Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.2.2.7 (heparinase)
1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we reported that, in vitro, lens cells proliferate, migrate or differentiate in response to low, medium and high concentrations of FGF respectively. To examine further the role of FGF in lens development we used immunohistochemistry to study the distribution of aFGF and bFGF in the eye of the 20 day rat foetus. Strong aFGF-like reactivity was localised in a band of cells near the lens equator which included the germinative zone where most cell proliferation occurs and the transitional zone where epithelial cells differentiate into fibres. The closely apposed inner epithelial layer of the ciliary and iridial retina also reacted strongly. Reactivity for aFGF was also found in the epidermis and in the corneal and conjunctival epithelia. In the neural retina, reactivity was found in the nerve fibre layer and in isolated cells of the inner plexiform layer. bFGF-like reactivity was found in the retinal ganglion cell layer, extra-ocular muscles and associated with endothelial cells of the hyaloid, lenticular and choroid vasculatures. Pre-digestion of sections with hyaluronidase caused loss of cell-associated reactivity but revealed strong bFGF-like reactivity in ocular basement membranes, in particular, the lens capsule. The sensitivity of this capsular bFGF localisation to heparinase indicates that bFGF in the extracellular matrix is complexed with heparan sulphate proteoglycans. The results of this study are consistent with the hypothesis that FGF plays an important role in lens development via both autocrine and paracrine mechanisms.
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PMID:Distribution of acidic and basic fibroblast growth factors (FGF) in the foetal rat eye: implications for lens development. 137 41

Basic fibroblast growth factor (bFGF) binds to cell surface receptors and to heparin sulfate proteoglycans. Heparan sulfate binding may limit bFGF degradation and be an obligatory step for bFGF cell interaction. Transforming growth factor-beta 1 (TGF-beta 1) is a potent regulator of proteoglycan production and composition. The possibility that TGF-beta 1 synergistically regulates bFGF activity by altering bFGF-proteoglycan interactions was investigated. TGF-beta 1 increased 125I-bFGF binding to the extracellular matrix (ECM) of Balb/c3T3 cells 2-4-fold by increasing the number of bFGF binding sites. Increased bFGF binding correlated with a 2-5-fold increase in the production of sulfated proteoglycans, including heparan sulfate proteoglycans. TGF-beta 1 selectively stimulated production of high molecular mass proteoglycans (190-300 kDa) in conditioned medium and stimulated all proteoglycans in ECM. 125I-bFGF bound to TGF-beta 1 induced proteoglycans immobilized onto cationic nylon filters. Furthermore, ECM isolated from TGF-beta 1-treated cells incorporated more mitogenically active bFGF than native ECM. The mitogenic potential of the ECM was significantly reduced by treatment with heparinase. These results suggest that the ability of TGF-beta 1 to stimulate binding of bFGF to ECM, increase ECM heparan sulfate proteoglycan, and potentiate the mitogenic activity of bFGF are linked. Thus one aspect of TGF-beta 1/bFGF synergy may involve modulation of the ECM.
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PMID:Transforming growth factor beta 1 stimulates the production of basic fibroblast growth factor binding proteoglycans in Balb/c3T3 cells. 140 Apr 36

Basic fibroblast growth factor (bFGF) was internalized at a rapid rate by Chinese hamster ovary (CHO) cells that do not express significant numbers of high affinity receptors for bFGF as well as CHO cells that have been transfected with cDNA encoding FGF receptor-1 or FGF receptor-2. Internalization of bFGF was completely blocked by the addition of 10 micrograms/ml heparin in the parental CHO cells but only partially inhibited in cells expressing transfected FGF receptors. Bovine aortic endothelial cells also exhibit heparin-sensitive and heparin-resistant internalization of bFGF. The internalization of bFGF through the heparin-resistant pathway in CHO cells was efficiently competed by addition of unlabeled bFGF, was proportional to the number of receptors expressed, and approached saturation, suggesting that the heparin-resistant internalization was due to high affinity receptors. Internalization of bFGF through the heparin-sensitive pathway was not efficiently competed by unlabeled bFGF and did not approach saturation at concentrations of bFGF up to 50 ng/ml, properties similar to the interaction of bFGF with low affinity heparan sulfate binding sites on the cell surface. Internalization of bFGF in CHO cells not expressing FGF receptors was inhibited by heparin, heparan sulfate, and dermatan sulfate, the same glycosaminoglycans that block binding to cell-surface heparin sulfates. Internalization of bFGF in the parental CHO cells was inhibited at the same concentrations of heparin that block binding to cell-surface heparan sulfates. Finally, inhibition of the sulfation of CHO cell heparan sulfates by the addition of chlorate or digestion of CHO cell heparan sulfates with heparinase inhibited bFGF internalization in the parental CHO cells. These results demonstrate that bFGF can be internalized through a direct interaction with cell-surface heparan sulfates. Thus, there are two pathways for internalization of bFGF: high affinity receptor-mediated and heparan sulfate-mediated.
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PMID:Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms. 142 68

