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)

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

The role of protein kinase C (PKC) was examined in the regulation of dopamine transport in C6 glioma cells stably expressing the human dopamine transporter. The PKC activating phorbol esters phorbol 12-myristate 13-acetate (PMA) and 4 beta-12,13-dibutyrate phorbol-ester (PDBu) inhibited [3H]dopamine uptake concentration dependently. These effects were attenuated by the PKC inhibitor staurosporine but were unaltered by another inhibitor, chelerythrine, or the phosphatase inhibitor okadaic acid. The potency of PMA in inhibiting [3H]dopamine uptake was similar to that in inhibiting the binding of 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]WIN 35,428), and again staurosporine, but not chelerythrine, weakened the effect of PMA. The reduction in dopamine transporter activity by PMA was caused by a decrease in the Vmax value of [3H]dopamine uptake, opposed by a smaller reduction in the Km value, whereas the effect of PMA on [3H]WIN 35,428 binding was caused by a reduction in the Bmax value without a change in the Kd value. The lower Km value in the presence of PMA was accompanied by a higher IC50 of dopamine in inhibiting [3H]WIN 35,428 binding; the latter effect was attenuated by the co-presence of staurosporine. The results are discussed in the context of transporter loss from the cell surface, or a model with phosphorylation affecting the shared dopamine and WIN 35,428 binding domain on the transporter as well as affecting a part of the dopamine binding domain lying outside that for WIN 35,428.
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PMID:Regulation of the functional activity of the human dopamine transporter by protein kinase C. 911 87

Deletions of all or part of chromosome 10 are the most common genetic alterations in high-grade gliomas. The PTEN gene (also called MMAC1 and TEP1) maps to chromosome region 10q23 and has been implicated as a target of alteration in gliomas and also in other cancers such as those of the breast, prostate, and kidney. Here we sought to provide a functional test of its candidacy as a growth suppressor in glioma cells. We used a combination of Northern blot analysis, protein truncation assays, and sequence analysis to determine the types and frequency of PTEN mutations in glioma cell lines so that we could define appropriate recipients to assess the growth suppressive function of PTEN by gene transfer. Introduction of wild-type PTEN into glioma cells containing endogenous mutant alleles caused growth suppression, but was without effect in cells containing endogenous wild-type PTEN. The ectopic expression of PTEN alleles, which carried mutations found in primary tumors and have been shown or are expected to inactivate its phosphatase activity, caused little growth suppression. These data strongly suggest that PTEN is a protein phosphatase that exhibits functional and specific growth-suppressing activity.
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PMID:Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. 935 75

Capacitative Ca2+ entry, a main pathway of Ca2+ entry evoked by receptor activation, is widely confirmed in various types of cells. However, the mechanism of the activation of capacitative Ca2+ entry is unknown. We checked the several candidates for the mechanism of capacitative Ca2+ entry pathway in rat glioma C6 cells using thapsigargin (TG), a microsomal Ca(2+)-ATPase inhibitor. Pretreatment with pertussis toxin did not affect the peak and sustained elevation of [Ca2+]i evoked by TG. Sodium nitroprusside and 8-bromo cyclic GMP did not affect an elevation of [Ca2+]i induced by TG. Phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), and staurosporine, an inhibitor of PKC, did not modify an increase in [Ca2+]i induced by TG. Okadaic acid, an inhibitor of phosphatase, did not affect an increase in [Ca2+]i evoked by TG. Pretreatment with colchicine and cytochalasin D, drugs disrupting cytoskeleton, had no effect on a rise of [Ca2+]i induced by TG. Genistein and erbastatin analog, inhibitors of tyrosine kinase, inhibited an elevation of [Ca2+]i evoked by TG in a dose-dependent manner. The present results suggest that tyrosine kinase regulates capacitative Ca2+ entry into rat glioma C6 cells.
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PMID:Involvement of tyrosine kinase in capacitative Ca2+ entry pathway in rat glioma C6 cells. 946 22

Cyclosporin A (CsA) exerts its immunosuppressive effect by inhibiting the activity of nuclear factor of activated T cells (NFAT), thus preventing transcriptional induction of several cytokine genes. This effect is mediated through inactivation of the phosphatase calcineurin, which inhibits translocation of an NFAT component to the nucleus. We have previously reported that CsA inhibits the growth of rat C6 glioma cells in a dose-dependent manner and induces apoptotic cell death. Here, we report that NFAT DNA-binding activity is present in the nuclear extracts from C6 glioma cells and that CsA treatment inhibits the formation of a functional NFAT complex. We provide evidence for the presence of a group of NFATc proteins in proliferating glioma cells. Immunoblot analyses show that stimulation of C6 glioma cells with a calcium-inducing agent, ionomycin, alters NFATc migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This alteration is inhibited by simultaneous treatment with CsA, suggesting a calcineurin involvement in the regulation of glioma NFATc proteins. Direct immunofluorescence reveals the presence of NFATc proteins in nuclei of proliferating glioma cells and their disappearance in CsA-treated cells. These data point to a new mechanism of transcription regulation in glioma cells and provide an explanation for the observed sensitivity of glioma cells to CsA.
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PMID:Nuclear factor of activated T cells (NFAT) as a new component of the signal transduction pathway in glioma cells. 964 59

