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)

It has previously been shown that stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol (DAG) and activating protein kinase C (PKC), accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, non-amyloidogenic peptides (APPs). This relationship has been demonstrated in human glioma and neuroblastoma cells as well as in transfected human embryonic kidney (HEK) cells and PC12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to DAG and PKC, similarly accelerates processing of APP into non-amyloidogenic APPs in hippocampal neurons and cortical astrocytes derived from normal fetal rats. The mGluR antagonist, L(+)-2-amino-3-phosphonopropionic acid (L-AP3), and GF 109203X, an inhibitor of PKC, both blocked the release of APPs from hippocampal neurons and astrocytes evoked by glutamate receptor stimulation. Inasmuch as glutamatergic neurons in cortex and hippocampus are known to be damaged in Alzheimer's disease, our findings suggest that amyloid formation may be enhanced by the resulting glutamate deficiency and that selective mGluR agonists may be useful in facilitating synaptic efficacy and treating the disease.
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PMID:Metabotropic glutamate receptors regulate APP processing in hippocampal neurons and cortical astrocytes derived from fetal rats. 862 10

APP is a multifunctional transmembrane glycoprotein and the only known natural source of beta A4 peptide-the major constituent of senile plaques in Alzheimer's disease (AD). The expression and cAMP-dependent regulation of the APP gene were investigated in primary cultures of rat astrocytes and two related glioma cell lines, BT4C and BT4Cn, which exhibit distinct invasive phenotypes. Besides the well-characterized 3.5 kb APP mRNA class, a robust expression of an unusual 2.8 kb APP mRNA class was revealed by Northern blotting in both glioma cell lines, but not in the astrocytes. Low amounts of the 2.8 kb APP mRNA species were also observed in rat liver and occasionally in aged rat brain. The 2.8 kb APP mRNA contained exons 1-18 and may thus be generated by truncation of the 3' untranslated region. For the first time, regulation of the APP gene via a cAMP-dependent mechanism was shown. Exposure to dBcAMP dramatically upregulated the 3.5 and 2.8 kb transcripts in BT4C cells, and, to a lesser extent, in BT4Cn cells where the constitutive expression of the APP gene was much higher. Elucidation of the factors involved in cAMP-dependent induction of APP mRNA in these cells may shed more light on the molecular mechanisms of APP overexpression.
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PMID:Two types of amyloid precursor protein (APP) mRNA in rat glioma cell lines: upregulation via a cyclic AMP-dependent pathway. 873 46

S100 beta, a calcium-binding protein synthesized by CNS astrocytes, has trophic effects in vitro (neurite extension and glial proliferation). In Alzheimer's disease and Down's syndrome, severely afflicted brain regions exhibit up to 20-fold higher levels of S100 beta protein, and astrocytes surrounding neuritic plaques exhibit highly elevated levels of S100 beta immunostaining. A major constituent of plaques, beta-amyloid, has been reported to have neurotoxic and neurotrophic effects in vitro. In our study we examined the responses of CNS glia to beta-amyloid. C6 glioma cells and primary rat astrocyte cultures were treated with beta A(1-40) peptide at doses up to 1 microM. Weak mitogenic activity, measured by [3H]thymidine incorporation, was observed. Northern blot analysis revealed increases of S100 beta mRNA within 24 h in a dose-dependent manner. Nuclear run-off transcription assays showed that beta A(1-40) specifically induced new synthesis of S100 beta mRNA in cells maintained in serum, but under serum-free conditions, there was a general elevation of several mRNA species. Corresponding increases of S100 beta protein synthesis were observed by immunoprecipitation of 35S-labeled cellular proteins. To evaluate whether this effect of beta-amyloid was mediated via neurokinin receptors or by calcium fluxes, various agonists and antagonists were tested and found to be ineffective at stimulating S100 beta synthesis. In sum, these in vitro data suggest that in neuropathological conditions, beta-amyloid itself is an agent which may provoke chronic gliosis and the production of trophic substances by astrocytes.
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PMID:beta-Amyloid regulates gene expression of glial trophic substance S100 beta in C6 glioma and primary astrocyte cultures. 875 Aug 67

Amyloid deposition characterizes the pathological lesions of Alzheimer's disease. We investigated the effect of serum deprivation on the regulation of beta-amyloid precursor protein (APP) mRNA expression in C6 glioma cells. Serum deprivation increased APP mRNA levels approximately 4-fold over controls. This increase was accompanied by changes in the pattern of alternative splicing, including the novel alternatively spliced site at exon 15. The proportion of isoforms containing exons 7 and 8 significantly increased from 61% to 68%, while isoforms lacking these exons decreased from 14% to 8%. The proportion of leukocyte-derived APP, which is a novel alternatively spliced isoform lacking exon 15, significantly increased from 19% to 40%. Among the six major isoforms produced by the two independent splicing sites, L-APP752 which contains exons 7 and 8, but lacks exon 15, increased the most (approximately 10-fold). Our findings provide evidence linking APP expression to alterations in alternative splicing at exon 15. These results demonstrate that in glial cells, APP mRNA regulation involves the alteration in alternative splicing at exons 7, 8 and 15, suggesting that not only increased expression but also an imbalance in the relative abundance of the six APP isoforms in stressed condition might affect the amyloidogenesis in Alzheimer's disease.
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PMID:Serum deprivation alters the expression and the splicing at exons 7, 8 and 15 of the beta-amyloid precursor protein in the C6 glioma cell line. 880 9

