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)

The creatine kinase isoenzymes play an important role in maintaining ATP levels in some cell types during times of high energy demand. We have previously shown in primary cell cultures from rat brain that glial cells express much higher levels of brain creatine kinase (CKB) mRNA than neurons. In a separate earlier study we observed that transcription of CKB mRNA in glial cells can be stimulated by a forskolin-mediated increase in cAMP via a pathway involving protein kinase A (PKA). In this report, we show that the level of CKB mRNA in human U87 glioblastoma cells can be increased by either prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), or cholera toxin (an activator of G alpha s proteins). The induction of CKB mRNA occurs rapidly (with maximal induction after 6 h), is at the level of transcription, and is mediated specifically through PKA. In addition, the results indicate that both PGE1 and PGE2 use the same or related signal transduction pathways to increase CKB transcription. These results suggest that in glial cells CKB mRNA can be regulated by extracellular signals acting through G-protein-coupled receptors. This study may contribute to an understanding of the mechanisms underlying the previously-reported, early postnatal increase in CKB enzyme activity in rat brain. The results are also discussed with regard to the potential involvement of the expression of prostaglandins and CKB during hypoxia and ischemia.
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PMID:Prostaglandin E1, E2, and cholera toxin increase transcription of the brain creatine kinase gene in human U87 glioblastoma cells. 892 40

In human glioblastoma A172 cells, interleukin-6 (IL-6) production was induced by interleukin-1 beta (IL-1 beta) and dibutyryl cyclic AMP. These cells have been shown to induce IL-6 production via a cAMP-protein kinase A system. Since calcitonin (CT) and calcitonin gene-related peptide (CGRP) are known to increase cAMP accumulation in murine and rat astrocytes, we examined whether these neuropeptides induced IL-6 production in A172 cells. Human CT and human CGRP increased IL-6 production and cAMP accumulation in a dose-dependent manner. A specific protein kinase A inhibitor, H-89, inhibited both CT- and CGRP-induced IL-6 production. CT and CGRP have been shown to cross-react with each other. To exclude the possibility of this cross-reactivity, we studied the additive effects of CT and CGRP and the inhibitory effects of specific inhibitors. When 100 nM CT was added, cAMP accumulation stimulated by 10 nM CGRP (the maximal dose) was increased. CGRP (8-37), a specific CGRP receptor inhibitor, inhibited cAMP accumulation and IL-6 production induced by CGRP, but did not inhibit these effects when they were induced by CT. Salmon CT (8-32), a specific inhibitor of the CT receptor, inhibited cAMP accumulation induced by CT, but did not inhibit the effect induced by CGRP. These results demonstrated that CT can induce IL-6 production via cAMP accumulation and the effects of CT are mediated via its own receptors.
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PMID:Protein kinase A-dependent IL-6 production induced by calcitonin in human glioblastoma A172 cells. 918 43

The expression of adrenomedullin (ADM) and its mRNA was studied in human glial cell tumors and cultured glioblastoma cell lines, T98G and A172. Northern blot analysis showed that ADM mRNA was expressed in all brain tumors examined (three anaplastic astrocytomas and two glioblastomas multiforme) and in the glioblastoma cell lines. Immunoreactive (IR-) ADM was detectable in these brain tumors by radioimmunoassay (0.31-2.0 pmol/g wet weight), except for one anaplastic astrocytoma. Reverse phase high performance liquid chromatography of the tumor extracts showed a single peak eluting in the position of ADM-(1-52). IR-ADM concentrations in the cultured media of T98G cells were 205.5 +/- 8.4 fmol/10(5) cells/24 h (mean +/- SEM, n = 5). Treatment of T98G cells with interferon gamma or interleukin 1 beta increased the expression levels of ADM mRNA and the IR-ADM concentrations in the cultured media, whereas tumor necrosis factor alpha decreased them in a dose-dependent manner. Treatment with synthetic ADM-(1-52) (10(-8) or 10(-7) mol/l) increased the cAMP concentrations in the cultured media of T98G cells. These findings suggest that ADM is secreted from glial cell tumors and is related to the pathophysiology of these tumors.
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PMID:Production and secretion of adrenomedullin from glial cell tumors and its effects on cAMP production. 939 51

