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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) is a potent mitogen consisting of heterodimers of two distinct but homologous polypeptide chains, denoted A and B. PDGF-like homodimers of the A- and B-chains have been isolated, as well as two distinct receptor types (alpha and beta), which discriminate among the PDGF isoforms. The PDGF A- and B-chains are encoded by distinct genes located on human chromosomes 7 and 22, respectively. Although PDGF has been implicated as an important participant in development, tissue repair, and numerous pathologic states including tumorigenesis, atherosclerosis and inflammation, the mechanisms which determine the rate of its synthesis are only beginning to be understood. Basal expression of the PDGF A- and B-chain genes has been characterized in a number of cell types and is directed in part by elements in the respective proximal promoter-regulatory regions of the two genes. In addition, the first intron of PDGF-B has been shown to contain both positive and negative regulatory elements. Transcription of the PDGF subunit genes is inducible by a wide variety of mitogenic growth factors, cytokines and other agonists. These agents produce a rapid increase in steady-state concentrations of PDGF A- and B-chain mRNAs, peaking within 4-8 h of stimulation. The inductive effects of protein kinase C-activating phorbol 12-myristate 13-acetate (PMA), thrombin and transforming growth factor-beta (TGF-beta) are mediated through increases in the transcription rates of both genes. In addition, cAMP blocks the increases in transcription of the B-chain gene induced by thrombin and TGF-beta. Studies have demonstrated the importance of sequences immediately upstream of the B-chain transcription start site for induction in response to PMA-initiated megakaryocyte differentiation, an effect which is dependent on protein synthesis. However, cis-acting elements which mediate more rapid transcriptional induction seen in endothelial cells and astrocytes have yet to be identified in the proximal 5'-flanking sequences of either the A- or B-chain genes, suggesting that such events may be mediated by elements located outside of this region.
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PMID:Transcriptional control of the platelet-derived growth factor subunit genes. 834 77

The clotting protease thrombin might contribute to cell damage following brain injury by its ability to retract processes on neurons and astrocytes. Protease nexin-1 (PN-1), a potent inhibitor of thrombin, is localized around cerebral blood vessels where it may protect these cells from extravasated thrombin during injury or alteration of the blood-brain barrier. Here we examined the effects of several injury-related factors on the regulation of PN-1 in cultured brain cells. Interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta stimulated the secretion of PN-1 by the neuroblastoma cell line SK-N-SH. This cell line comprises both neuronal and glial cells. Analyses using cloned derivatives of these two cell types showed that PN-1 was secreted by the glial cells; PN-1 secretion was stimulated 90-fold by interleukin-1, 15-fold by tumor necrosis factor-alpha, 10-fold by tumor growth factor-beta, and 4-fold by platelet-derived growth factor. Measurements of newly synthesised PN-1 demonstrated that these factors produced an equivalent stimulation of PN-1 synthesis. The neuronal cells secreted two thrombin-binding proteins distinct from PN-1. Interactions between these two cell types regulated the secretion of PN-1 and the two thrombin-binding proteins.
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PMID:Regulation of protease nexin-1 synthesis and secretion in cultured brain cells by injury-related factors. 842 47

The angiogenic factor, basic fibroblast growth factor (bFGF), is sequestered and protected by binding to heparan sulfate proteoglycans (HSPG) in the subendothelial extracellular matrix (ECM). Release of ECM-bound bFGF provides a novel mechanism for regulation of cell proliferation and neovascularization in normal and pathologic situations. Exposure of ECM to thrombin, the final activation product of the clotting cascade, resulted in release of high molecular weight HSPG-bFGF complex, as indicated by its immunoprecipitation with anti-bFGF antibodies, susceptibility to degradation by bacterial heparinase, and inhibition of its mitogenic activity in the presence of neutralizing anti-bFGF antibodies. The ECM-resident bFGF-HSPG complex was not released by thrombin in the presence of hirudin or antithrombin III, or by catalytically blocked thrombin preparations. A threefold to fivefold higher mitogenic activity was released by thrombin from ECM that was preheated (1 hour, 80 degrees C), as compared with native ECM. This difference is attributed to heat stable bFGF-HSPG complexes that are more readily released after heat treatment of the ECM and to activation and release of ECM-resident transforming growth factor-beta (TGF-beta) activity. Our results indicate that the large reservoir of proteolytic activity present in plasma in the form of prothrombin may participate in release from the subendothelial ECM of biologically active bFGF and TGF-beta, depending on the accessibility of thrombin. Thrombin may gain access to the subendothelium on clot formation after tissue injury and as a result of the conversion of prothrombin to thrombin induced by the ECM itself.
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PMID:Thrombin-induced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix. 850 69

