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)

The AP1 transcriptional complex is a heterodimer composed of proteins encoded by the fos and jun proto-oncogene families. Changes in the concentration and composition of AP1 occur after cells are perturbed in a variety of different ways (Curran, in Reddy et al., eds. "The Oncogene Handbook," Amsterdam: Elsevier, pp 307-325, 1988; Sonnenberg et al., Neuron 3:359-365, 1989). Transient changes in AP1 content presumably result in altered expression of AP1-regulated target genes, that help to mediate the cell's long-term response to changes in its environment. One factor that may be important in determining which target genes are regulated by AP1 in a given context is the identity of the jun family member present in the complex (Chiu et al., Cell 59:979-986, 1989; Schutte et al., Cell 59:987-997, 1989). Fos induction has been demonstrated after binding of beta-adrenergic ligands to their cell surface receptors (Barka et al., Mol Cell Biol 6:2984-2989, 1986; Gubits et al., Mol Brain Res 6: 39-45, 1989; Arenander et al., J Neurosci Res 24: 107-114, 1989; Mocchetti et al., Proc Natl Acad Sci USA 86:3891-3895, 1989). However, the response of the jun gene family to this treatment has not been reported. We have therefore examined the effect of beta-adrenergic receptor activation on the expression of c-fos, c-jun, and junB mRNA levels in C6 glioma cells. Our results indicate that c-fos and junB mRNA levels are increased by 52- and 2.7-fold, respectively, after 45 min of isoproterenol (IPR) treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-adrenergic treatment of C6 glioma cells produces opposite changes in c-fos and c-jun mRNA levels. 168 82

Diffuse invasion of brain tissue by single tumor cells is a characteristic feature of gliomas and a major reason why these tumors cannot be completely resected. The molecular basis of brain invasion is poorly understood. We regulated the expression of beta 1 integrins, the major group of extracellular matrix receptors, in astrocytic tumor cells by using a tetracycline-dependent transcription control system. Rat C6 glioma cells were stably transfected with (a) the tetracycline-controlled transactivator (tTA) gene, (b) antisense beta 1 cDNA under the control of a tTA/tetracycline-responsive promoter, and (c) the beta-galactosidase (lacZ) gene for histochemical identification. In one clone, C6TL beta, beta 1 protein levels were unaffected in the presence of tetracycline, but they were reduced by 60% in the absence of tetracycline because of production of antisense mRNA. C6TL beta cells were transplanted into the striatum of nude mice. After 14 days in the presence of tetracycline in the drinking water, tumors showed diffuse brain invasion, mainly along vascular basement membranes. In the absence of tetracycline, however, tumor cells were compact and generally well delineated from the surrounding brain tissue. These data, ie, blocking of brain invasion by antisense beta 1 mRNA, either because of disturbed interaction of beta 1 with brain extracellular matrix components or interference with beta 1-dependent signaling pathways, strongly suggest that beta 1 integrins are required for diffuse brain invasion of gliomas.
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PMID:Diffuse brain invasion of glioma cells requires beta 1 integrins. 897 77

The effect of the natriuretic peptides ANP, BNP and CNP on cGMP formation and immediate early gene expression was investigated in PC12 phaeochromocytoma and C6 glioma cell lines. The three natriuretic peptides were shown to rapidly induce c-fos, TIS8/egr-1 and junB mRNA expression in both cell lines, via stimulation of the cGMP pathway. CNP stimulated cGMP formation and gene induction more potently than the other peptides in C6 cells, and this was statistically significant. In contrast, the three peptides produced similar gene induction in PC12 cells, despite the higher cGMP accumulation evoked by ANP or BNP. CNP was also found to increase DNA binding activity of the transcription factor AP1 in both cell types, demonstrating that natriuretic peptides potentially regulate key cellular gene expression.
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PMID:Immediate early gene induction by natriuretic peptides in PC12 phaeochromocytoma and C6 glioma cells. 908 Apr 15

Because accurate regulation of toxin gene expression is critical for safe and effective gene therapy applications, the authors have examined the regulation of diphtheria toxin A (DTA) fragment expression in human glioma cell lines using two transcriptional control systems derived from Escherichia coli: the tetracycline (Tet) system and the lactose (Lac) system. The Tet system includes a tetracycline-controlled transactivator (tTA), a tTA-responsive minimum human cytomegalovirus (hCMV) promoter controlling the expression of the DTA gene, and tetracycline as an allosteric inhibitor. The Lac system includes the lac repressor (lacR), a lacR-regulated Rous sarcoma virus-long terminal repeat (RSV-LTR) promoter controlling the expression of the DTA gene, and isopropyl-thio-beta-D-galactoside (IPTG) as an allosteric inducer. Expression plasmids encoding either tTA or lacR were transfected into U-87MG and U-343MG glioma cells along with the responsive DTA plasmid. Cell killing was monitored by the ability of the toxin to abolish protein synthesis and was quantitated using a luciferase reporter gene. In the Tet system, tumor cell killing could be regulated by tetracycline up to 120-fold. In contrast, only a twofold IPTG-dependent regulation was obtained using the Lac system because of an incomplete repression of DTA expression in the uninduced state. Replacement of the RSV-LTR promoter with the heavy metal-inducible mouse metallothionein-1 promoter in the lacR-responsive unit, as well as the generation of a clonal glioma cell line expressing lacR, did not significantly enhance regulation of DTA in the Lac system. In conclusion, this study demonstrates that the Tet system is of potential use in gene therapy applications in which regulated expression of a therapeutic gene is an important issue.
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PMID:Regulated expression of the diphtheria toxin A gene in human glioma cells using prokaryotic transcriptional control elements. 920 71

