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)

We have demonstrated that the alpha 2,3 sialyltransferase (alpha 2,3 ST) from C6 cultured glioma cells was inhibited in vivo by W-7 and related Ca2+/Calmodulin (Ca/CaM) antagonists while protein kinase C effectors had no effect. Dephosphorylation of alpha 2,3 ST by the wide specificity alkaline phosphatase led to inactivation indicating that the enzyme is phosphorylated. The serine/threonine protein phosphatase inhibitors okadaic acid and Calyculin A led also to an inhibition of alpha 2,3 ST activity. In addition, Ca/CaM antagonists and phosphatase inhibitors led both to an inhibition of a alpha 2,3 sialoglycoprotein from C6 glioma cells as demonstrated with lectin affinity blotting. A concerted regulatory mechanism with phosphorylation/dephosphorylation of alpha 2,3 ST is then postulated.
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PMID:Study of O-glycan sialylation in C6 cultured glioma cells: regulation of a beta-galactoside alpha 2,3 sialyltransferase activity by Ca2+/calmodulin antagonists and phosphatase inhibitors. 132 69

The protein statin is found in nuclei of nonproliferating cells. Here we report that statin is a phosphoprotein, phosphorylated at serine residues in cultured cells. During immunoprecipitation with anti-statin (S44) antibody, a 45-kDa protein co-precipitates with the 57-kDa statin. In vitro kinase assays demonstrate that the S44 immunoprecipitates can phosphorylate, besides statin, immunoglobulins, enolase, and casein, at either serine or serine/threonine residues. Kinase assays with immunoprecipitated proteins performed on casein- or enolase-impregnated gels show that these substrates are phosphorylated by the 45-kDa (p45) protein. When the S44 immunoprecipitates from human cultured fibroblasts with different in vitro life-spans were compared, the p45 kinase activity was present only in young nongrowing and senescent cells, but not in young growing ones. In other cell cultures, the kinase is detected only in protein complexes precipitated from quiescent 3T3 cells, but not from cycling 3T3 cells or from transformed human glioma (U251-4) cells. Cell fractionation studies, indicating that the phosphorylating activity of S44 immunoprecipitates correlates both qualitatively and quantitatively with the amount of statin present, provide strong evidence that in vivo statin is specifically associated with the p45 kinase. These results suggest that the nonproliferation-specific nature of statin is indeed related to the phosphorylated property of this protein and maybe contributed by the associated kinase.
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PMID:Statin, a protein specifically present in nonproliferating cells, is a phosphoprotein and forms a complex with a 45-kilodalton serine/threonine kinase. 140 Apr 86

Rubrophilin, a unique brain specific polypeptide, was purified to apparent homogeneity from microsomal fractions of bovine brains. The peptide stains pink with Coomassie Brilliant Blue R-250 (C.I. No. 42660) under specific conditions, has an apparent Mr of 53,000, and is acidic with an apparent pI of 4.9. The purification involves initial solubilization of delipidated microsomes in sodium dodecyl sulfate, followed by ammonium sulfate fractionation, reversed ammonium sulfate gradient elution from diatomaceous earth, gel filtration on polyacrylamide (Biogel P-200), gradient elution chromatography from hydroxylapatite, and reverse-phase chromatography from phenyl-Sepharose. A yield of about 5 mg of rubrophilin was obtained from 9 g of microsomal proteins. Amino acid analysis shows that rubrophilin contains only nine amino acids with residues/mol as follows: alanine (102), glutamic acid (97), lysine (65), proline (55), aspartic acid (48), glycine (44), serine (37), threonine (35), and valine (10). Cysteine, methionine, tryptophan, tyrosine, isoleucine, phenylalanine, histidine, and arginine could not be detected. Relative rubrophilin content of vertebrate brains was as follows: mammals greater than birds greater than reptiles greater than fishes. It is present in mouse retina and human neuroblastoma cell cultures but could not be detected in octopus optic lobe or in cultured C-6 rat glioma cells.
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PMID:Purification and properties of rubrophilin: a novel brain specific membrane polypeptide. 380 7

