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)

Conditional expression of wild-type (wt) p53 protein in a glioblastoma tumor cell line has been shown to be growth inhibitory. We have now more precisely localized the position in the cell cycle where growth arrest occurs. We show that growth arrest occurs prior to or near the restriction point in late G1 phase of the cell cycle. The effect of wt p53 protein on the expression of four immediate-early genes (c-FOS, c-JUN, JUN-B, and c-MYC), one delayed-early gene (ornithine decarboxylase), and two late-G1/S-phase genes (B-MYB and DNA polymerase alpha) was also examined. Of this subset of growth response genes, only the expression of B-MYB and DNA polymerase alpha was significantly repressed. The possibility that decreased expression of B-MYB may be an important component of growth arrest mediated by wt p53 protein is discussed.
 ...
PMID:Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. 140 26

We investigated DNA-protein-interactions occurring in the promoter region of c-fos using two-dimensional electrophoresis and south-western-blotting. When nuclear extracts from the human glioblastoma cell line HeRoSV were tested for their DNA-binding behaviour to a 650 bp-fragment within the promoter region of c-fos, we found 4 proteins designated as 120/6.6, 75/5.4, 65/6.4 55/5.0 interacting with this fragment. An additional protein 60/6.0 was detected by using a digoxygenine-labelled probe. These observations let us to assume that beside the well characterized SRF and FOS-JUN proteins additional factors recognize the promoter sequence and may play a role in c-fos regulation.
 ...
PMID:A set of 4 nuclear proteins binds to a DNA sequence within the FOS promoter region. 166 Sep 58

Amplifications of cellular oncogenes and growth factor genes have previously been reported in gliomas. Here we have evaluated 21 gliomas for amplification of tumor related genes including NMYC, EGFR, TGFalpha, MET, CMYC, SRC, HRAS, NRAS, SEC, ROS1, JUN, and WNT1. Five amplifications were observed. The epidermal growth factor receptor (EGFR) gene was amplified in 4 glioblastomas. The oncogene MET was amplified in a glioblastoma which showed no EGFR gene amplification. Importantly, both genes are located on chromosome 7 and belong to a family with tyrosine kinase activity. There was no amplification found for TGFalpha which was previously reported to be amplified in gliomas. The finding of MET and EGFR independently amplified in glioma lends further support to a crucial role of chromosome 7 in the development of gliomas.
 ...
PMID:Two independent amplification events on chromosome 7 in glioma: amplification of the epidermal growth factor receptor gene and amplification of the oncogene MET. 801 63

We have studied the role of Jun/stress-activated protein kinase (JNK/SAPK) pathway in DNA repair and cisplatin resistance in T98G glioblastoma cells. JUN/SAPK is activated by DNA damage and phosphorylates serines 63 and 73 in the N-terminal domain of c-Jun, which is known to increase its transactivation properties. We show that treatment of T98G glioblastoma cells with cisplatin but not the transplatin isomer activates JNK/SAPK about 10-fold. T98G cells, which are highly resistent to cisplatin (IC50 = 140 +/- 13 microM), modified to express a nonphosphorylatable dominant negative c-Jun (termed dnJun) exhibit decreased viability following treatment with cisplatin, but not transplatin, in proportion (rPearson = 0.98) to the level of dnJun expressed leading to a 7-fold decreased IC50. Similar effects are observed in U87 cells, PC-3 cells, and MCF-7 cells, as well as in T98G cells modified to express TAM-67, a known inhibitor of c-Jun function. In contrast, no sensitization effect was observed in cells modified to express wild-type c-Jun. Furthermore, through quantitative polymerase chain reaction-stop assays, we show that dnJun expressing cells were inhibited in repair of cisplatin adducts (p = 0.55), whereas repair is readily detectable (p = 0.003) in parental cells. These observations indicate that the JNK/SAPK pathway is activated by cisplatin-induced DNA damage and that this response is required for DNA repair and viability following cisplatin treatment. Regulation of DNA repair following genotoxic stress may be a normal physiological role of the JNK/SAPK pathway.
 ...
PMID:The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. 916 25

