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)

Estradiol can protect the brain from a variety of insults by activating membrane-initiated signaling pathways, and thereby modulate gene expression and lead to functional changes in neurons. These direct neuronal effects of the hormone have been well documented; however, it is less understood what effects estradiol may have on nonneuronal cells of the central nervous system. There is evidence that estradiol levels can induce the release of glial-derived growth factors and other cytokines, suggesting that estradiol may both directly and indirectly protect neurons. To determine whether 17beta-estradiol (E2) can activate rapid signaling and modulate nonclassical transcription in astrocytes, we stably transfected the C6 rat glioblastoma cell line with human estrogen receptor (ER) alpha (C6ERalpha) or rat ERbeta (C6ERbeta). Introduction of a cAMP response element-luciferase reporter gene into C6, C6ERalpha, and C6ERbeta cells leads to the observation that E2 treatment reduced isoproterenol-stimulated luciferase activity by 35% in C6ERalpha but had no effect on reporter gene expression in C6ERbeta or untransfected C6 cells. A similar effect was seen with a membrane-impermeable estrogen (E2-BSA), suggesting the modulation of nonclassical transcription by estradiol treatment is mediated by the activation of a membrane-initiated signaling pathway. Furthermore, pretreatment with wortmannin (phosphatidylinsositol 3-kinase) or U73122 (phospholipase C) attenuated the E2-induced reduction in nonclassical transcription. We conclude that E2 treatment reduces cAMP response element-mediated transcription in glioma cells expressing ERalpha and that this reduction is dependent on the activation of membrane-initiated signaling. These findings suggest a novel model of estrogen rapid signaling in astrocytes that leads to modulation of nonclassical transcription.
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PMID:Estradiol reduces nonclassical transcription at cyclic adenosine 3',5'-monophosphate response elements in glioma cells expressing estrogen receptor alpha. 1643 53

Contrasting with its robust expression during embryogenesis, the glial cell line-derived neurotrophic factor (GDNF) is repressed in the adult organism. However, rapid induction of this neuronal growth factor is observed following diverse neuronal insults and it is now widely accepted that the control of its expression could constitute a powerful target in neuropharmacology. We investigated the effects of the neuroprotective drug, riluzole, on the GDNF gene expression in glial cells. Exposure of C6 glioma cells to riluzole (1 microM) significantly increased GDNF protein and mRNA levels. Using luciferase reporter gene constructs encoding fragments of the 5' untranslated region of the rat GDNF gene, we demonstrated that riluzole mediates its effect at the transcription level. Furthermore, luciferase assays revealed the presence of a negative regulatory region within the +343/+587 region of exon 1. This region was shown to contribute to the high sensitivity and specificity of the induction mediated by riluzole in the C6 glioma cell line at pharmacologically relevant concentrations. The effects of riluzole were inhibited by the mitogen-activated protein kinase extracellular signal-related kinase (MEK) inhibitor PD 98059. Together, these results indicated that the induction of GDNF release by riluzole in the C6 glioma cells results from the activation of its corresponding gene promoter through a signalling pathway involving MEK activity. This study suggests that the regulation of GDNF gene transcription in glial cells could contribute to the pharmacological properties of riluzole and possibly other neuroprotective drugs.
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PMID:Specific regulation of rat glial cell line-derived neurotrophic factor gene expression by riluzole in C6 glioma cells. 1652 82

The basic helix-loop-helix transcription factor OLIG2 is specifically expressed in cells of the oligodendrocyte lineage. It is also expressed in various tumors originating from glial cells; however, the expression of OLIG2 is rare or weak in glioblastomas, the most malignant gliomas. The role of OLIG2 in glioma remains unclear. To investigate the function of OLIG2 in glial tumor cells, we have established a glioblastoma cell line, U12-1, in which the expression of OLIG2 is induced by the Tet-off system. Induction of OLIG2 resulted in suppression of both the proliferation and anchorage-independent growth of U12-1. It also resulted in an increase in the expression of p27(Kip1). A luciferase assay revealed that the CTF site of the p27(Kip1) gene promoter was essential for OLIG2-dependent activation of p27(Kip1) gene transcription. Electrophoretic mobility shift assays confirmed that a nuclear extract of OLIG2-expressing U12-1 cells contained a protein complex that binds to the CTF site of the p27(Kip1) gene promoter. Furthermore, siRNA against p27(Kip1) rescued the OLIG2-mediated growth and DNA synthesis inhibition of U12-1 cells. These results indicate that OLIG2 suppresses the proliferation of U12-1 and that this effect is mediated by transactivation of the p27(Kip1) gene, and low expression of OLIG2 may be related to the malignant behavior of human glioblastoma.
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PMID:A novel function of OLIG2 to suppress human glial tumor cell growth via p27Kip1 transactivation. 1655 41