The C6 glioma in the immune-competent rat is a frequently used model in brain tumor gene therapy research. It displays the histologic hallmarks of the human glioblastoma and has been employed to demonstrate new mechanisms of anti-tumor immunity and therapeutic strategies. We noted that C6 tumors regressed spontaneously in three of five animals and that protective anti-tumor immunity ensued without therapeutic intervention. A review of the literature revealed that different rat strains are used as "syngeneic" host for the C6 cell glioma, namely, BDIX, BDX, Sprague-Dawley, and Wistar. Allelotyping of the RT1.A (rat MHC I homolog) by a serologic technique and of the RT1.B (rat MHC II homolog) by a newly developed molecular technique showed that C6 cells express the haplotype RT1u and are allogeneic in the preceding rat strains. Expression of the gene encoding the transactivator CIITA in C6 gliomas using an EBV-based transduction system led to induction of MHC I and II and thereby mimicked therapeutic responses that could not operate in syngeneic models. These data suggest that the C6 glioma model in the immune-competent rat should no longer be used to study gene therapy strategies, that the available data obtained in this model need to be critically reinterpreted, and that findings obtained in the C6 glioma model may not be sufficient to support a clinical trial in glioblastoma patients.
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PMID:Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model. 1002 34

Tight transcriptional regulation of transferred bacterial toxin genes represents a potential approach for gene therapy of cancer. We have previously shown that the gene for wild type diphtheria toxin A chain (DT-A) placed under transcriptional control of a tetracycline-responsive promoter cannot be silenced due to its extreme toxicity. We now have explored a tetracycline-regulated DT-A mutant involving the histidine-21 catalytic domain (H21A) which shows 120-fold reduced ADP-ribosylation activity. Cellular toxicity was determined in NIH 3T3 fibroblasts and C6 glioma cells after triple transfections with the DT-A construct, the Tet transactivator gene and a luciferase plasmid as the reporter. Marked toxicity, i.e. reduced luciferase expression by more than 98%, was observed both in the absence and in the presence of tetracycline, suggesting leakiness of the Tet system, and absence of regulation, possibly due to inhibition of DT-A synthesis by activated DT-A itself. In contrast, the lacZ gene which was driven by the same promoter could be regulated by up to 49-fold. We conclude that (1) expression but not toxicity of the DT-A mutant can be sufficiently controlled by a tetracycline-responsive promoter, and (2) tight regulation of transferred genes encoding toxins remains a challenge for gene therapy of cancer.
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PMID:Tetracycline-controlled expression but not toxicity of an attenuated diphtheria toxin mutant. 1035 25

beta 1-Adrenergic receptors (beta1-ARs) serve as important regulators of central nervous system (CNS)-mediated behavior and several neural functions, including mood, memory, neuroendocrine control, and stimulation of autonomic function. Using beta 1-AR-luciferase reporter recombinants, we have previously determined that important beta 1-AR genetic elements controlling expression within the C6 glioma cell line are contained within the region -396 to -299, relative to the translational start site. By conducting progressive internal deletions of the rat beta 1-AR 5' flanking region and with the use of beta 1-AR-luciferase recombinants, we have verified that this region contains the primary beta 1-AR promoter and/or major regulatory elements. To begin the identification of protein factors involved in beta 1-AR transcriptional activity conferred by this beta 1-AR region and flanking sequences, we conducted electrophoretic mobility shift assays using defined beta 1-AR DNA subregion probes. One probe (GS-1), encompassing the region -396 to -367, was found to produce two major and two minor mobility shift complexes when bound to nuclear extracts from the beta 1-AR expresser C6 cell line. UV-crosslinking of DNA-protein complexes, coupled with DNase I digestion, indicated that this beta 1-AR region interacts with one major protein of approximately 117 kDa molecular weight and additional minor proteins. GS-1 DNA-protein complexes were observed using beta 1-AR expresser tissues in the CNS, including cortex, hippocampus, and olfactory bulb. No DNA-protein complexes were observed when using nuclear extracts from beta 1-AR nonexpresser tissues; in some cases, using L6 cells, previously characterized to express little or no beta1-ARs, a reduction in intensities of the DNA-protein complexes was observed. Competition experiments indicate that nuclear protein binds to one of two subregions within the GS-1 sequence that contain AP-2-like consensus elements. Recombinant AP-2 protein will bind to both the beta 1-AR GS-1 promoter fragment and commercially available AP-2 consensus element control probes. Interestingly, using antibody supershift and immunoblotting experiments, no supershifts were observed and the major 117-kDa protein was not immunoreactive to antibodies recognizing either AP-2 alpha or AP-2 beta. These results support our contention that this beta 1-AR regulatory region contains AP-2 consensus elements that recognize novel transactivator proteins.
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PMID:Rat beta 1-adrenergic receptor regulatory region containing consensus AP-2 elements recognizes novel transactivator proteins. 1086 Aug 67

