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)

Induction of growth arrest by differentiation is an attractive therapeutic strategy against glioma cell proliferation and tumorigenicity. The observation that the expression of the JNK3 gene is lost in many human gliomas makes the JNK pathway an interesting target for investigation. Here, the influence of the JNK pathway on the differentiation of C6 glioma cells was investigated using pharmacological inhibition and JNK3 knockdown. Growth arrest induced the expression of JNK3 on transcriptional and translational level, whereas the expression of the cell cycle inhibitor p27kip was induced on the translational level only. Transient depletion of JNK3 in growth arrested C6 cells resulted in an about 40% decrease in cell adhesion and almost completely abolished the induction in p27kip protein. In addition, overexpression of wild type JNK3 in proliferating C6 cells led to a marked inhibition of proliferation. Beside synthesis, the amount of p27kip protein is regulated by its stability, which is known to be enhanced by phosphorylation at serine10 of p27kip. Here, the JNKs were identified as kinases that are able to phosphorylate p27kip at Ser10. As a result, the stability of p27kip protein is reduced by inhibition of the JNK pathway. These results suggest that the JNK pathway influences the stability of p27kip by phosphorylation of serine10 and that JNK3 is responsible for the translational activation of p27kip protein expression in growth arrested C6 glioma cells and therefore cell cycle arrest.
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PMID:Growth-arrest-dependent expression and phosphorylation of p27kip at serine10 is mediated by the JNK pathway in C6 glioma cells. 1851 91

Lysophosphatidylserine (LPS) was found to stimulate intracellular calcium increase in U87 human glioma cells. LPS also stimulated chemotactic migration of U87 human glioma cells, which was completely inhibited by pertussis toxin (PTX). Moreover, LPS was also found to stimulate ERK, p38 MAPK, JNK, and Akt activities in U87 cells. We observed that LPS-induced U87 chemotaxis was mediated by PI3K, p38 MAPK, and JNK. LPS-induced chemotactic migration in U87 cells was inhibited by Ki16425, an LPA(1/3) receptor-selective antagonist, which suggested that the Ki16425-sensitive G-protein coupled receptor (GPCR) played a role in this process. Moreover, U87 cells were found to uniquely express LPA(1) but not LPA(2-5). In addition, LPS failed to stimulate the NF-kappaB-driven luciferase activity in exogenously LPA(1)-transfected HepG2 cells. Taken together, we propose that LPS stimulates GPCR, which is in contrast to the well-known LPA receptors, thus resulting in the chemotactic migration in U87 human glioma cells.
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PMID:Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells. 1861 30

The properties of arsenic trioxide (arsenic) have been known for centuries. This compound has been used, among others, in the industrial production of paints and glass and also for the conservation of leather and wood. Although arsenic trioxide is highly toxic, this compound was shown to have a therapeutic potential as early as the fifteenth century. The period between the seventeenth and nineteenth centuries resulted in the development of new arsenic-based drugs which were applied for the treatment of skin diseases and acute promyelocytic leukemia. The mechanism of action of arsenic trioxide is mainly related to the induction of apoptosis (programmed cell death) in cancer cells. In particular it involves effects on the activities of JNK kinases, NF-kB transcription factor, glutathione, caspases, as well as pro- and anti-apoptotic proteins. Experiments investigating the effect of arsenic trioxide on cell lines such as glioma and prostate, breast, stomach, liver, and ovarian cancer are in progress. There are also clinical trials underway aimed at the use of arsenic trioxide with ascorbic acid, retinoid acid, and growth factors in combined therapy.
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PMID:[Selected mechanisms of the therapeutic effect of arsenic trioxide in cancer treatment]. 1880 35

Neurofibromatosis-1 (NF1) is a common tumor predisposition syndrome in which affected individuals develop benign and malignant tumors. Previous studies from our laboratory and others have shown that benign tumor formation in Nf1 genetically engineered mice (GEM) requires a permissive tumor microenvironment. In the central nervous system, Nf1 loss in glia is insufficient for glioma formation unless coupled with Nf1 heterozygosity in the brain. Our subsequent studies identified Nf1+/- microglia as a critical cellular determinant of optic glioma growth in Nf1 GEM. Using NF1 as an experimental paradigm to further characterize the role of microglia in glioma growth, we first examined the properties of Nf1+/- microglia in vitro and in vivo. Nf1+/- microglia exhibit increased proliferation and motility and express elevated levels of genes associated with microglia activation. We further show that Nf1+/- microglia harbor high levels of activated c-Jun-NH(2)-kinase (JNK) without any significant changes in Akt, mitogen-activated protein kinase (MAPK), or p38-MAPK activity. In contrast, Nf1-/- astrocytes do not exhibit increased JNK activation. SP600125 inhibition of JNK activity in Nf1+/- microglia results in amelioration of the increased proliferation and motility phenotypes and reduces the levels of expression of activated microglia-associated transcripts. Moreover, SP600125 treatment of Nf1 optic glioma-bearing GEM results in reduced optic glioma proliferation in vivo. Collectively, these findings suggest that Nf1+/- microglia represent a good model system to study the role of specialized microglia in brain tumorigenesis and identify a unique Nf1 deregulated pathway for therapeutic studies aimed at abrogating microenvironmental signals that promote brain tumor growth.
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PMID:Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. 1907 5

