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:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma, one of the best vascularized tumours in humans, appears well suited for an antiangiogenic therapy. VEGF (vascular endothelial growth factor), the most important angiogenesis factor identified to date, is highly expressed in glioblastoma. VEGF is particulary upregulated in palisading cells adjacent to necroses and has subsequently been shown to be hypoxia-inducible in glioma cells in vitro. VEGF-receptor tyrosine kinases, VEGF-R1 (flt-1) and VEGF-R2 (flk-1), are induced in a tumour stage dependent manner during glioma progression and are exclusively expressed in tumour vascular endothelial cells. These observations suggest that VEGF-receptors are promising targets for tumour endothelial cell specific therapy. The ability to block VEGF-signalling by the VEGF-R2 dominant-negative mutant identifies the VEGF/VEGF-R2 system as a major regulator of glioma angiogenesis. Several experimental approaches demonstrate that in rat gliomas tumour growth can be prevented by the inhibition of angiogenesis. These findings are of pivotal importance for the development of anti-angiogenic therapies in glioblastoma patients.
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PMID:Anti-angiogenic gene therapy of malignant glioma. 923 24

Exposure of cells to protein tyrosine phosphatase (PTP) inhibitors causes an increase in the phosphotyrosine content of many cellular proteins. However, the level at which the primary signaling event is affected is still unclear. We show that Jaks are activated by tyrosine phosphorylation in cells that are briefly exposed to the PTP inhibitor pervanadate (PV), resulting in tyrosine phosphorylation and functional activation of Stat6 (in addition to other Stats). Mutant cell lines that lack Jak1 activity fail to support PV-mediated [or interleukin 4 (IL-4)-dependent] activation of Stat6 but can be rescued by complementation with functional Jak1. The docking sites for both Jak1 and Stat6 reside in the cytoplasmic domain of the IL-4 receptor alpha-chain (IL-4Ralpha). The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Ralpha chain, fail to support Stat6 activation in response to either IL-4 or PV. Complementation of T98G cells with the IL-4Ralpha restores both PV-mediated and IL-4-dependent Stat6 activation. Murine L929 cells, which do not express the gamma common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation. Thus, Stat6 activation by PV is an IL-4Ralpha-mediated, Jak1-dependent event that is independent of receptor dimerization. We propose that receptor-associated constitutive PTP activity functions to down-regulate persistent, receptor-linked kinase activity. Inhibition or deletion of PTP activity results in constitutive activation of cytokine signaling pathways.
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PMID:Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. 923 16

The occurrence of brain tumors is associated with broad suppression of the immune system function; however, the mechanisms involved in this impairment are not fully characterized. In this study, we have examined mechanisms involved in diminished T lymphocyte reactivity in patients with glioblastomas as compared to patients with other types of brain tumors. We found that the proliferative response of T lymphocytes stimulated with phytohemagglutinin or anti-CD3 was significantly reduced in these patients as compared to patients with meningiomas, oligodendrogliomas and healthy individuals. Stimulated T cells appear to express lower levels of the alpha-subunit (p55) of the IL-2 receptor (IL-2R), and increased levels of soluble IL-2R in cell supernatants, whereas no significant differences were observed in the level of the beta (p75)- or gamma-subunits. In addition, we found that competent T cells of glioblastoma patients exhibit lower levels of tyrosine phosphorylation in response to IL-2 as compared with cells of healthy donors. The decrease in the levels of IL-2 and its receptor was selective since no significant changes were observed in the secretion of other Th1- and Th2-derived cytokines (IFN-gamma and IL-4) and the expression of their respective receptors. These results indicate that the diminished response of T cells obtained from patients with glioblastomas may be due to a selective defect in the production of IL-2 and in the expression of functional IL-2R due to a decreased expression of the membranal IL-2R alpha and to lower levels of tyrosine phosphorylation in response to IL-2.
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PMID:A selective impairment of the IL-2 system in lymphocytes of patients with glioblastomas: increased level of soluble IL-2R and reduced protein tyrosine phosphorylation. 932 45

