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)

Nervous system development involves a coordinated series of events, including regulation of cell proliferation and differentiation by specific extracellular factors. S100 beta is a neurotrophic protein that has been implicated in regulation of cellular proliferation, but direct evidence was lacking. In this report, nanomolar concentrations of S100 beta are shown to stimulate proliferation of rat C6 glioma cells and primary astrocytes. An S100 mutant with a single amino acid change was inactive. S100 beta also stimulated increases in the steady-state levels of c-myc and c-fos protooncogene mRNAs and complemented the effects of platelet-derived growth factor. Two neuroblastoma cell lines did not proliferate in response to S100 beta, suggesting that the mitogenic activity of S100 beta is selective for astroglial cells. These results suggest that S100 beta may be involved in the coordinate development and maintenance of the central nervous system by synchronously stimulating the differentiation of neurons and the proliferation of astroglia.
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PMID:Neurotrophic protein S100 beta stimulates glial cell proliferation. 190 67

The phenotypic effects of selectively decreasing the levels of S100 beta in cultured glial cells were analyzed. Two separate antisense approaches were utilized for inhibition of S100 beta production: analysis of clonal isolates of rat C6 glioma cells containing an S100 beta antisense gene under the control of a dexamethasone-inducible promoter, and analysis of C6 cells treated with S100 beta antisense oligodeoxynucleotides. Both antisense methods resulted in a decrease in S100 beta levels in the cell, as measured by RIA. The inhibition of S100 beta production correlated with three alterations in cellular phenotype: (a) a flattened cell morphology; (b) a more organized microfilament network; and (c) a decrease in cell growth rate. The studies describe here provide direct evidence for an involvement of S100 beta in glial cell structure and function, and suggest potential in vivo roles for S100 beta in regulation of glial cell morphology, cytoskeletal organization, and cell proliferation.
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PMID:Antisense inhibition of glial S100 beta production results in alterations in cell morphology, cytoskeletal organization, and cell proliferation. 222 84

S100 protein is a low molecular weight, EF-hand, Ca2(+)-binding protein widely distributed and conserved in the central nervous system of vertebrates. The gene coding for the beta subunit of human S100 protein (S100 beta) has been recently mapped to chromosome 21. In order to study the expression of this gene in normal and abnormal brain development, we have isolated and characterized overlapping genomic clones spanning the region coding for human S100 beta and its flanking sequences. The intron-exon organization of the human S100 beta gene is similar to that of the genes coding for several other members of the S100 protein subfamily of EF-hand proteins. The human S100 beta gene is composed of 3 exons, the first of which specifies the 5'-untranslated region, while the second and third each encode a single EF-hand, Ca2(+)-binding domain. The promoter region contains several potential regulatory transcription elements including the cAMP-responsive elements CRE and AP-2. A novel sequence motif, the S100 protein element, situated in close proximity to the TATA box of the genes of several members of the S100 protein subfamily, has been identified. In addition, multiple repeats with similar nucleotide sequence and location to the recently reported beta globin direct repeat elements have been also found in the human S100 beta promoter. A full length (17.3 kilobases) copy of the human S100 beta gene was constructed and transfected into rat glioma C6 cells. Stable transfectants were shown to express correctly initiated transcripts of the human S100 beta gene, indicating that the cloned sequences contain functional regulatory transcription elements.
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PMID:Cloning and expression of the human S100 beta gene. 239 38

We have analyzed the levels, subcellular distribution, and target proteins of two calcium-modulated proteins, S100 and calmodulin, in differentiated and undifferentiated rat C6 glioma cells. Undifferentiated and differentiated C6 cells express primarily the S100 beta polypeptide, and the S100 beta levels are four-fold higher in differentiated compared to undifferentiated cells. Double fluorescent labeling studies of undifferentiated cells demonstrated that S100 beta staining localized to a small region of the perinuclear cytoplasm and colocalized with the microtubule organizing center and Golgi apparatus. Analysis of differentiated C6 cells demonstrated that S100 beta distribution and S100 beta-binding protein profile changed significantly upon differentiation. In addition, the brain-specific isozyme of one S100-binding protein, fructose-1,6-bisphosphate aldolase C, can be detected in differentiated but not undifferentiated C6 cells. While changes in the subcellular distribution of calmodulin were not observed during differentiation, calmodulin levels and calmodulin-binding protein profiles did change. Altogether these data suggest that S100 beta and calmodulin regulate different processes in glial cells and that the regulation of the expression, subcellular distribution, and target proteins of S100 beta and calmodulin during differentiation is a complex process which involves multiple mechanisms.
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PMID:Analysis of the calcium-modulated proteins, S100 and calmodulin, and their target proteins during C6 glioma cell differentiation. 291 Aug 76

