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PubMed1994

Activation of rDNA transcription by FGF-2: key role of protein kinase CKII.

Basic Fibroblast Growth Factor-2 (FGF-2) promotes G1 to S transition of quiescent sparse adult bovine aortic endothelial cells. In addition to signal transduction through interaction with tyrosine kinase high affinity receptor, FGF-2 is translocated to the nucleus and accumulated into the nucleolus. These data suggest that FGF-2 functions directly in nuclear events. In vivo, correlations were established between the entrance of FGF-2 into the nucleus and an increase in rDNA transcription and in protein phosphorylation. In vitro, in experiments carried out with nuclei isolated from quiescent cells, addition of FGF-2 increases rDNA transcription by a factor of 5 and also increases protein phosphorylation. Nucleolin, a factor involved in control of rDNA transcription is preferentially phosphorylated. It has been shown that nucleolin and other factors implicated in rDNA transcription are substrates of protein kinase CKII. Using purified kinase CKII and nucleolin in an in vitro phosphorylation assay, we have shown that FGF-2 activates the protein kinase activity. These results suggest that FGF-2 could act as an activator of rDNA transcription through interactions with the protein kinase CKII.

Animals↗
PubMed1994

The FGF-4 promoter is required for transformation and is active in both embryonal and somatic cells.

We report the independent isolation of a rearranged FGF-4 gene from a patient with chronic myeloid leukaemia. We show that the FGF-4 gene has been truncated 30 nucleotides 3' to the coding sequence and has been fused to the RNA processing signals from a putative unknown gene on chromosome 15. We demonstrate that the promoter region of the FGF-4 gene is active in NIH3T3 cells and is indeed necessary for transformation. Using the luciferase reporter assay we have shown that the FGF-4 5' flanking sequences possess easily detectable promoter activity in both F9 and HeLa cell lines. 5' deletion analysis of the FGF-4 promoter has delineated regions containing cis-acting elements of functional importance. These regulatory regions are common to both embryonal and somatic cell lines. Electrophoretic mobility shift assay, using nuclear extracts from F9 and HeLa cells, has allowed detection of DNA-protein interactions occurring in the functionally significant regions. Subsequent comparison of the human and murine FGF-4 promoters show that the regions of functional significance are highly conserved. We suggest that the FGF-4 gene may be suppressed through a distal suppressor locus and becomes active when separated from this suppressor.

3T3 Cells↗
PubMed1994

Distribution of FGF-5 in the rhesus macaque retina.

PURPOSE: To determine the distribution of mRNA transcribed from the FGF-5 gene and the distribution of FGF-5 protein in the normal adult retina of the rhesus macaque. METHODS: Freshly enucleated globes from rhesus macaque were prepared for Northern blot analysis, in situ hybridization, and immunohistochemical studies. A 350 base pair sequence from the human FGF-5 was subcloned and used to prepare 35S-labeled cRNAs for Northern and in situ experiments. Antipeptide antibodies were raised against an aminoterminal sequence as well as an internal sequence and were affinity purified on recombinant FGF-5 coupled to AffiGel-10. The specificity of antibody probes was verified by dot blot and Western blot analyses. RESULTS: Ganglion cells and photoreceptors express the highest levels of FGF-5 mRNA, although all neurons and the retinal pigment epithelium (RPE) were clearly labeled. Immunohistochemical staining similarly revealed a widespread distribution of the protein, with prominent labeling observed in photoreceptor inner segments, especially in cone cells. Plexiform layers and RPE cells were also clearly labeled. CONCLUSIONS: Clear evidence was established for the expression of FGF-5 in the retina, where it may play an important extracellular role as a secreted member of the FGF gene family.

Amino Acid Sequence↗
PubMed1993

IGF-1 enhancement of FGF-induced lens fiber differentiation in rats of different ages.