We have detected a tyrosine phosphorylated 200 kDa glycoprotein (gp200) on the surface of two tumour cells of neural origin, namely A1235 glioma and A172 glioblastoma. gp200 (polypeptide mass of 165-170 kDa) has all the structural features of a growth factor receptor and it appears to display high basal tyrosine kinase activity, a characteristic associated with transforming proteins. Another interesting feature of gp200 is that it is immunologically highly related to the EGF receptor (polypeptide mass of 135 kDa), a member of the erb-B family of proteins; however, it lacks EGF binding activity. gp200 also differs from all other EGF-receptor-related oncogenic proteins, namely erb-B-2, erb-B-3 and erb-B-4 gene products, and hence appears to be yet another member of the erb-B family of proteins. This is further strengthened by the fact that both gp200 and the EGF receptor are also recognized by a conformation-specific anti-peptide antibody to the cytoplasmic domain of the beta-type PDGF receptor. In the EGF- and the PDGF receptors, this peptide epitope is cryptic and receptor phosphorylation unmasks this site [Panneerselvam K, Reitz H, Khan S A, and Bishayee S (1995) J Biol Chem 270, 7975-7979] indicating that this epitope might be important in biological message transmission. In this context, the expression of a novel EGF-receptor-related 200 kDa protein with high basal kinase activity in certain tumour cells of neural origin and the fact that it contains an important peptide epitope suggest its possible role in normal and abnormal cell growth.
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PMID:A novel 200 kDa plasma membrane glycoprotein with high basal tyrosine kinase activity in tumour cells. 934 24

Recent studies show that tyrosine phosphorylation by a number of neuropeptides may be an important intracellular pathway in mediating changes in cell function, particularly related to growth. Neuromedin B (NMB), a mammalian bombesin related peptide, functions through a distinct receptor, the neuromedin B receptor (NMB-R), of which little is known about its cellular basis of action. In the present study we explored the ability of NMB-R activation to cause tyrosine phosphorylation of focal adhesion kinase (p125(FAK)), an important substrate for tyrosine phosphorylation by other neuropeptides. NMB caused rapid increases in p125(FAK) phosphorylation which reached maximum at 2 min in both rat C6 glioblastoma cells which possess native NMB-Rs and rat neuromedin B receptor (rNMR-R) transfected BALB 3T3 cells. NMB had a half-maximal effect was at 0.4 nM and was 30-fold more potent than gastrin-releasing peptide (GRP). The stoichiometric relationships between increased p125(FAK) tyrosine phosphorylation and other cellular processes was similar in both C6 cells and rNMB-R transfected cells. TPA (1 microM) caused 45% and the calcium ionophore, A23187, 11% of maximal tyrosine phosphorylation of p125(FAK) seen with NMB. A23187 potentiated the effect of TPA. Pretreatment with the selective PKC inhibitor, GF109203X, inhibited TPA-induced p125(FAK) tyrosine phosphorylation, but it had no effect on the NMB stimulation. Pretreatment with thapsigargin completely inhibited NMB-stimulated increases in [Ca2+]i, but had no effect on NMB-stimulation of p125(FAK) phosphorylation either alone or with GF109203X. The tyrosine kinase inhibitor, tyrphostin A25, inhibited NMB-induced phosphorylation of p125(FAK) by 52%. However, tyrphostin A25 did not inhibit NMB-stimulated increases in [3H]inositol phosphates. Cytochalasin D, an agent which disrupts actin microfilaments, inhibited BN- and TPA-induced tyrosine phosphorylation of p125(FAK) completely. In contrast, colchicine, an agent which disrupts microtubules, had no effect. Pretreatment with Clostridium botulinum C3 exoenzyme which inactivates the small GTP-binding protein rho p21, also inhibited tyrosine phosphorylation of p125(FAK) by 55%. These results demonstrate that activation of NMB-R can cause rapid tyrosine phosphorylation of p125(FAK). NMB-induced tyrosine phosphorylation of p125(FAK) is independent of NMB-induced changes in [Ca2+]i or PKC. The integrity of the actin cytoskeleton but not of microtubules is necessary for NMB-stimulated phosphorylation of p125(FAK). The ras-related small GTP-binding protein rho p21 is at least partially involved in mediating NMB-induced tyrosine phosphorylation of p125(FAK). These results suggest that similar to some other neuropeptides, activation of this pathway may be an important mechanism in mediating cellular changes by this receptor such as growth.
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PMID:Neuromedin B receptor activation causes tyrosine phosphorylation of p125FAK by a phospholipase C independent mechanism which requires p21rho and integrity of the actin cytoskeleton. 940 68

