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)

C6 rat glioma cells respond to glia maturation factor (GMF) with characteristic morphological alterations. Observed under phase-contrast microscopy, the cells changed from a rounded morphology in random formation to a spindle-shaped appearance in parallel arrays. Observed under scanning electron microscopy, GMF led to a decrease in the number of microvilli and cell surface knobs. Transmission electron microscopy demonstrated the appearance of numerous microtubules aligned with the long axis of the cells after GMF stimulation. The change in cell shape and histotypic pattern was inhibited by vinblastin, further implicating the involvement of microtubules. Immunofluorescence using anti-alpha-tubulin revealed a well-defined cytoskeletal system in GMF-stimulated cells but not in the control cells. Finally, an increase in tubulin was confirmed with enzyme-linked immunosorbent assay (ELISA) on extracts from these cultures. The findings indicate that morphological alterations induced by GMF are associated with changes in the quantity and arrangement of microtubules.
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PMID:Induction of cytoskeletal alterations in C6 glioma by glia maturation factor. 350

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

The aim of this study was to investigate the antimigratory and antiinvasive potential of vincristine sulfate (VCR) on human glioma cells and to analyze whether phenytoin (5,5-diphenylhydantoin; DPH) might act synergistically with VCR. Vincristine affects the cytoplasmic microtubules; DPH has been reported to enhance VCR cytotoxicity in murine cells. In two human glioma cell lines, GaMG and D-37MG, we found VCR to reduce monolayer growth and colony formation in a dose-dependent fashion at concentrations of 10 ng/ml and above. Phenytoin increased the cytotoxic and cytostatic effects of VCR in monolayer cells but not in spheroids. Multicellular spheroids were used to investigate directional migration. A coculture system of GaMG and D-37MG spheroids with fetal rat brain aggregates was used to analyze and quantify tumor cell invasion. A dose-dependent inhibition of migration and invasion by VCR was observed in both cell lines without further enhancement by DPH. Immunofluorescence microscopy with antibodies against alpha-tubulin revealed dose-dependent morphological alterations in the microtubules when the cells were exposed to VCR but not after incubation with DPH. Based on the combination of standardized in vitro model systems currently in use and the present data, the authors strongly suggest that VCR inhibits migration and invasion of human glioma cells. This is not altered by DPH, which inhibits cell proliferation in combination with VCR.
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PMID:Differential effects of vincristine and phenytoin on the proliferation, migration, and invasion of human glioma cell lines. 753 63

We have reported that the three serine residues in alphaB-crystallin are phosphorylated under various stress conditions. We prepared affinity-purified antibodies recognizing each of the phosphorylated serine residues (Ser-19, Ser-45, and Ser-59, respectively) in alphaB-crystallin with peptides (p19S, p45S, or p59S) that contained the corresponding phosphorylated serine residue. Immunocytochemically anti-p45S antibodies stained the cytoplasm of mitotic cells (J. Biol. Chem. 273, 28,346-28,354). We have now found that the anti-p59S antibodies recognize centrosomes and midbodies of dividing cells. alphaB-Crystallin was the only protein recognized by the anti-p59S antibodies in Western blot analyses of isolated centrosome fractions. alphaB-Crystallin phosphorylated at Ser-59 was localized at the microtubule organizing centers by means of double staining with anti-beta-tubulin antibody in aster formation analysis and was co-localized with gamma-tubulin in centrosomes. Gamma-Tubulin was co-immunoprecipitated with alphaB-crystallin in U373 glioma cell extracts. On the other hand, the location of the phosphorylated alphaB-crystallin deviated from that of alpha-tubulin or gamma-tubulin in the midbody region. Taken together with the evidences that several chaperones are distributed to centrosomes, these results suggest that alphaB-crystallin as a chaperone might be also involved in the quality control of proteins.
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PMID:AlphaB-crystallin phosphorylated at Ser-59 is localized in centrosomes and midbodies during mitosis. 1183 87

