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)

The effects of toxin II (AaH II) isolated from the scorpion Androctonus australis Hector on sodium current in neuroblastoma X glioma NG 108-15 hybrid cells were analysed under patch clamp conditions in the whole cell configuration. AaH II (70 nM) induced a maintained sodium current, as well as increasing both fast and slow inactivation time constants and the amplitude of the peak current. This latter effect occurred via a shift of the activation-voltage curve towards negative voltage values by about 9 mV. Oleic acid (5 microM), which had no effect on INa under control conditions, decreased the AaH II-induced maintained current. It also reversed, or prevented the increase of the peak current induced by AaH II. However, it neither prevented nor modified the AaH II-induced increase in inactivation time constants. The binding of the toxin to its specific site and the number of binding sites for AaH II were not significantly modified by oleic acid. The oleic acid-induced effects could not be related to the activation of protein kinase C since PMA, a potent activator of this enzyme, did not produce oleic acid-like effects. From these results, it is concluded that AaH II has several independent effects on sodium channels, some of which could be modulated by the lipid environment of sodium channels in the membrane.
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PMID:Effects of toxin II from the scorpion Androctonus australis Hector on sodium current in neuroblastoma cells and their modulation by oleic acid. 253 22

The functional induction of c-fos in the sodium butyrate-induced differentiation of F-98 glioma cells was studied. Fos protein level was increased by butyrate. In contrast, c-Jun protein was constitutively expressed and was not affected by butyrate. Gel-retardation assay indicates Fos as a component of the complex formed between the consensus oligonucleotide of the TPA (PMA, phorbol 12-myristate 13-acetate) response element (TRE) and nuclear extract prepared from butyrate-treated cells. Transfection studies showed that butyrate increased transcription from a multimeric TRE-driven reporter construct, and the effect was mimicked by transfecting cells with fos-expression plasmid. Furthermore, under conditions of c-fos over-expression, transactivation by butyrate was essentially abolished. These data suggest that Fos induction had a functional role in gene activation. Characterization of stable c-fos transfectants demonstrated that these cells displayed alterations in morphology, showed serum-dependent growth, had slower growth rates and grew to lower saturation densities than did untransfected F-98 cells or transfected cells that did not express c-fos. Immunofluorescent staining indicated that fos transfectants also had elevated glial fibrillary acidic protein ('GFAP') expression. Transfection of the c-fos promoter-chloramphenicol acetyltransferase fusion gene into F-98 cells revealed that activation of c-fos by butyrate was exerted at the promoter level, and sequences located within nucleotides -757 to -402 of the c-fos promoter were responsible for butyrate induction. Our data indicate that transcriptional activation of c-fos through its promoter by butyrate resulted in increased Fos protein expression. Transfection studies show that both c-fos and butyrate activate TRE-containing genes, and fos may be a downstream mediator of butyrate. Furthermore, expression of c-fos plays a major role in modulating the growth properties of F-98 cells.
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PMID:Analysis of c-fos expression in the butyrate-induced F-98 glioma cell differentiation. 786 28

Tolerance to endotoxin (lipopolysaccharide, LPS) was shown to be mediated by an inhibition of cytokine production. We have studied the effect of 3-day pretreatment with LPS on production of IL-6 in response to a subsequent challenge with LPS in a mouse glioma. The results indicated that in this model, a complete blockage of IL-6 production is induced by LPS pretreatment. This is associated with a decrease of LPS-induced IL-6 mRNA levels. LPS-induced IL-6 production can be restored by PMA, as it was previously observed in vivo, suggesting that down-regulation of IL-6 response in LPS tolerance occurs at the transcriptional level, probably by down-regulating protein kinase C or some other PMA-activable signaling system. IL-6 production is also down-regulated by 3-day preincubation with IL-6 and, to a lesser extent, with IL-1 or TNF, indicating that IL-6 can down-regulate its own production.
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PMID:Suppression of interleukin-6 production in endotoxin tolerance in a mouse glioma cell line: reversal by phorbol ester. 845 31

