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: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flat, amorphous astroblasts in culture differentiate into rounded process-bearing cells after removal of serum from the media or following addition of dibutyryl cyclic-AMP (dbcAMP). We report here that addition of thrombin (10 nM) to rat primary astroglial cultures reversed both the spontaneous morphological differentiation of astroblasts caused by serum removal, and the more extensive morphological differentiation caused by pre-treatment with dbcAMP. The astroblasts retained the ability to differentiate upon removal of thrombin from the medium. Proteolytic activity of thrombin was required for the reversal of differentiation. Moreover, addition of serine protease inhibitors active against thrombin elicited a prolonged morphological differentiation rivaling that induced by dbcAMP, suggesting that inactivation of cell-associated thrombin might be sufficient for morphological differentiation to occur. Two other serine proteases with a cleavage specificity similar to thrombin were ineffective in reversing differentiation. Both the induction of morphological differentiation by dbcAMP and its reversal by thrombin were rapid, being essentially complete by 1 h. With more prolonged treatments, thrombin also reduced the dbcAMP-mediated increase in glutamine synthetase, a biochemical marker for astroglial differentiation. Thrombin also inhibited morphological differentiation in C6 glioma and altered the morphology of microglial cells; however, thrombin did not prevent neurite outgrowth in primary central neuronal cultures in contrast to its previously reported effects on the neuroblastoma 2a cell line. These findings indicate that a proteolytic mechanism mediated by thrombin and its inhibitors may underlie the regulation of astroglial differentiation.
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PMID:Thrombin and its inhibitors regulate morphological and biochemical differentiation of astrocytes in vitro. 197 84

Treatment of rat glioma C6 cells with a beta-adrenergic agonist leads to a rise in cAMP level and a subsequent change in cell morphology from an epithelial to an astrocyte type of appearance. This morphological change is reverted by the addition of thrombin. In 10-15 min the cells acquire their normal epithelial morphology. The reversion by thrombin is inhibited by hirudin, but not by antithrombin III (an inhibitor of the proteolytic action of thrombin). Using the intracellular Ca2(+)-indicator fura-2, we observed that the addition of thrombin to the glioma cells generated a Ca2(+)-signal which was inhibited by pretreatment of the cells with hirudin or with 1 mM neomycin. These results suggest that thrombin uses the phospholipid-inositol pathway to counteract the morphological response, which was induced by activation of the cAMP pathway.
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PMID:Thrombin reverts the beta-adrenergic agonist-induced morphological response in rat glioma C6 cells. 216 46

In the present studies we have compared the structural and biochemical properties of human protease nexin-I (PN-I) and a protease inhibitor present in the serum-free culture fluid of normal rat brain astrocytes. The inhibitor binds to and forms covalent complexes with human urokinase and thrombin. The inhibitor has an approximate Mr = 43,000 based on the size of the complexes (deduced from SDS-PAGE) and mediates the cellular binding and uptake of the proteases to which it links. Binding is heparin sensitive and occurs on a cell surface receptor that also binds complexes formed between proteases and a well-characterized cell-secreted protease inhibitor, human PN-I. In addition, the inhibitor co-migrates with PN-I on SDS-PAGE and cross-reacts with anti-PN-I antibody on immunoblots. A similar molecule, designated NPF, is produced by C6 glioma cells in culture and has neurite promoting activity on a neuroblastoma cell line.
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PMID:Identification of a protease inhibitor produced by astrocytes that is structurally and functionally homologous to human protease nexin-I. 304 Jan 75

Protease nexin-I (PN-I, Mr approximately 43,000) is representative of a newly described class of cell-secreted protease inhibitors. PN-I has been purified to apparent homogeneity, partially sequenced, and monospecific antibodies have been raised against it. PN-I is a potent inhibitor of urokinase, thrombin, plasmin, and trypsin. In addition, cells have specific receptors that mediate the uptake of covalently linked complexes formed between PN-I and its protease substrates. In the present studies, we have investigated the relationship between human PN-I and a protease inhibitor derived from C6 glioma cells in culture that has neurite-promoting activity. On the basis of co-purification on heparin-Sepharose, identical molecular weight, antibody cross-reactivity, and receptor cross-reactivity, we conclude that PN-I and the glioma-cell-derived inhibitor are equivalent molecules.
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PMID:The glioma cell-derived neurite promoting activity protein is functionally and immunologically related to human protease nexin-I. 304 Jul 80

