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)

Platelet-derived growth factor (PDGF) is a basic protein of relative molecular mass 30,000 (Mr 30K) composed of two polypeptide chains, designated PDGF A and PDGF B. The B-chain is encoded by the c-sis gene, the cellular counterpart of the simian sarcoma virus transforming gene v-sis. The PDGF A-chain cDNA clones recently isolated and sequenced from a transformed human clonal glioma cell line represent at least two alternatively spliced transcript species differing by 69 base pairs at the C-terminus. Here we demonstrate that the normal human umbilical vein endothelial cell (EC) A chain precursor lacks the 15 carboxy-terminal, highly basic amino acids encoded by the larger tumour cell cDNA. Surprisingly, culture media from monkey kidney cells (COS) transfected with the endothelial cDNA clone contained much less mitogenic activity than media from cells transfected with the longer tumour cell-derived A-chain cDNA. This functional difference appeared to be due to inefficient assembly or secretion of the recombinant endothelial-type growth factor. This suggests that some transformed cells may use alternative RNA splicing to modify normal growth factors and by so doing increase the efficiency of mitogen assembly or secretion.
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PMID:Alternative RNA splicing affects function of encoded platelet-derived growth factor A chain. 361 64

We have investigated the binding of soluble tenascin-C (TN-C) to several cell lines using a radioligand binding assay. Specific binding was demonstrated to U-251MG human glioma cells and to a line of bovine aortic endothelial cells, but hamster fibroblasts showed no specific binding. Recombinant proteins corresponding to specific domains of TN-C were used to map the binding site(s) in TN-C. The alternatively spliced segment (TNfnA-D) inhibited the binding of native TN-C most strongly, and itself bound to glioma and endothelial cells. Scatchard analysis of TNfnA-D binding indicated 2-5 x 10(5) binding sites per cell, with an apparent 2 nM dissociation constant. The cell surface receptor for TNfnA-D was identified as a 35-kD protein on the basis of blot binding assays and affinity chromatography of membrane extracts on native TN-C and TNfnA-D columns. Protein sequencing indicated that this 35-kD receptor was annexin II. Annexin II is well characterized as a cytoplasmic protein, so it was surprising to find it as a presumably extracellular receptor for TN-C. To confirm that it was the 35-kD receptor, we obtained purified annexin II and demonstrated its binding to TNfnA-D and TN-C at nM concentrations. Antibodies to annexin II prominently stained the external surface of live endothelial cells and blocked the binding of TNfnA-D to the cells. Thus annexin II appears to be a receptor for the alternatively spliced segment of TN-C, and may mediate cellular responses to soluble TN-C in the extracellular matrix.
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PMID:Cell surface annexin II is a high affinity receptor for the alternatively spliced segment of tenascin-C. 751 69

We have cloned an alternatively spliced glycosaminoglycan attachment domain (GAG-alpha) of human versican from cDNA libraries derived from U251MG glioma cells. Inserted carboxyl-terminal of the hyaluronan-binding region, this domain adds another 987 amino acids to the original versican (V1) core protein giving rise to the large V0 isoform with 3396 amino acids and 17-23 putative glycosaminoglycan attachment sites. The GAG-alpha domain is encoded by exon 7 of the human versican gene (Naso et al., J. Biol. Chem., 32999-33008). Sequence comparisons revealed a slight similarity to the alternative splice domain of PG-M, further supporting the notion that PG-M is the chicken homologue of versican. On immunoblots of a proteoglycan preparation from U251MG culture medium, anti-GAG-alpha antibodies reacted exclusively with the larger of two versican core proteins recognized by antibodies against the original GAG-beta domain. Using reverse transcription-polymerase chain reaction, we detected both the V0 and V1 isoforms in the cerebral cortex, aorta, intervertebral disc, liver, myometrium, and prostate, whereas keratinocytes exclusively expressed versican V1. In brain tissue, we identified a short versican variant (V2) including only the GAG-alpha domain. By expressing particular splice forms of versican, cells may control the hydration properties of their pericellular hyaluronan coat and thus could modulate interactions with the extracellular matrix or neighboring cells.
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PMID:A novel glycosaminoglycan attachment domain identified in two alternative splice variants of human versican. 780 29