Swelling of C6 glioma cells in hypotonic medium (180 mOsm) results in two- to three-fold activation of K+ (86Rb+) influx suppressed by 10 microM bumetanide. Bumetanide-sensitive transport of 86Rb+ is dependent on extracellular K+, Na+ and Cl- both in iso-osmotic conditions and under hypo-osmotic shock, supporting the notion that it is mediated by Na+,K+,2Cl- cotransport. Inhibitors of protein kinase C (10 microM polymyxin B and l microM staurosporine) had no significant effect on basal cotransport but reduced its hypotonic stimulation by 70-80%. Similar results were obtained with calmodulin antagonist R24571 (10 microM), indicating Ca2+/calmodulin-dependence of the process. Influence of polymyxin B and R24571 was not additive. Swelling-activated Na+,K+,2Cl- cotransport was also suppressed by protein kinase C activator PMA (l microM). By contrast, preincubation of cells with inhibitors of protein phosphatases (100 microM vanadate, 5 mM fluoride and 0.5 microM okadaic acid) activated greatly the bumetanide-sensitive 86Rb+ uptake in isotonic conditions, while a subsequent hypotonic swelling led to smaller or no increment. These results indicate the involvement of Ca2+/calmodulin-dependent staurosporine/polymyxin B-sensitive protein kinase other than protein kinase C in swelling-induced activation of Na+,K+,2Cl- cotransport in glial cells.
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PMID:Swelling-induced activation of Na+,K+,2Cl- cotransport in C6 glioma cells: kinetic properties and intracellular signalling mechanisms. 897 7

It has been well established that patients with malignant glioblastomas exhibit T cell anergy. In this report, we further investigate the nature of this T cell anergy. The results demonstrate that tumor size but not location correlates with decreased mitogen or anti-CD3 mAb responsiveness of T cells obtained from patients. Stimulation of the TCR/CD3 complex on these patients' T cells revealed defects in early transmembrane signaling. Both PHA and anti-CD3 mAb activated PBL and T cells obtained from patients exhibited a marked decrease in the tyrosine phosphorylation of a number of proteins. In particular, decreased phosphorylation of pp100 and phospholipase Cgamma1 (PLCgamma1) was observed. In addition, PLCgamma1 and p56(lck) protein levels were dramatically reduced in T cells obtained from patients harboring a glioma. In contrast, the protein levels of p59(fyn) were normal or only slightly reduced in T cells obtained from patients with gliomas. Quantitation of free intracellular calcium concentrations ([Ca2+]i) after mitogen (PHA) stimulation or ionomycin treatment of T cells obtained from patients revealed that they mobilize less calcium than do T cells obtained from normal subjects. Stimulation of T cells obtained from patients with PMA and ionomycin, which should bypass the requirement for PLCgamma1 activation as well as directly activate the p21(ras) signaling pathway, did not restore the proliferative capacity of these T cells to normal levels. These results indicate that the anergy observed in T cells obtained from these patients is a consequence of one or more defects in the early transmembrane signaling events associated with TCR/CD3 stimulation.
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PMID:T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. 937 40

A major factor in secondary brain injury following cerebral trauma is accumulation of lactic acid resulting in glial swelling. Further, evidence obtained in this context demonstrates activation of protein kinase C (PKC) under these circumstances. Glial swelling from acidosis is attributable to activation of the Na+/H(+)-exchanger, mediating influx of Na(+)-ions in exchange for the extrusion of H+ ions. The antiporter is activated following phosphorylation by PKC. The current study was made to elucidate the role of PKC activation in acidosis-induced glial swelling. For that purpose, suspended C6 glioma cells were used to examine changes of the cell volume and intracellular pH (pHi). Acidosis was induced by administration of isotonic lactic acid. Stimulation of PKC by the phorbol-ester PMA was significantly enhancing glial swelling from severe acidosis (pH 6.2), whereas the decrease of pHi was somewhat attenuated. On the other side, inhibition of PKC by staurosporine did not affect cell swelling nor the decrease of pHi from acidosis. The results indicate that activation of PKC in cerebral trauma or ischemia may enhance glial swelling from lactacidosis.
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PMID:Role of protein kinase C in acidosis induced glial swelling--current understanding. 941 29

