon of a rat prostate-specific Fgf-1 cDNA, a 220-bp product was amplified from mouse genomic DNA via PCR. Sequence analysis of this amplicon showed that there was 80% similarity with the corresponding region of the rat FGF-cDNA sequence. Primers designed from this amplicon and the Fgf-1 coding region were used to isolate multiple overlapping genomic clones spanning the entire mouse Fgf-1 gene. Sequencing analysis of the genomic sequence upstream from this novel 5'-untranslated exon did not reveal typical TATA, CCAAT sequences. It appears that the occurrence of multiple untranslated exons for FGF-1 is a highly conserved theme for this gene across species.

Animals↗
PubMed2005

Two nuclear localization signals required for transport from the cytosol to the nucleus of externally added FGF-1 translocated into cells.

Externally added FGF-1 is transported into the nucleus of cells. It was earlier shown that FGF-1 contains an N-terminal nuclear localization signal (NLS) implicated in the stimulation of DNA synthesis. We here provide evidence that FGF-1 contains a second putative NLS (NLS2), which is located near the C-terminus. It is a bipartite NLS consisting of two clusters of lysines separated by a spacer of 10 amino acids. A fusion protein of GFP and the bipartite NLS was more efficiently transported into the nucleus than GFP alone, indicating that it can act as an NLS in the living cell. FGF-1 mutated in the N-terminal NLS (NLS1) or in the first cluster of the bipartite NLS2 bound to heparin and FGF receptors and activated downstream signaling similarly to the wild-type growth factor. Mutations in the second cluster of NLS2 resulted in impaired interaction with heparin and reduced stability. When radiolabeled FGF-1 with mutated NLS1 or the first lysine cluster of NLS2 was added to NIH/3T3 cells, it was translocated into the cytosol, but not transported efficiently to the nucleus. Phosphorylation of FGF-1 occurs normally in the nucleus, and while wild-type FGF-1 was phosphorylated after addition to cells, the NLS mutants were not. It therefore appears that both NLS1 and NLS2 are important for efficient transport of FGF-1 to the nucleus. Stimulation of DNA synthesis by FGF-1 with mutations in both NLSs was reduced considerably indicating that efficient transport to the nucleus may be involved in the stimulation of DNA synthesis.

Active Transport, Cell Nucleus↗
PubMed2003

Fibroblast growth factor (FGF), intracellular adhesion molecule (sICAM-1) level in serum and follicular fluid of infertile women with polycystic ovarian syndrome, endometriosis and tubal damage, and their effect on ICSI outcome.