We have identified a tissue-kallikrein-binding protein in human serum and in the serum-free culture media from human lung fibroblasts (WI-38) and rodent neuroblastoma X glioma hybrid cells (NG108-15). Purified and 125I-labelled tissue kallikrein and human serum form an approximately 92,000-Mr SDS-stable complex. The relative quantity of this complex-formation is measured by densitometric scanning of autoradiograms. Complex-formation between tissue kallikrein and the serum binding protein was time-dependent and detectable after 5 min incubation at 37 degrees C, with half-maximal binding at 28 min. Binding of 125I-kallikrein to kallikrein-binding protein is temperature-dependent and can be inhibited by heparin or excess unlabelled tissue kallikrein but not by plasma kallikrein, collagenase, thrombin, urokinase, alpha 1-antitrypsin or kininogens. The kallikrein-binding protein is acid- and heat-labile, as pretreatment of sera at pH 3.0 or at 60 degrees C for 30 min diminishes complex-formation. However, the formed complexes are stable to acid or 1 M-hydroxylamine treatment and can only be partially dissociated with 10 mM-NaOH. When kallikrein was inhibited by the active-site-labelling reagents phenylmethanesulphonyl fluoride or D-Phe-D-Phe-L-Arg-CH2Cl no complex-formation was observed. An endogenous approximately 92,000-Mr kallikrein-kallikrein-binding protein complex was isolated from normal human serum by using a human tissue kallikrein-agarose affinity column. These complexes were recognized by anti-(human tissue kallikrein) antibodies, but not by anti-alpha 1-antitrypsin serum, in Western-blot analyses. The results show that the kallikrein-binding protein is distinct from alpha 1-antitrypsin and is not identifiable with any of the well-characterized plasma proteinase inhibitors such as alpha 2-macroglobulin, inter-alpha-trypsin inhibitor, C1-inactivator or antithrombin III. The functional role of this kallikrein-binding protein and its impact on kallikrein activity or metabolism in vivo remain to be investigated.
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PMID:Identification of a new tissue-kallikrein-binding protein. 364 93

Thrombin at nanomolar concentrations induces rapid changes in the second messenger Ca2+ in a glial astrocyte-type cell line. Continuous application of the protease thrombin causes regular [Ca2+]i oscillations (amplitude 109 nM, spike length 48 s) which are suppressed by hirudin. Reduction of [Ca2+]ex (from 1.8 mM to 50 microM) reversibly abolishes the oscillations indicating the contribution of Ca2+ influx to generation of the oscillations. Thrombin receptor-activating peptide (TRAP, 1-10 microM) causes similar Ca2+ oscillations which depend, like the oscillations induced by thrombin, on the continuous presence of agonist. Thus, we can deduce that cell surface receptors are responsible for the effect of thrombin on glioma cells.
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PMID:[Ca2+]i oscillations in single rat glioma cells induced by thrombin through activation of cell surface receptors. 766 79

Binding of plasmin(ogen) to rat C6 glioma cells is saturable and kringle-domain dependent. This interaction was studied as a model of plasmin(ogen) receptor interactions in nucleated mammalian cells. Apparent 125I-plasmin dissociation from C6 cell binding sites was slow; however, the dissociation rate was increased when the solution contained diisopropyl phosphoryl-plasmin (0.3 microM), fibrinogen (0.16 or 0.8 mg/ml), 1.08 mM D-Val-L-Leu-L-Lys-p-nitroanilide-HCl (S-2251), or epsilon-amino-n-caproic acid (EACA, 5.0 mM). EACA promoted the most rapid dissociation of plasmin. C6 cell-associated plasmin and plasmin in solution demonstrated similar amidase activity. Only specifically bound plasmin (75% of total binding) was active against S-2251. Plasmin that was initially bound to C6 cells digested fibrinogen in a time- and plasmin concentration-dependent manner. alpha 2-Antiplasmin (alpha 2AP, 0.1 microM) completely inhibited fibrinogenolysis by plasmin that was initially C6- or human umbilical vein endothelial-cell associated. Since alpha 2AP reacts selectively with plasmin in solution (minimally with plasmin bound to cells), fibrinogen digestion by cell-associated plasmin probably occurred only after the plasmin dissociated into solution. Crosslinked fibrin clots were formed in uniform layers over C6 cells. If the cells were incubated with plasmin before addition of fibrinogen and thrombin, the clots were rapidly lysed. alpha 2AP incompletely inhibited fibrinolysis when added after fibrin polymerization (44% inhibition with 0.1 microM alpha 2AP). Fibrinolysis was completely inhibited when alpha 2AP was added before fibrin polymerization. These studies suggest that plasmin must first dissociate from cellular binding sites to mediate fibrinogenolysis or fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinogenolytic and fibrinolytic activity of cell-associated plasmin. 767 97

