Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is a messenger molecule with diverse functions throughout the body. The inducible type of nitric oxide synthase (NOS) is considered to be a key molecule in the immune responses to bacteria, parasites, and tumors, and its gene expression is regulated by cytokines. We isolated 3 overlapping partial inducible NOS cDNA clones from a human glioblastoma cell line A-172 induced by IL-1, TNF-alpha, and IFN-gamma. The 3,963-bp human glioblastoma inducible NOS cDNA contained the longest open reading frame of 3,459 bp, which encoded a polypeptide of 1,153 amino acids with a calculated molecular mass of 131 kDa. This human inducible NOS possessed consensus recognition sites for the cofactors FMN, FAD, and NADPH and calmodulin recognition sites, and displayed 48.1% sequence identity with the endothelial type, 43.1% with the neuronal type, and 99.3% with the inducible type from hepatocytes, and 99.9% with the inducible type from chondrocytes and adenocarcinoma. An expression plasmid consisting of pSG5 expression vector and cDNA containing the entire putative coding sequence was constructed and transfected into COS-1 cells. COS-1 cells showed nitric oxide synthase activity together with a 130 kDa immunoreactive band on Western blot analysis.
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PMID:Cloning and functional expression of human inducible nitric oxide synthase (NOS) cDNA from a glioblastoma cell line A-172. 753 87

Nitric oxide (NO) is a newly identified, multifunctional biological mediator. However, it also has deleterious effects on biological materials. For instance, nucleic acids, proteins, and some prosthetic groups of enzymes can be modified by NO or its reaction products with other reactive oxygen species. Endogenous nitrosamine formation through the reaction of NO or its oxidized products with amines might be involved in carcinogenesis. These deleterious effects of NO are often associated with inflammatory processes both in experimental animals and human. We analyzed the molecular mechanism of control of expression of the inducible nitric oxide synthase (NOS) gene in mouse cells by cloning its putative promoter region. This promoter responded to various cytokines and endotoxin similarly to the endogenous NOS gene in mouse cells. No appreciable induction of NOS was observed in human peripheral blood cells, but induction was detected in a human glioblastoma cell line A-172. Therefore, the human inducible NOS cDNA was cloned from A-172 cells and its cDNA-deduced amino acid sequence found to have about 80% similarity to those of both mouse and rat inducible NOSs. The effects of various cytokines on the induction of the gene were somewhat different from those observed in mouse cells, but the mouse promoter responded to these cytokines similarly to the endogenous NOS gene in human cells, indicating functional similarity of cis-elements of the genes encoding both human and mouse inducible NOS. Structural analysis of the human inducible NOS gene by Southern blot analysis revealed putative genetic restriction fragment length polymorphism in intron 5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Implication of nitric oxide synthase in carcinogenesis: analysis of the human inducible nitric oxide synthase gene. 758 89

The accumulation of inducible nitric oxide synthase was caused by heat shock of human glioblastoma T98G cells but not of A-172 cells. The accumulation of hsp72 and p53 was observed in A-172 cells cocultivated with heat-shocked T98G cells, which was suppressed by the addition of aminoguanidine to the medium. The accumulation of these proteins was observed in A-172 cells after exposure to the conditioned medium of heat-shocked T98G cells, which was completely blocked by the addition of 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide to the medium. In addition, the accumulation of these proteins in A-172 cells was induced by the administration of S-nitroso-N-acetylpenicillamine to the medium. Finally, the thermosensitivity of A-172 cells was reduced in the conditioned medium of heat-shocked T98G cells compared with conventional fresh growth medium. Our findings demonstrate that the accumulation of stress-induced proteins and thermoresistance in NO recipient cells cocultivated with heat-shocked NO donor cells is induced through an intercellular signal transduction pathway initiated by NO without cell-to-cell interactions such as gap junctions.
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PMID:Intercellular signaling initiated by nitric oxide produced in heat-shocked human glioblastoma cells. 1036 88