The effects of and interactions between the six inflammatory mediators interleukin-1 (IL-1), tumour necrosis factor (TNF), gamma-interferon (INF-gamma), transforming growth factor-beta (TGF-beta), bradykinin (BK) and thrombin on prostanoid biosynthesis in primary cultures of human, dental, pulp fibroblasts were examined. IL-1 alpha, IL-1 beta, TNF-alpha and TNF-beta caused a time- and concentration-dependent enhancement of prostaglandin E2 (PGE2) formation in the fibroblasts. The onset of action was delayed 1-2 h and maximal response was seen after 24 h. In contrast, BK and thrombin caused a burst of PGE2 formation with maximal response after 10 min. BK (1 microM) and thrombin (3 U/ml) synergistically potentiated IL-1 alpha and IL-1 beta stimulated PGE2 formation in 24 h cultures. The effect of BK and thrombin on IL-1 beta enhanced PGE2 formation was seen both at suboptimal and optimal concentrations of IL-1 beta without affecting the sensitivity to IL-1 beta. BK and thrombin also synergistically potentiated the stimulatory effect of TNF-alpha and TNF-beta on PGE2 formation. The synergistic interactions between BK and IL-1 alpha, IL-1 beta and TNF-alpha were seen after 2-4 h of treatment. BK analogues with affinity to BK B2-receptors, but not to BK B1-receptors, were able to synergistically potentiate IL-1 beta and TNF-alpha-enhanced PGE2 production. The synergistic stimulation of PGE2 formation by IL-1, TNF and BK was abolished by indomethacin and flurbiprofen. Preincubation with IL-1 beta and TNF-alpha for 24 h resulted in a substantial amplification of the PGE2 response to a subsequent 24 h challenge with BK in the absence of cytokine. Similarly, when the pulp fibroblasts were preincubated with or without IL-1 beta or TNF-alpha for 24 h and then challenged with exogenous arachidonic acid for 60 min, PGE2 formation was significantly enhanced in cytokine pretreated cells. BK potentiated cytokine induced amplification of the PGE2 response to arachidonic acid. gamma-IFN and TGF-beta did not enhance PGE2 formation, nor did these cytokines potentiate IL-beta or TNF-alpha-induced PGE2 production. These data show that proinflammatory mediators such as BK and thrombin act in concert with IL-1 and TNF in stimulating prostanoid formation in human pulpal fibroblasts and that the action of BK is linked to BK B2-receptors. The results are compatible with the view that enhanced metabolism of arachidonic acid, probably due to increased activation or de novo synthesis of cyclooxy-genase(s), is involved in the mechanism by which IL-1, TNF, BK and thrombin interact.
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PMID:Bradykinin and thrombin synergistically potentiate interleukin 1 and tumour necrosis factor induced prostanoid biosynthesis in human dental pulp fibroblasts. 877 76

The syndecan family of transmembrane heparan sulfate proteoglycans is abundant on the surface of all adherent mammalian cells. Syndecans bind and modify the action of various growth factors/cytokines, proteases/antiproteases, cell adhesion molecules, and extracellular matrix components. Syndecan expression is highly regulated during wound repair, a process orchestrated by many of these effectors. Each syndecan ectodomain is shed constitutively by cultured cells, but the mechanism and significance of this shedding are not understood. Therefore, we examined (i) whether physiological agents active during wound repair influence syndecan shedding, and (ii) whether wound fluids contain shed syndecan ectodomains. Using SVEC4-10 endothelial cells we find that certain proteases and growth factors accelerate shedding of the syndecan-1 and -4 ectodomains. Protease-accelerated shedding is completely inhibited by serum-containing media. Thrombin activity is duplicated by the 14-amino acid thrombin receptor agonist peptide that directly activates the thrombin receptor and is not inhibited by serum. Epidermal growth factor family members accelerate shedding but FGF-2, platelet-derived growth factor-AB, transforming growth factor-beta, tumor necrosis factor-alpha, and vascular endothelial cell growth factor 165 do not. Shed ectodomains are soluble, stable in the conditioned medium, have the same size core proteins regardless whether shed at a basal rate, or accelerated by thrombin or epidermal growth factor-family members and are found in acute human dermal wound fluids. Thus, shedding is accelerated by activation of at least two distinct receptor classes, G protein-coupled (thrombin) and protein tyrosine kinase (epidermal growth factor). Proteases and growth factors active during wound repair can accelerate syndecan shedding from cell surfaces. Regulated shedding of syndecans suggests physiological roles for the soluble proteoglycan ectodomains.
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PMID:Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor receptor activation. 916 35