PROBLEM: The objective of this study was to determine the concentration of fibroblast growth factor (FGF) and soluble intracellular adhesions molecule (sICAM-1) in serum and follicular fluid (FF) of polycystic ovary (PCO), endometriosis and tubal factor infertility and male factor infertility patients, and to investigate the relationship between these parameters and the outcome of intracytoplasmic sperm injection (ICSI). METHOD OF STUDY: The concentration of FGF and sICAM-1 in serum and FF were determined in patients undergoing controlled ovarian hyperstimulation (COH) for ICSI therapy for various etiology of infertility and the results of cytokines concentration and ICSI outcome were compared between the groups. Twenty patients with PCO (G.I), 17 with endometriosis (G.II), 19 with tubal damage (G.III) and 19 with male factor infertility (G.IV) were enrolled in this study. Quantitative determination of levels of FGF and sICAM-1 was performed using enzyme-linked immunosorbent assays (ELISAs). RESULTS: The FGF level in serum of PCO patients (G.I) were 4.8 +/- 2.3 and in FF were 104.0 +/- 39.0 pg/mL. The corresponding values in the endometriosis patients group (G.II) were 5.9 +/- 3.1 and 125.4 +/- 74.9 pg/mL. The concentration of FGF in tubal factor infertility group (G.III) in serum was significantly higher (P = 0.009) than those observed in the PCO group (G.I) 7.4 +/- 4.5 pg/mL, whereas the concentration in FF was at the same level like the other groups investigated, 128.7 +/- 75.9 pg/mL. Besides, the sICAM-1 (pg/ml) concentration in FF showed a significant difference between the groups investigated (G.I, 175.3 +/- 52.8; G.II 194.4 +/- 32.2; G.III 233.1 +/- 54.3; and G.IV 215.1 +/- 54.4 ng/mL; P = 0.003). The sICAM-1 levels in serum were not significantly different between the groups (217.0 +/- 42.9; 216.3 +/- 73.6; 254.8 +/- 79.6; 237.56 +/- 78.4 ng/ml; P = 0.267). The fertilization rate was significantly higher in G.III (66.0 +/- 23.89%) in comparison to G.II (38.8 +/- 33.9%; P = 0.014) or G.IV (38.7 +/- 22.7%; P = 0.012). The pregnancy rates were similar in all groups (30, 35.3 and 35.0, 38.6%, respectively). CONCLUSION: Both, FGF and sICAM-1 are present in serum and FF of patients undergoing controlled ovarian hyperstimulation for ICSI therapy. The FGF concentration in serum differs significantly between the groups investigated, whereas, no significant difference could be observed in the FF concentration of FGF. On the other hand, the sICAM in serum showed no significant difference between the groups, whereas, sICAM in FF demonstrated a significant difference between the patient groups investigated. On the whole, the ICSI outcome was not related to serum or FF concentrations of FGF or sICAM-1. Therefore, the mean concentration of FGF and sICAM-1 in serum and in FF could not be used to predict the fertilization rate in an ICSI program.

Biomarkers↗
PubMed2000

Engineering of an FGF-proteoglycan fusion protein with heparin-independent, mitogenic activity.

In the absence of heparan sulfate (HS) on the surface of target cells, or free heparin (HP) in the vicinity of their receptors, fibroblast growth factor (FGF) family members cannot exert their biological activity and are easily damaged by proteolysis. This limits the utility of FGFs in a variety of applications including treatment of surgical, burn, and periodontal tissue wounds, gastric ulcers, segmental bony defects, ligament and spinal cord injury. Here we describe an FGF analog engineered to overcome this limitation by fusing FGF-1 with HS proteoglycan (PG) core protein. The fusion protein (PG-FGF-1), which was expressed in Chinese hamster ovary cells and collected from the conditioned medium, possessed both HS and chondroitin sulfate sugar chains. After fractionation, intact PG-FGF-1 proteins with little affinity to immobilized HP and high-level HS modification, but not their heparitinase or heparinase digests, exerted mitogenic activity independent of exogenous HP toward HS-free Ba/F3 transfectants expressing FGF receptor. Although PG-FGF-1 was resistant to tryptic digestion, its physiological degradation with a combination of heparitinase and trypsin augmented its mitogenic activity toward human endothelial cells. The same treatment abolished the activity of simple FGF-1 protein. By constructing a biologically active proteoglycan-FGF-1 fusion protein, we have demonstrated an approach that may prove effective for engineering not only FGF family members, but other HP-binding molecules as well.

Amino Acid Sequence↗
PubMed2001

FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemias.

An elevated level of fibroblast growth factor-2 (FGF-2) in peripheral blood is considered to play a role in regulating the growth of leukemia cells. Here, we show that the level of plasma FGF-2 is increased in 54% of B cell chronic lymphocytic leukemias (B-CLL) and in 44% of chronic myeloid leukemias (CML). Notably, white blood cells (WBCs) from B-CLL patients contain 18, 22 and 24 kDa isoforms of FGF-2 whereas WBCs from CML patients contain only the 24 kDa isoform. Furthermore, as cultured B-CLL WBCs release 18 kDa FGF-2 into the medium, they constitute a potential source of FGF-2 in the blood. In a receptor binding assay, 125I-FGF-2 binds weakly to B-CLL WBCs, whereas the ligand binds more strongly to CML WBCs. Correspondingly, FGF-2 is unable to activate mitogen-activated protein kinase kinase (MEK) and its substrate, extracellular signal-regulated kinase (ERK), in B-CLL cells, whereas phosphorylation of both these cell growth-related kinases increases following treatment of CML WBCs. We conclude that B-CLL WBCs secrete FGF-2 with no apparent autocrine actions. In contrast, WBCs in CML bind FGF-2 provided by other FGF-2-hyperproducing cells and activate the MEK/ERK kinase cascade, possibly to modulate cell growth.