We studied the effect of doxorubicin on the expression of c-myc and c-jun in the rat glioblastoma cell line C6 and its doxorubicin-resistant variant C6 0.5, at equitoxic exposures. For quantitation, the mRNA levels of these oncogenes were related to those of two domestic genes, beta-actin and glyceraldehyde phosphate dehydrogenase. After a transient overexpression of the genes during the first hour of incubation, there was a selective, dose-dependent down-regulation of both genes by doxorubicin in the sensitive cells. In the resistant cell line, c-myc expression was also decreased in response to doxorubicin incubation, but the expression of c-jun remained unchanged over the whole range of concentrations. In contrast, vincristine had no effect on the amounts of c-myc and c-jun mRNAs in either line. The effect of doxorubicin on the mRNA levels of c-jun was also observed on the JUN proteins by immunoblotting, but the MYC protein levels remained unchanged upon doxorubicin treatment. There was a significant correlation between the levels of c-myc and c-jun gene expression and the degree of growth inhibition induced by doxorubicin. In addition, doxorubicin induced a fragmentation of DNA in sensitive cells, but not in resistant cells, thus revealing a resistance to apoptosis in this line. Doxorubicin-induced cell death did not appear to be mediated by p53 in either cell line.
 ...
PMID:Doxorubicin-induced alterations of c-myc and c-jun gene expression in rat glioblastoma cells: role of c-jun in drug resistance and cell death. 971 16

The interleukin 13 alpha 2 receptor (IL-13Ra2) has been shown to be expressed in most malignant glioblastoma cells. Recent studies suggest that IL-13Ra2 serves as a dominant negative inhibitor or a decoy receptor for IL-13. To investigate the transcriptional regulation of this receptor, we cloned and characterized the promoter for the human IL-13Ra2 gene. Our results demonstrate that this promoter contains three TATA boxes and one CCAAT site. Several putative transcriptional factor binding sites for nuclear factor of activated T cells 1, AP1 (c-JUN and c-FOS), AP2, GABP, OCT1, GATA3, PRE, and C-ETS1 were predicted in the promoter region. Using the secreted alkaline phosphate reporter gene assay, we investigated the functional activity of the human IL-13Ra2 promoter by transient transfection in glioma cell lines U118, U87, and T98, which differ in their expression of the human IL-13Ra2 protein. The different secreted alkaline phosphate activities among these 3 cell lines suggest that the expression of human IL-13Ra2 is regulated at the transcriptional level. Methylation analysis showed that expression of IL-13Ra2 may not be the result of methylation of the CpG dinucleotides in the promoter region of the gene. Deletion analysis identified a 64 base pair (bp) region that is necessary for human IL-13Ra2 promoter activity. This 64-bp sequence contains cis-elements for AP1, nuclear factor of activated T cells, and AP2. The possible role of AP1 in the regulation of human IL-13Ra2 promoter activity was suggested by in vitro mutagenesis and c-JUN N-terminal kinase inhibition analysis.
 ...
PMID:Molecular cloning and identification of the human interleukin 13 alpha 2 receptor (IL-13Ra2) promoter. 1281 24

Glial cell line-derived neurotrophic factor (GDNF), a neurotrophic and differentiation factor, is expressed under several pathophysiological conditions but its regulatory signals have not yet been clarified. Here, we found that endoplasmic reticulum (ER) Ca(2+) discharge by thapsigargin induced GDNF mRNA as well as COX2 and GRP78 expression in rat C6 glioblastoma cells. GDNF mRNA was immediately induced and peaked at 2h by thapsigargin, and the alternative transcript consisting of exon 3 and exon 4 appeared to be most inducible. In spite of intracellular Ca(2+) perturbation, Ca(2+)-dependent PKC was not responsible for this induction. Instead, a PKCdelta-specific inhibitor, rottlerin, suppressed the thapsigargin-induced GDNF mRNA expression. On the other hand, thapsigargin transiently enhanced phosphorylation status of mitogen-activated protein kinase (MAPK) pathway, including extracellular signal-regulated kinase (Erk), p38 MAPK and c-JUN amino-terminal kinase1 (JNK1) simultaneously; whereas specific inhibitors against MEK1 and JNK only reduced the thapsigargin-induced GDNF mRNA expression. In addition, a pan-PKC inhibitor (Ro-31-8220) attenuated the thapsigargin-enhanced phosphorylation levels of Erk1/2 and JNK1, whereas rottlerin did not. Thus, the present study demonstrated that the thapsigargin-stimulated ER Ca(2+) discharge up-regulated GDNF gene expression through both MAPK-dependent and -independent pathways in C6 glioblastoma cells.
 ...
PMID:ER calcium discharge stimulates GDNF gene expression through MAPK-dependent and -independent pathways in rat C6 glioblastoma cells. 1683 15