PURPOSE: Previously, using lens epithelial explants from neonatal rats, we showed that both insulin and IGF-1 synergistically enhance the effectiveness of FGF as an inducer of fiber differentiation. The authors aimed to determine whether IGF-1 enhances FGF-induced fiber differentiation in lens epithelial cells at various ages and, in particular, whether it can counter a marked age-related decline in responsiveness to FGF noted previously. METHODS: The effects of IGF-1 and bFGF were assessed using lens epithelial explants from neonatal, weanling, and adult rats. Fiber differentiation (after 13 days' culture) was monitored by crystallin ELISAs of explant lysates and also by immunofluorescent localization of crystallins. RESULTS: IGF alone had minimal effects. For younger rats, FGF alone enhanced the accumulation of alpha-, beta- and gamma-crystallins throughout explants, the peripheral region being more responsive than the central region. For adult rats, only the peripheral region responded; small amounts of alpha- and beta-crystallins were detected, but gamma-crystallin was not. Combining IGF with FGF induced gamma-crystallin in explants from adult rats (peripheral region) and enhanced the accumulation of all crystallins more than additively at all ages, mainly in the central region (young rats) or only in the peripheral region (adults). Including IGF with FGF prevented an age-related decline in the beta/alpha-crystallin ratio but not in the gamma/beta-crystallin ratio. CONCLUSIONS: IGF-1 enhances the bFGF-induced fiber differentiation responses of lens epithelial cells in neonatal, weanling, and adult rats, partially restoring an age-related decline in the responsiveness of lens cells to FGF.

Aging↗
PubMed1995

Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation.

The FGF-2 mRNA of most mammals contains a long and inhibitory 5' UTR in addition to at least two CUG codons upstream and in frame with the AUG start codon. These CUGs are used for translation initiation to generate several polypeptides. Cells overexpressing the translation initiation factor 4E produce and secrete large amounts of FGF-2, and particularly the largest, CUG1-initiated form. Overexpression of FGF-2 is due to a translational enhancement of its mRNA, as indicated by its association with large polyribosomes in contrast to control cells, where it partitions mostly in fractions lighter than 80 S or small polyribosomes. Breast carcinomas expressing elevated eIF-4E also exhibited the large FGF-2 isoforms, which could play an important role in tumor angiogenesis. Translation of in vitro transcribed rat FGF-2 in reticulocyte lysates resulted in synthesis of four polypeptides, of similar size to those observed in vivo. Addition of purified eIF-4F preferentially increased translation of CUG1- and AUG-initiated isoforms. Since the different isoforms of FGF-2 may have different roles and intracellular distribution, the effects of the eIF-4 factors on FGF-2 expression could be important for the control of cell proliferation and differentiation.

Animals↗
PubMed1996

Effects of fibroblast growth factor-4 (k-FGF) on long-term cultures of human bone marrow cells.

Fibroblast growth factor-4 (FGF-4), a highly mitogenic protein encoded by the k-fgf/hst oncogene, stimulates the growth of a variety of cells of mesenchymal and neuroectodermal origin. Addition of FGF-4 to human long-term bone marrow cultures increased both the cell density of the stromal layer and the number of hematopoietic colony forming cells in the cultures in a dose-dependent manner. Hematopoiesis in the stromal layer persisted for up to 8 months. Erythropoiesis was maintained for up to 4 weeks, but granulocytes were the predominant nonadherent cell type. Cultures treated with FGF had increased numbers of monocytes compared with control cultures and some CD14+, CD45+ monocytes could still be detected after 8 months of continuous culture. The addition of the growth factor increased the rate of growth of the stromal layer and appeared to delay its senescence. Subcultures made in the presence of FGF-4 had up to 10-fold increases in plating efficiency and grew as relatively uniform monolayers. These subcultures retained the capacity to support hematopoiesis for several months, while untreated subcultures, made without FGF-4, grew erratically and generally lost the capacity to support hematopoiesis within 4 to 6 weeks. The improved growth after subculture greatly enhanced the reliability of limit-dilution assays of multipotential hematopoietic stem cells that use stromal cell monolayers. The primary effect of FGF-4 appeared to be on the stromal cells of the long-term bone marrow cultures, but a direct effect on hematopoietic progenitors could not be ruled out.

Bone Marrow Cells↗
PubMed1996

Molecular mechanisms of angiogenesis: experimental models define cellular trafficking of FGF-1.