Adult↗
PubMed2001

Serum induction of the fibroblast growth factor-binding protein (FGF-BP) is mediated through ERK and p38 MAP kinase activation and C/EBP-regulated transcription.

The fibroblast growth factor-binding protein (FGF-BP) modulates FGF activity through binding and release from the extracellular matrix. Consequently, the expression of FGF-BP in certain tumor types is a rate-limiting regulator of FGF-mediated angiogenesis. FGF-BP is upregulated in squamous cell carcinoma by treatment with mitogens such as EGF or TPA. In this study, we investigated the regulation of FGF-BP gene expression by serum. Treatment of serum-starved ME-180 cells with fetal bovine serum (FBS) resulted in a rapid increase in steady-state levels of FGF-BP mRNA and in the rate of FGF-BP gene transcription. Serum induction of FGF-BP mRNA was not mediated through EGF receptor activation but was dependent on PKC, as well as ERK kinase (MEK) and p38 MAP kinase activation. Promoter analysis showed that C/EBP is the main promoter element required for the serum response. Unlike EGF-activation of FGF-BP, transcriptional induction by serum is not significantly regulated through the AP-1 or E-box sites in the promoter. These results illustrate differences between the mechanism of induction in response to serum and EGF.

Blood Physiological Phenomena↗
PubMed2001

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer.

Epithelial ovarian cancers (EOCs) arise in the Ovarian Surface Epithelium (OSE). This tissue is a simple, poorly committed mesothelium which exhibits characteristics of epithelial and mesenchymal cells when grown in culture. In contrast, EOCs frequently exhibit properties of complex epithelial tissues of the female reproductive tract, such as oviductal, endometrial and cervical epithelia, and show induction of expression of epithelial markers such as E-cadherin. Fibroblast Growth Factor Receptor 2 isoform IIIb (FGF receptor 2-IIIb) is a spliced variant of FGF receptor 2 that binds the ligands FGF-1 and FGF-7 with high affinity, and is expressed exclusively by epithelial cells. We have studied the expression of FGF receptor 2-IIIb and its ligands in primary cultures of normal human OSE, EOC cell lines and snap frozen tissue from EOCs. Expression of FGF receptor 2-IIIb mRNA is undetectable in normal OSE, but is expressed in 16/20 (80%) of EOCs. FGFs 1 and 7 mRNAs are expressed in normal OSE, whilst only 4/20 (20%) and 12/20 (60%) of EOCs demonstrated expression for these ligands respectively. However, FGF-7 protein was detected in 70% (mean level=0.7 ng/ml) of ascitic fluids obtained from patients with EOC. FGFs 1 and 7 stimulate DNA synthesis in EOC cell lines that express FGF receptor 2-IIIb. Moreover, DNA synthesis in these cell lines can be partially blocked by blocking antisera to FGFs 1 and 7. It is suggested that induction of expression of FGF receptor 2-IIIb may play a role in the development of EOCs by rendering the OSE susceptible to paracrine and/or autocrine stimulation by its requisite FGF ligands.

Adult↗
PubMed2006

IRES-dependent regulation of FGF-2 mRNA translation in pathophysiological conditions in the mouse.