A cDNA coding for a human phosphodiesterase 4C (PDE4C2) was isolated from the mRNA prepared from the glioblastoma cell line, U87. The cDNA contained an ORF of 1818 bp corresponding to a 605 amino acid polypeptide. The sequence differed at the 5' end from the human PDE4C previously reported (Engels, P. et al, 1995 FEBs Letters 358, 305-310) indicating that it represents a novel splice variant of the human PDE4C gene. Evidence was also obtained for a third 5' splice variant. The PDE4C2 cDNA was transfected into both COS 1 cells and yeast cells, and shown to direct the expression of an 80 kD polypeptide by Western blotting using a PDE4C specific antiserum. The activity of cell lysates was typical of PDE4 being specific for cAMP and inhibitable by the selective inhibitor, rolipram. However, the Km for cAMP of the enzyme produced in COS cells was 0.6 microM compared to 2.6 microM for the yeast 4C activity. In addition the COS cell PDE4 activity was much more sensitive to R rolipram than the yeast PDE4 enzyme (IC50 of 23 nM compared to 1648 nM). This difference in rolipram sensitivity was associated with the detection of a high affinity [3H] R rolipram binding site on the COS cell 4C enzyme but not on the yeast expressed enzyme. The results indicate that the enzyme can adopt more than one active conformation, which are distinguished by their interaction with rolipram.
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PMID:Molecular cloning and expression of a human phosphodiesterase 4C. 942 61

We previously demonstrated that oxysterols inhibit the growth of experimental glioblastoma induced in the rat brain cortex. Mechanism of action of these compounds remains obscure. In this study, we investigated the effect of 7beta-hydroxycholesterol (7beta-OHCH) and 7ketocholesterol (7k-CH) on the growth and MAP kinase activity in three in vitro biological models: rat astrocyte primary cultures, primary cultures treated by dibutyryl-cAMP (reactive cells), and the C6 glioma cell line. The oxysterols are not lethal to primary astrocytes, even if MAP kinase activity is decreased, particularly when cells were treated with 7k-CH. Both oxysterols are toxic to reactive astrocytes, and as compared with untreated primary cultures, they amplified the MAP kinase activity decrease. However, the mechanism of action of oxysterols on reactive astrocytes seems not to be linked to the MAP kinase pathway. In highly proliferating C6 cell lines, only 7beta-OHCH has an antiproliferative effect and is cytotoxic. The inhibition of MAP kinase activity is a function of 7beta-OHCH concentration. PD098059, a MAP kinase pathway inhibitor, has only a time-limited antiproliferative effect on C6 cell growth. We conclude that in C6 cells, the MAP kinase activity decrease is correlated with the toxic effect of 7beta-OHCH and occurs at first stages of 7beta-OHCH action.
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PMID:Inhibition of p42/p44 mitogen-activated protein kinase by oxysterols in rat astrocyte primary cultures and C6 glioma cell lines. 967 Sep 91

Human SK-N-AS neuroblastoma and U-87MG glioblastoma cell lines were found to secrete relatively high levels of glial cell line-derived neurotrophic factor (GDNF). In response to growth factors, cytokines, and pharmacophores, the two cell lines differentially regulated GDNF release. A 24-hr exposure to tumor necrosis factor-alpha (TNFalpha; 10 ng/ml) or interleukin-1beta (IL-1,; 10 ng/ml) induced GDNF release in U-87MG cells, but repressed GDNF release from SK-N-AS cells. Fibroblast growth factors (FGF)-1, -2, and -9 (50 ng/ml), the prostaglandins PGA2, PGE2, and PGI2 (10 microM), phorbol 12,13-didecanoate (PDD; 10 nM), okadaic acid (10 nM), dexamethasone (1 microM), and vitamin D3 (1 microm) also differentially effected GDNF release from U-87MG and SK-N-AS cells. A result shared by both cell lines, was a two- to threefold increase in GDNF release by db-cAMP (1 mM), or forskolin (10 microM). In general, analysis of steady-state GDNF mRNA levels correlated with changes in extracellular GDNF levels in U-87MG cells but remained static in SK-N-AS cells. The data suggest that human GDNF synthesis/release can be regulated by numerous factors, signaling through multiple and diverse secondary messenger systems. Furthermore, we provide evidence of differential regulation of human GDNF synthesis/release in cells of glial (U-87MG) and neuronal (SK-N-AS) origin.
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PMID:Differential regulation of glial cell line-derived neurotrophic factor (GDNF) expression in human neuroblastoma and glioblastoma cell lines. 997 21

Drosophila transcription factor cubitus interruptus (Ci) and its co-activator CRE (cAMP response element)-binding protein (CBP) activate a group of target genes on the anterior-posterior border in response to hedgehog protein (Hh) signaling. In the anterior region, in contrast, the carboxyl-truncated form of Ci generated by protein processing represses Hh expression. In vertebrates, three Ci-related transcription factors (glioblastoma gene products (GLIs) 1, 2, and 3) were identified, but their functional difference in Hh signal transduction is unknown. Here, we report distinct roles for GLI1 and GLI3 in Sonic hedgehog (Shh) signaling. GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. Consistent with this, GLI3, but not GLI1, is processed to generate the repressor form. Transcriptional co-activator CBP binds to GLI3, but not to GLI1. The trans-activating capacity of GLI3 is positively and negatively regulated by Shh and cAMP-dependent protein kinase, respectively, through a specific region of GLI3, which contains the CBP-binding domain and the phosphorylation sites of cAMP-dependent protein kinase. GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. Thus, GLI3 may act as a mediator of Shh signaling in the activation of the target gene Gli1.
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PMID:Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. 1007 17

