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:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the human monocyte chemoattractant protein-1 (hMCP-1) is ubiquitous in various cell types and is increased by a wide variety of stimuli. We initially found that the effects of various stimuli, including IL-1 beta, TNF-alpha, and 2-O-tetradecanoylphorbol 13-acetate, on the expression of hMCP-1 mRNA were quite different among A172 glioblastoma cells, HT1080 fibrosarcoma cells, and SKLMS1 leiomyosarcoma cells. These findings suggested that hMCP-1 expression is regulated both in a stimulus-specific and a tissue-specific manner. To elucidate the mechanism underlying this stimulus-specific and tissue-specific regulation, we isolated a hMCP-1 5'-flanking genomic DNA fragment and sequenced it extensively up to bp 3011 upstream from the transcriptional start site. Among many putative cis-elements, we identified two cis-elements critical for the transcription of the hMCP-1 gene. The first element is a remote kappa B binding site located far upstream between bp -2612 and -2603 that was important for IL-1 beta-, TNF-alpha-, and 2-O-tetradecanoylphorbol 13-acetate-induced enhancer activity. Mutation at the kappa B consensus site resulted in a complete loss of these stimulus-induced enhancer activities. The second element is a GC box located between bp -64 and -59 that was important for the maintenance of basal transcriptional activity. Overexpression of rSp1 resulted in increased hMCP-1 transcriptional activity, possibly suggesting the role of Sp1 in controlling basal hMCP-1 transcription via this GC box. These results together indicate that hMCP-1 expression is controlled by at least two distinct regulatory elements: a kappa B site and a GC box that seem to be associated with stimulus-specific and tissue-specific regulation, respectively.
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PMID:NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. 805 10

The activation of the secretory pathway for the amyloid protein precursor (APP) by phorbol 12-myristate 13-acetate in human glioblastoma A-172 cells leads to a decrease in intracellular beta-amyloidogenic fragments derived from APP. The result suggests that a metabolic switch of APP from the endosomal/lysosomal pathway to a secretion route occurs after PMA treatment.
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PMID:Activation of the secretory pathway leads to a decrease in the intracellular amyloidogenic fragments generated from the amyloid protein precursor. 833 36

The present study demonstrates interleukin-1 (IL-1) production by human glioblastoma cells both in vitro and in vivo. The presence of IL-1 alpha and IL-1 beta transcripts was analyzed in 4 cell lines. IL-1 alpha mRNA was expressed constitutively in one cell line whereas constitutive IL-1 beta mRNA could not be detected in any of the cell lines. IL-1 alpha transcripts could be induced with phorbol myristate acetate (PMA) or PMA plus lipopolysaccharide (LPS) in 2 of 4 cell lines and IL-1 beta mRNA in 2 of 4 cell lines. Culture fluid from these cell lines was tested for the presence of IL-1 using a specific radio-immuno-assay for either IL-1 alpha or IL-1 beta. In agreement with the results on RNA, one of 4 cell lines was found to constitutively produce IL-1 alpha but not IL-1 beta. After treatment with PMA and LPS, IL-1 alpha was detected in the culture fluid from two other lines and IL-1 beta in the medium from three lines. That the IL-1 produced by these cell lines was biologically active was confirmed in a two step thymocyte proliferation assay. IL-1 like activity was detected in all samples that were positive in the radio-immuno-assay. Finally, immunohistological analysis on fresh frozen tumour sections provided evidence for IL-1 production by glioblastoma cells in vivo. Fourteen out of 28 glioblastomas were stained with an anti-IL-1 alpha monoclonal antibody while none of them was stained with an anti-IL-1 beta antibody.
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PMID:Expression and release of interleukin-1 by human glioblastoma cells in vitro and in vivo. 851 18

Cell culture techniques, high-resolution in vitro 1H NMR spectroscopy, and chromatographic analyses were used to compare the properties of three types of human brain and nervous system tumours. Cell lines were immunocytochemically characterized at all stages in culture with specific antibodies. Intracellular metabolites present in cell extracts were analysed by 1H NMR spectroscopy and by high performance liquid chromatography (HPLC). The spectra from meningiomas, neuroblastomas, and glioblastomas displayed, in addition to similarities-including the presence of signals from leucine, isoleucine, valine, threonine, lactate, acetate, glutamate, choline-containing compounds and glycine-certain distinguishing metabolic features. Spectra from meningiomas featured relatively high signals from alanine. Intense signals from creatine were present in neuroblastoma spectra, while in spectra from glioblastoma they were not detectable. We found statistically significant differences by 1H NMR spectroscopy in the amounts of alanine, glutamate, creatine, phosphorylcholine and threonine among the types of tumours examined. HPLC determinations confirmed that there were also other metabolites specific to a type of tumour, such as taurine, gamma-aminobutyric acid, and serine. We suggest that these findings have potential relevance for the development of non-invasive diagnosis of tumour lineage by 1H NMR spectroscopy in vivo.
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PMID:Characteristic metabolic profiles revealed by 1H NMR spectroscopy for three types of human brain and nervous system tumours. 873 81

