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 we identified three novel Schwann cell mitogens named GGF (glial growth factor)-I (34 kDa), GGF-II (59 kDa), and GGF-III (45 kDa), and provided evidence that they are three distinct but structurally related members of a larger family of factors, which includes heregulin, neu differentiation factor, and acetylcholine receptor-inducing activity (ARIA). We report here the characterization of the mitogenic and trophic activities for all three forms of GGF on rat Schwann cells and several other cell types. GGF-I, GGF-II, and GGF-III are potent mitogens for rat Schwann cells in vitro at nanomolar concentrations, whereas at lower concentrations they promote Schwann cell survival, in the absence of cAMP elevating agents. Forskolin, an adenylate cyclase activator, potently synergizes with the GGFs by an indirect mechanism, possibly involving transcriptional activation of GGF receptor(s). In addition, the GGFs stimulate DNA synthesis in rat glioma C6 cells, and in SK-BR-3 cells, which overexpress the p185 neu/erbB2. Fibroblasts obtained from different sources are weakly stimulated by GGFs, whereas PC12 cells are unable to respond under a variety of experimental conditions. These observations are consistent with the proposal that GGF-I, GGF-II, and GGF-III are a set of potent glial cell mitogens and putative ligands of members of the EGF receptor family, namely p185 neu/erbB2, p160/erbB3, and p180/erbB4, which may play important roles in the development, regeneration, and tumor biology of the peripheral nervous system.
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PMID:Glial growth factors I-III are specific mitogens for glial cells. 898 98

A cholinergic neuroblastoma x glioma hybrid cell line NG108-15 is able to form functional synapses, and contains both AChR-aggregating and AChR-inducing activities when cocultured with myotubes. Several lines of evidence indicate that the AChR-inducing activity of NG108-15 cells is derived from neuregulin. The conditioned medium of cultured NG108-15 cells induced the expression of AChR alpha-subunit as well as the tyrosine phosphorylation of erbB-3 receptor. NG108-15 cells expressed neuregulin with a protein of approximately 100 kDa in size and transcripts of approximately 6.8 kbp, approximately 2.6 kbp and approximately 1.8 kbp; mRNAs encoding beta1 and alpha2 isoforms of neuregulin were revealed. NG108-15 cells were induced to differentiate by chemicals, and the chemical-induced differentiation of NG108-15 cells increased the level of neuregulin mRNA expression approximately 3-fold while the expression of a housekeeping gene remained relatively unchanged. The activity of neuregulin in the conditioned medium of NG108-15 cells was reduced by treating the medium with heparin and anti-neuregulin antibody. In addition, NG108-15 cells were transfected with antisense neuregulin cDNA and its expression of neuregulin was reduced, while its neuregulin-induced tyrosine phosphorylation activity was markedly decreased. This is the first direct demonstration that the NG108-15 cell-induced AChR upregulation on cultured myotubes is mediated by neuron-derived neuregulin.
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PMID:NG108-15 cells express neuregulin that induces AChR alpha-subunit synthesis in cultured myotubes. 942 27

The activation of autocrine loops involving proto-oncogene related receptor tyrosine kinases has led to the analysis of a large number of growth factor systems in human glioma specimens and cell lines. The ErbB-2 system, also called HER-2 or neu, is analogous to the epidermal growth factor receptor system (EGF-R, ErbB-1). Neuregulins consist of a large family of proteins arising from alternative mRNA splicing of a single gene located at 8p22-p11. Activation of ErbB-2 by neuregulins occurs in heterodimeric complexes with ErbB-3 and ErbB-4. A panel of human glioma cell lines, which had previously been analyzed for ErbB-2 expression, was examined for ErbB-3 and ErbB-4 expression. Coordinate expression of ErbB-2, -3 or -4 was not observed in these cell lines. Despite the presence of a complete system capable of signaling in about half the cell lines, no constitutive activation of ErbB-2, -3 or -4 was observed, and autophosphorylation of ErbB-2 in response to heregulin was observed only in one cell line from the panel, NCE-G84. Moreover, the addition of recombinant heregulin or antibodies capable of disrupting ErbB-2/ErbB-3 complexes had no effect on cell proliferation. We conclude that the role of neuregulins and its receptors in the control of glioma cell proliferation may be limited or may be context dependent on in situ conditions which are lost in vitro. Alternatively, neuregulins may be involved in cell differentiation or survival in the central nervous system. Data supporting these conclusions are described in more detail herein.
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PMID:Heregulins and the ErbB-2/3/4 receptors in gliomas. 944 30

ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT-PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which amplified a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the 'full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with different intracellular signalling pathways and therefore influence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the C-terminal transcripts as CT-a (full-length) and CT-b which lacks the P13K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.
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PMID:Two erbB-4 transcripts are expressed in normal breast and in most breast cancers. 978 9

Laminins and their receptors influence neoplastic growth and invasiveness. We recently reported the abnormal expression of a laminin receptor, alpha6beta4 integrin, in human astrocytomas. To further investigate the role of alpha6beta4 in gliomas, we produced an experimental model of glioma in rat by transplacental ethylnitrosourea (ENU) administration. This animal model allowed us to study the timing of alpha6beta4 expression during tumor development and the topography of expression in the tumor and the surrounding tissue. Immunohistochemistry, in situ hybridization, and immunoprecipitation studies demonstrated that alpha6beta4 heterodimer forms in experimental gliomas, and confirmed that alpha6beta4 is expressed diffusely in neoplastic cells and reactive astrocytes, but not in normal glia surrounding the tumors. Interestingly, alpha6beta4 was expressed from the early phases of tumor development, and more highly expressed by cells in the proliferative centers of the tumors. Both neoplastic cells and reactive astrocytes also expressed the glial growth factor (neuregulin) receptors, Erb-B2 and Erb-B3. Finally, alpha6beta4 expression was reduced in a subset of tumor blood vessels. Thus, this study suggests a potential role for alpha6beta4 in the pathogenesis of gliomas. Furthermore, this is the first description of altered integrin expression in experimental gliomas; transplacental ENU-induced gliomas in rat will provide a useful model to study the role of altered adhesion in the pathogenesis of human gliomas.
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PMID:Laminin receptor alpha6beta4 integrin is highly expressed in ENU-induced glioma in rat. 1008 72

Human Schwann cells (SCs) can be isolated and expanded with mitogens using cell culture techniques. These cells have been demonstrated to promote axonal regrowth in both the central and peripheral nervous system. Primary rat SCs can be immortalized with long-term exposure to mitogens. Transplantation of these cells into an autogenic host sciatic nerve results in the formation of tumors. Human cells are, in general, relatively more resistant to malignant transformation, but any potential risk for inducing tumor after transplantation of SCs in humans must be excluded. In this study, the malignant potential of mitogen expanded human SCs injected into the sciatic nerve of immunodeficient mice was investigated. Human SCs were isolated from human peripheral nerves and placed in cell culture, expanded with mitogens (heregulin and forskolin) for many passages (0-6 times), and then injected within the sciatic nerve of Severe Combined Immunodeficient (SCID) rat or mice. As a positive control for tumor formation in this xenograft model, human glioma cells were also injected. The proliferation index (PI) of the human SCs gradually decreased with each passage in cell culture. SC purity remained stable until the 6th passage, and then decreased significantly for older passages, so that the cultures were over-grown with fibroblasts. The incidence for rat or human glioma cells to induce tumors was 100% and 92%, respectively. In contrast, there was no tumor induced by human primary or mitogen expanded SCs. Demyelination, remyelination and formation of connective sheath at the injection site were observed in some cases after injection of the human SCs. Thus, mitogen-expanded human SCs do not produce tumors when transplanted in vivo, which suggests that these cells are safe, and deserve further study towards their use in clinical transplantation.
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PMID:Assessment of the malignant potential of mitogen stimulated human Schwann cells. 1044 86

