Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptide Y (NPY) regulates neurotransmitter release through activation of the Y2 receptor subtype. We have recently characterized a human glioblastoma cell line, LN319, that expresses exclusively NPY Y2 receptors and have demonstrated that NPY triggers transient decreases in cAMP and increases in intracellular calcium responses. The present study was designed to further characterize calcium signalling by NPY and bradykinin (BK) in LN319 cells. Both agonists elevated free intracellular calcium ([Ca(2+)](i)) without soliciting calcium influx. NPY appeared to activate two distinct signalling cascades that liberate calcium from thapsigargin- and ryanodine-insensitive compartments. One pathway proceeded through phospholipase C (PLC)-dependent phosphatidylinositol turnover, while the other triggered calcium release through a so far unidentified mediator. Part of the response was sensitive to pertussis toxin (PTX) under conditions where the toxin totally abolished the NPY-mediated effects on cAMP. The calcium release induced by BK on the other hand was largely PTX-insensitive, PLC-dependent, and from both thapsigargin- and ryanodine-sensitive stores. Following stimulation with NPY, subsequent [Ca(2+)](i) responses to NPY were strongly depressed. Partial heterologous desensitization occurred, when BK was used as the first agonist, whereas NPY had no effect on a subsequent stimulation with BK. These data suggest that NPY-induced calcium mobilization in LN319 cells involves two different G proteins and signalling mediators, and a hitherto unidentified calcium compartment. Homologous desensitization of NPY signalling might be explained by receptor-G protein uncoupling, while heterologous desensitization by BK could be the result of either transient depletion or inhibition of a mediator in the calcium signalling cascades activated by NPY.
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PMID:Neuropeptide Y Y2 receptor signalling mechanisms in the human glioblastoma cell line LN319. 1128 92

Cellular effects of thrombin are mediated by members of a new subfamily of G protein-coupled receptors designated proteinase-activated receptors (PARs) with the prototype PAR-1. Investigation of PAR-1-induced signaling has been shown to be very important in clarifying thrombin's role in cell metabolism, differentiation, and growth. We evaluated connection of PAR-1 with the cAMP/PKA pathway in SNB-19 glioblastoma cells. Alpha-thrombin and the synthetic PAR-1 agonist SFLLRN stimulated PKA as shown by increased PKA activity and translocation of the catalytic PKA alpha subunits (PKA(cat)alpha) into the nucleus. However, no effect on cAMP could be observed. PKA(cat)alpha was found to be associated with nuclear factor-kappa B (NF-kappaB) p65 and its inhibitor protein IkappaB in SNB-19 cells. After PAR-1 stimulation, this association was markedly diminished. We conclude that PAR-1 mediates PKA activation without altering cAMP levels but includes NF-kappaB-associated PKA(cat)alpha in SNB-19 glioblastoma cells. This is the first evidence for a cAMP-independent PKA signaling by a G protein-coupled receptor.
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PMID:A novel PAR-1-type thrombin receptor signaling pathway: cyclic AMP-independent activation of PKA in SNB-19 glioblastoma cells. 1135 44

DEC1 (BHLHB2)/Stra13/Sharp2, a basic helix-loop-helix (bHLH) transcription factor has been suggested to be involved in the control of proliferation and/or differentiation of several cells including nerve cells, fibroblasts and chondrocytes. In the present study, we examined the effect of parathyroid hormone (PTH), dibutyryl cAMP (Bt2cAMP) and forskolin on the expression of DEC1 in various cells. In rabbit chondrocyte cultures, PTH or Bt2cAMP increased the DEC1 mRNA level within 1 h. Thereafter, the DEC1 mRNA level rapidly decreased to the basal level at 3 h, and increased at 6-24 h. In cultures of a mouse embryo prechondrogenic cell line ATDC5, PTH or forskolin, an activator of adenylate cyclase, also increased the DEC1 mRNA level within 1 h. Furthermore, in all evaluated cell lines of human fibroblasts, canine epithelial cells, human carcinoma, human glioblastoma and human melanoma, Bt2cAMP increased the DEC1 mRNA level within 1-3 h. Studies with actinomycin D and cycloheximide indicated that the enhancement of DEC1 mRNA by cAMP was not due to mRNA stabilization and did not require new protein synthesis. These findings suggest that DEC1 is a novel direct target for cAMP in wide types of cells, and that the bHLH protein is involved in the control of gene expression in cAMP-activated cells.
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PMID:Induction of basic helix-loop-helix protein DEC1 (BHLHB2)/Stra13/Sharp2 in response to the cyclic adenosine monophosphate pathway. 1143 22

