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)

Injection of the human neurotropic polyomavirus, JCV, into neonatal hamsters causes tumors of glial origin. Previously, a rapidly proliferating cell line, HJC-15, which expresses high levels of the viral T-antigen, had been established from JCV-induced hamster glial tumors. In our analyses of the mechanisms involved in the control of glial cell proliferation in these tumor cells, we have focused our attention on E2F1, a DNA-binding transcription factor which modulates the activity of genes involved in the S-phase of the cell cycle. Here, we report the identification of a novel nucleo-protein complex that forms between select E2F1-binding sites and nuclear proteins from HJC-15 and normal hamster glial cells. In comparison to the previously characterized E2F1 complexes, this complex exhibited distinct mobility, binding and biochemical characteristics. This slower migrating complex also contained several unique Glial E2F1-associated proteins, (GEAP), which have a distinct molecular mass. Of particular, unlike the classical E2F1 whose DNA binding activity is increased during S-phase, the level GEAPs remained constant throughout the cell cycle. GEAPs appeared to confer an increased basal transcriptional activity of promoters containing select E2F1 sites in HJC-15 cells. Interestingly, the increased transcriptional activity modulated by GEAPs in HJC-15 cells was overcome by overexpression of E2F1 in these cells. These data point to the presence of novel members of the E2F family in hamster glial cells with the potential to regulate expression of S-phase specific genes in glial tumors obtained upon intracerebral injection of JCV. The importance of these findings in the pathogenesis of viral-induced tumors and the role of cell cycle regulatory proteins in brain tumor formation is discussed.
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PMID:Evidence for GEAPS, novel Glial E2F1-Associated Proteins in hamster glioma cells induced by the human neurotropic polyomavirus, JCV. 864 30

Glioma cell lines show variable responses to radiation in a manner influenced by their p53 status. Irradiation of glioma cell lines does not generally induce apoptosis. When wild-type p53 is present, these cells undergo a G1 arrest that is closely associated with increased radiosensitivity as measured by clonogenic survival. Previously, others have shown that dysregulated overexpression of E2F1 induces apoptosis in cell lines with either functional or inactivated p53. We found that regardless of p53 status, apoptosis induced by overexpression of E2F1 in glioma cell lines was further enhanced by treatment with ionizing radiation. BAX induction did not follow E2F1 overexpression or irradiation in the glioma cell lines tested. Thus, the apoptotic response of glioma-derived cells to irradiation can be enhanced by E2F1 by a mechanism that does not involve the induction of BAX.
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PMID:Overexpression of E2F1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation. 1130 49

Scatter factor/hepatocyte growth factor (SF/HGF) expression has been linked to malignant progression in glial neoplasms. Using two glioma cell lines, U373MG and SNB-19, we have demonstrated that SF/HGF stimulation allows cells to escape G(1)/G(0) arrest induced by contact inhibition or serum withdrawal. SF/HGF induced effects on two mechanisms of cell cycle regulation: suppression of the cyclin-dependent kinase inhibitor p27 and induction of the transcription factor c-Myc. Regulation of p27 by SF/HGF was posttranslational and is associated with p27 nuclear export. Transient transfections of U373MG and SNB-19 with wild-type p27 and a degradation-resistant p27T187A mutant were insufficient to induce cell cycle arrest, and SF/HGF downregulation of p27 was not necessary for cell cycle reentry. Analysis of Cdk2 kinase activity and p27 binding to cyclin E complexes in the presence of exogenous wild-type p27 or p27T187A demonstrated that Cdk2 activity was not necessary for SF/HGF-mediated G(1)/S transition. Similarly, overexpression of dominant-negative forms of Cdk2 did not block SF/HGF-triggered cell cycle progression. In contrast, SF/HGF transcriptionally upregulated c-Myc, and overexpression of c-Myc was able to prevent G(1)/G(0) arrest in the absence of SF/HGF. Transient overexpression of MadMyc, a dominant-negative chimera for c-Myc, caused G(1)/G(0) arrest in logarithmically growing cells and blocked SF/HGF-mediated G(1)/S transition. c-Myc did not exert its effects through p27 downregulation in these cell lines. SF/HGF induced E2F1-dependent transcription, the inhibition of which did not block SF/HGF-induced cell cycle progression. We conclude that SF/HGF prevents G(1)/G(0) arrest in glioma cell lines by a c-myc-dependent mechanism that is independent of p27, Cdk2, or E2F1.
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PMID:Scatter factor/hepatocyte growth factor stimulation of glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation, or E2F1-dependent transcription. 1190 63

The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. We studied differential expression of these forms in normal brain as well as glial tumors, by semiquantitative RT-PCR. The expression of p73 was low or undetectable in normal brain tissues. Most of the tumors and non-tumor brain tissues also lacked significant expression of p73 in patients with low-grade astrocytomas. In contrast, most high-grade glial tumors displayed strong up-regulation of TAp73, whereas only a few displayed DeltaNp73 expression. These aberrations may reflect the inactivation of retinoblastoma pathway in these tumors which result in the activation of E2F transcription factors, since TAp73 is a known target of E2F1 gene. The study of TAp73 expression in brain tumors may serve as a means to evaluate the retinoblastoma pathway-dependent tumor progression.
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PMID:Expression of TAP73 and DeltaNP73 in malignant gliomas. 1513 75

ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation. Here, we report for the first time the pro-apoptosis role of ATF5 and identify Cyclin D3 as an ATF5-targeted apoptosis-related gene. The ectopic expression of ATF5 in HeLa cells could markedly increase cisplatin-induced apoptosis and the cleavage of Caspase-3, and induce Cyclin D3 mRNA expression via cooperation with E2F1 transcription factor. Moreover, the interference of Cyclin D3 expression by transfection with Cyclin D3 RNAi could protect cells from ATF5-mediated apoptosis induced by cisplatin, indicating the contribution of Cyclin D3 in ATF5-mediated apoptosis. Taken together, these results suggest that ATF5 increases cisplatin-induced apoptosis through up-regulation of Cyclin D3 transcription, which elicits survival signals in HeLa cells.
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PMID:ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells. 1630 Jul 31

Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.
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PMID:Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells. 1661 45

During 2007, approximately 200,000 people in the United States will be diagnosed with brain tumors. Gliomas account for 77% of primary malignant brain tumors, and the prognosis has hardly changed in the past 20 years, with only 30% of patients with malignant glioma surviving 5 years after diagnosis. Oncolytic adenoviruses are promising therapies for the treatment of gliomas. Here, report the antiglioma activity of the tumor-selective ICOVIR-5 adenovirus, which encompasses an early 1A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, substitution of the E1A promoter for E2F-responsive elements, and an RGD-4C peptide motif inserted into the adenoviral fiber to enhance adenoviral tropism. Mechanistic studies showed a dramatic addiction of ICOVIR-5 to the E2F1 oncogene in vitro and in vivo. This addiction was mediated by the occupancy of the ectopic adenoviral E2F1-responsive elements by the endogenous E2F1 protein resulting in high level of E1A expression in cancer cells and potent antiglioma effect. Importantly, we showed for the first time the ability of oncolytic adenoviruses to enhance E2F transcriptional activity in vivo, and we provided direct evidence of the interaction of the E2F1 protein with native and ectopic adenovirus promoters. Restoration of Rb function led to the association of Rb/E2F1 repressor complexes with ICOVIR-5 ectopic E2F1 promoter and subsequent down-modulation of E1A, dramatically impairing adenoviral replication. In xenografted mice, intratumoral injection of ICOVIR-5 resulted in a significant improvement of the median survival (P < 0.0001), and furthermore, led to 37% of long-term survivors free of disease. The antitumor activity of ICOVIR-5 suggests that it has the potential to be an effective agent in the treatment of gliomas.
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PMID:ICOVIR-5 shows E2F1 addiction and potent antiglioma effect in vivo. 1780 40

The authors have monitored C6 glioma cell invasive growth, proliferation and transcriptional regulation after pretreatment with endothelin-1 and ERK1/2 specific inhibitor PD98059. To explore proliferation of C6 glioma cells in different growth conditions, they were treated in vitro with endothelin-1 and implanted into the brain. In vitro studies have indicated that PD98059 inhibited the proliferation of cultured C6 glioma cells and induced the activation of E2F1 and Myc-Max transcriptional factors. Endothelin-1 strongly increased C6 glioma cell proliferation. The model used in this study is experimental, but it may provide an insight into the specific behavior of in vitro cultured invasive cells.
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PMID:[Intracerebral progression of the transplanted rat C6 glioblastoma cells pretreated with neuropeptides and MAPK inhibitor]. 1841 19

The invasive growth, proliferation, and transcriptional regulation of glioma C6 cells treated with endothelin-1 and PD98059, a specific inhibitor of ERK1/2 were studied. The proliferation of glioma C6 cells was assessed in different growth conditions by prior in vitro treatment with endothelin-1 followed by implantation into the brain. In vitro studies showed that PD98059 inhibited the proliferation of cultured glioma C6 cells and activated transcription factors E2F1 and Myc-Max. Endothelin-1 significantly increased the proliferation of glioma C6 cells. The model used in this study was experimental and may allow the specific features of the in vitro behavior of cultured invasive cells to be identified.
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PMID:Intracerebral development of transplanted glioblastoma C6 cells in rats after preliminary exposure to neuropeptides and an MAPK inhibitor. 1897 8

Gamma-linolenic acid (GLA) is an inhibitor of tumor cell proliferation in both in vitro and in vivo conditions. The aim of this study was to investigate the effects of 150 muM GLA on the expression of E2F1, cyclin D1, bax, bcl2, Ku70, and Ku80 in C6 rat glioma cells. The Ku proteins were chosen as previous studies have shown that loss or reduction in their expression causes increased DNA damage and micronucleus formation in the presence of radiation. The fact that GLA exposure is known to enhance the efficacy of radiation treatment raised the question whether the Ku proteins could be involved in this effect as seen for other molecules such as roscovitine and flavopiridol. GLA altered the mRNA expression of E2F1, cyclin D1, and bax, but no changes were found for bcl2, Ku70, and Ku80. Alterations in protein expression were observed for bax, Ku80, and E2F1. The 45% decrease in E2F1 expression was proportional to decreased cell proliferation (44%). Morphological analysis found a 25% decrease in mitotic activity in the GLA-treated cells, which was accompanied by a 49% decrease in S-phase by FACS analysis. A 39% increase in the number of micronuclei detected by Hoechst fluorescence points to GLA's effects on cell division even at concentrations that do not produce significant increases in apoptosis. Most important was the finding that Ku80 expression, a critical protein involved in DNA repair as a heterodimer with Ku70, was decreased by 71%. It is probable that reduced Ku80 is responsible for the increase in micronucleus formation in GLA-treated cells in a similar manner to that found in Ku80 null cells exposed to radiation. The decreased expression of Ku80 and E2F1 could make cells more susceptible to radiotherapy and chemotherapy.
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PMID:Gamma-linolenic acid alters Ku80, E2F1, and bax expression and induces micronucleus formation in C6 glioma cells in vitro. 1918 Jun 67


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