Numerous studies have established that stimulation of cell growth by members of the fibroblast growth factor (FGF) family of polypeptides is dependent upon an extracellular pathway. Acidic FGF (FGF-1), however, lacks a classical signal sequence for secretion, thereby making it difficult to evaluate regulation of biological activity by this growth factor. Efforts in this laboratory have utilized molecular techniques of retrovirology and transgenic modeling to introduce cDNA sequences encoding either an intracellular or extracellular form of FGF-1 into primary diploid cells to examine trafficking and compartmentalization of FGF-1. Several lines of evidence obtained from these models provide a compelling argument that the stimulation of FGF-1-associated cellular transformation is restricted to an extracellular, receptor-mediated pathway, involving protein tyrosine phosphorylation and nuclear localization. In addition, an unconventional secretion pathway for intracellular FGF-1 has been identified that involves mechanisms associated with oxidative stress.

Animals↗
PubMed1998

Involvement of NF-kappaB associated proteins in FGF-mediated mesoderm induction.

In this report, we have used mRNA injection to study the action of mutants of XrelA, a Xenopus homolog of the RelA (p65) component of NF-kappaB, on the induction of mesoderm in Xenopus embryos. A region of the rel homology domain of XrelA was deleted to create XrelA deltaSP, which retains the dimerization and activation domains, but no longer binds to DNA. We also made an analogous derivative of mammalian NF-kappaB1 (p50). We show that both constructs have dominant inhibitory activity. When message encoding either is injected into eggs or oocytes, DNA binding of rel family members is suppressed, as is transactivation of a kappaB-dependent promoter in embryos. Expression of XrelA deltaSP in animal caps blocks the induction of mesoderm by bFGF. In addition, this mutant prevents elongation movements generated by activin, but has little effect on posterior dorsal cytodifferentiation, which in marked contrast is blocked by inhibition of the FGF signal transduction pathway between the receptor and MAP kinase. The specificity of the XrelA deltaSP effect on FGF signaling is shown by rescue of mesodermal marker expression when XrelA deltaSP is co-expressed with a specific rel inhibitor. The target of these dominant negative constructs seems to be neither XrelA itself, nor p50, but rather some other molecule with which XrelA, rather than NF-kappaB1, heterodimerizes. We show that XrelA deltaSP blocks FGF induction of mesoderm downstream of MAP kinase and Xbra expression. Thus it prevents the maintenance of Xbra expression by inhibiting its autoregulation by embryonic FGF (eFGF). We suggest that XrelA deltaSP differs from other reported inhibitors of FGF signaling because it inhibits only gastrula stage FGF signaling and not the maternally programmed signaling at the blastula stage. Our results therefore suggest that zygotic FGF action is required for cell movements rather than dorsal differentiation.

Activins↗
PubMed1998

The stimulation of neo-angiogenesis in the ischemic heart by the human growth factor FGF.

BACKGROUND: The present article deals with the conduct of our animal experiments with the human growth factor FGF (fibroblast growth factor) and the results obtained therefrom. METHODS: In order to establish the angiogenetic potential of FGF, this factor was first obtained from a genetically transformed strain of E. Coli, and then isolated and highly purified. Afterwards the growth factor FGF has been used in several in vitro- and in vivo experiments in order to prove its influence on neo-angiogenesis in ischemic tissue. RESULTS: In cultures of endothelial cells from the human great saphenous vein it has been possible to stimulate growth successfully with FGF obtained in this way, and a further increase in its action was brought about by the addition of heparin. In tritium-thymidine assays, the endothelial cell stimulating action of FGF was confirmed. It could also be shown angiographically that administering FGF to the ischemic myocardium of these animals initiates the development of new vessels, and we could demonstrate that a myocardial capillary network sprouting directly from the coronary vessels themselves can establish an alternative blood flow. These results were confirmed histologically by the significantly greater capillary density which appeared following the use of the growth factor. CONCLUSIONS: By using the human growth factor FGF, we have been able for the first time to understand the physiological processes of angiogenesis as they come into play during wound healing or the development of collaterals following tissue ischemia, and to use this knowledge for the production of new vessels in the ischemic hearts of rats and rabbits. Decisive for the future use of the factor in human patients -- particularly for the treatment of coronary heart disease (CHD) are the results of experimental investigations designed to exclude the possibility of the growth factor initiating or stimulating neoplasia.

Animals↗
PubMed1997

[The effect of different way of using FGF on wound healing].