Adrenomedullin is a secreted peptide hormone with multiple functions. Although a number of reports have indicated that adrenomedullin may be involved in tumor progression, its mechanism of action remains obscure. In this study, we have analysed the signal transduction pathway activated by adrenomedullin in human glioma cells. Our results revealed that adrenomedullin induced the phosphorylation of both c-Jun and JNK in glioblastoma cells. Silencing JNK expression with siRNA reversed the phosphorylation of c-Jun induced by adrenomedullin, indicating that JNK is responsible of c-Jun activation. In addition, electrophoretic mobility-shift assays showed that the increase in phosphorylation of c-Jun was associated with increased AP-1 DNA binding activity. Supershift assays and co-immunoprecipitation demonstrated that c-Jun and JunD are part of the AP-1 complex, indicating that activated c-Jun is dimerized with JunD in response to adrenomedullin. Furthermore, adrenomedullin was shown to promote cell transit beyond cell cycle phases with a concomittant increase in cyclin D1 protein level, suggesting that adrenomedullin effects cell proliferation through up-regulation of cyclin D1. The inhibition of JNK activation or the suppression of c-Jun or JunD expression with siRNA impaired the effects of adrenomedullin on cell proliferation and on cyclin D1. Taken together, these data demonstrate that activation of cJun/JNK pathway is involved in the growth regulatory activity of adrenomedullin in glioblastoma cells.
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PMID:Adrenomedullin promotes cell cycle transit and up-regulates cyclin D1 protein level in human glioblastoma cells through the activation of c-Jun/JNK/AP-1 signal transduction pathway. 1916 30

The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells. We also assessed the experimental therapeutic effects of combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition. PTEN significantly inhibited HGF-induced proliferation, cell cycle progression, migration, and invasion of glioblastoma cells. PTEN attenuated HGF-induced changes of signal transduction proteins Akt, GSK-3, JNK, and mTOR as well as cell cycle regulatory proteins p27, cyclin E, and E2F-1. Combining PTEN restoration to PTEN-null glioblastoma cells with c-Met and HGF inhibition additively inhibited tumor cell proliferation and cell cycle progression. Similarly, combining a monoclonal anti-HGF antibody (L2G7) with the mTOR inhibitor rapamycin had additive inhibitory effects on glioblastoma cell proliferation. Systemic in vivo delivery of L2G7 and PTEN restoration as well as systemic in vivo deliveries of L2G7 and rapamycin additively inhibited intracranial glioma xenograft growth. These preclinical studies show for the first time that PTEN loss amplifies c-Met-induced glioblastoma malignancy and suggest that combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition is worth testing in a clinical setting.
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PMID:Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy. 1919 Jan 20

Malignant glioma is resistant to the induction of apoptosis, resulting in a subsequent failure of chemotherapy in clinical treatment strategies. Downregulation of bcl-2 and bcl-xl expression in glioblastoma cells can induce apoptosis. BH3-only proteins, which include Bmf, are essential initiators of stress-induced cell death and apoptosis. Whether PS-341 regulates expression of BH3-only proteins in glioblastoma cells during the procedure of apoptosis is unclear. This study was designed to investigate the effects of PS-341 on glioma cell death and its possible signaling pathway. Our results demonstrate that Bmf is upregulated by PS-341 in A172 and T98G cells, and Bmf has a crucial role in PS-341-mediated cell death. In addition, we found that expression of Bmf is regulated by JNK phosphorylation.
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PMID:Bmf is upregulated by PS-341-mediated cell death of glioma cells through JNK phosphorylation. 1926 18