Treatment of rat glioma C6 cells with the beta-adrenergic agonist L-isoproterenol leads to a rise in cAMP level and a subsequent change in cell morphology from an epithelial to an astrocytic type of appearance. This morphological response is reverted by the addition of sphingosine-1-phosphate (S1P) with an EC50 of 10 nM. In rat glioma C6 cells loaded with the Ca2+ indicator Fura-2, S1P evoked Ca2+ release from internal stores and Ca2+ influx from the external medium. Half-maximal stimulation of the Ca2+ increase was 10-20 nM. A similar Ca2+ signal was observed in primary rat astrocytes loaded with the Ca2+ indicator fluo-3. Pretreatment of the C6 cells with PMA (162 nM) prevented both the S1P-induced Ca2+ increase and the morphological reversion. Ca2+ ions therefore seem essential for the morphological reversion by S1P. Pretreatment of the cells with the Clostridium botulinum C3 exoenzyme did not affect the reversion of the morphological response by S1P, indicating that the small GTP-binding protein Rho is not involved in the S1P-induced reversion.
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PMID:Sphingosine-1-phosphate induces a Ca2+ signal in primary rat astrocytes and a Ca2+ signal and shape changes in C6 rat glioma cells. 958 87

Glial cells extrude acid equivalents to maintain pHi. Although four mechanisms have been described so far, pHi-control under physiological conditions is still not sufficiently explained. We therefore investigated whether a H+-translocating ATPase is involved in glial pHi homeostasis using an established glial cell line (C6 glioma). In the absence of bicarbonate, the inhibition of H+-ATPases by NEM led to a pHi decrease. The application of a more specific inhibitor (NBD-Cl) showed that the H+-ATPase involved is of the vacuolar type. Inhibition went along with delayed cell swelling. Together with the fact that glial acidification was far more pronounced in Na+-free media, this may serve as evidence for a secondary activation of Na+/H+-exchange once an activation setpoint is reached, which in turn causes secondary swelling from Na+-uptake. Stimulation of Na+/H+-exchange by PMA can increase the setpoint. pHi-recovery after an acid load was blocked by the inhibition of v-type H+-ATPase, if pHi did not reach 6.6 during the acid load. The inhibition of Na+/H+-exchange by amiloride inhibited recovery only if acidification was below the threshold. Finally, in bicarbonate-free media a v-type H+-ATPase contributes to pH-regulation in glial cells, especially during pH-homeostasis at physiological conditions, while Na+/H+-exchange gains significance during severe acid loads.
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PMID:A proton-translocating H+-ATPase is involved in C6 glial pH regulation. 965 71

Glioblastoma multiforme (GBM) is the most malignant astroglial-derived tumors which has the propensity to aggressively infiltrate normal regions of the brain surrounding the tumor. The interaction of tumor cells with the extracellular matrix (ECM) is an integral step in the process of tumorigenesis and may play a role in the local invasion of the GBM cells. Our study investigated the role of the nuclear transcription factor NF-kappaB on GBM integrin expression and cell attachment. Our results show that treatment of GBM cell lines, SNB-19 and T98G with PMA, an inducer of NF-kappaB, increased the expression of fibronectin and vitronectin genes. Accordingly, ectopic over-expression of NFkappaB subunits in GBM cells elevated the levels of fibronectin gene expression, providing direct evidence for a regulatory role for NF-kappaB in ECM protein production. Cell attachment to the ECM proteins including fibronectin, vitronectin and laminin was increased in GBM and normal astrocytic cells. Interestingly, treatment of cells with PMA augmented attachment of SNB-19 and T98G cells to fibronectin and vitronectin, however it had no effect on attachment of normal astrocytes. Addition of the tripeptide arginine-glycine-asparatic acid (RGD), the recognition site for many integrins, significantly inhibited SNB-19 and T98G cell attachment to fibronectin and vitronectin. Finally, activation of NFkappaB upon treatment of SNB cells with PMA led to an increase in the levels of mRNA for the beta3 and the alphav integrin subunits. Collectively, these data demonstrate a possible role for NF-kappaB in glioma cell attachment.
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PMID:Integrin involvement in glioblastoma multiforme: possible regulation by NF-kappaB. 1086 46