Four different isoforms of mammalian phospholipase C delta (PLCdelta) have been described. PLCdelta1, the best-understood isoform, is activated by an atypical GTP-binding protein. It has been suggested that it is a calcium signal amplifier. However, very less is known about other subtypes, including PLCdelta3. Therefore, in the present study, we examined the expression of PLCdelta3 in different human tissues. Moreover, the cellular underlying regulation for PLCdelta3 was studied in different cell lines. Our study showed that the mRNA and protein levels differed significantly among human tissues. The human PLCdelta3 gene was composed of 15 exons and 1 putative cAMP response element in the 5'-end promoter region. PLCdelta3 mRNA expression was downregulated by cAMP and calcium in both the human normal embryonic lung tissue diploid WI38 cell line and the glioblastoma/astrocytoma U373 cell line. However, mRNA expression showed no impact by PKC activators or inhibitors. This study shows the human PLCdelta3 expression pattern and is the first report that PLCdelta3 gene expression is downregulation by cAMP and calcium.
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PMID:Downregulation of phospholipase C delta3 by cAMP and calcium. 1150 33

The expression of transforming growth factor-beta2 (TGF-beta2) appears to play a strong role in the establishment and progression of glial tumors. In particular, elevated expression of TGF-beta2 appears to be responsible for the impaired cell-mediated immunity often observed in patients with a glioblastoma. This study examined the regulation of the TGF-beta2 at the transcriptional level in the U87MG glioblastoma cell line. We demonstrate that a cAMP response element/activating transcription factor (CRE/ATF) site and an E-box motif located just upstream of the transcription start site are essential for the transcription of the TGF-beta2 gene in U87MG cells. Gel mobility analysis determined that activating transcription factor-1, and possibly cAMP-responsive element binding protein, binds to the CRE/ATF site, and upsteam stimulatory factor (USF) 1 and USF2 bind to the E-box motif. Interestingly, expression of a dominant negative USF protein down-regulates TGF-beta2 activity by 80-95% in glioblastoma cells. We conclude that the binding of transcription factors, in particular the USF proteins, to the TGF-beta2 promoter is essential for its expression and possibly its up-regulation in glioblastomas.
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PMID:Transcriptional regulation of the transforming growth factor-beta2 gene in glioblastoma cells. 1177 74

The effects of a vasoactive intestinal peptide (VIP) receptor antagonist (VIPhyb) on human glioblastoma cells were characterized. Pituitary adenylate cyclase activating polypeptide (125I-PACAP-27) bound with high affinity to U87, U118, and U373 cells. Specific 125I-PACAP-27 binding to U87 cells was inhibited, with high affinity, by PACAP but not VIP or VIPhyb (IC50 = 10, 1500, and 500 nM, respectively). By reverse transcriptase-polymerase chain reaction (RT-PCR), a major 305 bp band was observed indicative of PAC1 receptors. PACAP-27 caused cAMP elevation and the increase in cAMP caused by PACAP-27, was inhibited by the VIPhyb. Also, PACAP-27 caused cytosolic Ca2+ elevation in Fura-2AM loaded U87 cells and the VIPhyb inhibited this increase. Using the MTT growth assay, the VIPhyb was shown to inhibit glioblastoma growth in a concentration-dependent manner. Using a clonogenic assay in vitro, 10 microM VIPhyb significantly inhibited proliferation of U87, U118, and U373 cells. In vivo, 0.4 microg/kg VIPhyb inhibited U87 xenograft proliferation in nude mice. These results suggest that the VIPhyb antagonizes PAC1 receptors on glioblastoma cells and inhibits their proliferation.
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PMID:A vasoactive intestinal peptide antagonist inhibits the growth of glioblastoma cells. 1185 29

Serotonin 5-HT(7) receptors are present in astrocytes. Understanding their role in this type of cell would greatly benefit from the identification of astroglial cell lines expressing this receptor type. The aim of the present study was to assess the expression of native 5-HT(7) receptors and 5-HT(7) receptor mRNA in a number of human glioblastoma cell lines, by means of cAMP measurements, Western blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. 5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced concentration-dependent stimulations of cAMP accumulation in the human glioblastoma cell lines, U-373 MG, U-138 MG, U-87 MG, DBTRG-05MG, T98G, H4, CCF-STTG1 and Hs 683. The rank order of potency was 5-CT>5-HT=5-MeOT>>8-OH-DPAT. The effect of 5-CT was inhibited in a concentration-dependent manner by the selective 5-HT(7) receptor antagonist SB-269970 in all human glioblastoma cells. Schild analyses yielded slope factors close to unity (0.89-1.13) and pA(2) values of 8.69-9.05. Western blot analysis revealed the presence of immunoreactive bands corresponding to the human 5-HT(7) receptor in extracts of all human glioblastoma cell lines. The presence of the three splice variants of the 5-HT(7) receptor (5-HT(7(a/b/d))) was visualized by RT-PCR analysis with specific primers in all human glioblastoma cell lines. In conclusion, human glioblastoma cell lines express functional 5-HT(7) receptors and the three splice variants of the corresponding mRNA. These cell lines could serve as model systems of native 5-HT(7) receptors in glial cells to investigate their putative role in processes like release of neurotrophic factors or inflammatory cytokines.
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PMID:Functional expression of the serotonin 5-HT7 receptor in human glioblastoma cell lines. 1533 60