9-Methoxy-N2-methylellipticinium acetate (MMEA) is representative of a series of quaternized ellipticines that exhibited selective cytotoxicity for human brain tumor cell lines of glial origin in the in vitro primary screen of the U.S. National Cancer Institute. The present investigation was initiated to determine whether membrane potential contributes to the cellular accumulation of this lipophilic cation by selected brain tumor and non-brain tumor cell lines. The results indicate that accumulation of MMEA by drug-sensitive cell lines, but not drug-resistant cell lines, is reduced by experimental conditions that depolarize the plasma membrane, e.g., stepped increases in the extracellular potassium concentration. These experimental conditions result in increased cellular fluorescence of cells stained with the voltage-sensitive anionic dye bis(1,3-dibutylbarbituric acid)trimethine oxonol, suggesting that decreased accumulation of MMEA is the result of decreased membrane potential. Membrane potential measurements using the null point method indicated that the mean membrane potential of selected MMEA-sensitive cell lines (-39.4 +/- 6.8 mV) was significantly lower (P < .005) than MMEA-resistant cell lines (-17 +/- 3.8 mV). Ultrastructural studies with the MMEA-sensitive U-251 glioblastoma indicated that the first morphological effects of MMEA occurred in mitochondria, where dissolution of cristae was observed, followed by engulfment of mitochondria in multilamellar phagocytic vesicles. Electron microscopic autoradiographic studies with tritium-labeled MMEA revealed that the drug was localized in mitochondria and nuclei.
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PMID:Role of membrane potential in the accumulation of quaternized ellipticines by human tumor cell lines. 893 Feb 12

To examine whether protein kinase C (PKC) contributes to p53-dependent WAF1 induction after heat treatment, the effects of calphostin C (CAL), a specific inhibitor of PKC, on WAF1 induction were analyzed by PKC activity and gel mobility-shift assays and Western blot analysis in human glioblastoma cell lines. Heat-induced accumulation of WAF1 in A-172 cells carrying wild-type p53 (wtp53) was suppressed by CAL in a dose-dependent manner. In T98G cells carrying mutant p53 (mp53), no significant accumulation of WAF1 was observed after heat treatment and CAL exerted no significant effects on this response of T98G cells. In accordance with the accumulation of WAF1, heat-induced activation of the binding ability of p53 to p53 consensus sequence (p53 CON) was suppressed by CAL in A-172 cells but no DNA-binding activity was observed in the mp53 in T98G cells. PKC in A-172 cells was activated rapidly (within 5 min) after heat treatment in the membrane fraction but not in the cytosolic fraction. When the cell lines were treated with the PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), WAF1 was accumulated in A-172 cells in a dose-dependent manner but not in T98G cells. In addition, the cellular contents of WAF1 after heating did not increase in A-172 cells transformed with mp53. These results suggest that PKC contributes to heat-induced signal transduction leading to p53-dependent WAF1 induction in a way that PKC is involved in the specific DNA-binding activation of p53.
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PMID:Contribution of protein kinase C to p53-dependent WAF1 induction pathway after heat treatment in human glioblastoma cell lines. 947 48

Coculture of T98G glioblastoma cells with the myeloid and monocytic cell lines, HL-60, and THP-1 produced minimal amounts of interleukin-8 (IL-8). Pretreatment of HL-60 or THP-1 cells with phorbol myristate acetate (PMA) enhanced their capacity to induce IL-8 production by T98G cells. In contrast, the murine macrophage cell lines J774 A.1 and RAW 264.7 induced high levels of IL-8 production by T98G cells without PMA activation. To determine the molecules responsible for the induction of IL-8 by T98G cells, we carried out coculture experiments with a membrane fraction prepared from RAW cells and indicated that membrane-associated and free forms of murine IL-1alpha acted on human T98G cells to produce IL-8. RAW cells were unique in that increasing the number of RAW cells relative to the number of T98G cells (RAW/T98G ratio > 4:1) significantly suppressed IL-8 production by T98G cells. Because RAW cells produce large amounts of nitric oxide (NO), we assumed that the suppression of IL-8 production was ascribable to the NO produced by the RAW cells. This was supported by the inverse relationship between increasing concentrations of NO and IL-8 production seen in this coculture system. The involvement of NO in the suppression of IL-8 production was confirmed by the finding that N-monomethyl-L-arginine (NMMA), which inhibits NO production, reversed this suppression, whereas S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a strong NO generator, suppressed IL-8 production. Our results indicate that high levels of NO suppress IL-8 production by T98G cells, and murine IL-1alpha plays a major role in the induction of IL-8 production by T98G cells. It is, therefore, possible that excessive production of NO during the interaction of glioma cells with macrophages may play a regulatory role in chemokine production, thus mitigating inflammatory responses.
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PMID:Nitric oxide-mediated modulation of interleukin-8 production by a human glioblastoma cell line, T98G, cocultured with myeloid and monocytic cell lines. 980 27

