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)

Recently mitogen-activated protein kinase (MAPK) has been reported to play an important role in phosphorylation cascades governing cell growth and protein expression in numerous cell types. In order to explore the signaling mechanism by which inducible nitric oxide synthase (iNOS) is regulated in C6 glioma cells, we investigated the role of MAPK in iNOS expression by using the specific MAPK inhibitors. First the induction of nitric oxide by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), alone or their combination, was studied in C6 glioma cells. Administration of LPS, TNFalpha, or IFNgamma alone had no detectable stimulatory effect on the production of nitric oxide (NO). However, combination of the three factors elicited a significant elevation of NO level in C6 cell culture medium. Subsequently pretreatment of C6 cells with a specific inhibitor of p38 MAPK, SB202190, resulted in a dose-dependent inhibition of NO production and iNOS expression, but PD98059, an inhibitor of p42/p44 MAPK activation, had no effect. These data suggest that p38 MAPK mediates iNOS expression in C6 glioma cells, but p42/p44 MAPK is not involved in this process.
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PMID:P38 MAPK, but not p42/p44 MAPK mediated inducible nitric oxide synthase expression in C6 glioma cells. 1119 29

Fas transduces not only apoptotic signals through various pathways but also angiogenic and proinflammatory responses in vivo. Human glioma cells express Fas although sensitivity to Fas-mediated cell death is variable, suggesting that Fas may have functions other than apoptosis in these cells. In this study, we addressed alternative functions of Fas expressed on human gliomas by Fas ligation in three human glioma cell lines, CRT-MG, U373-MG, and U87-MG, and the in vivo expression of Fas and chemokines in human glioblastoma multiforme (GBM). Herein, we demonstrate that: (a) stimulation with agonistic anti-Fas monoclonal antibody CH-11 and human recombinant soluble Fas ligand induces expression of the CC chemokine MCP-1 and the CXC chemokine interleukin-8 by human glioma cell lines at the mRNA and protein levels in a dose- and time-dependent manner; (b) selective pharmacological inhibitors of MEK1 (U0126 and PD98059) and p38 mitogen-activated protein kinase (MAPK) (SB202190) suppress Fas-mediated chemokine expression in a dose-dependent manner; (c) Fas ligation on human glioma cells leads to activation of both extracellular signal-regulated kinases ERK1/ERK2 and p38 MAPK; and (d) GBM samples express higher levels of Fas compared with normal control brain, which correlates with increased interleukin 8 expression. These findings indicate that Fas ligation on human glioma cells leads to the selective induction of chemokine expression, which involves the ERK1/ERK2 and p38 MAPK signaling pathways. Therefore, the Fas-Fas ligand system in human brain tumors may be involved not only in apoptotic processes but also in the provocation of angiogenic and proinflammatory responses.
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PMID:Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. 1130 91

This study has demonstrated the mechanism of protein kinase A (PKA)-dependent inhibition of astrocytic nitric oxide production and inducible NO synthase mRNA expression induced by lipopolysaccharide. In C6 glioma cells, the stimulation with lipopolysaccharide (LPS; 1 microg/ml) evoked increases of nitric oxide (NO) production, NO synthase (iNOS) mRNA expression, phosphorylation of p38 mitogen activated protein kinase (p-p38), and the activation of NF kappa B. LPS-induced NO production and iNOS mRNA expression were inhibited by the pretreatment with forskolin (FSK; 5 microM) in a dose-dependent manner, and which were reversed by PKA inhibition by compound H89. Furthermore, LPS-induced increases of p-p38, but not activation of NF kappa B, were also reduced by FSK and H89 reversed the FSK-induced inhibition response. The dose-dependent inhibition of NO production and iNOS mRNA expression by compound SB203580 (p38 inhibitor) suggests the participation of p38 in PKA-dependent inhibition of LPS-induced NO production and iNOS mRNA expression. However, the activation of NF kappa B by LPS also not affected by SB203580. Therefore, our results suggest that, in C6 glioma cells, LPS-induced NO production and iNOS gene expression may be regulated by PKA pathway through the reduction of activity of p38 kinase. This inhibitory role of PKA may not involve the activation of NF kappa B.
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PMID:Forskolin inhibits expression of inducible nitric oxide synthase mRNA via inhibiting the mitogen activated protein kinase in C6 cells. 1131 70

It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)
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PMID:HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway. 1146 47