Nitric oxide is known to be a multifunctional physiological substance. Recently, it was suggested that nitric oxide is involved in p53-dependent response to many kinds of stress, such as heat shock and changes in cellular metabolism. To verify this hypothesis, we examined the effect of nitric oxide produced endogenously by heat-shocked cells on nonstressed cells using a human glioblastoma cell line, A-172, and its mutant p53 (mp53) transfectant (A-172/mp53). The accumulation of inducible nitric oxide synthase was caused by heat treatment of the mtp53 cells but not of the wild-type p53 (wtp53) cells. The accumulation of heat shock protein 72 (hsp72) and p53 was observed in nontreated mtp53 cells cocultivated with heated mp53 cells, and the accumulation of these proteins was suppressed by the addition of a specific inducible nitric oxide synthase inhibitor, aminoguanidine, to the medium. Furthermore, the accumulation of these proteins was observed in the wtp53 cells after exposure to the conditioned medium by preculture of the heated mp53 cells, and the accumulation was completely blocked by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. In addition, the accumulation of hsp72 and p53 in the wtp53 cells was induced by the administration of an nitric oxide-generating agent, S-nitroso-N-acetylpenicillamine, to the medium. Finally, the thermosensitivity of the wtp53 cells was reduced in the conditioned medium by preculture of the heated mp53 cells as compared with conventional fresh growth medium. Our finding of the accumulation of hsp72 and p53 in nitric oxide-recipient cells cocultivated with heated nitric oxide-donor cells provides the first evidence for an intercellular signal transduction pathway via nitric oxide as intermediate without cell-to-cell interactions such as gap junctions.
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PMID:Nitric oxide is an initiator of intercellular signal transduction for stress response after hyperthermia in mutant p53 cells of human glioblastoma. 1039 71

In nearly all human cells IFN-gamma stimulation leads to an activation of indoleamine 2,3-dioxygenase (IDO) activity, which is responsible for anti-toxoplasma and anti-chlamydia effects. We have recently shown that IDO activation is also a defense mechanism against extracellular beta-hemolytic streptococci groups A, B, C and G in human glioblastoma cells, fibroblasts and macrophages. Similar effects were also seen with enterococci and in approximately 65% of staphylococci tested, including multiresistant strains of both species. In addition, we have found that IDO activity is differentially regulated in different cells. For example we have found that TNF-alpha enhances IFN-gamma induced IDO activity and antimicrobial effect in human glioblastoma cells whereas both IFN-gamma mediated effects were blocked by TNF-alpha as well as by IL-1 in a human uroepithelial cell line. We were able to show that the IL-1 and TNF-alpha mediated inhibition of IFN-gamma-induced IDO activity in uroepithelial cells is due to stimulation of inducible nitric oxide synthase. In human astrocytoma cells, IL-1 and TNF-alpha did not inhibit IDO activity and in concordance with this finding these cells did not show a detectable nitric oxide production.
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PMID:IFN-gamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. 1072 Oct 95

To elucidate whether nitric oxide secreted from irradiated cells affects cellular radiosensitivity, we examined the accumulation of inducible nitric oxide synthase, TP53 and HSP72, the concentration of nitrite in the medium of cells after X irradiation, and cellular radiosensitivity using two human glioblastoma cell lines, A-172, which has a wild-type TP53 gene, and a transfectant of A-172 cells, A-172/mp53, bearing a mutated TP53 gene. Accumulation of inducible nitric oxide synthase was caused by X irradiation of the mutant TP53 cells but not of the wild-type TP53 cells. Accumulation of TP53 and HSP72 in the wild-type TP53 cells was observed by cocultivation with irradiated mutant TP53 cells, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase, aminoguanidine, to the medium. Likewise, accumulation of these proteins was observed in the wild-type TP53 cells after exposure to conditioned medium from irradiated mutant TP53 cells, and the accumulation was abolished by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. The radiosensitivity of wild-type TP53 cells was reduced when the cells were cultured in conditioned medium from irradiated mutant TP53 cells compared to conventional fresh growth medium. Collectively, these findings indicate the potential importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to ionizing radiation.
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PMID:Induction of radioresistance by a nitric oxide-mediated bystander effect. 1118 88