Our previous studies established in U87-MG glioblastoma cells that elevated cAMP increased transcription of the endogenous as well as a transiently-transfected brain creatine kinase (CKB) gene, despite the absence of a cAMP response element (CRE) in the CKB proximal promoter. This report employed transfection to show that the transcription of CKB in U87 cells is induced by transcription factor AP2alpha, which is known to be activated by cAMP. Dominant-negative forms of AP2alpha not only prevented the AP2alpha-mediated activation of CKB but also blocked the cAMP-mediated increase in CKB transcription caused by forskolin treatment. The mutation of the four potential AP2 elements within the CKB proximal promoter showed that induction of CKB by AP2 was mediated principally through the AP2 element located at -50 bp in the promoter. Electromobility shift assays revealed a protein in U87 nuclear extracts that bound to a consensus AP2alpha element as well as to the (-50) AP2 element in CKB. Interestingly, the CKB (-50) AP2 element contains GCCAATGGG which also bound NF-Y, the CCAAT-binding protein, suggesting that interplay between AP2 and NF-Y may modulate CKB transcription. This is the first report of a role for AP2 in the regulation of CKB transcription and of an AP2 element within which an NF-Y site is located.
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PMID:Transcription of brain creatine kinase in U87-MG glioblastoma is modulated by factor AP2. 1577 31

A promising attempt in the field of tumour therapy is the modulation of intracellular, proliferation-associated signalling pathways. The role of cyclic nucleotide phosphodiesterases (PDEs), key enzymes in cAMP/cGMP signal transduction, was investigated in two human CNS tumour cell lines as well as in the rat glioblastoma cell line C6 in comparison with rat cerebellar astrocytes with the emphasis on target evaluation. We found differential PDE expression patterns in human CNS tumour cell lines as well as in CNS cells of rat origin. In human glioblastoma cells, intracellular cAMP and Ca(2+) levels correlated well with the PDE expression pattern. There were, however, marked differences in PDE expression and Ca(2+) kinetics between the human glioblastoma cell lines. In contrast to human epithelial tumour cells, shown earlier by us to express significantly enhanced cAMP-specific PDE activity, this was not the case in rat glioblastoma cells compared with non-malignant rat astrocytes. Despite different levels of PDE1 and PDE4 expression and activity, cyclic nucleotide and Ca(2+) levels in non-malignant and malignant rat CNS cells were similar. These in vitro data do not support the concept of PDE1C representing a target exploitable for drug treatment of malignant CNS tumours.
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PMID:Differential phosphodiesterase expression and cytosolic Ca2+ in human CNS tumour cells and in non-malignant and malignant cells of rat origin. 1581 55

We have studied the expression of CC-chemokine receptor 5 (CCR5) at the protein level in human fetal neural stem/progenitor and glioblastoma cells in differentiation, using immunocytochemistry, routine fluorescence microscopy and confocal laser microscopy analysis. Neural stem/progenitor cells were isolated from the brain of 18-21 weeks old fetuses aborted due to medical indications, and propagated in vitro as neurospheres. Glioblastoma cells were isolated from tumour biopsies and propagated in vitro as spheres according to the same methods as fetal neural cells. Two stem/progenitor cell neurosphere and two glioblastoma spheroid cultures were initiated to differentiate using RA and cAMP. The cells were fixed and analyzed immunocytochemically on the 1st, 3rd, and 8th days of the differentiation. The expression of CCR5 was localized mainly in the cell nuclei, and was usually much weaker, if at all, in cytoplasm. Confocal laser microscopy analysis confirmed the same location. The expression of CCR5 was the highest one on the 3rd day of differentiation in all cultures, but showed also distinct differences between cultures, and in normal fetal differentiated stem/progenitor cells the expression of CCR5 was much weaker than in differentiated glioblastoma spheric cells.
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PMID:Chemokine receptor CCR5 expression in in vitro differentiating human fetal neural stem/progenitor and glioblastoma cells. 1627 45


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