Neuregulins have been implicated in a number of events in cells in the oligodendrocyte lineage, including enhanced survival, mitosis, migration, and differentiation. At least two signaling pathways have been shown to be involved in neuregulin signaling: the phosphatidylinositol (PI)-3 kinase and the mitogen-activated protein kinase pathways. In the present studies, we examined the signaling pathway involved in the survival function of heregulin, focusing on heregulin-induced changes in Akt activity in cultured glial cells, and the consequences of Akt activation in cells in the oligodendrocyte lineage. Heregulin binds erbB receptors, and in our studies, primary cultures of both oligodendrocyte progenitor cells and differentiating oligodendrocytes expressed erbB2, erbB3, and erbB4 receptors. In C6 glioma cells and primary cultures of oligodendrocytes, heregulin induced time- and dose-dependent Akt phosphorylation at Ser(473) in a wortmannin-sensitive manner. To investigate further the signaling pathway for heregulin in glial cells, BAD was overexpressed in C6 glioma cells. In these cells, heregulin induced phosphorylation of BAD at Ser(136). Apoptosis of oligodendrocyte progenitor cells induced by growth factor deprivation was effectively blocked by heregulin in a wortmannin-sensitive manner. Overexpression of dominant negative Akt but not of wild-type Akt by adenoviral gene transfer in primary cultures of both oligodendrocytes and their progenitors induced significant apoptosis through activation of the caspase cascade. The present data suggest that the survival function of heregulin is mediated through the PI-3 kinase/Akt pathway in cells in the oligodendrocyte lineage and that the Akt pathway may be quite important for survival of cells in this lineage.
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PMID:Akt-mediated survival of oligodendrocytes induced by neuregulins. 1102 22

Gliomas are the most frequently diagnosed adult primary brain malignancy. These tumors have a tendency to invade diffusely into the surrounding healthy brain tissue, thereby precluding their successful surgical removal. In this report, we examine the potential for the neuregulin-1/erbB receptor signaling network to contribute to this process by modulating glioma cell motility. Neuregulin-1 is expressed throughout the immature and adult central nervous system and has been demonstrated to influence the migration of a variety of cell types in the developing brain. In addition, erbB2, an integral member of the heterodimeric neuregulin-1 receptor, has been shown to be overexpressed in human glioma biopsies. Using antibodies specific for erbB2 and erbB3, we show that these receptors localize preferentially in regions of the plasma membrane which are involved in facilitating cellular movement. Here, erbB2 colocalizes and coimmunoprecipitates with members of the focal complex including beta1-integrin and focal adhesion kinase. Further, erbB receptor activation by neuregulin-1 enhances cell motility in two-dimensional scratch motility assays and stimulates cell invasion in three-dimensional Transwell migration assays. These effects of neuregulin-1 appear to involve the activation of focal adhesion kinase, which occurs downstream from erbB2 receptor stimulation. Taken together these data suggest that neuregulin-1 plays an important modulatory role in glioma cell invasion.
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PMID:Neuregulin-1 enhances motility and migration of human astrocytic glioma cells. 1260 Sep 89

The shedding mechanism for the tomoregulin (TR) ectodomain, which contains two follistatin modules and a single epidermal growth factor (EGF)-like domain, remains unclear. Our study provides the first evidence that proinflammatory cytokines, IL-1beta and TNF-alpha, induce TR-ectodomain shedding in cultured A172 human glioma cells, without affecting TR mRNA expression. In addition, it appears that this shedding process is induced via activation of the NF-kappaB signaling pathway; with consequent increase in the production of metalloproteinases. Furthermore, since due to erbB4 tyrosine phosphorylation TR may have functions similar to EGF/neuregulin (NRG) family growth factors, our results suggest that following inflammation-induced injury, increases in TR shedding may contribute to tissue growth and repair in the central nervous system.
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PMID:Tomoregulin ectodomain shedding by proinflammatory cytokines. 1287 94

Receptor tyrosine kinases of the EGFR family transmit extracellular signals that control diverse cellular functions such as proliferation, differentiation and survival. Signaling function of a member of this family, HER3, is believed to be impaired due to deviations in its kinase consensus motifs. Here we address the functional role and signaling mechanisms of HER3. HER3 preferentially forms heterodimers with HER2 inducing the most potent mitogenic signal among EGFR family members. Our data show that in a glioma-derived cell line the cytoplasmic tyrosine kinase PYK2 is constitutively associated with HER3 and that stimulation with Heregulin results in PYK2 tyrosine phosphorylation. HER3, but not HER2, mediates the phosphorylation of the C-terminal region of PYK2 to promote a mitogenic response through activation of the MAPK pathway. A central role of PYK2 in signaling downstream of HER3 is substantiated by the demonstration that expression of a dominant-negative PYK2-KM construct abrogates the Heregulin-induced MAPK activity and inhibits the invasive potential of glioma cells. These results suggest a novel Heregulin/HER3-stimulated signaling pathway in glioblastoma-derived cell lines that involves phosphorylation of PYK2 and mediates invasiveness of glioma cells.
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PMID:Tyrosine phosphorylation of PYK2 mediates heregulin-induced glioma invasion: novel heregulin/HER3-stimulated signaling pathway in glioma. 1549 13


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