The extracellular matrix protein heparin sulfate proteoglycans (HSPG) has been found in the neurofibrillary pathology of Alzheimer disease. This study was performed to determine if similar proteoglycans might be present in the fibrillary inclusions of other neurodegenerative diseases. Basic fibroblast growth factor (bFGF) binding to heparinase sensitive sites was used as an assay for HSPGs. We found that the inclusions of Pick and Parkinson diseases as well as progressive supranuclear palsy contained heparinase sensitive bFGF binding sites while the inclusions of diffuse Lewy body disease lacked bFGF binding sites. These findings indicate that HSPG's interactions and possible role in the formation of intraneuronal inclusions are not limited to Alzheimer disease.
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PMID:Basic fibroblast growth factor binds to filamentous inclusions of neurodegenerative diseases. 162 22

Basic fibroblast growth factor (bFGF) was radiolabeled and used in axonal transport studies to determine whether certain neuronal populations express functional receptors for bFGF. Unlike 125I-NGF, 125I-bFGF was not retrogradely transported in the adult rat sciatic nerve or from iris to trigeminal ganglion or superior cervical ganglion. However, after intraocular injection of 125I-bFGF into the posterior chamber of the eye of adult rats, radioactivity was detected within the retinal ganglion cell projections. This radioactivity was localized to the ipsilateral optic nerve and in the contralateral lateral geniculate body and the contralateral superior colliculus by using autoradiographic techniques. Direct measurement of the radioactivity in dissected brain regions was used to study the process of 125I-bFGF uptake and transport by retinal ganglion cells. The uptake and transport were specific for biologically active bFGF since neither denatured, biologically inactive 125I-bFGF nor 125I-NGF was taken up and transported. The uptake and transport of 125I-bFGF were saturable phenomena since they were blocked in the presence of excess, unlabeled bFGF. Wheat germ agglutinin, but not heparinase, blocked uptake and transport of 125I-bFGF, a finding that is consistent with the uptake being mediated by high-affinity bFGF receptors. Radioactivity from 125I-bFGF was transported in retinal ganglion cell axons in an anterograde direction at a maximum rate in excess of 1.7 mm/hr. No specific retrograde transport of bFGF to the retina was detected after 125I-bFGF was injected into the superior colliculus. The radioactivity from 125I-bFGF that accumulated in the superior colliculus was lost from this tissue with a half-life of about 22 hr. Autoradiography of proteins separated by SDS-PAGE demonstrated that 125I-bFGF was not substantially degraded in the retina after internalization within retinal ganglion cells. During anterograde transport, however, 125I-bFGF underwent limited proteolytic cleavage resulting in 3 prominent 125I-bFGF derivatives of molecular weights greater than 7000 Da. Although these were the major radioactive species recovered from the superior colliculus after intraocular injection, some intact 125I-bFGF was also detected within the innervated target. These results indicate that retinal ganglion cells express high-affinity receptors for bFGF, that these receptors mediate the internalization of bFGF, that internalized bFGF undergoes limited proteolytic cleavage, and that bFGF and its derivatives are anterogradely transported to the lateral geniculate body and the superior colliculus. These data raise the possibility that bFGF or its derivatives may act as an anterograde trophic factor in the visual system, a system that is known to undergo anterograde transneuronal cell death.
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PMID:Basic fibroblast growth factor: receptor-mediated internalization, metabolism, and anterograde axonal transport in retinal ganglion cells. 169 44

Basic fibroblast growth factor has multivariate effects in stimulating cell growth and the processes that surround tissue repair. Pathophysiologic studies have been hampered by the stability of the compound. Though very potent, basic fibroblast growth factor is rapidly degraded when injected or ingested. Controlled release of basic fibroblast growth factor would allow for examination of the chronic effects of this compound. Conventional matrix polymer-based release devices were fabricated and basic fibroblast growth factor released in a sustained fashion, but 99% of basic fibroblast growth factor mitogenic activity was lost. The source of these losses was identified and preventative measures examined. Preservation and stabilization of basic fibroblast growth factor was accomplished by binding the factor to heparin-Sepharose beads. This permitted prolonged storage, repeated handling, and the encapsulation of basic fibroblast growth factor within a microspherical controlled-release device using a naturally occurring polymer material, alginate. Encapsulation was accomplished with 77% efficiency and 87.5 +/- 12% of the basic fibroblast growth factor was released in a biologically active form. Release activation and regulation was achieved when cleavage of the basic fibroblast growth factor-heparin bonds was enhanced (e.g. by enzymatic bond cleavage with heparinase). Kinetic profiles were identified for a variety of experimental conditions and the effects of the controlled release of basic fibroblast growth factor on BALBc/3T3 fibroblasts examined.
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PMID:Controlled and modulated release of basic fibroblast growth factor. 174 4