Protein tyrosine phosphorylation was examined on a human glioblastoma cell line, T98G, after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of a 125 kDa protein at 30 min after stimulation. The 125-kDa molecule phosphorylated was revealed to be a focal adhesion kinase (FAK). Tyrosine phosphorylation of p125FAK continued at least up to 5 h, and decreased after 8 h concomitant with apoptosis. Tyrosine phosphorylation of p125FAK was blocked by herbimycin A, a potent inhibitor of protein tyrosine kinases, while apoptosis was accelerated. When T98G cells were incubated with FAK antisense oligonucleotide, apoptosis was also accelerated. These results suggest that tyrosine phosphorylation of p125FAK plays a suppressive role in hydrogen peroxide-induced apoptosis.
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PMID:A suppressive role of p125FAK protein tyrosine kinase in hydrogen peroxide-induced apoptosis of T98G cells. 943 84

Annexin II is a calcium and phospholipid binding protein and a substrate for protein-tyrosine kinases. Increased levels of annexin II are observed in various cancer cells and tissues, and the molecule has been proposed as a marker of malignancy in vivo. Annexin II was expressed in four glioma cell lines (D-54MG, D-37MG, U251MG and GaMG), as determined by Western blot analyses, immunofluorescence staining and flow cytometric measurements. In addition, annexin II expression was also found in cryostat sections obtained from 15 consecutive brain tumor biopsies: Ten were histologically classified as glioblastomas, one as an astrocytoma, two as meningiomas and two as brain metastases. Cultured spheroids from the glioma cell lines and from three of the glioblastoma biopsies showed lower levels of annexin II, than found in the monolayers of the cell lines and in the freshly cut biopsies. The annexin II expression of the cell lines were not found to be related to their proliferative, migratory or invasive properties. These findings indicate that although annexin II may serve as a marker of malignancy in vivo, its expression can be reduced in vitro, and appear unrelated to malignant features of glioma cell lines.
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PMID:Expression of annexin II in glioma cell lines and in brain tumor biopsies. 954 53