Translocation of [3H]dopamine and binding of [3H]WIN 35,428 were measured in intact C6 glioma cells expressing the cloned human dopamine transporter (hDAT) under identical conditions of assay buffer (phosphate-Krebs) and temperature (25 degrees C) with uptake at initial velocity and binding at equilibrium. In the intact cells, [3H]dopamine uptake was a one-component process; in contrast, [3H]WIN 35,428 binding included both a high-affinity component, inhibitable by micromolar concentrations of dopamine, and a low-affinity component only partially inhibited by millimolar concentrations of dopamine. Binding (high-affinity) over uptake Ki ratios were on the average 2.3 for the inhibitors WIN 35,428, cocaine, GBR 12909, and BTCP. The potency of dopamine in inhibiting its own translocation was close to that in inhibiting [3H]WIN 35,428 binding consonant with a more rapid reorientation step of the DAT in the C6-hDAT system than in rat striatal synaptosomes. The similarity in turnover values of the DAT estimated in the current experiments with the C6-hDAT system and in our previous study on rat striatal synaptosomes, performed under comparable conditions, suggest that all DAT's inserted into the C6 cell membrane are functionally active.
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PMID:Translocation of dopamine and binding of WIN 35,428 measured under identical conditions in cells expressing the cloned human dopamine transporter. 887 59

Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the neuritic plaques of Alzheimer's disease, activates astrocytes and enhances production and processing of beta-amyloid precursor protein (beta-APP). Activated astrocytes, overexpressing S100 beta, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100 beta have been implicated in the formation of dystrophic neurites overexpressing beta-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100 beta and beta-APP overexpression and dystrophic neurite formation in Alzheimer's disease. To more directly assess this driver potential for IL-1, we analyzed IL-1 induction of S100 beta expression in vivo and in vitro, and of beta-APP expression in vivo. Synthetic IL-1 beta was injected into the right cerebral hemispheres of 13 rats. Nine additional rats were injected with phosphate-buffered saline, and seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100 beta in tissue sections from IL-1-injected brains was 1.5 fold that of either control group (p < 0.01), while tissue S100 beta levels were approximately threefold that of controls (p < 0.05). The tissue levels of two beta-APP isoforms (approximately 130 and 135 kDa) were also significantly elevated in IL-1-injected brains (p < 0.05). C6 glioma cells, treated in vitro for 24 h with either IL-1 beta or IL-1 alpha, showed significant increases in both S100 beta and S100 beta mRNA levels. These results provide evidence that IL-1 upregulates both S100 beta and beta-APP expression, in vivo and vitro, and support the idea that overexpression of IL-1 in Alzheimer's disease drives astrocytic overexpression of S100 beta, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic beta-amyloid plaques.
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PMID:In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. 889 49

Basic fibroblast growth factor (FGF-2) is abundant in the developing and adult brain and has been linked with the origin and growth of neuronal and glial cells. Glial cells produce high levels of FGF-2, stimulating autocrine growth as well as the survival and function of neurons in a paracrine manner. Abnormal levels of FGF-2 have been linked with Alzheimer's, Huntington's, and Parkinson's diseases. Recent evidence has suggested that a component of the mitogenic response of glial cells is exerted on FGF-2 at the transcriptional level. To assess transcriptional regulation of this potent growth factor, we cloned a 1.4-kb genomic fragment containing the rat FGF-2 promoter region. DNA blotting results indicated that the rat FGF-2 gene exists as a single copy in the genome. The promoter region contains no TATA box but appears to rely instead on multiple GC-rich start sites (P0, P1, and P2) for transcription initiation in rat brain as well as C6 glioma cells. One of these sites (P0) was located within four nucleotides of the reported 5' end of the rat brain cDNA and constituted part of a consensus Egr-1 binding site (5'-GCGGGGGCG-3'). Transcription from this site could be stimulated in C6 glioma cells in response to phorbol ester treatment. The induction of a "new" site (P1) with phorbol ester also suggested a mechanism to explain the discrepancy between the reported "starts" for the ovarian versus brain cDNAs. A hybrid luciferase gene directed by rat FGF-2 5'-flanking DNA (-1,058/+54) was expressed in rat glioma C6, heart myoblast H9c2, and human astrocytoma U87-MG cells after gene transfer. The level of transfected FGF-2 promoter activity was higher in glial cells (C6 and U87-MG) compared with nonglial (H9c2) cells. Also, expression of this hybrid FGF-2/luciferase gene was increased in response to phorbol ester or serum treatment of C6 cells. Deletion analysis revealed the presence of both positive and negative regulatory regions that are involved in the transcriptional control of rat FGF-2 gene by mitogenic stimuli.
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PMID:Cloning of the rat fibroblast growth factor-2 promoter region and its response to mitogenic stimuli in glioma C6 cells. 904 34