To understand better the mechanisms involved in the transduction of a calcium signal into an intracellular response via multiple calcium-modulated proteins, we have examined the calcium-modulated proteins, S100 and calmodulin, and their intracellular targets in rat C6 glioma cells. Subconfluent, confluent, and postconfluent C6 cells contain predominantly, if not exclusively, the S100 beta polypeptide. The level of S100 beta in C6 cells increases approximately 20-fold from subconfluency to postconfluency whereas the level of calmodulin increases only about two-fold. The subcellular distribution of S100 beta and calmodulin in mitotic cells is similar. However, the subcellular distribution of these proteins in interphase cells is different and appears to change with cell density. Gel overlay analysis demonstrated that the S100- and calmodulin-binding protein profiles are significantly different and that some of the binding proteins appear to change in intensity with cell density. These data demonstrate that S100 beta is the predominant S100 polypeptide in C6 cells and suggest that changes in S100 beta and S100 beta-binding proteins may be involved in regulating S100-mediated intracellular processes in C6 cells. Our studies also suggest that the levels of S100 and calmodulin may be differentially regulated in C6 cells.
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PMID:Levels and distribution of the calcium-modulated proteins S100 and calmodulin in rat C6 glioma cells. 327 41

S100 protein is a calcium-binding protein found in vertebrate nervous tissue. Synthesis of S100 protein in the rat glioma cell line, C6, is inhibited by the addition of anti-microtubular drugs. We have cloned a cDNA for the beta subunit of S100 protein from rat brain in a lambda gt 11 expression vector and used this cDNA to measure the amounts of S100 beta subunit mRNA in C6 cells after treatment with anti-microtubular drugs. Levels of alpha-tubulin and beta-actin mRNAs were also measured. All measurements were performed using RNA-RNA hybridization techniques at high stringency with rat mRNA-specific probes. After 24 h of treatment, the S100 beta subunit mRNA was reduced to levels of 25% by colchicine and 32% by vinblastine when compared to untreated controls. In contrast, the levels of tubulin and actin mRNAs were only slightly changed by these treatments. These studies demonstrate that disruption of the microtubular cytoskeleton causes a specific reduction in the level of S100 protein mRNA in C6 cells.
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PMID:Reduction in S100 protein beta subunit mRNA in C6 rat glioma cells following treatment with anti-microtubular drugs. 381 55

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

Using a rat S100A1 cDNA probe, S100A1 expression has been documented in rat C6 glioma cells, a cell line previously thought to express only the S100B protein. To identify the molecular mechanisms which target S100A1 gene expression to specific cell types, the rat S100A1 gene was cloned, and functional analysis of the 5' flanking region of the gene was performed. The rat S100A1 gene was located in an 8.5 kb BamHI genomic fragment which contained 3 exons plus 1.6 kb of 5'-upstream and 0.37 kb of 3'-downstream flanking sequence. A single transcription initiation start site and a single polyadenylation signal were identified in this gene. A number of potential regulatory consensus sequences were identified in the rat S100A1 gene including general transcription factor binding sequences (TATA box, GC box and CCAAT box), cAMP regulated sequences (CRE), skeletal muscle specific sequences (E-box and M-CAT), an S100 protein element, and a (GCT) trinucleotide repeat. Analysis of an S100A1 promoter-CAT construct by ribonuclease protection assay demonstrated that this gene is functional in three S100A1 expressing cell lines, C6 cells, PC12 cells and L6 cells. CAT constructs containing progressive deletions of the S100A1 promoter region revealed a positive regulatory element in skeletal muscle (L6) cells between -1600/-1081. The fact that these same sequences were negative in glial (C6) cells and neutral in neuronal (PC12) cells suggests that this region plays a major role in targeting S100A1 expression to specific cell types. The -1081/+10 region contained both positive and negative elements, some of which were cell-type specific. Thus, S100A1 expression is under complex transcriptional control which involves positive and negative elements as well as cell type specific elements.
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PMID:Expression of the rat S100A1 gene in neurons, glia, and skeletal muscle. 879 2

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

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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