Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At pH 4.1, bovine thrombin reacts rapidly with N-bromo-succinimide to yield modified enzyme containing oxidized tryptophan residue. Both fibrinogen clotting activity and esterase activity are reduced considerably when three moles of tryptophan residues per mole of thrombin are oxidized, but the Michaelis constants for synthetic substrates are not appreciably altered. Reaction of NBS also results in a decrease in the affinity of thrombin for heparin. The dissociation constant for heparin-thrombin complex is increased by 2.6-fold due to the modification of one tryptophan residue. However, the magnitude of the increase in the dissociation constant remains the same for modified enzymes containing approximately two or three oxidized tryptophan residues. The rate constant for the inactivation of thrombin by antithrombin III is increased by 2.5-fold due to the modification of a single tryptophan residue. This increase in rate constant is not further amplified when more than one tryptophan residue is oxidized. In contrast, in the presence of heparin the rate of inactivation of modified and unmodified thrombins by antithrombin III are not significantly different. Thus, the heparin-sensitized inactivation of thrombin by antithrombin III is affected by the modification of one tryptophan residue. Spectrophotometric titrations of the phenolic hydroxyl groups suggest that the structural environments of tyrosyl groups for both unmodified and modified thrombin containing one oxidized tryptophan residue, are similar. The temperature for half loss of catalytic activity of control and NBS-modified thrombin, containing one oxidized tryptophan, are 52 and 51.5 degrees C respectively. It appears that the one tryptophan residue of thrombin is situated at or close to the binding site of heparin.
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PMID:Catalytic and regulatory functions of N-bromosuccinimide-modified bovine thrombin. 652 42

Thrombin, a serine protease that regulates hemostasis, has been shown to stimulate the formation of cGMP in murine neuroblastoma cells. The nervous system in vivo thus may be postulated to respond to this blood-borne factor after it breaches the blood-brain barrier, as in trauma. Human alpha-thrombin was radiolabeled with 125I and shown to bind rapidly, reversibly, and with high affinity to human brain and spinal cord. These findings indicate the presence of specific thrombin-binding sites in nervous tissue and may have important clinical implications.
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PMID:Thrombin binding to human brain and spinal cord. 664 28

We performed coagulation studies in 16 patients with advanced neuroblastoma. Four of these patients had major hemorrhagic or thromboembolic complications. Abnormal coagulation screening tests were seen in all patients with active metastatic disease. We also measured plasma fibrinopeptide A, a sensitive measure of intravascular thrombin generation. Increased concentrations of fibrinopeptide A were found in each patient studied with active metastatic disease. Coagulopathy is a frequent finding in metastatic neuroblastoma and may cause severe morbidity. Laboratory studies suggesting either hyper- or hypocoagulability are frequent findings.
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PMID:Coagulopathy of disseminated neuroblastoma. 687 12

A study was conducted to characterize the platelet aggregation induced by neuroblastoma tissue to investigate the mechanism of hypercoagulability in patients with neuroblastoma. The patients whose tumor tissues were examined had been shown clinically to have enhanced platelet activity. Platelet aggregation induced by neuroblastoma tissue extract was compared with that of other pediatric tumors. The effects of pretreatment with an antithrombin agent and prostacyclin (PGI2) on the platelet aggregation induced by tumor tissue extracts were also evaluated. Tissue extracts of 12 of 15 neuroblastomas, 3 of 3 Wilms' tumors, and 1 pheochromocytoma were demonstrated to have an activity that potentiated platelet aggregation in vitro. The platelet aggregation induced by tissue extracts of neuroblastomas and other tumor tissues was suppressed almost completely by pretreatment with a PGI2 analogue. The aggregation induced by neuroblastomas and the pheochromocytoma was also suppressed by pretreatment with an antithrombin agent, argatroban, whereas the aggregation induced by Wilms' tumors was not suppressed by this agent. These results suggest that (1) malignant tumors in children also have some chemical substances that sensitize platelet activity, such as those in adult cancers, and (2) thrombin is one of the mediators stimulating platelet aggregation in cases of neuroblastoma, although it is unlikely to be a contributing factor in other pediatric malignancies such as Wilms' tumor.
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PMID:Characterization of platelet activity in neuroblastoma. 751 11

Thrombin has been reported to inhibit neurite outgrowth from neuroblastoma cells grown in serum-containing medium after switching to serum-free medium. A test of the serum and substrate-dependence of this inhibition became possible with the development of Neurobasal/B27 serum-free medium. Inhibition of sprouting of Nb2a neuroblastoma cells by thrombin occurred from the substrate where it was bound to material adsorbed from serum. Neuritogenesis of primary hippocampal neurons was unaffected by exogenous thrombin on polylysine substrates with or without serum treatment. However, sprouting of hippocampal neurons was stimulated by treating the substrate with hirudin, a highly specific thrombin inhibitor. This suggests that hippocampal neurons are not directly responsive to added thrombin, perhaps because they produce their own thrombin.
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PMID:Exogenous thrombin inhibits neuritogenesis in cultured neuroblastoma cells but not in rat hippocampal neurons. 755 63