Malignant gliomas remain refractory to adenovirus serotype 5 (Ad5) gene therapy because of the lack of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on tumor cells. To bypass the dependence on CAR, we investigated the expression of adenovirus serotype 3 (Ad3) receptor, or CD46, on glioma cells. First, we analyzed the expression of CD46 by RT-PCR on primary and passaged glioma cells. We then performed immunofluorescence studies to examine protein expression of CAR and CD46 on the same tumor lines. Finally, we constructed a replication-defective Ad vector that binds to CD46 and contains a luciferase transgenic cassette in place of the deleted E1 region: Ad5/3 (containing tail/shaft domain of Ad5 and knob domain of Ad3). These vectors were analyzed in vitro and in vivo against malignant glioma and compared with wild-type Ad5 or control vector Ad3/5 (containing tail of Ad5, shaft of Ad3, and knob of Ad5). The chimeric vector Ad5/3 showed a significant increase in the transduction efficiency of glioma tumor cells. At the same time, blocking the CD46 receptor caused a 65% inhibition of adenoviral infection when using Ad5/3. Taken together, these results indicate that CD46 is overexpressed by malignant glioma. Retargeting to the Ad3 receptor enhances gene transfer and offers a novel target for gene therapy of malignant brain tumors.
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PMID:CD46 represents a target for adenoviral gene therapy of malignant glioma. 1671 12

Glutamate transporters (excitatory amino acid transporters, EAAT) play an important role in maintaining extracellular glutamate homeostasis and regulating glutamate neurotransmission. However, very few studies have investigated the regulation of EAAT expression. A binding sequence for the regulatory factor X1 (RFX1) exists in the promoter region of the gene encoding for EAAT3, a neuronal EAAT, but not in the promoter regions of the genes encoding for EAAT1 and EAAT2, two glial EAATs. RFX proteins are transcription factors binding to X-boxes of DNA sequences. Although RFX proteins are necessary for the normal function of sensory neurons in Caenorhabditis elegans, their roles in the mammalian brain are not known. We showed that RFX1 increased EAAT3 expression and activity in C6 glioma cells. RFX1 binding complexes were found in the nuclear extracts of C6 cells. The activity of EAAT3 promoter as measured by luciferase reporter activity was increased by RFX1 in C6 cells and the neuron-like SH-SY5Y cells. However, RFX1 did not change the expression of EAAT2 proteins in the NRK52E cells. RFX1 proteins were expressed in the neurons of rat brain. A high expression level of RFX1 proteins was found in the neurons of cerebral cortex and Purkinje cells. Knockdown of the RFX1 expression by RFX1 antisense oligonucleotides decreased EAAT3 expression in rat cortical neurons in culture. These results suggest that RFX1 enhances the activity of EAAT3 promoter to increase the expression of EAAT3 proteins. This study provides initial evidence for the regulation of gene expression in the nervous cells by RFX1.
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PMID:The transcription factor regulatory factor X1 increases the expression of neuronal glutamate transporter type 3. 1672 57

In mammals, the principal circadian oscillator resides in the hypothalamic suprachiasmatic nucleus. However, the basic components and the ability to generate a circadian rhythm are also characteristic of most peripheral tissues and some cell lines. In our present study, we show that the rat C6 glioma cell line displays circadian oscillations of reporter luciferase bioluminescence driven by the mouse Per2 promoter and of clock-related gene transcripts. Per2::luc expressing C6 cells display circadian rhythm in their bioluminescence levels for more than seven days. In addition, clock and clock-controlled genes show dynamic circadian oscillation in C6 cells after exposure to dexamethasone. It is also significant that Per1 is not induced in C6 cells by a calcium ionophore, which is in stark contrast to Rat-1 cells. The C6 glioma cell line has therefore the potential to be a useful tool in future investigations of the underlying molecular machinery of the circadian clock.
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PMID:Circadian rhythm generation in a glioma cell line. 1675 May 13

Hypoxia strongly up-regulates tissue factor and promotes plasma clotting by glioblastoma multiforme, but transcriptional mechanisms remain undefined. Here, we investigated the potential roles of early growth response gene-1 (Egr-1), Sp1, nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and hypoxia-inducible factor-1 (HIF-1) in the hypoxic regulation of tissue factor by glioblastoma multiforme cells in vitro. Hypoxia (1% O2) strongly induced Egr-1 mRNA within 1 hour and led to nuclear localization of Egr-1 protein. Using luciferase reporter plasmids in glioma cells, we found that hypoxia dramatically increased luciferase activity in cells with constructs containing Egr-1-binding sites but not in cells with constructs containing AP-1- or NF-kappaB-binding sites. Electrophoretic mobility shift assays revealed hypoxia-induced Egr-1, but not Sp1, binding to oligonucleotides containing the Egr-1/Sp1 motif of tissue factor gene promoter. Using an expression vector containing the minimal tissue factor promoter (-111 to +14 bp) and small interfering RNA (siRNA) directed at Egr-1 and Sp1 mRNAs, we found that Egr-1 was required for maximal hypoxic induction of promoter activity. Forced overexpression of Egr-1 but not Sp1 by cDNA transfection caused up-regulation of tissue factor in glioma cells under normoxia (21% O2), whereas siRNA directed at Egr-1 strongly attenuated hypoxia-induced tissue factor expression. To examine the effects of HIF-1alpha on tissue factor expression, we used glioma cells stably transfected with a HIF-1alpha siRNA expression vector and found that HIF-1alpha mRNA silencing did not affect tissue factor expression under hypoxia. We conclude that hypoxic up-regulation of tissue factor in glioblastoma multiforme cells depends largely on Egr-1 and is independent of HIF-1.
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PMID:Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. 1684 52