Eukaryotic proteins with a carboxyl-terminal CaaX motif are modified by isoprenylation and subsequently processed by proteolysis of the three terminal amino acids and carboxylmethylation of the exposed cysteine residue. The myelination-associated 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) has a C-terminal CTII sequence and is isoprenylated; however, no examples of subsequent processing exist when threonine, a polar residue, is located adjacent to the cysteine. Here we show that CNP is capable of being carboxylmethylated in both insect cells and glioma cells. This processing is dependent upon isoprenylation of the cysteine and can be inhibited with the isoprenylated cysteine derivative, N-acetyl-S-farnesyl-L-cysteine. Although the role of the methyl group at the C-terminus of other isoprenylated proteins is not fully understood, modulation of signal transduction pathways is strongly indicated. This modification of CNP may similarly regulate cell biological processes in myelinogenesis.
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PMID:C-terminal CTII motif of 2',3'-cyclic nucleotide 3'-phosphodiesterase undergoes carboxylmethylation. 789 87

1. To approach the mechanisms underlying desensitization of the opioid receptor-mediated Ca2+ channel inhibition, the effects of prolonged application of [D-Ala2, D-Leu5]enkephalin (DADLE) on Ba2+ currents (I(Ba)) through Ca2+ channels were analysed in NG108-15 neuroblastoma x glioma hybrid cells. 2. Inhibition of I(Ba) by 100 nM DADLE desensitized by 57% with a time constant of 4.4 min. 3. Maximal desensitization of the delta-opioid receptor-Ca2+ channel coupling was attained by 1 microM DADLE. The EC50 value for desensitization was estimated to be 78 nM. 4. RNA blot hybridization analysis and immunoblot analysis revealed the expression of beta-adrenoceptor kinase-1 (betaARK1) in NG108-15 cells. 5. Heparin, an inhibitor of betaARK, significantly reduced the magnitude and rate of desensitization, whereas Rp-cyclic AMPS and PKI (14-24)amide, inhibitors of cyclic AMP-dependent protein kinase (PKA), or long-term treatment with phorbol 12-myristate 13-acetate to induce down-regulation of protein kinase C (PKC) had no significant effect. 6. Recovery from desensitization (resensitization) proceeded with a time constant of 6.7 min. Okadaic acid, an inhibitor of serine/threonine phosphatases 1 and 2A, significantly attenuated the degree of resensitization. 7. In summary, we have characterized the time course and concentration-dependence of the desensitization of DADLE-induced I(Ba) inhibition in NG108-15 cells. This desensitization was reversible after removal of DADLE. It is suggested that betaARK, but neither PKA nor PKC, is involved in desensitization, while serine/threonine phosphatases mediate resensitization.
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PMID:Desensitization and resensitization of delta-opioid receptor-mediated Ca2+ channel inhibition in NG108-15 cells. 955 94