Experimental investigation of glioma biology and therapy requires a representative model and a convenient technique for regulating gene expression. We have established an in vivo model in which genetically modified rat C6 glioma cells (C6TL cells) are transplanted into nude mice brain, followed by specific transcriptional control of a transgene. Histologically, the tumors exhibit an astrocytic phenotype and closely resemble human malignant gliomas including diffuse brain invasion. Due to a stably integrated lacZ gene, individual tumor cells can be unequivocally identified in tissue sections by histochemistry for beta-galactosidase. Since C6TL cells carry the tet transactivator (tTA) gene, any additional gene under control of a tetracycline/tTA-responsive promoter can be transcriptionally regulated by the concentration of tetracycline. C6TL cells stably transfected with a tetracycline/tTA-responsive luciferase reporter gene showed 23-fold regulation of luciferase activity in vitro. After intracerebral transplantation a regulation of 4.5- to 8.3-fold was obtained, dependent on the concentration and the type of tetracycline in the drinking water. This model should be useful for studying the functional role of candidate genes in tumor biology as well as for experimental gene therapy studies.
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PMID:In vivo glioma model enabling regulated gene expression. 1086 92

We have demonstrated that secreted protein acidic and rich in cysteine (SPARC) is highly expressed in human gliomas and it promotes glioma invasion and delays tumor growth in vitro and in vivo. cDNA array analyses were performed to determine whether SPARC, which interacts at the cell surface, has an impact on intracellular signaling and downstream gene expression changes, which might account for some of its effects on invasion and growth. Using a doxycycline (dox)-controlled gene expression system, two cDNA array analyses were performed using a parental U87T2 clone (-SPARC) transfected with the dox-controlled transactivator and a U87T2 parental-derived SPARC-transfected clone, A2b2 (+SPARC). Array analysis performed between the parental and the SPARC-transfected clone (-dox) identified 13 upregulated genes and 14 downregulated genes. With the exception of PAI-1 and MMP2, the identified genes are novel with respect to SPARC's mechanism of action. Array analysis performed using the SPARC-transfected clone ( +/- dox) identified 2 types of gene regulation; one reversible upon SPARC suppression, the other irreversible. Two of the SPARC-induced genes, BIGH3 (irreversible by dox) and PAI-1 (reversible by dox) were further studied in additional SPARC-transfected clones, human astrocytoma tissues, and human glioma cell lines by RT-PCR and Northern blot analyses. The results indicate that: (1) the array results were validated, (2) the dox regulation was validated, and (3) the differential expression identified by the array analyses was present between normal brain and in human astrocytoma tissues and cell lines. Therefore, we conclude that these cDNA array analyses provide candidate genes involved in SPARC-mediated effects on glioma cell cycle progression, signaling, and migration, and that SPARC may induce reversible and irreversible gene expression changes. Further investigation of these candidates may shed insights into SPARC's role in glioma cell proliferation and invasion, and potential use as a therapeutic target.
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PMID:cDNA array analysis of SPARC-modulated changes in glioma gene expression. 1251 Jul 73

An autoregulated tetracycline-inducible recombinant adeno-associated viral vector (rAAV-pTet(bidi)ON) utilizing the rtTAM2 reverse tetracycline transactivator (rAAV-rtTAM2) was used to conditionally express the human GDNF cDNA. Doxycycline, a tetracycline analog, induced a time- and dose-dependent release of GDNF in vitro in human glioma cells infected with rAAV-rtTAM2 serotype 2 virus. Introducing the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) downstream to the rtTAM2 coding sequence, resulted in a more rapid induction and a higher basal expression level. In vivo, 8 weeks after a single injection of the rAAV-rtTAM2-GDNF vector encapsidated into AAV serotype 1 capsids in the rat striatum, the GDNF protein level was 60 pg/mg tissue in doxycycline-treated animals whereas in untreated animals, it was undistinguishable from the endogenous level ( approximately 4 pg/mg tissue). However, a residual GDNF expression in the uninduced animals was evidenced by a sensitive immunohistochemical staining. As compared to rAAV1-rtTAM2-GDNF, the rAAV1-rtTAM2-WPRE-GDNF vector expressed a similar concentration of GDNF in the induced state (with doxycycline) but a basal level (without doxycycline) approximately 2.5-fold higher than the endogenous striatal level. As a proof for biological activity, for both vectors, downregulation of tyrosine hydroxylase was evidenced in dopaminergic terminals of doxycycline-treated but not untreated animals. In conclusion, the rAAV1-rtTAM2 vector which expressed biologically relevant doses of GDNF in the striatum in response to doxycycline with a basal level undistinguishable from the endogenous striatal level, as measured by quantitative ELISA assay, constitutes an interesting tool for local conditional transgenesis.
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PMID:Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector. 1722 6


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