The progression of glioma to more malignant phenotypes results from the stepwise accumulation of genetic alterations and the consequent disruption of the apoptotic pathway and augmentation of survival signaling. REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of the growth of several human cancers; however, to date it has not been identified in brain tumors. We compared the gene and protein expression of REIC/Dkk-3 in human malignant glioma and normal brain tissues using quantitative real-time PCR, Western blotting, and immunohistochemistry. We also performed small interfering REIC/Dkk-3 (siREIC/Dkk-3) knockdown and REIC/Dkk-3 overexpression experiments to examine the role of REIC/Dkk-3 in human malignant glioma cells in vitro. In brain tissue from patients with malignant glioma, the gene and protein expression of REIC/Dkk-3 was lower than in normal brain tissue and was related to the malignancy grade. In the primary glioblastoma cell line, REIC/Dkk-3 transfection led to apoptosis owing to the activation of phosphorylated JUN, caspase-9, and caspase-3 and the reduction of beta-catenin; in REIC/Dkk-3 knockdown experiments, cell growth was augmented. Our results suggest that REIC/Dkk-3 regulates the growth and survival of these cells in a caspase-dependent and -independent way via modification of the Wnt signaling pathway. Our work is the first documentation that the gene and protein expression of REIC/Dkk-3 is down-regulated in human malignant glioma. Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy.
 ...
PMID:REIC/Dkk-3 induces cell death in human malignant glioma. 1844 32

How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that the formation of vascular microthrombi contributes to tumor necrosis, prompting investigation of coagulation cascades. Here, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade in glioblastoma. P14ARF transcriptionally upregulated TFPI2, a Kunitz-type serine protease in the tissue factor pathway that inhibits the initiation of thrombosis reactions. P14ARF activation in tumor cells delayed their ability to activate plasma clotting. Mechanistically, P14ARF activated the TFPI2 promoter in a p53-independent manner that relied upon c-JUN, SP1, and JNK activity. Taken together, our results identify the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by glioma cells. Stimulation of this pathway might be used as a therapeutic strategy to reduce aggressive phenotypes associated with necrotic tumors, including glioblastoma.
 ...
PMID:P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway. 2439 74

Glioblastoma (GBM) is a primary brain cancer with an extremely poor prognosis. GBM tumors contain heterogeneous cellular components, including a small subpopulation of tumor cells termed glioma stem cells (GSCs). GSCs are characterized as chemotherapy- and radiotherapy-resistant cells with prominent tumorigenic ability. Studies in Drosophila cancer models demonstrated that interclonal cooperation and signaling from apoptotic clones provokes aggressive growth of neighboring tumorigenic clones, via compensatory proliferation or apoptosis induced proliferation. Mechanistically, these aggressive tumors depend on activation of Jun-N-terminal kinase (upstream of c-JUN), and Drosophila Wnt (Wg) in the apoptotic clones. Consistent with these nonmammalian studies, data from several mammalian studies have shown that c-JUN and Wnt are hyperactivated in aggressive tumors (including GBM). However, it remains elusive whether compensatory proliferation is an evolutionarily conserved mechanism in cancers. In the present report, we summarize recent studies in Drosophila models and mammalian models (e.g., xenografts of human cancer cells into small animals) to elucidate the intercellular interactions between the apoptosis-prone cancer cells (e.g., non-GSCs) and the hyperproliferative cancer cells (e.g., GSCs). These evolving investigations will yield insights about molecular signaling interactions in the context of post-therapeutic phenotypic changes in human cancers. Furthermore, these studies are likely to revise our understanding of the genetic changes and post-therapeutic cell-cell interactions, which is a vital area of cancer biology with wide applications to many cancer types in humans.
 ...
PMID:Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies. 2523 84


1 2 Next >>