We examined the effect of amino acid substitutions of the GPGR (glycine-proline-glycine-arginine) tip sequence at the V3 domain of the Env protein of human immunodeficiency virus type 1 (HIV-1) on its cell tropism and coreceptor use. We changed the GPGR sequence of a T-cell line (T)- and macrophage (M)-tropic (R5-R3-X4) HIV-1 strain, GUN-1wt, to GA(alanine)GR (the resulting mutant was designated GUN-1/A), GL(leucine)GR (GUN-1/L), GP(proline)GR (GUN-1/P), GR(arginine)GR (GUN-1/R), GS(serine)GR (GUN-1/S), or GT(threonine)GR (GUN-1/T). GUN-1/A, GUN-1/S, and GUN-1/T mutants infected brain-derived cells such as a CD4-transduced glioma cell line, U87/CD4, and a brain-derived primary cell strain, BT-20/N, as well as T-cell lines in a CD4-dependent manner, although the plating of these mutants onto macrophages was inhibited. GUN-1/L, GUN-1/P, and GUN-1/R mutants showed both T- and M-tropism, but did not plate onto the brain-derived cells. A CCR3, CCR5, CCR8, or CXCR4 gene was introduced into a CD4-positive glioma cell line, NP-2/CD4, which demonstrated complete resistance to various HIV-1 strains. Not only HIV-1 strains, which were infectious to macrophages, such as GUN-1wt, GUN-1v, GUN-1/L, and GUN-1/P, but also an HIV-1 strain, GUN-1v, which was hardly infectious to macrophages, grew well in NP-2/CD4 cells expressing CCR3 or CCR5. However, the M-tropic GUN-1/R mutant could not efficiently use CCR5 nor CCR3. No point mutants, except GUN-1/L, grew well in NP-2/CD4 cells expressing CCR8. These findings indicate that the cell tropism of HIV-1 to macrophages and brain-derived cells and their use of the coreceptors were markedly, though not always concomitantly, affected by the tip sequence of the V3 domain.
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PMID:Changes in and discrepancies between cell tropisms and coreceptor uses of human immunodeficiency virus type 1 induced by single point mutations at the V3 tip of the env protein. 1038 57

Activation of the A(2A) adenosine receptor (A(2A)AR) contributes to the neuromodulatory and neuroprotective effects of adenosine in the central nervous system. Here we demonstrate that, in rat C6 glioma cells stably expressing an epitope-tagged canine A(2A)AR, receptor phosphorylation on serine and threonine residues can be increased by pretreatment with either the synthetic protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or endothelin 1, which increases PKC activity via binding to endogenous endothelin(A) receptors. Under conditions in which PMA was maximally effective, activation of other second messenger-regulated kinases was without effect. While basal and PMA-stimulated phosphorylation were unaffected by the A(2A)AR-selective antagonist ZM241385, they were both blocked by GF109203X (a selective inhibitor of conventional and novel PKC isoforms) and rottlerin (a PKCdelta-selective inhibitor) but not Go6976 (selective for conventional PKC isoforms). However, coexpression of the A(2A)AR with each of the alpha, betaI, and betaII isoforms of PKC increased basal and PMA-stimulated phosphorylation. Mutation of the three consensus PKC phosphorylation sites within the receptor (Thr298, Ser320, and Ser335) to Ala failed to inhibit either basal or PMA-stimulated phosphorylation. In addition, phosphorylation of the receptor was not associated with detectable changes in either its signaling capacity or cell surface expression. These observations suggest that multiple PKC isoforms can stimulate A(2A)AR phosphorylation via activation of one or more downstream kinases which then phosphorylate the receptor directly. In addition, it is likely that phosphorylation controls interactions with regulatory proteins distinct from those involved in the classical cAMP signaling pathway utilized by this receptor.
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PMID:Stimulation of A(2A) adenosine receptor phosphorylation by protein kinase C activation: evidence for regulation by multiple protein kinase C isoforms. 1055 65