Alpha-thrombin is a multifunctional serine proteinase that is concentrated at sites of vascular injury and has been implicated in vascular healing responses following balloon injury. In addition to its well-known hemostatic effects, thrombin stimulates smooth muscle cell (SMC) proliferation via binding of protease activated receptor-1 (PAR-1), a seven transmembrane, G-protein-coupled cell surface receptor. Following activation of this receptor, SMC produce and secrete various autocrine growth factors, including platelet-derived growth factor-AA (PDGF-AA), basic fibroblast growth factor (bFGF), heparin binding epidermal growth factor (HBEGF), and transforming growth factor-beta (TGFbeta). The role that autocrine growth factors play in alpha-thrombin-induced proliferation will be discussed in this review.
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PMID:The role of secondary growth factor production in thrombin-induced proliferation of vascular smooth muscle cells. 957 35

Glomerular fibrin deposition is thought to be one of the factors causing progressive glomerular injury and may be related to defective intraglomerular fibrinolysis. Recently, it was shown that tissue plasminogen activator (t-PA) is produced by mesangial cells and is associated with degradation of the extracellular matrix. This study was designed to clarify the factors regulating t-PA production in human mesangial cells. The levels of t-PA activity, t-PA antigen and t-PA inhibitor-1 (PAI-1) antigen were estimated in the supernatants of cultured human fetal mesangial cells incubated for 72 h with thrombin, IL-Ibeta, IL-6, IL-10, and transforming growth factor-beta (TGF-beta). The t-PA activity was measured by an amidolytic assay, and the levels of t-PA antigen and PAI-1 antigen were also measured by enzyme-linked immunosorbent assay. Thrombin increased t-PA activity and TGF-beta decreased it in parallel with t-PA antigen level, although these agents did not affect the synthesis of PAI-1. Incubation with IL-1beta, IL-6 and IL-10 did not change the t-PA activity. It was concluded that the release of t-PA from human fetal mesangial cells was stimulated by thrombin and inhibited by TGF-beta in parallel with that of t-PA antigen. These factors may participate in the glomerular fibrin deposition and the accumulation of extracellular matrix.
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PMID:Regulation of tissue plasminogen activator production in cultured human fetal mesangial cells. 980 22

1. Endothelin (ET) and its mRNA are present in endometrium. Expression of ET varies across the menstrual cycle, reaching maximal levels in the premenstrual phase, suggesting a paracrine role in endometrial bleeding and/or repair. 2. The major cellular source of ET is the epithelium, although endothelium and decidualized stroma are additional sites of production. Epithelial ET is the ET-1 isoform and this is able to contract rat thoracic aortic rings ex vivo. 3. Endothelin-1 production by cultured endometrial epithelial cells is markedly increased by serum and, to a lesser extent, by transforming growth factor-beta and interleukin-1 alpha, but not by epidermal growth factor, oxytocin, arginine vasopressin, thrombin or angiotensin II, which stimulate ET production in other tissues. 4. Endothelin-1 has mitogenic actions on endometrial stromal cells; it stimulates the uptake of [3H]-thymidine, acting via the AP-1 cis element c-jun. 5. Neutral endopeptidase (NEP), a membrane-bound ectoenzyme that is capable of degrading ET, is localized principally in endometrial stroma and immunoreactivity is maximal in the secretory phase of the cycle. 6. A potential role for ET in regulating endometrial bleeding is suggested by studies on endometrium from two groups of women who were experiencing abnormal uterine bleeding: users of the contraceptive Norplant (Leiras Co., Turku, Finland) and subjects with documented menorrhagia. In both groups, ET-1 immunoreactivity in endometrial epithelium was markedly reduced compared with the normal menstrual cycle and did not vary cyclically, while NEP immunoreactivity, particularly in the epithelium, was increased. Thus, ET may be involved in endometrial bleeding, as a vasoconstrictor before the onset of menstruation when vasoconstriction is intense and, subsequently, when it may be required in the cessation of menstrual bleeding. Furthermore, the mitogenic actions of ET may play a role in endometrial regeneration and remodelling during the menstrual cycle, particularly following menstruation.
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PMID:Endometrial endothelin: regulator of uterine bleeding and endometrial repair. 1006 38

