Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Phorbol myristate acetate (PMA), a protein kinase C (PKC) activator significantly decreased in a time- and dose-dependent manner taurine uptake by rat astroglial but not neuronal cells. The PMA-induced inhibition of taurine uptake by rat astrocytes was prevented by chelerythrine, a potent and selective inhibitor of PKC. The differential effect of PMA on rat neuronal and astroglial taurine transport was also obtained with the protein phosphatase inhibitor okadaic acid. This was not only the feature of rat cells since the same differential effects were obtained with human glioma GL15 and human neuroblastoma IMR32 cell lines. The results suggest that the neuronal and astroglial taurine transporter may be structurally different.
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PMID:Activation of protein kinase C down-regulates glial but not neuronal taurine uptake. 884 83

We have shown that ethanol inhibits uptake of adenosine by a specific nucleoside transporter in NG108-15 neuroblastoma x glioma cells and that cAMP-dependent protein kinase (PKA) activity is required for this inhibition. After chronic exposure to ethanol, adenosine uptake is no longer inhibited on rechallenge with ethanol, i.e. transport has become tolerant to ethanol. Here we show that protein kinase C (PKC) contributes to ethanol-induced tolerance of adenosine transport. Activation of PKC by phorbol esters in control cells results in an ethanol-tolerant phenotype, similar to that produced by chronic ethanol exposure. In addition, chronic exposure to ethanol increases the amounts of alpha, delta, and epsilon PKC. However, reducing PKC activity by inhibition with chelerythrine during chronic exposure to ethanol or down-regulation by phorbol esters prevents the development of ethanol-induced tolerance of adenosine transport. By contrast, the inhibition of PKA activity produces tolerance to ethanol inhibition of adenosine uptake. When protein phosphatase inhibitors are present, inhibiting PKA activity has no effect on ethanol sensitivity of adenosine uptake, suggesting a role for protein phosphatases in the regulation of ethanol sensitivity of uptake. Taken together, our results suggest that PKA and PKC have opposing effects on the ethanol sensitivity of adenosine transport; PKA activity is required for ethanol sensitivity, and PKC activation produces tolerance. Based on these data, we propose that chronic ethanol exposure increases PKC activity, leading to the activation of a protein phosphatase (1 or 2A). This phosphatase then dephosphorylates a PKA-phosphorylated site, which is required for ethanol to inhibit adenosine uptake. Therefore, the sensitivity of adenosine transport to ethanol appears to be maintained by a balance of PKA and protein phosphatase activities, and PKC may regulate phosphatase activity.
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PMID:The role of protein kinase C in cellular tolerance to ethanol. 891 Jun 14

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

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 effects of immunosuppressant cyclosporin A (CsA) on nitric oxide (NO) production and inducible NO synthase (iNOS) mRNA expression in rat C6 glioma cell line were investigated. CsA applied simultaneously with iNOS activator IFN-gamma caused dose-dependent reduction of NO synthesis in confluent C6 cells, as determined by measuring accumulation of nitrite, an indicator of NO production, in 48 h culture supernatants. IFN-gamma-induced expression of iNOS, but not interferon regulatory factor-1 (IRF-1) mRNA was reduced in CsA-treated cells. The enzymatic activity of iNOS was not changed by CsA, since it failed to affect NO production in cells in which iNOS had already been induced with IFN-gamma and any further induction was blocked by protein synthesis inhibitor cycloheximide (CHX). FK506 was not able to mimic inhibitory effect of CsA on NO production in C6 cells, suggesting calcineurin-independent mechanism of CsA action.
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PMID:Cyclosporin A inhibits activation of inducible nitric oxide synthase in C6 glioma cell line. 987 97

