Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With regard to diabetic retinopathy, in addition to the demonstration by the DCCT study that prevention is achieved by good metabolic control, our present knowledge on physiopathology leads us to imagine three types of possible therapeutic approach; inhibition of glucotoxicity, improvement of capillary flow, blockade of angiogenesis. 1) Inhibition of glucotoxicity Aldose reductase inhibitors can prevent cataract in diabetic or galactosemic rats. The effect of these drugs on retinopathy, evaluated in some clinical trials, remains controversial, suggesting a minor role. Aminoguanidine is an inhibitor of formation of advanced glycosylation end-products (AGE). This compound has been tested on a model of experimental retinopathy in rats. Parallel to the AGE decrease in retina, formation of microaneurysms and loss of endothelial cells in capillaries were delayed. Clinical tolerance allows human application and randomised trials will give further information on this potentially efficient drug. 2) Improvement of capillary flow This objective can be obtained by drugs inhibiting platelet aggregation or improving erythrocyte or leucocyte deformability. Clinical trials using such compounds were not very conclusive. 3) Blockade of angiogenesis Proliferation of new vessels is a rather severe stage of diabetic retinopathy. Angiogenesis is due to factors locally produced (as FGF, TGF and u-PA produced by anoxic tissues), systemic (IGF-1) or released by inflammatory reaction (IL1, TNF alpha and beta). One imagines usage of drugs which inhibit these factors and prevent angiogenesis. At the present time, two approaches have been used in proliferative retinopathy worsening despite panphotocoagulation; analogues of somatostatin and interferon alpha. The promissing results of these pilot studies have to be confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Outlook for the future in the treatment of diabetic retinopathy]. 752 51

nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor beta 1 (TGF beta 1) signal transduction. In an earlier study we decreased nm23 mRNA levels 2- to 8-fold by antisense phosphorothiolated oligonucleotides in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGF beta 1. Only TGF beta 1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility. HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23 mRNA levels, while HD3 cell motility was conversely decreased by TGF beta 1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGF beta 1 or TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGF beta 1 and 5-fold by TGF alpha, but not by scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of proteases or modulation of their levels by TGF beta 1. Both HD3 and U9 cells displayed equal levels of urokinase activity and mRNA, equal expression of the metalloproteinase inhibitor TIMP-1, and no detectable collagenases by zymography. No differential response to TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.
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PMID:Colon carcinoma cells with inactive nm23 show increased motility and response to motility factors. 755 87

The fibroblast growth factor-2 (FGF-2) low-affinity binding sites, heparan sulfate proteoglycans (HSPGs), function as modulators of FGF-2 activity. It is noteworthy that HSPG binding protects FGF-2 from denaturation and proteolytic degradation, provides a matrix-bound or cell-surface reservoir of this factor for the cells and is required for the activation of FGF high-affinity receptors. In our study we investigated the biological meaning of FGF-2 internalization mediated through its low-affinity binding sites, HSPGs. Using as model system L6 myoblasts lacking endogenous FGF receptors (FGFRs), we demonstrated that these cells internalize FGF-2 efficiently through an HSPG-mediated pathway. FGF-2 internalization occurring through HSPGs was paralleled by an increase in the activity of urokinase plasminogen activator (u-PA). The u-PA-inducing activity of FGF-2 was strictly correlated to its internalization, as chlorate treatment, which causes a strong inhibition of FGF-2 internalization, abrogated the u-PA-inducing activity of FGF-2. In addition, expression of functional FGF high-affinity receptors (FGFR-1) did not enhance u-PA in L6 myoblasts upon FGF-2 stimulation. According to our results we propose that FGF-2 internalization mediated through HSPGs may transduce FGF-2 signalling such as u-PA-activity stimulation. Thus, HSPGs may act as direct transducers of FGF signalling and indeed, different FGF-signalling pathways must exist.
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PMID:Heparan sulfate proteoglycans as transducers of FGF-2 signalling. 769 17