Expression of vascular endothelial growth factor (VEGF), an angiogenic factor and endothelial cell-specific mitogen, is induced by hypoxia in various cell lines as well as in solid tumors. In this study, we report that cell density has a profound effect on the expression of VEGF in human glioblastoma cells (U87) and human fibrosarcoma cells (HT1080), an effect that is independent of hypoxia. Northern blot analysis revealed that VEGF mRNA levels were four- to eightfold higher in cells seeded at high density compared to cells seeded at low density. This upregulation of VEGF message in response to seeding at high density was not seen with other mRNAs such as those for TGF-beta1 or GAPDH. Conditioned medium switch experiments between sparse and dense cells suggested that soluble factor(s) may not account for the observed changes in VEGF expression. Incubation with genistein, a protein tyrosine kinase inhibitor, for 3 h following seeding resulted in the reduction of the VEGF mRNA levels in highly confluent cultures but not in sparse cultures. To identify protein tyrosine kinases involved in the upregulation of the steady-state levels of VEGF mRNA in highly dense cultures, we analyzed the phosphorylation state of the c-src tyrosine kinase, in high versus low confluency cultures of U87 and HT1080 cells. Interestingly, an increased phosphorylation at Tyr416 of c-src was noted in high compared to low confluency, suggesting the activation of c-src in highly confluent cultures. Because extracellular signal-regulated kinases (ERKs) such as MAP kinase have been shown to be activated by extracellular stimuli and act downstream of c-src, we examined their possible involvement in this process. We found that the tyrosine phosphorylation level of MAP kinase is higher in dense compared to sparse cultures and, moreover, 6-thioguanine (6-TG), a potent inhibitor of ERKs, reduced VEGF mRNA levels in high but not low confluency. Furthermore, reintroduction of wild-type, but not mutant, von Hippel-Lindau (VHL) gene product in 786-O cells (a renal carcinoma cell line) specifically abrogated the induction of VEGF mRNA due to high cell density. Taken together, these data suggest that VEGF gene expression is regulated by cell density, and the protooncogene c-src and the tumor-suppressor VHL are modulators of this regulation.
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PMID:High cell density induces vascular endothelial growth factor expression via protein tyrosine phosphorylation. 957 97

The tyrosine kinase family includes growth factor receptor and cytoplasmic enzymes. It plays a key role in normal cell division and abnormal cell proliferation and differentiation. The most common tyrosine kinases are the epidermal-growth factor (EGFR) and platelet-derived growth factor (PDGF) receptors, and a chromosome Philadelphia product, the Bcr-abl oncogene. Many studies have attempted to correlate clinical evolution of tumors with tyrosine kinase expression. However, clinical application of these new prognostic factors has not yet been demonstrated. More recently, tyrosine-phosphorylation inhibitors (tryphostin) have been developed in phase I studies. Results that were obtained show some objective responses in patients with glioblastoma and polymetastatic cancer. Another approach to block tyrosine kinase expression is the use of monoclonal antibodies. Trials using such antibodies have shown interesting preliminary results.
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PMID:[Tyrosine kinase: implications in tumor pathology and therapeutic perspectives]. 977 78

Grb2-associated binder-1 (Gab-1) has been identified recently in a cDNA library of glioblastoma tumors and appears to play a central role in cellular growth response, transformation, and apoptosis. Structural and functional features indicate that Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR). Therefore, the aim of the study was to characterize the phosphorylation of recombinant human Gab-1 (hGab-1) protein by EGFR in vitro. Using the pGEX system to express the entire protein and different domains of hGab-1 as glutathione S-transferase proteins, kinetic data for phosphorylation of these proteins by wheat germ agglutinine-purified EGFR and the recombinant EGFR (rEGFR) receptor kinase domain were determined. Our data revealed similar affinities of hGab-1-C for both receptor preparations (KM = 2.7 microM for rEGFR vs 3.2 microM for WGA EGFR) as well as for the different recombinant hGab-1 domains. To identify the specific EGFR phosphorylation sites, hGab-1-C was sequenced by Edman degradation and mass spectrometry. The entire protein was phosphorylated by rEGFR at eight tyrosine residues (Y285, Y373, Y406, Y447, Y472, Y619, Y657, and Y689). Fifty percent of the identified radioactivity was incorporated in tyrosine Y657 as the predominant peak in HPLC analysis, a site exhibiting features of a potential Syp (PTP1D) binding site. Accordingly, GST-pull down assays with A431 and HepG2 cell lysates showed that phosphorylated intact hGab-1 was able to bind Syp. This binding appears to be specific, because it was abolished by changing the Y657 of hGab-1 to F657. These results demonstrate that hGab-1 is a high-affinity substrate for the EGFR and the major tyrosine phosphorylation site Y657 in the C terminus is a specific binding site for the tyrosine phosphatase Syp.
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PMID:Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro. 989 Aug 93


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