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)

In glioma C6 cells, extracellular ATP generates inositol 1,4,5-trisphosphate (InsP3), indicating the presence of purinergic receptors coupled to phosphoinositide turnover. To identify the effect of ATP (acting via InsP3) and thapsigargin (acting without InsP3 production as a specific inhibitor of the endoplasmic reticulum Ca(2+)-ATPase) on intracellular Ca2+ pools we used video imaging of Fura-2 loaded into single, intact glioma C6 cells. It has been shown that ATP and thapsigargin initiate Ca2+ response consistent with the capacitative model of Ca2+ influx. When the cells were stimulated by increasing concentrations of ATP (1, 10, 50 and 100 microM) the graded, quantal Ca2+ response was observed. In the absence of extracellular Ca2+ thapsigargin and ionomycin-releasable Ca2+ pools are overlapping, demonstrating that Ca2+ stores are located mainly in the endoplasmic reticulum. After maximal Ca2+ mobilization by ATP, thapsigargin causes further increase in cytosolic Ca2+ concentration, whereas emptying of thapsigargin-sensitive intracellular stores prevents any further Ca2+ release by ATP. Thus, the thapsigargin-sensitive intracellular pool of Ca2+ in glioma C6 cells seems to be larger than that sensitive to InsP3. Two hypothesis to explain this result are proposed. One postulates a presence of two different Ca2+ pools, sensitive and insensitive to InsP3 and both discharged by thapsigargin, and the other, the same intracellular pool of Ca2+ completely emptying by thapsigargin and only partially by InsP3. These results may contribute to understanding the mechanism of Ca2+ signalling mediated by ATP, the most potent intracellular Ca2+ mobilizing agonist in all types of glial cells.
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PMID:Intracellular Ca2+ signals induced by ATP and thapsigargin in glioma C6 cells. Calcium pools sensitive to inositol 1,4,5-trisphosphate and thapsigargin. 918 65

In recent years, there is increasing recognition of polyphenotypic high-grade malignancies in the non-central nervous system (CNS) tumor literature. Some of these tumors have been regarded as variants of primitive neuroectodermal tumor (PNET) or as extrarenal malignant rhabdoid tumors (MRTs). This report concerns two posterior fossa neoplasms, both of which displayed a "polyphenotypic" expression of neural, epithelial, myogenic, and glial markers, including synaptophysin, neurofilament, vimentin, glial fibrillary acidic protein, S-100, neuron-specific enolase, desmin, S antigen, MIC2, cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen. One tumor showed complex intercellular junctions, cytoplasmic intermediate filaments, well-developed rough and smooth endoplasmic reticulum and Golgi apparatus, cilia, and neurosecretory granules. The other neoplasm showed pools of glycogen, desmosomes, and tonofilaments. The histological and ultrastructural appearances were inconsistent with glioma, PNET, meningioma, ependymoma, choroid plexus carcinoma, sarcoma, germ cell tumor, and other tumors in the World Health Organization classification. Although the polyphenotype raises the issue that these may represent variants of MRT or the atypical teratoid-rhabdoid tumor, the morphologic findings in the two cases were very dissimilar. Our two cases underscore the problems in nosology and classification of polyphenotypic tumors of the CNS. This is particularly significant, as therapeutic protocols for PNET, MRT, and non-CNS polyphenotypic tumors are different. We review the literature on polyphenotypic tumors and reiterate the difficulties in precise classification of these complex tumors.
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PMID:"Polyphenotypic" tumors in the central nervous system: problems in nosology and classification. 918 18

To elucidate the reasons for glycolytic deviation commonly found in brain tumors, hexokinase (HK) activity, mitochondria-HK binding, oxidative phosphorylation and mitochondrial ultrastructure were studied in 4 human xenografted gliomas. Lactate/pyruvate ratios were increased 3-4 fold and HK activity was of 2-4 fold lower than that of normal rat brain tissue, used as the control. The mitochondria-bound HK (mHK) fraction varied considerably and represented 9 to 69% of the total HK of that normal rat brain. The respiratory activity of glioma mitochondria, assessed by polarography and spectrophotometry, was within the normal range. However, the mitochondrial content of gliomas was lower than in the rat brain tissue, as revealed by the markedly decreased, activities of two unrelated mitochondrial enzymes, cytochrome c oxidase and citrate synthase in glioma homogenates. Electron microscopical studies confirmed the reduced number of mitochondria in 3 out of the 4 gliomas. Profound alterations of mitochondrial ultrastructure, namely of cristae and matrix densities, were observed in the 4 gliomas. The intercrista space was wider in all gliomas and the crista area was larger in 3 out of the 4 gliomas than in normal rat brain. Finally, the outer membrane of glioma mitochondria interacted intimately and extensively with the rough endoplasmic reticulum (RER) and/or nuclear membrane. These results suggest that, because of the very low content of normally functioning mitochondria, gliomas shift their energy metabolism towards a high-level glycolysis to generate their cellular ATP supply, probably through RER-mitochondria interactions and transformation-dependent redistribution of particulate HK from non-mitochondrial to mitochondrial receptors.
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PMID:Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. 921 43