Hypoxia and necrosis are fundamental features of glioblastoma (GBM) and their emergence is critical for the rapid biological progression of this fatal tumor; yet, underlying mechanisms are poorly understood. We have suggested that vaso-occlusion following intravascular thrombosis could initiate or propagate hypoxia and necrosis in GBM. Tissue factor (TF), the main cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Epidermal growth factor receptor (EGFR) amplification and PTEN loss are two common genetic alterations seen in GBM but not in lower-grade astrocytomas that could be responsible for TF up-regulation. The most frequent EGFR mutation in GBM involves deletion of exons 2 to 7, resulting in the expression of a constitutively active receptor, EGFRvIII. Here, we show that overexpression of EGFR or EGFRvIII in human glioma cells causes increased basal TF expression and that stimulation of EGFR by its ligand, EGF, leads to a marked dose-dependent up-regulation of TF. In all cases, increased TF expression led to accelerated plasma coagulation in vitro. EGFR-mediated TF expression depended most strongly on activator protein-1 (AP-1) transcriptional activity and was associated with c-Jun NH(2)-terminal kinase (JNK) and JunD activation. Restoration of PTEN expression in PTEN-deficient GBM cells diminished EGFR-induced TF expression by inhibiting JunD/AP-1 transcriptional activity. PTEN mediated this effect by antagonizing phosphatidylinositol 3-kinase activity, which in turn attenuated both Akt and JNK activities. These mechanisms are likely at work in vivo, as EGFR expression was highly correlated with TF expression in human high-grade astrocytoma specimens.
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PMID:Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. 1927 85

Glial cell line-derived neurotrophic factor (GDNF) is highly expressed both in neurons and astrocytes in injured tissues. Astrocytes support neurons by releasing neurotrophic factors including GDNF. It has been reported that various agents including cytokines such as interleukin (IL)-1beta induce GDNF mRNA expression and the release in astrocytes. However, the mechanism behind the GDNF synthesis and release remains unclear. Herein, we investigated the mechanisms of the IL-1beta-induced GDNF release from rat C6 glioma cells. IL-1beta time dependently stimulated GDNF release from C6 cells. IL-1beta induced the phosphorylation of inhibitor kappa B (IkappaB), p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and signal transducer and activator of transcription (STAT) 3. The IL-1beta-stimulated levels of GDNF were suppressed by wedelolactone, an inhibitor of IkappaB kinase, SB203580, an inhibitor of p38 MAP kinase, PD98059, an inhibitor of MAP kinase kinase 1/2 or Janus family of tyrosine kinase (JAK) inhibitor I, an inhibitor of upstream kinase of STAT3. On the contrary, SP600125, an inhibitor of SAPK/JNK, failed to reduce the IL-1beta-effect. These results strongly suggest that IL-1beta stimulates GDNF release through the pathways of IkappaB-nuclear factor kappa B, p38 MAP kinase, p44/p42 MAP kinase and JAK-STAT3, but not through the SAPK/JNK pathway in glioma cells.
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PMID:Mechanisms of interleukin-1beta-induced GDNF release from rat glioma cells. 1936 79

Glial cell line-derived neurotrophic factor (Gdnf) promotes neurite outgrowth and survival of neuronal cells, but its transcriptional regulation is poorly understood. Here, we sought to investigate the mechanism underlying fibroblast growth factor-2 (FGF2) induction of Gdnf expression in astrocytes. We found that FGF2 stimulation of rat astrocytes induced expression of Egr-1 at a high level. Sequence analysis of the rat Gdnf gene identified three overlapping Egr-1-binding sites between positions -185 and -163 of the rat Gdnf promoter. Transfection studies using a series of deleted Gdnf promoters revealed that these Egr-1-binding sites are required for maximal activation of the Gdnf promoter by FGF2. Chromatin immunoprecipitation analysis indicated that Egr-1 binds to the Gdnf promoter. Furthermore, the induction of Gdnf expression by FGF2 is strongly attenuated both in C6 glioma cells stably expressing Egr-1-specific small interfering RNA and in primary cultured astrocytes from the Egr-1 knock-out mouse. Additionally, we found that stimulation of the ERK and JNK pathways by FGF2 is functionally linked to Gdnf expression through the induction of Egr-1. These data demonstrate that FGF2-induced Gdnf expression is mediated by the induction of Egr-1 through activation of the ERK and JNK/Elk-1 signaling pathways.
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PMID:Egr-1 is necessary for fibroblast growth factor-2-induced transcriptional activation of the glial cell line-derived neurotrophic factor in murine astrocytes. 1972 Nov 35


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