The activation of P2-purinergic receptors on C6-2B rat glioma cells caused a transient increase in cytosolic-free Ca2+ concentration ([Ca2+]i) as detected by Fura 2 fluorescence ratio imaging of single cells. These purinergic receptors are of the P2U subtype because UTP and ATP were equipotent and substantially more potent than the P2X- and P2Y-selective agonists alpha,beta-methylene ATP and 2-methylthio ATP, respectively. There was homologous desensitization of the Ca2+ responses between UTP and ATP but no heterologous desensitization between these nucleotides and another Ca(2+)-mobilizing receptor agonist, alpha-thrombin. The UTP-induced peak [Ca2+]i rise was insensitive to chelation of extracellular Ca2+ with EGTA. However, the response was abolished after either depletion of intracellular Ca2+ stores with the microsomal Ca(2+)-ATPase inhibitor thapsigargin or blockade of Ca2+ release from intracellular stores with the muscle relaxant dantrolene. The activation of P2U-purinergic receptors and thrombin receptors increased the formation of total inositol phosphates (IPs) and inhibited cAMP accumulation elicited with either the beta-adrenergic receptor agonist (-)-isoproterenol, or forskolin, a direct activator of adenylyl cyclase. UTP- and alpha-thrombin-induced changes in the levels of IPs, cytosolic Ca2+, and agonist-elicited cAMP accumulation were dramatically inhibited (> 80%) by acute treatment of the cells with the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate but not with the inactive ester 4 alpha-phorbol 12,13-didecanoate. We conclude that in C6-2B cells, the increase in [Ca2+]i after activation of P2U-purinergic receptors is primarily a result of IPs-mediated release of Ca2+ from intracellular stores with secondary influx of Ca2+ by capacitative mechanisms. Also, the inhibition by UTP and alpha-thrombin of agonist-elicited cAMP accumulation is mediated through an increase in [Ca2+]i.
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PMID:P2U-purinergic receptors on C6-2B rat glioma cells: modulation of cytosolic Ca2+ and cAMP levels by protein kinase C. 826 55

Extracellular proteinases may be selectively targeted to cell surfaces by specific receptors or binding sites. In previous studies, we have characterized cellular binding sites for plasminogen and plasmin on rat C6 glioma cells. In this investigation, we studied the response of C6 cells to alpha-thrombin and plasmin by measuring the rapid kinetics of free intracellular Ca2+ concentrations ([Ca2+]i). Thrombin produced a strong, concentration-dependent rise in [Ca2+]i with an onset within 3 s and peak levels achieved in less than 10 s. A similar response was also evoked by an SFLLRN-containing thrombin-agonist peptide. C6 cells did not respond to plasmin (25 nM-1.5 microM). By contrast, pretreatment of C6 cells with 100 nM plasmin significantly inhibited the [Ca2+]i response to thrombin and the thrombin-agonist peptide. The peak [Ca2+]i response to thrombin, in cells pretreated with plasmin, was reduced by approx. 50%. The effect of plasmin on the cellular response to thrombin was selective, as pretreatment of the cells with plasmin did not affect the [Ca2+]i response to platelet-activating factor. Di-isopropylphosphorylplasmin and plasminogen did not inhibit the cellular response to thrombin, indicating that plasmin activity is required and that occupancy of cellular plasmin(ogen)-binding sites alone is insufficient. These studies demonstrate that plasmin does not directly induce a response in C6 cells, but may affect cellular function by specifically modulating the thrombin response.
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PMID:Plasmin modulates the thrombin-evoked calcium response in C6 glioma cells. 828 96

Serotonin 5-HT2 receptor-mediated intracellular Ca2+ mobilization was investigated in rat glioma C6BU-1 cells. The receptors became desensitized after previous exposure to 5-HT in a time- and concentration-dependent manner. The desensitization of 5-HT2 receptor-mediated intracellular signaling appeared to be homologous because previous exposure to 5-HT did not alter the response to other transmitters such as thrombin or isoproterenol and because previous exposure to thrombin or isoproterenol did not diminish the response to 5-HT. The desensitization induced by pretreatment with 5-HT was potently prevented by the naphthalenesulfonamide derivative W-7, a calmodulin antagonist, when it was cosupplied with 5-HT. Furthermore, the preventive effect of W-7 was greater than that of W-5, a weak analogue of W-7, and than that of H-7, a nonselective inhibitor of protein kinases. These results suggest that 5-HT2 receptor-mediated Ca2+ mobilization can be desensitized homologously after prolonged exposure to 5-HT in a calmodulin-dependent manner in rat glioma C6BU-1 cells.
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PMID:Homologous desensitization of serotonin 5-HT2 receptor-stimulated intracellular calcium mobilization in C6BU-1 glioma cells via a mechanism involving a calmodulin pathway. 836 Jun 72


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