The 9L rat glioma cells grown in culture, when subjected to a mechanical injury (scratch wound) and/or a chemical injury (CdCl2) manifest changes which are characteristic of an astrocyte reaction (astrogliosis) in the central nervous system. Such changes include cell hypertrophy and an increase in immunostaining for the astrocytic marker proteins, glial fibrillary acidic protein and J1-31 antigen. Mitochondria also increase in size and number, and the endoplasmic reticulum expands in area. These mechanical and chemical injuries are coordinated, and act synergistically to induce a considerably more intense astroglial reaction by 9L cells than can be elicited with either injurious agent alone, and this occurs without any interactions with microglia, neurons or oligodendroglia. The phenomenon suggests that more than one transcriptional mechanism is involved in the activation of astrocytes, and that mechanical and CdCl2-induced injuries, respectively, probably affect different receptors and second- and third-messenger pathways. There are a number of questions concerning the molecular biology of reactive astrocytes which can be addressed through the use of the 9L rat glioma cell model. This model offers certain advantages over primary cultures of astrocytes, namely a low basal level of reactivity (because the cells are not subjected to mechanical injury prior to experimentation), an absence of contaminating microglial cells, greater ease of reproducibility of results, lower costs and avoidance of the use of animals.
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PMID:Up-regulation of reactive astrogliosis in the rat glioma 9L cell line by combined mechanical and chemical injuries. 936 21

In non-excitable cells, stimulation of phosphoinositide (PI) turnover and inhibition of the endoplasmic reticulum (ER) Ca2+-ATPase are methods commonly used to deplete calcium stores, resulting in a capacitative Ca2+ influx (i.e., Ca2+ release-activated Ca2+ influx). Since this Ca2+ influx in glial cells has not been thoroughly investigated, we have used C6 glioma cells as a glial cell model to study this phenomenon. On adding cyclopiazonic acid (CPA) or thapsigargin (TG) (two ER Ca2+-ATPase inhibitors) in Ca2+-free medium, only a small transient increase in intracellular Ca2+ was seen. After depletion of the stored Ca2+, a marked Ca2+ influx, followed by a prolonged plateau, was seen on re-addition of extracellular Ca2+ ions (2 mM), i.e., capacitative Ca2+ influx. A similar effect was seen on adding ATP, known to deplete the inositol triphosphate (IP3)-sensitive Ca2+ store in C6 cells. After various degrees of store depletion, the amplitude of the capacitative Ca2+ influx was found to be highly dependent on the amount of Ca2+ remaining in the store. This Ca2+ influx was markedly inhibited by (1) La3+ and Ni2+, (2) SK&F 96365, econazole, and miconazole, and (3) membrane depolarization, clearly showing that this Ca2+ influx after store depletion in C6 cells is a capacitative mechanism. Interestingly, the capacitative Ca2+ influx can be inhibited by a reduction in intracellular ATP (ATPi) levels in glial cells. The role of ATPi in the capacitative Ca2+ influx is discussed.
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PMID:Capacitative Ca2+ influx in glial cells is inhibited by glycolytic inhibitors. 938 40

We have isolated a cDNA encoding a rabbit carboxylesterase (CE; EC 3.1.1.1) that converts the camptothecin-derived prodrug irinotecan (CPT-11) to the potent topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin. NH2-terminal amino acid sequencing of a purified rabbit CE allowed the design of redundant oligonucleotides to perform PCR from rabbit liver cDNA. DNA sequencing of the PCR product confirmed the identity of the clone, and after both 5' and 3' rapid amplification of cDNA ends, oligonucleotide primers were designed to amplify the entire cDNA. The 1698-bp open reading frame encoded a 565-amino acid protein containing the characteristic CE B-1 and B-2 motifs, a hydrophobic NH2-terminal leader sequence, and the COOH-terminal residues HIEL that are thought to be responsible for protein localization in the endoplasmic reticulum. Transient expression of the cDNA in COS-7 cells resulted in CE activity in cell extracts and increased the sensitivity of cells to CPT-11. Additionally, stable expression of the rabbit liver CE cDNA in the human glioma U-373 MG cell line resulted in a 56-fold decrease in the IC50 value for CPT-11, whereas the expression of a human alveolar macrophage cDNA encoding a highly homologous CE produced no change in drug sensitivity.
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PMID:Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). 963 92