In addition to fibrinolysis, plasminogen activators may be involved in other processes relevant to atherogenesis such as smooth muscle cell migration, proliferation and extracellular matrix remodeling. Because mitogens such as basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) are positive regulatory factors and heparin is a negative regulatory factor for smooth muscle cell proliferation and migration, we have looked at the effects of these factors (plus serum and phorbol ester) on urokinase (uPA) and tissue plasminogen activator (tPA) of smooth muscle cells. PDGF, bFGF and serum increased tPA (serum > PDGF > FGF). Heparin inhibited the effect of serum, but not PDGF on tPA. Heparin actually increased the stimulatory effect of bFGF on tPA. Of interest, heparin was also able to inhibit mitogenesis mediated by serum, but not by PDGF or bFGF. Serum decreased and phorbol ester increased uPA, while PDGF and bFGF had no effect Heparin shifted uPA from the cell layer to the medium of serum or phorbol ester treated but not PDGF or bFGF treated cells. These data demonstrate that PDGF, bFGF and serum can differentially regulate smooth muscle cell plasminogen activators and that heparin can either increase or decrease levels of tPA or shift the localization of uPA depending on the mitogen used.
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PMID:Regulation of baboon arterial smooth muscle cell plasminogen activators by heparin and growth factors. 770 77

New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (delta 4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity; (iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response to hormone stimulation for tPA and PAI-1 secretion.
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PMID:Regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured rat Sertoli and Leydig cells. 876 Apr 71

Basic fibroblast growth factor (FGF-2) induces cell proliferation and urokinase-type plasminogen activator (uPA) production in fetal bovine aortic endothelial GM 7373 cells. In the present paper we investigated the role of the interaction of FGF-2 with tyrosine-kinase (TK) FGF receptors (FGFRs) in mediating uPA up-regulation in these cells. The results show that FGF-2 antagonists suramin, protamine, heparin, the synthetic peptide FGF-2(112-155), and a soluble form of FGFR-1 do not inhibit FGF-2-mediated uPA up-regulation at concentrations that affect growth factor binding to cell surface receptors and mitogenic activity. In contrast, tyrosine phosphorylation inhibitors and overexpression of a dominant negative TK- mutant of FGFR-1 abolish the uPA-inducing activity of FGF-2, indicating that FGFR and its TK activity are essential in mediating uPA induction. Accordingly, FGF-2 induces uPA up-regulation in Chinese hamster ovary cells transfected with wild-type FGFR-1, -2, -3, or -4 but not with TK- FGFR-1 mutant. Small unilamellar phosphatidyl choline:cholesterol vesicles loaded with FGF-2 increased uPA production in GM 7373 cells in the absence of a mitogenic response. Liposome-encapsulated FGF-2 showed a limited but significant capacity, relative to free FGF-2, to interact with FGFR both at 4 degrees C and 37 degrees C and to be internalized within the cell. uPA up-regulation by liposome-encapsulated FGF-2 was quenched by neutralizing anti-FGF-2 antibodies, indicating that the activity of liposome-delivered FGF-2 is mediated by an extracellular action of the growth factor. Taken together, the data indicate that a distinct interaction of FGF-2 with FGFR, quantitatively and/or qualitatively different from the one that leads to mitogenicity, is responsible for the uPA-inducing activity of the growth factor.
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PMID:A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells. 886 66

In this communication we approach the events leading to fertilization in mammals by examining the triangle of egg, sperm and oviductal cell taking account of the local physiology and focussing on auto/paracrine interactions. The expression of growth factors and extra-cellular matrix (ECM)-components in bovine ovarian granulosa- and theca-cells, the oocyte-cumulus complex (OOC) and oviductal epithelium, as well as some of the corresponding secreted proteins can be detected through the estrous cycle. Components of the insulin-like (IGF), fibroblast (FGF) and transforming (TGF) growth factor systems, and also metalloproteinase 1 (MMP1) and urokinase (uPA) are found to be modulated in these cells prior to fertilization. Different expression levels between the cell types are found, each representative of a specific reaction window within that particular stage of the cycle. Our findings support the concept that most of the observed tissue in the reproductive tract is dependent upon on the effects of gonadotropins or steroids, but that the fine-regulation is conveyed by, for example, growth factors and ECM-components. We suggest a sophisticated, auto/paracrine and species-specific crosstalk of growth factors and ECM components between the different cell types involved, enabling fertilization and development of the embryo at the right time and in the right location.
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PMID:Egg-cumulus-oviduct interactions and fertilization. 936 6

Fibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture plastic promotes adhesion and spreading of bovine and human endothelial cells that are inhibited by anti-FGF-2 antibody. Heat-inactivated FGF-2 retains its cell-adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors or to cell-surface heparan sulfate proteoglycans. Recombinant glutathione-S-transferase-FGF-2 chimeras and synthetic FGF-2 fragments identify two cell-adhesive domains in FGF-2 corresponding to amino acid sequences 38-61 and 82-101. Both regions are distinct from the FGF-receptor-binding domain of FGF-2 and contain a DGR sequence that is the inverse of the RGD cell-recognition sequence. Calcium deprivation, RGD-containing eptapeptides, soluble vitronectin (VN), but not fibronectin (FN), inhibit cell adhesion to FGF-2. Conversely, soluble FGF-2 prevents cell adhesion to VN but not FN, thus implicating VN receptor in the cell-adhesive activity of FGF-2. Accordingly, monoclonal and polyclonal anti-alphavbeta3 antibodies prevent cell adhesion to FGF-2. Also, purified human alphavbeta3 binds to immobilized FGF-2 in a cation-dependent manner, and this interaction is competed by soluble VN but not by soluble FN. Finally, anti-alphavbeta3 monoclonal and polyclonal antibodies specifically inhibit mitogenesis and urokinase-type plasminogen activator (uPA) up-regulation induced by free FGF-2 in endothelial cells adherent to tissue culture plastic. These data demonstrate that FGF-2 interacts with alphavbeta3 integrin and that this interaction mediates the capacity of the angiogenic growth factor to induce cell adhesion, mitogenesis, and uPA up-regulation in endothelial cells.
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PMID:alphavbeta3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells. 939 67

The broad spectrum protease urokinase-type plasminogen activator (uPA) has been implicated in muscle regeneration in vivo as well as in myogenic proliferation and differentiation in vitro. These processes are known to be modulated by basic fibroblast growth factor (FGF-2) and serum. We therefore investigated the mechanism(s) underlying the regulation of uPA expression by these two stimuli in proliferating and differentiating myoblasts. The expression of uPA mRNA and the activity of the uPA gene product were induced by FGF-2 and serum in proliferating myoblasts. uPA induction occurred at the level of transcription and required the uPA-PEA3/AP1 enhancer element, since deletion of this site in the full promoter abrogated induction by FGF-2 and serum. Using L6E9 skeletal myoblasts, devoid of endogenous FGF receptors, which have been engineered to express either FGF receptor-1 (FGFR1) or FGF receptor-4 (FGFR4), we have demonstrated that both receptors, known to be expressed in skeletal muscle cell precursors, were able to mediate uPA induction by FGF-2, whereas serum stimulation was FGF receptor-independent. The induction of uPA by FGF-2 and serum in FGFR1- and in FGFR4-expressing myoblasts required the mitogen-activated protein kinase pathway, since treatment of cells with a specific inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase-2 kinase, PD98059, blocked uPA promoter induction. Although FGF-2 and serum induced uPA in proliferating myoblasts, their actions on cell-cell contact-induced differentiating myoblasts differed dramatically. FGF-2, but not serum, repressed uPA expression in differentiation-committed myoblasts, and these effects were also shown to occur at the level of uPA transcription. Altogether, these results indicate a dual regulation of the uPA gene by FGF-2 and serum, which ensures uPA expression throughout the whole myogenic process in different myoblastic lineages. The effects of FGF-2 and serum on uPA expression may contribute to the proteolytic activity required during myoblast migration and fusion, as well as in muscle regeneration.
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PMID:Differential regulation of urokinase-type plasminogen activator expression by basic fibroblast growth factor and serum in myogenesis. Requirement of a common mitogen-activated protein kinase pathway. 944 43

The spindle-shaped cell line TTB was recently isolated from highly vascularized skin lesions of BKV/HIV-1 tat transgenic mice and shown to possess an autocrine loop for hepatocyte growth factor (HGF). We show that fibroblast growth factor-2 (FGF-2) stimulates TTB cell migration and promotes polarization of uPAR at the leading edge of migrating cells. FGF-stimulated TTB cells presented the typical migratory phenotype, with a triangular cell shape and concomitant breakdown of actin stress fibers and smooth muscle-specific actin isoform. FGF-2-stimulated migration was blocked by antibodies against urokinase-type plasminogen activator (uPA) or uPA receptor (uPAR) and by neutralizing anti-HGF antibodies. The latter also inhibited uPAR relocalization at the cell surface of FGF-2-treated TTB cells. This points to a crosstalk between FGF-2 and HGF that might mediate TTB cell migration by modulating the localization of cell surface uPAR.
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PMID:FGF-2 stimulates migration of Kaposi's sarcoma-like vascular cells by HGF-dependent relocalization of the urokinase receptor. 970 75


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