HuD belongs to a family of neurospecific RNA binding proteins found in man, frog and fly [49]. To investigate whether this protein is involved in regulation of neuronal differentiation of rodent cells in vivo and in vitro, the cDNA of the rat homolog gene (r-HuD) was cloned, its expression was studied in rat brain and in neurogenic cell lines, and the splicing of its RNA was analyzed. Coding sequences of HuD from man and rat were found to be 99.5 and 95% identical at protein and DNA level, respectively. In rat brain r-HuD transcripts 3.7 and 4.2 kb in length were detected by Northern blot analysis. RT-PCR and in situ hybridization revealed that rodent homologues of HuD transcripts are present in P19 mouse embryo carcinoma and in PC12 rat pheochromocytoma cell lines both able to differentiate into neurons. In contrast, r-HuD transcripts were not detectable in the rat glioma cell line C6. In P19 cells a strong induction of HuD mRNA was observed after triggering neuronal differentiation by retinoic acid, whereas in PC12 cells the mRNA was present before and after nerve growth factor (NGF) induced neuronal differentiation. In both neuronal cell lines and in brain of adult rat and mouse HuD mRNA is alternatively spliced in a region which encodes a proline rich linker domain between the second and third RNA recognition motif. This RNA processing event seems to be differently regulated in PC12 cells on the one hand, and in P19 cells and brain of rat and mouse on the other.
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PMID:The RNA binding protein HuD: rat cDNA and analysis of the alternative spliced mRNA in neuronal differentiating cell lines P19 and PC12. 871 65

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

Glial cells express three splicing variants of a receptor-type protein tyrosine phosphatase called RPTP beta. Two are receptor forms that differ in a large extracellular domain. The third is a secreted proteoglycan called phosphacan that lacks the cytoplasmic phosphatase domains. We have now identified, by immunoblotting, proteins corresponding to these three forms of RPTP beta in rat C6 glioma cells and brain. The short receptor form is much more prevalent than the full-length receptor in C6 glioma cells. Phosphacan is much more abundant than either of the receptor forms in rat brain, and its expression increases progressively during embryonic development, while the receptor forms show only moderate changes. In contrast to the long form and phosphacan that were detected as proteoglycans, the short receptor form, lacking the large alternatively spliced domain, was not detected as a chondroitin sulfate proteoglycan. We recently showed that phosphacan binds to the neuron-glia cell adhesion molecule, Ng-CAM, and we now report that glia expressing RPTP beta adhere and extend processes on substrates coated with Ng-CAM. After one day in culture, however, the glia retract their processes and often lift off the substrate. Conditioned medium from glial cells, which contains large amounts of phosphacan, inhibits glial adhesion to Ng-CAM, and depletion of phosphacan from the conditioned medium by immunoadsorption reduces the inhibitory activity. The results show that phosphacan increases dramatically during development, and indicate that secreted forms of RPTP beta can modulate glial cell adhesion and behavior.
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PMID:Expression of polypeptide variants of receptor-type protein tyrosine phosphatase beta: the secreted form, phosphacan, increases dramatically during embryonic development and modulates glial cell behavior in vitro. 898 99

In this report we focus on the characterization of appican, the chondroitin sulfate proteoglycan form of amyloid precursor protein (APP), and the role that it and other proteoglycans may play in AD. Appican is expressed by certain transformed cell lines of neural origin, namely C6 cells and N2a neuroblastomas. It is detected in both human and rat brain and in primary cultures is expressed by astrocytes, but not neurons. The core protein of appican has been shown to be an alternatively spliced isoform of APP, lacking exon 15 of the APP gene, originally identified in leukocytes (L-APP). Splicing out of exon 15 results in the joining of exons 14 and 16, and formation of an Asp-Xaa-Ser-Gly consensus sequence for chondroitin sulfate chain attachment to serine 619 of L-APP, which lies 16 amino acids upstream of the A beta peptide sequence. Mutation of this serine residue to an alanine prevented chondroitin sulfate chain addition to the core protein. Levels of appican expression could be regulated by growth conditions independently of APP, suggesting that these molecules may serve distinct physiological roles within the cell. Morphological changes were also observed in both astrocytic and transformed cell cultures, that appeared to reflect changes in levels of appican expression. Preliminary data suggest that appican may be a strong cell adhesion molecule. Transfected C6 glioma cells overexpressing appican remained attached to tissue culture dishes markedly better than either C6 cells over-expressing exon-15 containing APP or WT C6 cells. Appican-enriched extracellular matrix (ECM) was also observed to serve as a much better substrate for attachment of N2a neuroblastomas, pheocromocytoma PC12 cells and primary astrocytes compared to APP enriched ECM.
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PMID:Characterization of appican, the chondroitin sulfate proteoglycan form of the Alzheimer amyloid precursor protein. 911 61