Protein kinase C (PKC) plays a central role in signal transduction pathways that mediate the action of certain growth factors, tumor promoters, and cellular oncogenes. To explore whether PKC might be an appropriate target for the chemotherapy of human brain tumors, cell lines were established from five glioblastomas, one mixed gliosarcoma and glioblastoma, two astrocytomas, and one choroid plexus carcinoma. The staurosporine derivative CGP 41251, an inhibitor of PKC, inhibited cell proliferation in all nine cell lines with an IC50 in the range of 0.4 micrometer. Drug withdrawal and clonogenicity assays showed that CGP 41251 induced an irreversible growth arrest. Three cell lines were examined in detail: two human glioblastoma cell lines, GB-1 and GB-2, and one gliosarcoma cell line, GS-1. All of these three cell lines were highly aneuploid and displayed morphologies and immunohistochemical markers characteristic of the glial lineage. The compound 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter and activator of PKC, also inhibited the growth of these cell lines. CGP 41251 in combination with TPA caused further growth inhibition. Cultures treated with CGP 41251 displayed an increase in the fraction of cells in G2-M, a decrease of cells in S phase, and no consistent effect on G0-G1. Immunohistochemical analyses demonstrated that growth inhibition by CGP 41251 was associated with the formation of giant nuclei with extensive fragmentation and apoptotic bodies. These effects of CGP 41251 were abrogated by withdrawal of serum from the medium or by exposure of these cells to aphidicolin, actinomycin D, cycloheximide, or TPA. In contrast to the effects seen with the glioblastoma cell lines, nontransformed astrocyte lines remained viable in the presence of 0.4 and 0.8 micrometer CGP 41251 and displayed only a slight increase in the fraction of giant nuclei with fragmentation. The antitumor activity of CGP 41251 was demonstrated in vivo against xenografts of the glioblastoma cell lines U87 MG and U373 MG. These findings suggest that CGP 41251 might be a useful agent for the treatment of glioblastomas.
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PMID:Inhibition of the growth of glioblastomas by CGP 41251, an inhibitor of protein kinase C, and by a phorbol ester tumor promoter. 981 63

Prior studies using rat primary hippocampal cultures indicated induction of matrix metalloproteinases (MMPs) in response to beta-amyloid (A beta). Hence, it was of interest to determine whether MMP activity in a human cell line is influenced by A beta. A beta, but not interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS), stimulated an active form of MMP-2 in human U87 glioblastoma cells, as well as increased the expression of the well-known activator of MMP-2, membrane-type (MT)-MMP. Activation experiments carried out with amino phenyl mercuric acetate (APMA), immunoprecipitation, as well as immunoblotting, suggest that the lower molecular weight, gelatin-degrading activity was an activated form of MMP-2. Furthermore, it was demonstrated that a synthetic furin convertase inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, decreased the production of A beta-induced active MMP-2 in U87 cells. The induction of MMP-3 by cytokines, but not by A beta, suggests that the effect of A beta on MMP-2 is selective. Although A beta stimulated tissue inhibitor of metalloproteinase-1 (TIMP-1), there was no obvious effect of A beta on TIMP-2 production in U87 cells. These results demonstrate that A beta induces an active form of MMP-2 likely by increasing the expression of MT-MMP in a human glioblastoma cell line. Active MMP-2 may degrade A beta or act on ECM components critical in neuronal survival mechanisms and possibly play a role in Alzheimer's disease (AD) neuropathology.
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PMID:Activated isoforms of MMP-2 are induced in U87 human glioma cells in response to beta-amyloid peptide. 989 Apr 33

Aberrant expression of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), has been demonstrated to be associated with most human solid tumors. Both transcriptional and post-transcriptional mechanisms have been shown to modulate VEGF expression in a multitude of cell types. Here we report that when protein kinase C (PKC) pathways were activated in human glioblastoma U373 cells by phorbol 12-myristate 13-acetate (PMA), VEGF mRNA expression was up-regulated via a post-transcriptional mRNA stabilization mechanism. PMA treatment exhibited no increase in VEGF-specific transcriptional activation as determined by run-off transcription assays and VEGF promoter-luciferase reporter assays. However, PMA increased VEGF mRNA half-life from 0.8 to 3.6 h which was blocked by PKC inhibitors but not by protein kinase A or cyclic nucleotide-dependent protein kinase inhibitors. When U373 cells were transfected with antisense oligonucleotide sequences to the translation start sites of PKC-alpha, -beta, -gamma, -delta, -epsilon, or -zeta isoforms, both PKC-alpha and -zeta antisense oligonucleotides showed substantial inhibition of PMA-induced VEGF mRNA. In addition, overexpression of PKC-zeta resulted in a strong constitutive up-regulation of VEGF mRNA expression. This study demonstrates for the first time that specific PKC isoforms regulate VEGF mRNA expression through post-transcriptional mechanisms.
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PMID:Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells. 1033 29


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