To investigate the best way of using fibroblast growth factor (FGF) in wound healing, the following experiments were performed. Twelve Wistar rats were chosen. Four 1.5 cm x 1.5 cm middle-thick skin wounds were made in the back of each rat, 2 in each side, and labelled as number 1 to 4. Number 1 wound of each rat was used as control, only PBS was applied to the wound, 50 microliters per time, twice a day from the first day to 11th day. Number 2 wound was sustained medication group, 50 microliters 4 micrograms/ml FGF was applied twice a day from the first day to 11th day; Number 3 wound was early medication group, 50 microliters 8 micrograms/ml FGF was applied twice a day from the first day to 5th day; Number 4 wound was late medication group, 50 microliters 8 micrograms/ml FGF was added twice a day from the 5th day to 11th day. By day 4, 8, 12 and 16, the area of wounds were measured, and the healing time of each wound was recorded. The elastic fiber, collagen fiber and DNA content were measured by immunohistological method. The result showed that the elastic fiber, collagen fiber and DNA content in the groups of FGF used were more than those in the control group. The healing time of the control group was 14.4 days while that of the early meduation group was 13.4 days, late medation group was 13.5 days and sustained medication group was 12.2 days. It was suggested that FGF could accelerate the wound healing, and sustained use of FGF was the best way of giving the drug.

Animals↗
PubMed1996

Expression and localization of FGF-1 in the developing rat olfactory system.

Primary olfactory axons project from the nasal olfactory neuroepithelium to glomeruli in the olfactory bulb where they synapse with mitral cells, the second-order olfactory neurons. We have shown that the heparin-binding growth factor FGF-1 is expressed by olfactory nerve ensheathing cells which surround fascicles of primary olfactory axons en route to the olfactory bulb. These cells are believed to modulate olfactory axon growth between the olfactory neuroepithelium and the olfactory bulb. During late embryogenesis, FGF-1 expression is turned on in the mitral cells, and the FGF-1 peptide becomes confined to layers of synaptic neuropil in the postnatal olfactory bulb. FGF-1 is selectively present in glomeruli and the external plexiform layer. In cultures of olfactory neuroepithelial cells, complexes between FGF-1 and an appropriate activating heparan sulfate proteoglycan stimulated morphological differentiation of both olfactory nerve ensheathing cells and primary sensory olfactory neurons. Thus, the spatiotemporal expression and the functional properties of FGF-1 in this system suggest that this molecule plays an important regulatory role in the formation of the olfactory pathway.

Animals↗
PubMed1996

FGF receptor-1 (flg) expression is correlated with fibre differentiation during rat lens morphogenesis and growth.

Our previous studies indicate an important role for fibroblast growth factor (FGF) in lens development. Here we study the expression of the flg variant of FGF receptor 1 (FGFR1) during lens development by immunohistochemistry and in situ hybridisation. FGFR1 was expressed throughout lens development. Prominent FGFR1 immunoreactivity was associated with cell nuclei, particularly in differentiating lens fibres, suggesting internalisation and nuclear translocation of the receptor. FGFR1 immunoreactivity was also associated with basolateral membranes of cells in the equatorial region and at lens sutures. FGFR1 mRNA was only weakly expressed during early lens morphogenesis but expression increased with the onset of lens fibre differentiation. Once the lens acquired its distinct polarity, an anteroposterior gradient in both protein reactivity and mRNA signal was evident. Anteriorly, central epithelial cells showed weak expression for FGFR1, whereas more posteriorly, in the germinative and transitional zones of the lens where cells maximally proliferate and undergo early stages of fibre differentiation, respectively, expression was significantly stronger. The anteroposterior gradient of increased expression of FGFR1 in the lens coincides with the previously documented anteroposterior gradient of FGF stimulation. In lens epithelial explants, FGF stimulation was found to upregulate FGFR1 expression. Such upregulation may be an important mechanism for generating a high level of FGF stimulation and ensuring a fibre differentiation response. In postnatal rat lenses, there was a significant age-related decline in FGFR1 expression; this correlates with the reduced rate of lens fibre differentiation with age. Overall, these studies support the hypothesis that FGF and FGFR1 are important for regulation of lens fibre differentiation throughout lens development.

Animals↗
PubMed1997

Basic fibroblast growth factor (FGF-2) induced transdifferentiation of retinal pigment epithelium: generation of retinal neurons and glia.