We previously showed that the aggregated form of Hsp27 in cultured cells becomes dissociated as a result of phosphorylation with various types of stress. In order to clarify the signal transduction cascade involved, the effects of various inhibitors of protein kinases and dithiothreitol on the dissociation of Hsp27 were here examined by means of an immunoassay after fractionation of cell extracts by sucrose density gradient centrifugation. The dissociation of Hsp27 induced by exposure of U251 MG human glioma cells to metals (NaAsO2 and CdCl2), hypertonic stress (sorbitol and NaCI), or anisomycin, an activator of p38 mitogen-activated protein (MAP) kinase, was completely suppressed by the presence of SB 203580 or PD 169316, inhibitors of p38 MAP kinase, but not by PD 98059 and Uo 126, inhibitors of MAP kinase kinase (MEK), nor by staurosporine, Go 6983, and bisindolylmaleimide I, inhibitors of protein kinase C. Phorbol ester (PMA)-induced dissociation of Hsp27 was completely suppressed by staurosporine, Go 6983, or bisindolylmaleimide I and partially suppressed by SB 203580, or PD 169316 but not by PD 98059 or Uo 126, indicating mediation by 2 cascades. The presence of 1 mM dithiothreitol in the culture medium during exposure to chemicals suppressed the dissociation of Hsp27 induced by arsenite and CdCl2 but not by other chemicals. These results suggest that the phosphorylation of Hsp27 is catalyzed by 2 protein kinases, p38 MAP kinase-activated protein (MAPKAP) kinase-2/3 and protein kinase C. In addition, metal-induced signals are sensitive to reducing power.
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PMID:Protein kinase inhibitors can suppress stress-induced dissociation of Hsp27. 1152 38

The mitogen-activated protein kinase (MAPK) pathway is believed to function as an important mediator of inducible nitric oxide synthase (iNOS) expression. In the present study, we investigated the role of the p38 MAPK signaling pathway in advanced glycosylation end products (AGEs)-induced iNOS expression in C6 glioma cells. AGEs caused a dose-dependent increase of nitrite accumulation in C6 glioma cells. The AGEs-stimulated nitrite production from C6 glioma cells was inhibited by actinomycin D, cyclohexamide, and the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), suggesting that the increase of AGEs-induced nitrite release is due to iNOS up-regulation. Consistently, treatment of C6 glioma cells with AGEs induced iNOS protein expression. AGEs-stimulated nitrite production was inhibited by pretreatment of C6 glioma cells with anti-AGEs antibodies (1:100 or 1:50). The tyrosine kinase inhibitor (genistein and tyrphostin), the Ras-farnesyl transferase inhibitor (FPT inhibitor-II), or the p38 MAPK inhibitor (SB203580) suppressed AGEs-induced iNOS expression and nitrite release from C6 glioma cells. AGEs activated p38 MAPK in C6 glioma cells, and this effect was blocked by genistein (20 microM), tyrphostin (30 microM), FPT inhibitor-II (20 microM), and SB203580 (10 microM). Taken together, our data suggest that AGEs may activate the pathways of tyrosine kinase and Ras to induce p38 MAPK activation, which in turn induces iNOS expression and NO production in C6 glioma cells.
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PMID:Advanced glycosylation end products induce nitric oxide synthase expression in C6 glioma cells: involvement of a p38 MAP kinase-dependent mechanism. 1169 58

We have shown previously that the transduction of a number of human tumor cell lines with an adenovirus (AV1Y28) expressing a single-chain antibody fragment (scFv) directed against Ras proteins results in radiosensitization. Because Ras is involved in the regulation of a number of transcription factors, we have determined the effects of this adenovirus on the activation of nuclear factor-kappaB (NF-kappaB), a radiation-responsive transcription factor associated with cell survival. In U251 human glioma cells, radiation-induced NF-kappaB was significantly attenuated by prior transduction of the anti-Ras scFv adenovirus. This effect appeared to involve an inhibition of IkappaB kinase activity and IkappaBalpha phosphorylation. Inhibitors to the Ras effectors mitogen-activated protein kinase kinase, phosphatidylinositol 3-kinase, and p38, however, did not reduce radiation-induced NF-kappaB. Whereas AV1Y28 inhibited NF-kappaB activation by hydrogen peroxide and ferricyanide, it had no effect of tumor necrosis factor-alpha-induced NF-kappaB activation. These results are consistent with a novel Ras-dependent, oxidant-specific signaling pathway mediating the activation of NF-kappaB. In additional cell lines radiosensitized by AV1Y28, radiation-induced NF-kappaB activation was also inhibited by the anti-Ras scFv, whereas in cell lines not radiosensitized, radiation did not activate NF-kappaB. This correlation suggested that AV1Y28-mediated radiosensitization involved the inhibition of radiation-induced NF-kappaB activation. However, inhibition of NF-kappaB activation via the expression of a dominant-negative form of IkappaBalpha in U251 cells had no effect on radiation-induced cell killing and did not influence AV1Y28-mediated radiosensitization. Therefore, whereas AV1Y28 inhibits radiation-induced NF-kappaB activation, this process does not appear to play a direct role in its radiosensitizing actions.
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PMID:Inhibition of radiation-induced nuclear factor-kappaB activation by an anti-Ras single-chain antibody fragment: lack of involvement in radiosensitization. 1195 90