As concerns human adult brain neoplasms, the biological behaviour of glioblastoma, a high-grade neuro-ectodermal tumour, is among the most disadvantageous. Glioblastoma may develop either as a primary tumour without clinical and histological evidence of a prior precursor lesion, or as the final stage of malignant transformation of a low-grade or anaplastic astrocytoma. There are conflicting reports in connection with the association of the p53 tumour suppressor gene mutation with the clinical and histological progression of gliomas. Previous studies likewise led to contradictory results concerning the significance of ras oncogenes in different histological malignancies, and especially in neuro-epithelial tumours. The possible roles of p53 and ras gene alterations in the development of "primary" and "transformed" glioblastomas were studied in this work. Eighteen tumours were investigated by means of immunohistochemistry and polymerase chain reaction-assisted-single strand conformation polymorphism (PCR-SSCP) sequence analysis in a search for molecular genetic differences between primary and transformed glioblastomas. An increased incidence of p53-immunopositive cells was observed in both types of glioblastomas but there was no significant difference between the transformed tumours and the primary form. All samples were screened for point mutation in codons 12 and 61 of the H-, K-, and N-ras oncogenes and exons 5-8 of the p53 gene. No aberrant band or mutation was found in the H-, K- and N-ras oncogenes. Aberrant bands were seen in only 2 (11%) of the 18 tumours in the SSCP analyses of exons 6 and 8. Sequence analysis of the 2 abnormal cases revealed G --> C transmission in the second nucleotide of codon 280 on exon 8, which resulted in a change in the encoded amino acid from arginine to threonine (case 15). A ttagtct --> ttggtct transmission on intron 5 (case 8) was also found. No genetic difference could be identified between the primary and the transformed glioblastoma forms as concerns their p53 and ras oncogenes. There are two possible explanations for these findings: (a) The p53 and ras gene mutations were not primary events in the morphological transformations. Alterations in these genes may therefore take place at an early stage in glioma progression. (b) The different genetic changes may accumulate during glioblastoma development. These specific genetic events may additionally play a role in multistep tumourigenesis.
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PMID:Sporadic p53 mutations and absence of ras mutations in glioblastomas. 1092 24

Protein kinase C is a family of serine/threonine protein kinases involved in many cellular responses, including cell survival and apoptosis. We have recently found that specific inhibition of the PKCalpha isoform by nucleic acid enzymes induced apoptosis in sensitive cells. Here we show that in PKCalpha DNA enzyme-treated glioma cells the activation of MAP kinases ERK1/2 is inhibited, whereas their total level was not significantly affected by the treatment. Similar results were obtained when the overall activity of the PKC was inhibited by calphostin, a specific inhibitor for PKC. These results would indicate that the ERK1/2 signaling pathway plays an important role in glioma cell survival and that the PKCalpha isoform is the main modulator of this pathway. Furthermore, we show that the ERK1/2 signaling pathway is required for the constitutive expression of the basic fibroblast growth factor, a potent mitogen for glioma cell growth.
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PMID:Protein kinase Calpha isoform regulates the activation of the MAP kinase ERK1/2 in human glioma cells: involvement in cell survival and gene expression. 1117 Aug 40

Checkpoint mechanism plays a crucial role in ensuring genomic integrity during cell cycle. Loss of checkpoint function is known to induce genomic instability and to alter ploidy of dividing cells. In this study, we examined mechanisms of hyperploid formation in glioma cells by treatment with nocodazole, which activates spindle assembly checkpoint by inhibiting microtubule polymerization. By prolonged nocodazole treatment, U251MG human glioma cell, which has a p53 mutation, underwent transient arrest at mitosis, and subsequently exited from mitotic arrest (termed 'mitotic slippage') followed by DNA replication without cytokinesis, resulting in hyperploid formation. Additionally, the heterogeneity in the number of centrosomes per cell increased during the hyperploid formation, suggesting that these hyperploid cells have genomic instability. By employing LN382 glioma cell that has a temperature-sensitive p53 mutation, we found that the activation of p53 prevents hyperploid formation after the prolonged nocodazole treatment. Furthermore, staurosporine, an inhibitor for a broad range of serine/threonine kinases including cdc2, was found to enhance hyperploid formation in U251MG cells by accelerating the induction of mitotic slippage. Interestingly, inhibitors specific for cdc2 kinase prevented the G2 to M transition but did not accelerate mitotic slippage, suggesting that staurosporine-sensitive kinases other than cdc2 are required for maintenance of spindle assembly checkpoint. Moreover, the enhancement of hyperploid formation by staurosporine was also blocked by p53-dependent G1 checkpoint. These results suggest that abrogation of G1 checkpoint is a critical factor for formation of hyperploid cells after the mitotic slippage.
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PMID:Mechanism of hyperploid cell formation induced by microtubule inhibiting drug in glioma cell lines. 1131 73


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