Apolipoprotein E (ApoE) is the major genetic risk factor for Alzheimer's disease (AD). The ApoE4 allele is associated with earlier disease onset and greater cerebral deposition of the amyloid beta peptide (Abeta), the major constituent of senile (amyloid) plaques. The molecular mechanism underlying these effects of ApoE4 remains unclear; ApoE alleles could have different influences on Abeta production, extracellular aggregation, or clearance. Because the missense mutations on chromosomes 14 and 21 that cause familial forms of AD appear to lead to increased secretion of Abeta, it is important to determine whether ApoE4 has a similar effect. Here, we have examined the effects of all three ApoE alleles on the processing of betaAPP and the secretion of Abeta in intact cells. We established neural (HS683 human glioma) and non-neural (Chinese hamster ovary) cell culture systems that constitutively secrete both ApoE and Abeta at concentrations like those in human cerebrospinal fluid. betaAPP metabolites, generated in the presence of each ApoE allele, were analysed and quantified by two methods: immunoprecipitation and phosphorimaging, and ELISA. We detected no consistent allele-specific effects of ApoE on betaAPP processing in either cell type. Our data suggest that the higher amyloid burden found in AD subjects expressing ApoE4 is not due to increased amyloidogenic processing of betaAPP, in contrast to findings in AD linked to chromosome 14 or 21. These co-expressing cell lines will be useful in the further search for the effects of ApoE on Abeta aggregation or clearance under physiologically relevant conditions.
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PMID:Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing. 917 1

Appicans are secreted or cell-associated brain chondroitin sulfate proteoglycans produced by glia cells and containing Alzheimer amyloid precursor protein (APP) as a core protein. Here, we report that rat C6 glioma cells transfected with appican displayed a dramatic change in their phenotypic appearance compared with untransfected cells or cells transfected with APP. Appican-transfected cells lost the round appearance of the untransfected control C6 cells, acquired a flat morphology, and elaborated more processes than control cells. Untransfected, or APP-transfected C6, cells were completely dissociated from their substrate after 40 min of treatment with cell dissociation solution. Under the same conditions, however, <20% of the appican-transfected C6 cells were dissociated from their substrate, suggesting that the appican-transfected glia cells attach more avidly to their substrate than do untransfected or APP transfected control cells. In contrast, appican-transfected fibroblast cells showed no morphological changes and dissociated from their substrate similarly to untransfected fibroblast cells. Extracellular matrix (ECM) prepared from appican-transfected C6 cell cultures contained high levels of appican and was a significantly better substrate for the attachment of C6 cells than ECM from either untransfected or APP-transfected cultures. Furthermore, cell adhesion to ECM was independent of the level of appican expression of the plated cells. ECM from appican-transfected C6 cultures stimulated adhesion of other neural cells including primary astrocytes, Neuro2a neuroblastoma, and PC12 pheochromocytoma, but not fibroblast cells. Conditioned media from appican-transfected C6 cultures failed to promote cell adhesion. Together, these data suggest that secreted appican incorporates into ECM and promotes adhesion of neural cells. Furthermore, our data suggest that the chondroitin sulfate chain engenders APP with novel biological functions.
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PMID:Appican expression induces morphological changes in C6 glioma cells and promotes adhesion of neural cells to the extracellular matrix. 918 36

S100 beta is a calcium-binding protein produced and secreted by glial cells in the central and peripheral nervous systems. S100 beta promotes neuronal differentiation and survival but may be detrimental to cells if overexpressed. The selective overproduction of S100 beta has been implicated in the progression of the neuropathological changes in Alzheimer's disease. In addition, at high concentrations, S100 beta stimulates toxic intracellular pathways in cultured cells. To begin to define the regulation of S100 beta expression, we characterized the human S100 beta promoter and mapped its upstream regulatory elements by using a luciferase reporter system. The functional S100 beta promoter was localized to a region -168/ +697 containing 168 bp upstream of the transcription initiation site of the gene. This minimal promoter was active in a variety of cell types, including those of glial, neuronal, and non-neural origin. The human S100 beta promoter activity is regulated by both positive and negative regulatory elements located upstream in the 5' flanking DNA regions. The regions -788/ -391 and -1012/ -788 contain strong positive, cell type-specific regulatory elements. Negative regulatory elements were mapped to the more distal -4437/ -1012 and -1012/ -788 regions of the gene. The -4437/ -1012 negative element suppressed promoter activity in all cell types examined, except C6 glioma cells. These data demonstrate that the expression of the human S100 beta gene is under complex transcriptional regulation that allows for precise control of the S100 beta level in the nervous system.
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PMID:Transcriptional regulation of the human S100 beta gene. 919 Oct 95


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