The mRNA coding for FGF-2 (fibroblast growth factor 2), a major angiogenic factor, is translated by an IRES (internal ribosome entry site)-dependent mechanism. We have studied the role of the IRES in the regulation of FGF-2 expression in vivo, under pathophysiological conditions, by creating transgenic mice lines expressing bioluminescent bicistronic transgenes. Analysis of FGF-2 IRES activity indicates strong tissue specificity in adult brain and testis, suggesting a role of the IRES in the activation of FGF-2 expression in testis maturation and brain function. We have explored translational control of FGF-2 mRNA under diabetic hyperglycaemic conditions, as FGF-2 is implied in diabetes-related vascular complications. FGF-2 IRES is specifically activated in the aorta wall in streptozotocin-induced diabetic mice, in correlation with increased expression of endogenous FGF-2. Thus, under hyperglycaemic conditions, where cap-dependent translation is blocked, IRES activation participates in FGF-2 overexpression, which is one of the keys of diabetes-linked atherosclerosis aggravation. IRES activation under such pathophysiological conditions may involve ITAFs (IRES trans-acting factors), such as p53 or hnRNP AI (heterogeneous nuclear ribonucleoprotein AI), recently identified as inhibitory or activatory ITAFs respectively for FGF-2 IRES.

Animals↗
PubMed2003

Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour.

OBJECTIVE: Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor-2 (FGF-2). Given this background, we have determined the expression of PTTG, PBF, FGF-2 and its receptor FGF-R-1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour. PATIENTS AND METHODS: We used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analyses to measure PTTG, PBF, FGF-2 and FGF-R-1 expression in ex vivo pituitary tumours (N = 121). Clinical data, including accurate radiological assessment of tumour characteristics, were used to determine any associations between gene expression and tumour behaviour. RESULTS: PTTG was increased significantly (fivefold, P = 0.005) in adenomas compared with normal pituitaries. We also demonstrated that PBF was similarly raised in adenomas (sixfold, P = 0.0001), and was significantly correlated with PTTG expression. FGF-2 and its receptor FGF-R-1 were also raised in adenomas compared with normal pituitary tissue. Moreover, significantly enhanced expression of FGF-R-1 was observed in invasive adenomas compared with other pituitary tumours. CONCLUSIONS: Our data support a fundamental role for PTTG-mediated upregulation of FGF-2 signalling in pituitary tumorigenesis and growth, and suggest that receptor-mediated mechanisms of growth factor action may be critically important. Further prospective studies are required to determine whether measurement of FGF-R-1 mRNA will be of clinical use as a prognostic marker in patients with pituitary adenomas.

Adenoma↗
PubMed2003

Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers.

BACKGROUND: Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake. METHODS: Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points. RESULTS: FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet. CONCLUSION: Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.

Adult↗
PubMedDate not supplied

Modulation of protein synthesis in rabbit inner cell mass-derived cells by FGF-2.

Gastrulation is a critical step in vertebrate development, that depends on synergistic effects of several signalling molecules, including fibroblast growth factor-2 (FGF-2). To follow this phenomenon in vitro we isolated rabbit inner cell masses (ICMs) at embryonic day 4 and we exposed ICM-derived cells to FGF-2. Then, we analysed the quantitative differences in rates of protein synthesis from day 3 to day 5 of culture by two-dimensional (2D) gel electrophoresis. Here we show that both up- and down-regulation of protein synthesis took place in ICM-derived cells upon their exposure to FGF-2. The effect of FGF-2 was most pronounced at day 4 of culture, when the changes were very much in favour of a set of down-regulated proteins. To test the significance of this period of time for FGF-2-mediated regulation of protein synthesis, cells were grown without FGF-2 and then they were pulse-treated with FGF-2 at the end of day 4. When compared to the continuous culture with FGF-2, the FGF-2 pulse resulted in a quite indistinguishable pattern of up- and down-regulated proteins. Thus, the readiness of ICM-derived cells to accept and respond to the FGF-2 signals may be of limited duration.

Animals↗