Recombinant rat glia-derived nexin was expressed in insect cells using the baculovirus system. The kinetics for the inhibition of thrombin by this recombinant material were indistinguishable from those observed with natural glia-derived nexin and recombinant nexin expressed in yeast. In addition, the dependence of the rate of inactivation on the concentration of heparin was similar for the three preparations. At the optimal heparin concentration, the association rate constant was 330-fold higher than that observed in the absence of heparin. A putative heparin-binding site is found in glia-derived nexin between residues 71 and 86; heparin-binding sites are found in homologous regions of antithrombin III and heparin cofactor II. Lysines in this region were mutated to glutamates, and the kinetics for the inhibition of thrombin by mutant proteins were determined. Concurrent mutation of all seven lysines in this region (residues 71, 74, 75, 78, 83, 84, and 86) did not affect the rate constant for the association of glia-derived nexin with thrombin in the absence of heparin, but it resulted in complete loss of the heparin acceleration of the rate of association. Mutations of residues 83, 84, and 86 together also caused a marked decrease in the acceleration by heparin of the reaction between glia-derived nexin and thrombin. These results support the hypothesis that the heparin-binding sites of glia-derived nexin, antithrombin III, and heparin cofactor II are found in homologous regions of the molecules. Heparin was also found to potentiate the ability of wild-type glia-derived nexin to inhibit the thrombin-induced retraction of neurites from neuroblastoma NB2a cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of the heparin-binding site of glia-derived nexin/protease nexin-1 by site-directed mutagenesis. 801 37

A human neuroblastoma cell line, GOTO, extends neurite-like processes upon withdrawal of serum from culture medium. This morphological change was accompanied by a 5-fold increase in the neurofilament (NF)-L and a 10-fold increase in the NF-M mRNA levels after 24 h. The addition of a protein kinase inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) also induced the extension of neurite-like processes; however, it did not increase the NF mRNA levels. Thrombin inhibited the extension of neurite-like processes in serum-free culture without affecting the increase in the NF mRNA levels. There was no difference in the number of cells progressing through the S phase between serum-containing and -free cultures at 24 h. This indicates that the increase in the NF mRNA levels upon withdrawal of serum was not preceded by the growth arrest. Treatment with actinomycin D and cycloheximide inhibited the increase in the NF mRNA levels. The half life of the NF gene transcripts was prolonged in the serum-free condition. These results indicate that the serum depletion-induced increase in the NF-L and -M mRNA levels was regulated by both transcriptional and post-transcriptional mechanisms, and the increase in the expression of the NF genes was not simply mediated by growth arrest but controlled by unknown regulator proteins.
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PMID:Serum depletion increases the neurofilament protein mRNA levels in a neuroblastoma cell line, GOTO. 838 95

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

Gangliosides, sialic acid-containing glycosphingolipids, enhance platelet adhesion to collagen and consequent platelet activation. For example, gangliosides shed by neuroblastoma tumor cells (NBTG) added to a subthreshold (non-activating) concentration (1 microgram/ml) of collagen, cause platelet aggregation (59 +/- 10%) and ATP release (2.3 +/- 0.2 nmol) equivalent to that caused by 10 micrograms/ml collagen alone. Here we report further studies to characterize this effect. Platelet aggregation and ATP release were not induced by NBTG in combination with subthreshold concentrations of adenosine diphosphate, epinephrine, thrombin or arachidonic acid, suggesting that NBTG specifically influences collagen-mediated platelet activation. Maximal platelet aggregation and ATP release required extracellular magnesium and only a short (1 min) preincubation with NBTG, suggesting a collagen receptor-mediated mechanism of this ganglioside activity. Since gangliosides interact with several integrin receptors, we determined whether NBTG influences alpha 2 beta 1, a major integrin collagen receptor on platelets. Incubation of platelets with a monoclonal antibody directed against the alpha 2 chain (5E8) blocked the increase in platelet aggregation (9 +/- 3% vs. 80 +/- 2%) and ATP release ( < 0.2 vs 2.5 +/- 0.1 nmol) induced by NBTG and 1 microgram/ml collagen. Incubation with an antibody to the non-integrin collagen receptor, CD36, or with an isotype control antibody did not abrogate the effect of NBTG. Finally, NBTG and its major component, GD2, enhanced alpha 2 beta 1-mediated platelet adhesion to immobilized collagen in an antibody 5E8-inhibitable manner. These findings implicate the alpha 2 beta 1-collagen interaction as a target of the effect of tumor-derived gangliosides.
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PMID:Tumor gangliosides enhance alpha2 beta1 integrin-dependent platelet activation. 863 39

Neurite retraction and reversal of astrocyte stellation triggered by the serine protease thrombin are receptor-mediated events. This article summarizes the current knowledge about the cellular effects that are induced by thrombin and its receptor in neural cells. The data presented show that the thrombin receptor messenger RNA is expressed in cultured astrocytes and that the reversal of stellation caused by thrombin in these cells is prevented by the protein kinase inhibitor staurosporine. Peptides based in sequence on the tethered ligand domain of the thrombin receptor were shown to mimic the effect of thrombin in most systems investigated. Platelets of some species, however, aggregate only in response to thrombin but not to the peptides. This observation is confirmed here. Rodent receptor-activating peptides did not cause aggregation of rat or mouse platelets. In contrast, all peptides triggered reversal of stellation in rat astrocytes and neurite retraction in mouse neuroblastoma cells, supporting the proposed mechanism of cleavage-induced receptor activation in neural cells. Finally, evidence is presented that serum withdrawal causes a decrease in the amount of the thrombin receptor mRNA in different types of neuronal cells. The possible role played by the thrombin receptor in the nervous system is discussed.
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PMID:The thrombin receptor in the nervous system. 880 8


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