Sodium-L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 5,6-benzylidene-L-ascorbate and sodium-6-beta-O-galactosyl-L-ascorbate, which produce ascorbyl radicals during the oxidative degradation, also induced cytotoxicity against cultured human renal carcinoma (TC-1) and glioblastoma multiform tumor (T98G) cell lines. On the other hand, L-ascorbic acid 2-phosphate magnesium and L-ascorbic acid 2-sulfate dipotassium salt, which do not produce the ascorbyl radical, were inactive. This suggests the possible role of the ascorbyl radical for cell death induction. T98G cells were more resistant to ascorbate analogs than TC-1 and HL-60 cells, possibly due to higher intracellular glutathione concentrations. Ascorbate treatment induced rapid elevation of both intracellular concentration of cAMP and Ca2+ in HL-60 cells, but not in TC-1 and T98G cells. However, the elevation of cAMP by theophyline and N,2-dibutyryl adenosine 3,5 cyclic monophosphate (dibutyryl cAMP) resulted in a decrease in the viable cell number. This suggests the possible role of cAMP for ascorbate-induced cell death.
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PMID:Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. 1065 1

The hormone leptin is implicated in the regulation of appetite and body weight in rodents, primates and humans. We reported that the leptin gene (ob) is expressed in the brain, but the factors which control ob expression in the central nervous system are not known. We previously showed that brain-derived rat C6 glioblastoma cells express ob mRNA and protein. In the present study we examined the regulation of ob expression in C6 cells. Leptin and leptin receptor immunoreactivity was detected in C6 cells, suggesting a possible autocrine role for leptin. The identity of the leptin immunoreactivity (OB-ir) in C6 cells was confirmed by immunoprecipitation and Western blotting using two leptin specific polyclonal antibodies. Using RT-PCR analysis a product of the expected size for the short, but not the long, leptin receptor isoform was detected in C6 cells. Cells were maintained in serum-free (SF) media for 0-24 h in the presence of various regulators of leptin expression. Leptin mRNA levels were significantly higher in cells treated with dbcAMP (1 mM), IGF 1 (100 ng/ml) or insulin (5 microg/ml) compared to SF controls. In contrast, corticosterone (10(-7)M) reduced leptin mRNA. In the presence of dbcAMP, C6 cells undergo a dramatic alteration in morphology which is coincident with an apparent increase in the number of leptin-ir nuclei and an increase in leptin immunoreactivity. In contrast to C6 cells, glucocorticoids are reported to increase leptin levels in adipocytes/adipose tissue, while increases in intracellular cAMP levels are reported to reduce leptin levels. Overall, our in vitro data suggest that the regulation of leptin gene expression in C6 glioblastoma cells is different from that in adipocytes.
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PMID:The regulation of leptin gene expression in the C6 glioblastoma cell line. 1094 Apr 88

Compounds that could block tumor angiogenesis and induce tumor cell differentiation in malignant gliomas represent a very valuable tool in anticancer treatments. In this paper, we demonstrate that more selective drugs, which interfere with specific cellular targets, could treat glioma more effectively. 8-Cl-cAMP and tiazofurin (TR) are site-specific analogs that selectively inhibit PKAI and IMP dehydrogenase, are directly involved in cell proliferation and apoptosis, and mediate the mitogenic effects of different oncogenes and growth factors. In this study, we have examined influence of 8-Cl-cAMP and TR on the production of an angiogenic factor [vascular endothelial growth factor (VEGF)] by human glioblastoma U251 MG cells, as well as their influence on the expression of a differentiating marker [glial fibrillary acidic protein (GFAP)]. Using a cell proliferation assay, VEGF enzyme-linked immunoassay and GFAP immunocytochemistry we demonstrated the effects of these compounds. Our results demonstrate that 8-Cl-cAMP and TR decrease VEGF production by U251 MG cells, and that under the influence of both agents these cells increase GFAP expression and change their morphology, becoming more differentiated. These findings also suggest that 8-Cl-cAMP and TR may have potential for further investigation of their antiangiogenic and differentiational role in malignant disease such as human gliomas.
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PMID:8-Cl-cAMP and tiazofurin affect vascular endothelial growth factor production and glial fibrillary acidic protein expression in human glioblastoma cells. 1112 40


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