Detyrosination/tyrosination of tubulin is a post-translational modification that occurs at the C-terminus of the alpha-subunit, giving rise to microtubules rich in either tyrosinated or detyrosinated tubulin which coexist in the cell. We hereby report that the tyrosine analogue, azatyrosine, can be incorporated into the C-terminus of alpha-tubulin instead of tyrosine. Azatyrosine is structurally identical to tyrosine except that a nitrogen atom replaces carbon-2 of the phenolic group. Azatyrosine competitively excluded incorporation of [14C]tyrosine into tubulin of soluble brain extract. A newly developed rabbit antibody specific to C-terminal azatyrosine was used to study incorporation of azatyrosine in cultured cells. When added to the culture medium (Ham's F12K), azatyrosine was incorporated into tubulin of glioma-derived C6 cells. This incorporation was reversible, i.e. after withdrawal of azatyrosine, tubulin lost azatyrosine and reincorporated tyrosine. Azatyrosinated tubulin self-assembled into microtubules to a similar degree as total tubulin both in vitro and in vivo. Studies by other groups have shown that treatment of certain types of cultured cancer cells with azatyrosine leads to reversion of phenotype to normal, and that administration of azatyrosine into animals harbouring human proto-oncogenic c-Ha- ras prevents tumour formation. These interesting observations led us to study this phenomenon in relation to tubulin status. Under conditions in which tubulin was mostly azatyrosinated, C6 cells remained viable but did not proliferate. After 7-10 days under these conditions, morphology changed from a fused, elongated shape to a rounded soma with thin processes. Incorporation of azatyrosine into the C-terminus of alpha-tubulin is proposed as one possible cause of reversion of the malignant phenotype.
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PMID:Post-translational incorporation of the antiproliferative agent azatyrosine into the C-terminus of alpha-tubulin. 1285 82

It has previously been implicated that nerve growth factor (NGF) with its high-affinity receptor tyrosine kinase A (TrkA) could play an important role in the growth modulation of human tumor cells, such as glioblastoma multiform cell lines and human breast cancer cell lines. However, the direct mitogenic effects of NGF and TrkA in these tumor cells still remain to be elucidated. Herein we show, by immunofluorescence staining, that NGF was colocalized with gamma-tubulin at the centrosomes or the spindle poles throughout the cell cycle and phosphorylated TrkA was colocalized with alpha-tubulin at mitotic spindle in the glioma cell line U251. The results suggest that NGF concentrated to centrosome can recruit its receptor TrkA there and cause phosphorylation of the latter. The phosphorylated TrkA with the tyrosine kinase activity may phosphorylate the tubulin and promote the mitotic spindle assembly. By these mechanisms, NGF can modulate the mitosis of human glioma cells.
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PMID:Localization of NGF and TrkA at mitotic apparatus in human glioma cell line U251. 1618 9

We describe an unusual form of non-accidental cell death marked by ectopic microtubules in the nucleus of a subpopulation of cisplatin-treated C6 glioma astrocytes in culture. At electron microscopy, the perinuclear condensed chromatin did not completely adhere to the nuclear envelope of these cells being separated by single or loosely bundled 20-nm-thick microtubules located in an electron-lucid slit-like zone; the presence of alpha-tubulin lining the inner membrane of the nuclear envelope was confirmed by immunolabeling at confocal microscopy. Since tufts of microfilaments-like fibers also occurred in their central nuclear areas, these cells are referred to as CIMMs (Cells with Intranuclear Microtubules and Microfilaments). The nuclear reorganization of CIMMs also involved nucleolar segregation and formation of heterogeneous ectopic ribonucleoprotein (RNP)-derived structures, indicating disruption of the RNP-based transcription machinery. The cytoplasmic organelles of CIMMs were structurally intact, and propidium iodide did not accumulate intracellularly under vital conditions while the plasma membrane was often Annexin V-positive. All these findings suggest that CIMMs were lethally damaged and committed to an atypical programmed cell death resembling early apoptosis (this is also supported by the presence of a limited number of TUNEL-positive CIMMs). CIMMs appeared well before the main cisplatin-induced cycling arrest of the cell population (G2/M block at 72 h) and had mostly G1 DNA content: this suggests that they may represent the cohort of cells which passed cisplatin-altered mitoses with intranuclear retention of microtubules from an incompletely disassembled mitotic spindle.
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PMID:Intranuclear microtubules are hallmarks of an unusual form of cell death in cisplatin-treated C6 glioma cells. 1628 54