Protease nexin I is a 43-50 kDa glycoprotein capable of inhibiting a number of serine proteases. In cultured differentiated human skeletal muscle (myotubes), we previously found that protease nexin I was localized in patches at their surface where it was active and able to inhibit thrombin. To understand the role of skeletal muscle protease nexin I after injury or in inflammatory conditions where thrombin might be extravasated by blood vessels, we examined the role of inflammatory factors on protease nexin I synthesis and secretion by myotubes in culture. By enzyme-linked immunosorbent assay (ELISA) and Western blotting, we found that this serine protease inhibitor is secreted by cultured human myotubes. Protease nexin I secretion is stimulated by tumor necrosis factor-alpha, transforming growth factor-beta and interleukin-1. Complex formation experiments with labeled thrombin reveal active protease nexin I bound to the surface of the treated cells. Secreted protease nexin I-thrombin complex was enhanced in the presence of transforming growth factor-beta and tumor necrosis factor-alpha. Protease nexin I mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis. Whatever the conditions, no significantly different levels were observed, indicating that the changes in cell and media protease nexin I concentration are elicited at the translational/posttranslational levels. Immunocytochemical studies on human skeletal muscle biopsies of patients suffering from inflammatory myopathies showed an overexpression of protease nexin I together with the above inflammatory factors. These findings suggest that skeletal muscle protease nexin I might play a role after injury or inflammatory pathologies.
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PMID:Protease nexin I expression is up-regulated in human skeletal muscle by injury-related factors. 1022 49

Tissue factor pathway inhibitor (TFPI) is the primary physiological inhibitor that regulates tissue factor-induced blood coagulation. TFPI is thought to be synthesized, in vivo, primarily by microvascular endothelial cells. Little is known about how TFPI is regulated under pathophysiological conditions. In this study, we determined mechanisms by which TFPI expression is regulated by human pulmonary artery smooth muscle cells (PASMC), because these cells contribute to remodeling of the pulmonary vasculature in disease. PASMC in culture constitutively synthesize and secrete TFPI. Exposure of PASMC to phorbol myristate acetate, lipopolysaccharide, tumor necrosis factor alpha, thrombin, interleukin-1, and transforming growth factor-beta had no significant effect on expression of TFPI by PASMC. By contrast, treatment of PASMC with serum and basic fibroblast growth factor (bFGF)/heparin markedly upregulated the expression of TFPI activity and antigen. On Western blot analysis, a protein consistent with full-length TFPI (42 kD) was identified in the conditioned media of PASMC, and the levels of the protein were much higher in the conditioned media of serum and bFGF/heparin-treated cells. Northern blot analysis showed that PASMC constitutively express TFPI mRNA, and treatment of cells with serum and bFGF/heparin had a minimal effect on the steady-state levels of TFPI mRNA. Nuclear run-on analysis did not show a significant increase in the transcriptional rate of TFPI gene in PASMC treated with serum or bFGF/heparin. Cycloheximide, but not actinomycin-D, treatment inhibited the serum and bFGF/heparin-induced increase in TFPI activity in PASMC. In conclusion, our data demonstrate that PASMC constitutively synthesize and secrete TFPI and serum or bFGF upregulate its expression, suggesting that growth factors that can stimulate the vessel wall in vivo might locally regulate TFPI expression. Our study also suggests that control of TFPI expression by serum or bFGF occurs via translational rather than transcriptional regulation.
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PMID:Regulation of tissue factor pathway inhibitor expression in smooth muscle cells. 1039 25


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