Irradiation is one of the cornerstones used in the treatment of malignant glioma. However, the effect is modest and glioma cells generally display a pronounced radio-resistance. In this study, the effect of irradiation, alone and in combination with the antimicrotubule drug estramustine (EaM), was investigated in vitro using the BT4C rat glioma cell line, and in vivo the BT4C rat intracerebral glioma model was used. Apoptosis was detected by analysing DNA laddering, in situ end labelling (ISEL) and Annexin V reactivity. In addition, phosphorylation status of MAPK, JNK, p38, and AKT, proteins involved in pro- and anti-apoptotic signalling pathways was analysed by Western blotting. Irradiation did not induce apoptosis, neither in vitro nor in vivo. EaM, however, induced apoptosis in vivo and in vitro, regardless of whether EaM was given alone, before or after irradiation. When BT4C cells were treated with the caspase-3 inhibitor Ac-DEVD-CHO prior to EaM, the number of apoptotic cells was decreased, indicating an involvement of caspase-3. The signalling pathways regulating apoptosis are complex and involve kinases such as MAPK, JNK, p38 and AKT. Irradiation did not induce any changes in the expression levels or phosphorylation status of these proteins. On the other hand, the phosphorylation level of AKT was reduced after EaM treatment, which might, in part, propose how EaM induces apoptosis in glioma cells.
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PMID:The antimicrotubule drug estramustine but not irradiation induces apoptosis in malignant glioma involving AKT and caspase pathways. 1199 15

Hepatocyte growth factor (HGF) and its receptor c-Met are expressed in inappropriately high abundance in gliomas and are further upregulated during the transition from low- to high-grade malignancy. In these cells HGF induces expression of c-Met via PKC, Ras and mitogen activated protein kinase (MAPK) pathway. Here we report that secretion and expression of HGF in U87 astrocytoma is increased by a PKC activator, PMA, an effect which is abolished by a PKC inhibitor, Go6976, specific for PKCalpha and PKCbeta1. Activating PKA by forskolin, on the other hand, had no effect. Furthermore, messenger molecule downstream of PKC, i.e. MEK mediates such effect of PKC as specific MEK inhibitors (PD98059 and U0126) abolished PMA induced HGF secretion by U87 cells. Accordingly, PMA induced rapid phosphorylation of MEK substrate, i.e. Erk1/2 (p42/44 MAPK). In addition, such effect of PKC is Ras-dependent as specific Ras inhibitor L-744,832 attenuated both PMA mediated induction of Erk 1/2 phosphorylation as well as HGF secretion. Moreover, a specific p38 MAPK inhibitor (SB203580) almost completely inhibited basal HGF secretion to an undetectable level. Increased secretion of HGF is most likely exerted at the transcriptional level since inhibitor of transcription, actinomycin D abolished such increase. Furthermore, when assessed by Northern blot analysis, PMA increased HGF transcripts while U0127 and SB203580 inhibited. Therefore, our data reveal that HGF secretion in U87 cells is regulated by Ras-dependent PKC, MEK cascade and in parallel by p38 MAPK pathway. Since the Raf-PKC-MEK cascade is used for HGF's signaling via its receptor in astrocytoma cells, our data revealing similar regulatory mechanism for HGF secretion in these cells would help to explain the feed forward nature of HGF action in glioma cells that would further accentuate its basal secretion, exacerbating its effects on the progression of gliomas in an autocrine fashion.
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PMID:PKC, p42/44 MAPK and p38 MAPK regulate hepatocyte growth factor secretion from human astrocytoma cells. 1219 96

Levels and phosphorylation states of the two small molecular chaperones, alphaB-crystallin and Hsp27, in disused rat soleus muscles were determined by Western blot analysis of extracts with antibodies recognizing each of the two proteins and their phosphorylated serine residues. Increased phosphorylation and relocalization to insoluble fractions were found within a few days of hind-limb suspension. High phosphorylation of alphaB-crystallin at Ser-59 (and to a certain extent, at Ser-45) and of Hsp27 at Ser-15 and Ser-85, along with phosphorylated, active states of p38 and p44/42 mitogen-activated protein kinases were maintained during hind-limb suspension but promptly returned to control levels within a 5-day recovery period. These results are similar to those observed with U373 MG glioma cells exposed to proteasome inhibitors (16). However, the responses of alphaB-crystallin and Hsp27 in suspended soleus muscles did not appear with ipsilateral transection of the sciatic nerve trunk, indicating mediation by nerve activity. The fact that ubiquitinated proteins accumulated in the insoluble fractions of suspended soleus muscle further suggests participation of alphaB-crystallin and Hsp27 in quality control of proteins in disused soleus muscle, with involvement of nerve activity-dependent processes.
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PMID:Innervation-dependent phosphorylation and accumulation of alphaB-crystallin and Hsp27 as insoluble complexes in disused muscle. 1220 38


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