Loss of the tumor suppressor MMAC1 has been shown to be involved in breast, prostate and brain cancer. Consistent with its identification as a tumor suppressor, expression of MMAC1 has been demonstrated to reduce cell proliferation, tumorigenicity, and motility as well as affect cell-cell and cell-matrix interactions of malignant human glioma cells. Subsequently, MMAC1 was shown to have lipid phosphatase activity towards PIP3 and protein phosphatase activity against focal adhesion kinase (FAK). The lipid phosphatase activity of MMAC1 results in decreased activation of the PIP3-dependent, anti-apoptotic kinase, AKT. It is thought that this inhibition of AKT culminates with reduced glioma cell proliferation. In contrast, MMAC1's effects on cell motility, cell - cell and cell - matrix interactions are thought to be due to its protein phosphatase activity towards FAK. However, recent studies suggest that the lipid phosphatase activity of MMAC1 correlates with its ability to be a tumor suppressor. The high rate of mutation of MMAC1 in late stage metastatic tumors suggests that effects of MMAC1 on motility, cell - cell and cell - matrix interactions are due to its tumor suppressor activity. Therefore the lipid phosphatase activity of MMAC1 may affect PIP3 dependent signaling pathways and result in reduced motility and altered cell - cell and cell - matrix interactions. We demonstrate here that expression of MMAC1 in human glioma cells reduced intracellular levels of inositol trisphosphate and inhibited extracellular Ca2+ influx, suggesting that MMAC1 affects the phospholipase C signaling pathway. In addition, we show that MMAC1 expression inhibits integrin-linked kinase activity. Furthermore, we show that these effects require the catalytic activity of MMAC1. Our data thus provide a link of MMAC1 to PIP3 dependent signaling pathways that regulate cell - matrix and cell - cell interactions as well as motility. Lastly, we demonstrate that AKT3, an isoform of AKT highly expressed in the brain, is also a target for MMAC1 repression. These data suggest an important role for AKT3 in glioblastoma multiforme. We therefore propose that repression of multiple PIP3 dependent signaling pathways may be required for MMAC1 to act as a tumor suppressor.
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PMID:The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin-linked kinase activity. 1064 97

Calcineurin, a ubiquitous calcium-activated serine phosphatase, plays an important role in the signal transduction. We have previously reported that cyclosporin A (CsA) inhibits the growth and survival of the rat C6 glioma cells due to the inhibition of signaling pathway involving calcineurin and transcription factor nuclear factor of activated T cells (NFAT). In the present study, we show that CsA affects the survival of reactive astrocyte cultures derived from striatal trauma. Exposure of reactive astrocytes to doses of CsA >50 microg/ml for 24--72 h produces morphological changes, including cell body shrinkage and loss of extensions, followed by cell death. This death was accompanied by apoptotic changes in nuclear morphology and DNA fragmentation, as revealed by Hoechst 33258 and positive TUNEL staining. We demonstrated the presence of calcineurin A subunit in reactive astrocytes and corpus callosum (brain structure enriched in astrocytes) and an additional calcineurin-like protein occurring solely in reactive astrocytes. FK506, a calcineurin inhibitor unrelated to CsA, inhibits proliferation of astrocytes and induces death accompanied by apoptotic changes in nuclear morphology and DNA fragmentation. Since calcineurin is a major target for both CsA and FK506, the results suggest that this phosphatase is involved in the regulation of reactive astrocyte survival.
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PMID:Cyclosporin A-sensitive signaling pathway involving calcineurin regulates survival of reactive astrocytes. 1122 21

Muscarinic acetylcholine receptors in NG108-15 neuroblastoma x glioma cells, and beta-adrenergic or angiotensin II receptors in cortical astrocytes and/or ventricular myocytes, utilize the direct signaling pathway to ADP-ribosyl cyclase within cell membranes to produce cyclic ADP-ribose (cADPR) from beta-NAD+. This signal cascade is analogous to the previously established transduction pathways from bradykinin receptors to phospholipase Cbeta and beta-adrenoceptors to adenylyl cyclase via G proteins. Upon receptor stimulation, the newly-formed cADPR may coordinately function to upregulate the release of Ca2+ from the type II ryanodine receptors as well as to facilitate Ca2+ influx through voltage-dependent Ca2+ channels. cADPR interacts with FK506, an immunosuppressant, at FKBP12.6, FK506-binding-protein, and calcineurin, or ryanodine receptors. cADPR also functions through activating calcineurin released from A-kinase anchoring protein (AKAP79). Thus, some G(q/11)-coupled receptors can control cADPR-dependent modulation in Ca2+ signaling.
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PMID:Signal transduction from bradykinin, angiotensin, adrenergic and muscarinic receptors to effector enzymes, including ADP-ribosyl cyclase. 1125 66

In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.
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PMID:Pten signaling in gliomas. 1208 51

Glioblastoma is a severe type of primary brain tumor and its invasion is strongly correlated with the secretion of matrix metalloproteinases (MMPs). To investigate a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in various glioma cells with or without a functional PTEN gene. The secretion of MMP-9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting the activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1 and -2 were increased, finally resulting in the inhibition of invasion by HA in vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase-deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma cells lacking functional PTEN, U251MG, and U373MG. These findings strongly suggest the possibility that PTEN may block HA-induced MMP-9 secretion and invasion through its protein phosphatase activity.
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PMID:PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. 1241 63


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