Neurofibrillary tangles (NFT) are abnormal filamentous inclusions that develop in neurons in Alzheimer disease and other disorders. When neurons die, the neurofibrillary tangles that persist in the extracellular space show ultrastructural and antigenic changes. Both intra- and extracellular NFT have recently been shown to contain heparan sulfate proteoglycans (HSPGs). HSPGs are also present in other amyloid deposits in the brain and in systemic amyloidoses. Basic fibroblast growth factor (bFGF) is a heparin binding growth factor which is involved in angiogenesis and also has neurite promoting activity. We now report that bFGF binds avidly to extracellular NFT. Alz-50, a monoclonal antibody (MAb) to an abnormal form of tau and bFGF binding label mutually exclusive subpopulations of neurofibrillary tangles. bFGF binding is abolished by heparinase or heparitinase treatment and therefore is most likely based on the presence of HSPG. Binding of bFGF is a specific and sensitive morphological method to distinguish intra- from extracellular NFT. As intracellular NFT, which also contain HSPGs, are not labeled by bFGF binding, this finding also suggests that HSPGs are modified when the NFT become extracellular.
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PMID:Basic fibroblast growth factor binding is a marker for extracellular neurofibrillary tangles in Alzheimer disease. 186 6

Basic fibroblast growth factor (bFGF) binds to heparin-like molecules present in the extracellular matrix (ECM) of transformed fetal bovine aortic endothelial GM 7373 cells. Binding of bFGF to ECM can be competed by heparin or heparan sulfate, and ECM-bound bFGF can be released by treating the cells with heparinase or heparatinase. After binding to ECM, bFGF is slowly released into the medium in a biologically active form, as shown by its capacity to induce an increase of cell-associated plasminogen activator activity and cell proliferation. The increase is prevented upon removal of ECM-bound bFGF by a neutral 2 M NaCl wash. Soluble heparin and heparan sulfate reduce the amount of ECM-bound bFGF released into the medium, possibly competing with ECM polysaccharides for heparinase-like enzymes produced by endothelial cells, suggesting that these enzymes are involved in the mobilization of ECM-bound bFGF.
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PMID:Basic fibroblast growth factor is released from endothelial extracellular matrix in a biologically active form. 250 Apr 52

The binding of [125I]-recombinant basic FGF (rec bFGF) to rat hepatic plasma membranes was investigated. [125I] rec bFGF bound to an apparent single class of high affinity binding sites (KD = 69 pM; Bmax = 9.61 fmoles/mg proteins). The absence of low affinity sites was confirmed by the inability of sulphated polysaccharides and heparinase to interfere with FGF binding. A good correlation existed between the ability of bovine pituitary-derived bFGF, rec bFGF and bovine brain-derived aFGF to displace [125I]rec bFGF from these binding sites and their in vitro potency on bovine aortic endothelial cell proliferation.
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PMID:High affinity binding sites for basic fibroblast growth factor in rat hepatic plasma membranes. 256 19

Dissociated embryonic chick ciliary ganglion cells in culture were used as a bioassay to isolate a cholinergic growth-promoting protein from extracts of autopsied adult human muscle. An active protein was purified after acid and salt precipitation of extract, cation exchange, molecular sieving, heparin affinity chromatography, and in some cases, SDS-PAGE. This protein increased levels of choline acetyltransferase activity and ACh synthesis with time in culture. The protein was identified as basic FGF by several criteria. It shared the high affinity for heparin and was the same approximate molecular weight, 18 kD, as basic FGF. Activity was removed from solution by antibodies specific for basic FGF. Recombinant human basic FGF was equally effective in stimulating CAT activity, but was not additive with our purified protein at saturating concentrations. Basic FGF was also found in extracellular matrix and conditioned medium from cultured embryonic chick muscle. The activity could be released from extracellular matrix by treatment with heparinase or high salt extraction. Basic FGF stimulates neurite outgrowth as well as the capacity for transmitter synthesis. Thus, basic FGF is present in embryonic and adult muscle and capable of acting as a growth regulator for cholinergic neurons.
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PMID:Identification of basic fibroblast growth factor as a cholinergic growth factor from human muscle. 274 97


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