Agonist-induced intracellular signal transduction often involves activation of protein kinase C by diacylglycerol (DAG) released from membrane phospholipids by phospholipases. Using either DAG kinase or HPLC assays to quantitatively determine DAG mass, we observed a time-dependent increase in DAG accumulation upon incubation of rat C6 glioma cells with 200 nM endothelin-1 (ET-1). Total cell DAG rapidly increased by 25-35% from a basal level of 4.5 +/- 0.3 nmol/mg protein during one min of ET-1 treatment and remained constant or slightly decreased between 1 and 2 min. Thereafter, DAG increased to a maximum (1.6-fold above basal) by 5-10 min. and remained elevated to 30 min. Resolution of DAG molecular species by HPLC after incubation of cells with ET-1 revealed that accumulation of DAG species differed in total cell lysate and subcellular compartments. In plasma membrane, major DAG species increased at 1 min. followed by a decrease at 10 min. whereas in microsomes DAG species did not change at 1 min. and decreased at 10 min. Although phospholipid sources of DAG species were not identified specifically, there was preferential hydrolysis of molecular species of phospholipid for DAG production. We propose that molecular species of DAG produced at the plasma membrane may be transferred to the endoplasmic reticulum so that phospholipid resynthesis can replenish molecular species initially utilized in signal transduction.
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PMID:Diacylglycerol molecular species in plasma membrane and microsomes change transiently with endothelin-1 treatment of glioma cells. 964 11

Differential display polymerase chain reaction was used to identify genes regulated by the mood-stabilizing drug valproate (VPA). Four differentially displayed valproate-regulated gene fragments were isolated in rat cerebral cortex after i.p. injection of sodium VPA (300 mg/kg) for 3 weeks, and their expression was confirmed by Northern and slot blot analysis in rat cerebral cortex and C6 glioma cells. Sequencing analysis revealed three previously unidentified cDNA fragments in addition to a sequence with 100% homology with a molecular chaperone, 78-kDa glucose-regulated protein (GRP78). VPA treatment did not increase mRNA expression of 70-kDa heat shock protein, which is a related stress-induced molecular chaperone protein. All four candidate genes, including GRP78, showed similar VPA concentration-dependent increases in mRNA abundance. Another commonly prescribed mood-stabilizing anticonvulsant, carbamazepine, also increased GRP78 mRNA expression in C6 glioma cells, whereas lithium had no effect at doses up to 2 mM. Immunoblotting revealed that GRP78 protein levels were also increased in C6 glioma cells treated with VPA under the same conditions. Nuclear runoff analysis showed that VPA increased GRP78 gene transcription. Because GRP78 possesses molecular chaperone activity, binds Ca2+ in the endoplasmic reticulum, and protects cells from the deleterious effects of damaged proteins, the present findings suggest that VPA (and possibly carbamazepine) treatment may target one or more of these processes.
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PMID:Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78. 1005 36

Although the mechanism of the capacitative Ca2+ entry is still a mysterious process, it has been presently accepted that it occurs through plasma membrane channel pores rather than through a carrier mechanism. As it has been proposed by Putney (Cell Calcium, 1986, 7, 1-12), Ca2+ entry is directly dependent on the state of filling of the endoplasmic reticulum Ca2+ stores, i.e. it is activated by the depletion of the endoplasmic reticulum Ca2+ pool. However, the nature of the signal for activation of Ca2+ entry is still unknown. The biphasic capacitative Ca2+ entry involves inositol phosphate system and is ubiquitous in all nonexcitable cells. We have shown that glioma C6 cells belong to such type of cells and are characterized by a typical capacitative Ca2+ entry pathway. The characteristics of this Ca2+ influx is summarized and the hypotheses about its mechanism of activation are discussed.
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PMID:Capacitative calcium entry. Glioma C6 as a model of nonexcitable cells. 1042 44

Although calreticulin (Crt) is primarily localized to the endoplasmic reticulum (ER), our results using biotinylation and immunocytochemical methods indicate that a small but significant amount of Crt is present and forms large patches on the surface of NG108-15 cells (a mouse neuroblastoma-rat glioma hybrid cell line). (35)S-labelled Crt molecules begin to reach the cell surface after only 10 min of labelling and disappear slowly from the cell surface. After 4 hr of labelling, approximately half of the newly synthesized Crt molecules are on the cell surface. We believe that some Crt molecules may escape from the KDEL receptor-mediated salvage pathway as they are synthesized and proceed through the secretory pathway to the cell surface. Immunoprecipitation from the culture medium shows that Crt is not released from the cell surface to the medium, suggesting tight binding to surface molecules. NH(4)Cl can block the degradation of Crt; therefore, Crt is presumably degraded in the lysosome pathway. However, blockage of the disappearance of surface Crt is less efficient than that of internal Crt. This suggests that the disappearance of Crt from the cell surface may not be due solely to its degradation, but may reflect transport into another cell compartment such as the ER.
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PMID:Calreticulin is transported to the surface of NG108-15 cells where it forms surface patches and is partially degraded in an acidic compartment. 1056 93


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