Grade 4 malignant glioma (GBM) is a fatal disease despite aggressive surgical and adjuvant therapies. The hallmark of GBM tumors is the presence of pseudopalisading necrosis and microvascular proliferation. These tumor cells are hypoxic and express hypoxia-inducible factor-1 (HIF-1), a prosurvival transcription factor that promotes formation of neovasculature through activation of target genes, such as vascular endothelial growth factor. Here, we evaluated whether 2-methoxyestradiol, a microtubule and HIF-1 inhibitor, would have therapeutic potential for this disease in a 9L rat orthotopic gliosarcoma model using a combination of noninvasive imaging methods: magnetic resonance imaging to measure the tumor volume and bioluminescence imaging for HIF-1 activity. After imaging, histologic data were subsequently evaluated to elucidate the drug action mechanism in vivo. Treatment with 2-methoxyestradiol (60-600 mg/kg/d) resulted in a dose-dependent inhibition of tumor growth. This effect was also associated with improved tumor oxygenation as assessed by pimonidazole staining, decreased HIF-1alpha protein levels, and microtubule destabilization as assessed by deacetylation. Our results indicate that 2-methoxyestradiol may be a promising chemotherapeutic agent for the treatment of malignant gliomas, with significant growth inhibition. Further studies are needed to assess the effect of low or intermediate doses of 2-methoxyestradiol in combination with chemotherapeutic agents in clinical studies focused on malignant gliomas. In addition to showing tumor growth inhibition, we identified three potential surrogate biomarkers to determine the efficacy of 2-methoxyestradiol therapy: decreased HIF-1alpha levels, alpha-tubulin acetylation, and degree of hypoxia as determined by pimonidazole staining.
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PMID:Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model. 1717 98

Diazinon and cypermethrin are pesticides extensively used in sheep dipping. Diazinon is a known anti-cholinesterase, but there is limited information regarding its molecular mechanism of action. This paper describes the effects of diazinon and cypermethrin at a morphological and molecular level on differentiating mouse N2a neuroblastoma and rat C6 glioma cell lines. Concentrations up to 10 microM of both compounds and their mixture had no effect on the viability of either cell line, as determined by methyl blue tetrazolium reduction and total protein assays. Microscopic analysis revealed that 1 microM and 10 microM diazinon but not cypermethrin inhibited the outgrowth of axon-like processes in N2a cells after a 24-h exposure but neither compound affected process outgrowth by differentiating C6 cells at these concentrations. Under these conditions, 10 microM diazinon inhibited AChE slightly compared to the control after a 4-h exposure but not after 24 h. Western blotting analysis showed that morphological changes were associated with reduced cross-reactivity with antibodies that recognize the neurofilament heavy chain (NFH), microtubule associated protein MAP 1B and HSP-70 compared to control cell extracts, whereas reactivity with anti-alpha-tubulin antibodies was unchanged. Aggregation of NFH was observed in cell bodies of diazinon-treated N2a cells, as determined by indirect immunofluorescence staining. These data demonstrate that diazinon specifically targets neurite outgrowth in neuronal cells and that this effect is associated with disruption of axonal cytoskeleton proteins, whereas cypermethrin has no effect on the same parameters.
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PMID:The effects of diazinon and cypermethrin on the differentiation of neuronal and glial cell lines. 1723 17

The aims of this work were to compare the effects of methyl mercury chloride and thimerosal on neurite/process outgrowth and microtubule proteins in differentiating mouse N2a neuroblastoma and rat C6 glioma cells. Exposure for 4h to sublethal concentrations of both compounds inhibited neurite outgrowth to a similar extent in both cells lines compared to controls. In the case of N2a cells, this inhibitory effect by both compounds was associated with a fall in the reactivity of western blots of cell extracts with monoclonal antibody T1A2, which recognises C-terminally tyrosinated alpha-tubulin. By contrast, reactivity with monoclonal antibody B512 (which recognises total alpha-tubulin) was unaffected at the same time point. These findings suggest that decreased tubulin tyrosination represents a neuron-specific early marker of mercury toxicity associated with impaired neurite outgrowth.
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PMID:Reduced tubulin tyrosination as an early marker of mercury toxicity in differentiating N2a cells. 1755 60


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