Calcium is one of the most universal signal-transduction elements in a large variety of cells ranging from bacteria to specialized neurons. Ca2+ acts as a second messenger controlling such processes as secretion, cell differentiation or signal transmission. In order to be able to execute their specific functions and to react in a coordinated way to stimuli, multicellular organs need a precise orchestration of cellular functions. For this purpose cells have developed different forms of intercellular communication (IC). In this study we investigated a number of mechanisms of intracellular propagation and IC using experiments with fluorescent Ca(2+)-indicators, confocal microscopy and digital imaging techniques. In ROS 17/2.8 osteoblasts, retinal pigment epithelial cells (RPE) and CPAE endothelial cells, a small mechanical deformation of the plasma membrane results in a transient increase of free cytoplasmic Ca2+ concentration ([Ca2+]i). This Ca(2+)-rise starts at the site of stimulation and propagates concentrically to neighboring cell layers. The intracellular Ca(2+)-wave in RPE and ROS cells is caused by Ca(2+)-influx followed by Ca(2+)-release from the intracellular stores and by intercellular propagation of the Ca(2+)-wave. The [Ca2+]i-transient upon mechanical stimulation of LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes was limited and/or variable. In CPAE cells only the intracellular release is important for evoking the Ca(2+)-transient, and is followed by IC. IC can occur via gap junctions (GJ) consisting of membrane-spanning proteins, connexins (Cx). It was demonstrated that IC and GJ in RPE and ROS cells can be reversibly blocked by gap-junction inhibitors such as heptanol or halothane. We demonstrated important differences in modulation of gap junctional communication between these cell types. While in RPE cells stimulation of PKC activity was able to inhibit IC, this was not the case in ROS cells. We screened LE-RPE cDNA via PCR using specific primers for different connexins and found no effect of high glucose solutions, which cause decreased intercellular communication, on the Cx-isoforms expressed. Cx43 is the only Cx-isoform present at the protein level for which Western blot analysis revealed the presence of different forms corresponding to different phosphorylated states. Increased phosphorylation of Cx43 was only seen after direct PKC activation by PMA, but not by indirect PKC activation by high glucose levels. The decreased communication by high glucose concentrations was however associated by a decreased expression of cellular Cx43 to about 3/4 of the level in control conditions. High glucose concentrations therefore decrease Cx43 at the protein level via a PKC effect that appears to be independent of the direct activation of PKC by phorbolesters. Mechanical stimulation did not evoke intercellular Ca(2+)-waves in LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes. In CPAE-endothelial cells, the contribution of gap junctions to IC following mechanical stimulation is negligible, and modulation of gap junctions via phosphorylation or high glucose solutions is absent. Perfusion experiments and pharmacological studies demonstrated that IC following mechanical stimulation of these cells occurs via release of an extracellular mediator. Our experiments provide strong evidence in favor of purinergic agonists as mediators, such as ATP but mainly ADP. In conclusion we can say that cells contain a wide spectrum of mechanisms for intra- and intercellular communication, and that widely different mechanisms can evoke the same phenomenon of intra- and intercellular Ca(2+)-waves.
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PMID:[Intra- and intercellular Ca(2+)-signal transduction]. 1119 79


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