The Na+/Ca2+ exchanger is a major transporter of Ca2+ in neurons and glial cells. The Na+/Ca2+ exchanger gene NCX1 expresses tissue-specific isoforms of the Na+/Ca2+ exchanger, and the isoforms have been examined here quantitatively using primary cultures of astrocytes and neurons. We present a PCR-based quantitative method, quantitative end-labeled reverse transcription-PCR (QERT-PCR), to determine the relative amounts of the NCX1 isoforms present in these cells. Six exons (A, B, C, D, E, and F) are alternatively spliced to produce the known NCX1 isoforms. Three exon B-containing isoforms (BDEF, BDF, and BD) are the predominant transcripts in primary rat cortical astrocytes and in C6 glioma cells. In contrast, exon A-containing isoforms (ADF and AD) are the predominant transcripts in primary rat hippocampal neurons. Functional differences between full-length constructs of NCX1 containing either the astrocyte isoform BD or the neuron isoform AD were examined in a Xenopus oocyte expression system. Although both isoforms function normally, the activity of the AD isoform can be increased 39% by activation of protein kinase A (PKA), whereas that of the BD isoform is not affected. We conclude that specific NCX1 isoforms are expressed in distinct patterns in astrocytes and neurons. Furthermore, the activity of a neuronal (but not glial) isoform of the Na+/Ca2+ exchanger can be altered by the activation of the PKA pathway.
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PMID:Isoform-specific regulation of the Na+/Ca2+ exchanger in rat astrocytes and neurons by PKA. 963 49

CD95 targeting is a novel approach of immunotherapy for malignant glioma that might be antagonized by the release of soluble CD95 by the tumor cells. An alternatively spliced CD95 mRNA that encodes a secreted CD95 variant has been detected in glioma cell lines in vitro and in human tumors in vivo. Here, we report that the levels of soluble CD95 in the serum of malignant glioma patients do not differ from those of lumbar disk disease patients. Soluble CD95 was detected in the CSF in 2 of 20 malignant glioma patients by ELISA. Bioassay studies indicate that these low levels of soluble CD95 in the CSF of some patients with malignant glioma cells are unlikely to interfere with CD95-based immunotherapy of malignant gliomas in vivo.
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PMID:Soluble CD95 (Fas/APO-1) in malignant glioma: (no) implications for CD95-based immunotherapy? 1006 95

The fibroblast growth factor-2 (FGF-2) gene is bidirectionally transcribed to produce the FGF-2 mRNA and a 1.5 kb antisense (FGF-AS) transcript complementary to the 3' untranslated region of the FGF-2 transcript. The FGF-AS RNA has been postulated to play a role in the post-transcriptional regulation of FGF-2, but this function has not been conclusively demonstrated. We characterized FGF-AS cDNAs from rat brain and C6 glioma cells, and investigated their role in regulation of FGF-2 expression. Three FGF-AS cDNAs were isolated; the full-length FGF-AS mRNA and two alternative splice variants lacking exon 2 or exons 2 and 3 of the FGF-AS sequence. The alternatively spliced FGF-AS RNAs are widely expressed in the CNS, whereas liver predominantly expressed the full-length transcript. The full-length and first splice variant encode 35 and 28 kDa isoforms of GFG, a MutT-related nuclear protein, whereas the second splice variant was not translated. The effect of FGF-AS RNA on FGF-2 expression was evaluated in stable C6 transfectants over-expressing the full-length or alternatively spliced FGF-AS RNA forms. All three constructs suppressed cellular FGF-2 protein (but not FGF-2 mRNA) levels, and this effect correlated directly with the level of FGF-AS RNA. Cellular FGF receptor content was increased and cell proliferation inhibited compared to wild type or vector-transfected cells, indicating disruption of the FGF-2 autocrine pathway by FGF-AS RNA. These findings demonstrate for the first time that the FGF-AS RNA regulates FGF-2 expression in mammalian cells, and suggest that this effect is exerted predominantly at the level of translation.
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PMID:Expression of alternatively spliced FGF-2 antisense RNA transcripts in the central nervous system: regulation of FGF-2 mRNA translation. 1116 6


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