There has been a recent upsurge of interest in radiation-induced bystander effects. Previously we reported that the accumulation of inducible nitric oxide (NO) synthase (iNOS) was induced only in human glioblastoma mutant (m) p53 cells by acute irradiation with X-rays, suggesting a suppression of iNOS induction after acute irradiation with X-rays in wtp53 cells. NO secreted from the irradiated mp53 cells induced the accumulation of p53 in unirradiated wtp53 cells. The radiosensitivity of wtp53 cells was reduced by exposure to the conditioned medium from irradiated mp53 cells, suggesting that NO is an initiator of radiation-induced bystander effects. In the present study, we found that the accumulation of iNOS in wtp53 cells was induced by chronic irradiation with gamma-rays followed by acute irradiation with X-rays, but not by each one. It is suggested that the accumulation of iNOS may be due to the depression of acute irradiation-induced p53 functions by pre-chronic irradiation. We found that chronic irradiation with gamma-rays did not inhibit the accumulation of p53 after exposure to the conditioned medium from the irradiated mp53 cells. However, the decay of accumulated p53 was stimulated by chronic irradiation with gamma-rays. At the same time, the accumulation of Hdm2 was observed; suggesting that chronic irradiation with gamma-rays may stimulate the degradation of p53 accumulated by NO-mediated bystander effects.
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PMID:Indirect influences of radiation on unirradiated cells through irradiated cells. 1467 5

Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of alpha and beta subunits. The alpha subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors alpha and beta, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation.
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PMID:Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. 1583 Dec 32

BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea) is the mainstay in glioblastoma multiform chemotherapy with only minimal effects. BCNU may kill tumor cells via carbamoylating cytotoxicity, which irreversibly inhibits glutathione reductase with resultant accumulation of oxidized form of glutathione causing oxidative stress. S-nitrosoglutathione (GSNO) is a product of glutathione and nitric oxide interaction. We report that GSNO formation may underlie carbamoylating chemoresistance mediated by activation of inducible nitric oxide synthase. Transactivation of hypoxia-inducible factor-1 (HIF-1)-responsive genes reduces oxidative stress caused by glutathione depletion. We also noted that preconditioning of C6 glioma cells to induce HIF-1 and its downstream genes confers chemoresistance against carbamoylating cytotoxicity of BCNU.
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PMID:S-nitrosoglutathione and hypoxia-inducible factor-1 confer chemoresistance against carbamoylating cytotoxicity of BCNU in rat C6 glioma cells. 1596 67

In an earlier study, we reported that nitric oxide is involved in lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate-induced malignant transformation via increases in metalloproteinase 9 enzyme activity and inducible nitric oxide synthase gene expression in rat glioma C6 cells, however the mechanism has remained undefined. Lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate, but not lipopolysaccharide or 12-o-tetradecanoylphorbol 13-acetate alone, induced transformation in glioma C6 cells (but not in human glioblastoma cells GBM-8401 cells) without affecting their viability. An increase in inducible nitric oxide synthase protein expression, nitric oxide production, and metalloproteinase 9 enzyme activity is identified lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-treated C6 cells, however lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate and 12-o-tetradecanoylphorbol 13-acetate (but not lipopolysaccharide) addition shows the similar inductive pattern on metalloproteinase 9 enzyme activity without affecting inducible nitric oxide synthase protein expression and nitric oxide production in GBM-8401 cells. Treatment of C6 cells with lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate increases the expression of phosphorylated extracellular regulated protein kinases and Jun N-terminal kinases, but not p38, proteins, and an addition of the extracellular regulated protein kinases inhibitor PD98059 or Jun N-terminal kinases inhibitors SP600125, but not the p38 inhibitor SB203580, significantly blocked lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced inducible nitric oxide synthase protein expression and metalloproteinase 9 enzyme activity accompanied by blocking morphological transformation in C6 cells. Among 19 structurally related flavonoids, kaempferol and wogonin exhibit significant inhibitory effects on lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced morphological transformation and colony formation, and attenuation of inducible nitric oxide synthase, phosphorylated extracellular regulated protein kinases protein expression, and metalloproteinase 9 enzyme activity was observed. 2'-OH flavone at a dose of 100 microM inhibition of lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced events via apoptosis induction is identified. Furthermore, lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate, but not lipopolysaccharide or 12-o-tetradecanoylphorbol 13-acetate, induces tumoral invasion and migration in vitro and in vivo, and those are blocked by kaempferol and wogonin addition. These data suggest that combination of lipopolysaccharide and 12-o-tetradecanoylphorbol 13-acetate promotes tumoral progression via activating metalloproteinase 9 enzyme activity and inducible nitric oxide synthase gene expression, which is located downstream of mitogen-activated protein kinases activation, in rat glioma cells C6. Kaempferol and wogonin exhibit effective inhibitory effects on lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced events, and thus possess the potential for further development.
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PMID:Lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate induction of migration and invasion of glioma cells in vitro and in vivo: Differential inhibitory effects of flavonoids. 1658 Jul 79


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