Approaches to improve the oncolytic potency of replication-competent adenoviruses include the insertion of therapeutic transgenes into the viral genome. Little is known about the levels and duration of in vivo transgene expression by cells infected with such "armed" viruses. Using a tumor-selective adenovirus encoding firefly luciferase (AdDelta24CMV-Luc) we investigated these questions in an intracranial mouse model for malignant glioma. Luciferase expression was detected by bioluminescence imaging, and the effect of the immunosuppressive agent cyclophosphamide (CPA) on transgene expression was assessed. Intratumoral AdDelta24CMV-Luc injection led to a localized dose-dependent expression of luciferase. Surprisingly, this expression decreased rapidly during the course of 14 days. In contrast, mice injected with nonreplicating Ad.CMV-Luc demonstrated stable transgene expression. Treatment of mice with CPA in combination with AdDelta24CMV-Luc retarded the loss of transgene expression. Staining of mouse brains for inflammatory cells demonstrated decreased tumor infiltration by immune cells in CPA-treated mice. Moreover, in immunodeficient NOD/SCID mice loss of transgene expression was less rapid and not prevented by CPA treatment. Together, our data demonstrate that transgene expression and viral replication decrease rapidly after intratumoral injection of oncolytic adenovirus in mouse brains and that treatment with the immunomodulator CPA prolongs viral-mediated gene expression.
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PMID:Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging. 1699 14

Neuroblastoma is one of the most common solid tumors in childhood. With the aim of developing a targeting vector for neuroblastoma, we cloned and characterized an enhancer in the 5'-flanking regions of the MASH1 gene by a random-trap method from a 36 kb cosmid DNA. The enhancer-containing clone was identified by the expression of GFP when transfected into neuroblastoma cell lines. The enhancer-luciferase activity is higher in neuroblastoma cell lines, IMR32, BE2 and SH-SY5Y, compared with those in non-neuroblastoma cell lines, U1242 glioma, N417 small cell lung cancer and EOMA hemangioma. The core enhancer was determined within a 0.2 kb fragment, yielding three- to fourfold higher activity than that of the MASH1 promoter alone in IMR32 and BE2. This area possesses GATA- and CREB-binding sites, as well as the E-box. EMSA on this area demonstrated that CREB/ATF could bind the DNA. Chromatin immunoprecipitation assay revealed that N-myc, CREB, and co-activators CBP and PCAF, but not HDAC1, are bound to the core enhancer at the same time as the co-activators and N-myc bind to the promoter. This supports the idea that the commonly overexpressed genes HASH1 and N-myc are regulated in concert, confirming their importance as prognostic markers or targets for therapy.
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PMID:A novel MASH1 enhancer with N-myc and CREB-binding sites is active in neuroblastoma. 1712 8

The promoter of alpha subunit of the rat calcium/calmodulin-dependent protein kinase II (alphaCaMKII) gene was identified to contain an essential TATA element. Cell-based functional assay showed that the rat promoter displayed greater activity in neuronal cells than in non-neuronal cells. To characterize the human alphaCaMKII promoter, we have developed a promoter-reporter gene assay using different cell lines. A 2047 base pairs (bp) human alphaCaMKII gene promoter was cloned from human genomic DNA. Unlike the rat alphaCaMKII promoter, DNA sequence analysis showed that the human promoter was devoid of TATA element. We made series deletions of the promoter and fused the different sizes of the human promoter sequences to a luciferase reporter gene. The promoter-reporter constructs were transfected into human neuroblastoma SH-SY5Y, human neuroblastoma BE(2)-M17, and rat pheochromocytoma PC12 neuronal cell lines as well as human embryonic kidney HEK293 and human glioma U251 non-neuronal cell lines. The reporter gene assay demonstrated that the human alphaCaMKII promoter displayed high activity in the neuronal cell lines, while the activity was low in non-neuronal cell lines. All-trans retinoic acid (RA) enhanced the promoter activity in SH-SY5Y cells. Further analysis showed that there were two RA response elements located between +11 and +136 and -1911 to -593. In addition, we have identified a potent silencer at position -179 to -244 of the human alphaCaMKII promoter.
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PMID:Identification of the RA response element and transcriptional silencer in human alphaCaMKII promoter. 1722 Dec 87


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