In the present study we report that basic fibroblast growth factor (bFGF, FGF-2) promotes the transdifferentiation of Xenopus laevis larval retinal pigment epithelium (RPE) into neural retina. Using specific antibodies we have examined the cellular composition of the regenerated retinal tissue. Our results show that, in addition to retinal neurons and photoreceptors, glial cells were also regenerated from the transdifferentiated RPE. These results were specific to FGF-2, since other factors that were tested, including acidic FGF (aFGF, FGF-1), epidermal growth factor (EGF), laminin, ECL, and Matrigel, exhibited no activity in inducing retinal regeneration. These results are the first in amphibians demonstrating the functional role of FGF-2 in inducing RPE transdifferentiation. Transplantation studies were carried out to investigate retinal regeneration from the RPE in an in vivo environment. Sheets of RPE implanted into the lens-less eyes of larval hosts transformed into neurons and glial cells only when under the influence of host retinal factors. In contrast, no retinal transdifferentiation occurred if the RPE was implanted into the enucleated orbit. Taken together, these results show that the amphibian RPE is capable of transdifferentiation into neuronal and glial cell-phenotypes and implicate FGF-2 as an important factor in inducing retinal regeneration in vitro.

Animals↗
PubMed2004

Evaluation of thermoreversible polymers containing fibroblast growth factor 9 (FGF-9) for chondrocyte culture.

We previously evaluated a thermoreversible polymer gel composed of N-isopropylacrylamide and acrylic acid as a cell culture substrate and cell-delivery vehicle. The copolymer promoted phenotype expression and amplification of chondrocytes. In this study, we determined whether addition of fibroblast growth factor 9 (FGF-9), which is mitogenic for chondrocytes, would further enhance cell proliferation and phenotype expression in the polymer. We tested the hypothesis that the thermoreversible polymer containing FGF-9 would promote increased chondrocyte proliferation and phenotype expression. Articular chondrocytes (1 x 10(5)/150 microL) were plated onto control (without gel) and gel containing 24-well plates. The gels were prepared in media alone or in media containing heparin (100 microg/mL) and FGF-9 (5 microg/mL). The cultures were incubated at 37 degrees C in 5% CO(2) for 3 days. Cells remained viable in the thermoreversible polymer in the presence or absence of FGF-9. Addition of FGF-9 to the copolymer did not induce proliferation and the cell numbers did not increase. Reverse transcription polymerase chain reaction (RT-PCR)-determined expression of chondrocyte markers collagen type II and aggrecan. FGF-9 did not enhance chondrocyte proliferation nor alter the phenotype after 3 days in culture. These findings suggest the poly(NiPA-co-AAc) gel alone may provide the optimal 3D environment for propagation of chondrocytes.

Biocompatible Materials↗
PubMed2006

PGF2alpha increases FGF-2 and FGFR2 trafficking in Py1a rat osteoblasts via clathrin independent and importin beta dependent pathway.

Previous studies showed that prostaglandin F2alpha (PGF2alpha) stimulated fibroblast growth factor-2 (FGF-2) and fibroblast growth factor receptor 2 (FGFR2) cytosolic and nuclear accumulation, however, the endocytic pathway has not been elucidated. This study demonstrates that although PGF2alpha increased the formation of clathrin-coated structures in Py1a rat osteoblasts, they were not involved in FGF-2 and FGFR2 trafficking. PGF2alpha increased binding of FGF-2 and FGFR2 and co-localization of reactive sites in addition to nuclear translocation at the nuclear pore complex level. FGF-2 and FGFR2 were in close spatial correlation with importin beta, further supporting nuclear import of the FGF-2/FGFR2 complex. Immunogold and immunofluorescence techniques as well as Western blotting demonstrated increased importin beta protein labeling in response to PGF2alpha. Similar to PGF2alpha, phorbol 12-myristate 13-acetate (PMA) also increased importin beta protein. These data strongly suggest that prostaglandins may regulate osteoblast metabolism via FGF-2/FGFR2/importin beta nuclear trafficking.

Animals↗
PubMed2003

FGF-2 modulates expression and distribution of GAP-43 in frog retinal ganglion cells after optic nerve injury.