The PTEN gene (also called MMAC1 and TEP1) at chromosome 10q23 is mutated in a variety of predominantly late-stage tumors and has been shown to suppress glioma cell growth in vitro and in vivo. Here we sought to determine the mechanism by which PTEN mediates growth inhibition. Using the mutant PTEN glioma cell line, U87MG, as a transfection recipient for a series of PTEN alleles, we provide direct evidence that this capacity requires phosphatase activity. Mutations mapping upstream, within, and downstream of the catalytic domain ablated activity toward a 3' phosphorylated phosphoinositide substrate of PTEN, whereas alleles with mutations flanking the catalytic domain retained activity toward the acidic protein polymer substrate, Glu4Tyr1. Thus, catalytic activity toward phosphoinositide substrates was required for growth suppression, whereas activity toward the protein substrate was dispensable for growth suppression. Finally, we used apoptotic and cell proliferation analyses to show that PTEN-mediated growth inhibition under reduced serum conditions was due to a G1 cell cycle block rather than to an induction of apoptosis.
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PMID:The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. 982 98

The MMAC/PTEN tumor suppressor gene encodes for a phosphatase that recently has been shown to have phosphotidylinositol phosphatase activity, implicating its possible involvement in phosphatidylinositol 3'-kinase-mediated signaling. To investigate possible alterations in growth factor-mediated signal transduction, an adenovirus containing MMAC/PTEN, Ad-MMAC, previously shown to inhibit growth and tumorigenicity in glioma cells, was used to acutely express the transgene. Human glioma cells infected with Ad-MMAC but not with control adenoviruses exhibited an inhibition of phosphorylation of both activating residues of Akt, Ser-473, and Thr-308, along with Akt's serine/threonine kinase activity, without significantly altering Akt expression. The effects of functional MMAC/PTEN expression were relatively specific, because members of several other growth factor-mediated signaling pathways showed no altered responses. The presence of MMAC/PTEN also inhibited phosphorylation of BAD, although no evidence of apoptosis in the in situ treated cells was observed. However, U251 glioma cells infected with Ad-MMAC were induced to undergo anoikis at a significantly higher rate than U251 cels treated with control viruses or mock infected with media. These results demonstrate that the acute administration of MMAC/PTEN results in the inhibition of Akt-mediated signaling, growth inhibition, and anoikis, implying that loss of MMAC/PTEN increases cellular proliferation and significantly augments a cell's survival potential during cellular processes that are associated with malignancy.
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PMID:Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. 985 49

The PTEN gene, which encodes a tumor suppressor with phosphatase activity, is located on chromosome 10q23 and is mutated in different tumors, including glioblastomas (GBM). We found evidence for a PTEN-related sequence (PTEN-rs) on genomic DNA of GBM and non-neoplastic cells. PTEN-rs does not contain introns and presents several conserved missense mutations, including a T to G transversion at the initiation codon. Rsa I digestion may help to identify this putative PTEN pseudogene which, according to RT-PCR analysis on glioma, fibroblast, brain and lung cells, does not appear to be transcribed.
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PMID:Identification of PTEN-related sequences in glioma cells and in non-neoplastic cell lines. 1037 66

In this study we established the simultaneous status of TP53, p16, p14ARF and PTEN tumor suppressor genes in 34 randomly chosen human glioma cell lines. Nine cell lines (26.4%) harbored mutations or deletions in all four tumor suppressor genes and 22 cell lines (64%) had alterations in at least three. Mutations/deletions were found at the following frequencies: TP53 (76.5%), p14ARF (64.7%), p16 (64.7%), PTEN (73.5%). Thus, there was a high incidence of alterations in the cellular pathways involving the p53 transcription factor (94.1%), the retinoblastoma protein (64.7%) and the PTEN phosphatase (73.5%) and 91% of cell lines carried mutations in two or more pathways. This provides the first clear genetic evidence that these tumor suppressors participate in biological pathways which are functioning separately/independently in glioma cells. The status of the gene alterations did not correlate with tumorigenicity in immunocompromized mice or any clinical parameters. Although the mutation rate was higher in glioma cell lines than that reported for glioma tissues, the alterations were molecularly representative of those found in adult de novo glioblastoma. This study highlights the importance of developing therapeutic approaches applicable to tumors with a broad range of genetic alterations and also provides an invaluable panel of glioma cell lines to make this possible.
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PMID:Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. 1041 87

The tumor suppressor PTEN negatively controls the phosphoinositide 3-kinase pathway for cell survival by dephosphorylating the phospholipid substrates phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. PTEN has been proposed to dephosphorylate focal adhesion kinase and is implicated in the regulation of cell spreading and motility. We analyzed the role of PTEN in invasion using the two highly infiltrative glioma cell lines U87MG (which lacks functional PTEN) and LN229 (wild-type PTEN). After constitutive overexpression of wild-type and phosphatase-deficient (C124S) PTEN, we found significant inhibition of invasion (50-70%) independent of the PTEN status of the cell and of the catalytic core domain of PTEN. Although wild-type but not mutant (C124S) PTEN decreased PKB/Akt phosphorylation and induced a stellate morphology in U87MG cells, an accompanying reduction of focal adhesion kinase phosphorylation was not seen. We conclude that phosphatase-independent domains of PTEN markedly reduced the invasive potential of glioma cells, defining a structural role for PTEN that regulates cell motility distinct of the PKB/Akt pathway.
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PMID:The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells. 1055 22


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