Basic fibroblast growth factor (bFGF or FGF-2) has been implicated as a trophic factor that promotes survival and neurite outgrowth of neurons. We found previously that application of FGF-2 to the proximal stump of the injured axon increases retinal ganglion cell (RGC) survival. We determine here the effect of FGF-2 on expression of the axonal growth-associated phosphoprotein (GAP)-43 in retinal ganglion cells and tectum of Rana pipiens during regeneration of the optic nerve. In control retinas, GAP-43 protein was found in the optic fiber layer and in optic nerve; mRNA levels were low. After axotomy, mRNA levels increased sevenfold and GAP-43 protein was significantly increased. GAP-43 was localized in retinal axons and in a subset of RGC cell bodies and dendrites. This upregulation of GAP-43 was sustained through the period in which retinal axons reconnect with their target in the tectum. FGF-2 application to the injured nerve, but not to the eyeball, increased GAP-43 mRNA in the retina but decreased GAP-43 protein levels and decreased the number of immunopositive cell bodies. In the tectum, no treatment affected GAP-43 mRNA but FGF-2 application to the axotomized optic nerve increased GAP-43 protein in regenerating retinal projections. We conclude that FGF-2 upregulates the synthesis and alters the distribution of the axonal growth-promoting protein GAP-43, suggesting that it may enhance axonal regrowth.

Animals↗
PubMed2006

FGF ligand family mRNA expression profile for mouse preimplantation embryos, early gestation human placenta, and mouse trophoblast stem cells.

Signaling by fibroblast growth factor (FGF) is essential is for trophoblast stem (TS) cells and preimplantation embryos. FGF4 provides essential signaling, but the expression of the complete set of 23 FGF family members has not been analyzed. Here, semi-quantitative RT-PCR and microarray analyses were used to define expression of all FGF ligand mRNA. RT-PCR was done for developmentally important FGF subfamilies, FGF10/FGF22 and FGF8/FGF17/FGF18 as well as FGF11. FGF4 and FGF18 are detected at highest levels by RT-PCR and microarrays. FGF10 was detected at low levels in both assays. FGF11 was detected at moderate levels by microarray, but not by RT-PCR. FGF17 was detected at low levels by array and moderate levels by RT-PCR. FGF8 and FGF22 were detected by RT-PCR, but not by microarrays during late cleavage divisions. FGF8, FGF5, and FGF9 were detected in the oocyte by microarray. FGF2, FGF3, and FGF7 were not detected by RT-PCR or microarrays and FGF13, FGF14, and FGF23 were not detected by microarray. Since a major role of FGF is to maintain TS cells, we tested human and mouse placental cell lines and early gestation human placenta for expression of FGF ligands. Expression in mouse TS cells was compared with preimplantation embryos, and human placental cell line expression was compared with human placenta, to infer which ligands are expressed in placental lineage vs. other cell lineages. The data suggest that human and mouse placenta share FGF18 and its high expression suggests preimplantation and early placental function.

Animals↗
PubMed2003

Differential expression of specific FGF ligand and receptor isoforms during angiogenesis associated with prostate cancer progression.

BACKGROUND: The aim of this study was to elucidate how changes in temporal and spatial expression patterns of individual components of the fibroblast growth factor (FGF) signaling axis correlate with prostate cancer-associated angiogenesis to contribute to the progression of this disease. METHODS: The temporal and spatial expression patterns of specific FGF ligands and receptors were characterized by immunoblot, in situ hybridization, and immunohistochemical analyses in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. RESULTS: We detected expression of high molecular weight isoform of FGF-2 in PIN lesions and detected both high and low molecular weight isoforms of FGF-2 in advanced tumors. Expression of the mRNA encoding the FGFR1iiib isoform was found to be specifically and differentially expressed in tumor vasculature in TRAMP but was not detected in prostate-associated vasculature in nontransgenic mice. Expression of the FGFR2iiic isoform was observed to be elevated in the epithelial component of PIN lesions in TRAMP mice. CONCLUSION: By using the TRAMP model, the expression of FGFR1iiib in intraductal vasculature and expression of FGF-2 protein were found to be concomitant with the emergence of PIN. These observations implicate specific changes in the FGF axis with the initiation and progression of prostate cancer and underscore the utility of animal models to identify specific molecular changes in early disease.

Adenocarcinoma↗