UMLS:C0017636 - FACTA Search

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)

The rat Zfhep gene encodes a member of the Zfh family of transcription factors having a homeodomain-like sequence and multiple zinc fingers. We examined expression of Zfhep in the rat forebrain during embryonic and postnatal development. Zfhep mRNA was strongly expressed in the progenitor cells of the ventricular zone around the lateral ventricles on E14 and E16, but showed little expression in cells that had migrated to form the developing cortex. Dual labeling with PCNA demonstrated expression of Zfhep mRNA in proliferating cells. Expression of Zfhep in the ventricular zone decreases during late development as the population of progenitor cells decreases. This pattern is distinctly different from other members of the Zfh family. We also examined the expression of Zfhep protein during retinoic acid-induced neurogenesis of P19 embryonal carcinoma cells. Zfhep is highly expressed in P19 neuroblasts, and expression decreases by the time of morphological neurogenesis. Hence, both P19 cells and embryonic brain demonstrate a loss of Zfhep expression during the transition from proliferating precursor to differentiated neural cells. We investigated a possible link between Zfhep and proliferation by treating human glial cell lines with Zfhep antisense phosphorothioate oligodeoxynucleotides. Two Zfhep antisense oligonucleotides repressed proliferation of either U-138 or U-343 glioblastoma cells more than control oligonucleotides. Based on the expression patterns of Zfhep in vivo and in the P19 cell model of neurogenesis, we suggest that Zfhep may play a role in proliferation or differentiation of neural cells.
...
PMID:Developmental and functional evidence of a role for Zfhep in neural cell development. 1173 Oct 9

The molecular mechanisms underlying the heterogeneous effects of retinoic acid (RA) treatment on malignant glioma cells remain poorly understood. In this study, we present the first evidence of a functional role of the signal transduction factors (STATs) in RA-induced proliferation, in a human glioblastoma GL-15 cell line. We first observed that STAT-3 was constitutively activated and present in the GL-15 cell nuclei. We then showed that at low doses (0.01-1 microM) RA increased both the proliferation rate of GL-15 cells and the phosphotyrosine (PY) activation of STAT-3. This RA effect involved transcriptional processes and the transactivation of RA target genes, including RA receptors isoforms RARalpha2, -beta2, and -gamma2. At higher concentrations, however, RA (5-10 microM) inhibits GL-15 proliferation, induces apoptosis, and fails to activate STAT-3. An inhibitory effect on GL-15 proliferation was also observed with the synthetic retinoids CD-437 and CD-2325, two structurally related RARgamma agonists, which also fail to activate STAT-3. In addition, the phorbol ester PMA, an inducer of GL-15 differentiation, and staurosporine, a broad inhibitor of protein kinases, abrogate the stimulatory effects of RA at low concentrations. Together these observations suggest that, in GL-15 cells, activation of STAT-3 and cell proliferation share common mechanisms and that STAT transcription factors may be involved in a switch between proliferation, differentiation, and apoptosis. The proliferating effect observed at low doses of RA may be related to the failures in RA efficiency observed in clinical assays in relapsing malignant gliomas. Combining specific inhibitors of tyrosine kinases with RA might optimize the clinical outcome.
...
PMID:Retinoic acid increases proliferation rate of GL-15 glioma cells, involving activation of STAT-3 transcription factor. 1189 79

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional.
...
PMID:Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity. 1204 41

Since malignant glioma displays moderate resistance to conventional therapy, a new treatment modality is needed to improve the outcome of patients with these tumors. In this study, we examined whether combination stimulation with interferon alpha (IFN-alpha) and retinoic acid (RA) affected proliferation of the glioblastoma cell line GB 12 in vitro. Stimulation with IFN-alpha alone inhibited the GB 12 cell proliferation in a dose/time-dependent fashion, as assessed by WST-1 assay and uptake of 3H-thymidine, while RA limited it only slightly. The anti-proliferative action of IFN-alpha against glioblastoma cells was enhanced by the addition of RA. The IFN-alpha/RA combination also induced apoptosis in a substantial portion of the cells, compared with either reagent alone. Bcl-2 family proteins, regulating apoptosis, were altered by these stimuli: Bcl-2 was down-regulated, while Bax-alpha was up-regulated, especially by the combination. These findings suggest that the IFN-alpha/RA combination would synergistically affect glioblastoma cell growth, probably through apoptosis induction as well as a decreased cellular DNA synthesis.
...
PMID:Combined stimulation with interferon alpha and retinoic acid synergistically inhibits proliferation of the glioblastoma cell line GB12. 1239 8

High-grade gliomas are characterized by a rapid proliferation rate, invasiveness and angiogenesis. Our previous data indicated that the combination of ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptor (RAR) induces apoptosis of breast cancer cells in vitro and in a murine model. In this study, we have shown that 11 glioblastoma cell lines and nine fresh glioblastoma tissue samples from patients expressed high-levels of PPARgamma. In contrast, glia from nine healthy human brains expressed very low levels of PPARgamma. No mutations or polymorphisms of the PPARgamma gene were observed in these cell lines. The effect of the PPARgamma ligand Pioglitazone (PGZ) either in the absence or in the presence of a RAR ligand [all-trans retinoic acid (ATRA)] on the proliferation and apoptosis of glioblastoma cells was examined using two glioblastoma cell lines (N39 and DBTRG05MG). PGZ and/or ATRA inhibited significantly the proliferation of both cell lines. Flow cytometry analysis showed that G1 cell cycle arrest was induced by these ligands. In addition, apoptosis occurred in both cell lines treated with either PGZ or ATRA, which was associated with a downregulation of bcl-2 and an upregulation of bax proteins. An enhanced effect was observed when PGZ and ATRA were combined. Furthermore, treatment of fresh glioblastoma tissue from patients with PGZ, either alone or in combination with ATRA, induced a significant level of tumor cell apoptosis together with a downregulation of bcl-2 protein level as compared with untreated control brain tissue. Taken together, our data demonstrated that PGZ, either alone or in combination with ATRA, induced apoptosis and inhibited proliferation of glioblastoma cells, and more interestingly, induced apoptosis of fresh glioblastoma cells from patients. Therefore, we conclude that these ligands may possess adjuvant therapeutic potential for patients with glioblastoma.
...
PMID:Ligands for PPARgamma and RAR cause induction of growth inhibition and apoptosis in human glioblastomas. 1468 29

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors and belong to the nuclear hormone receptor superfamily. They form heterodimers with the retinoid X receptor and bind to specific peroxisome proliferator-response elements. The latter are direct repeat elements of two hexanucleotides with the consensus sequence TG(A/T)CCT separated by a single nucleotide spacer. Such a sequence, or a similar one, has been found in numerous PPAR-inducible genes. We developed an affinity method to isolate human genomic fragments containing binding sites for PPARs and to identify novel PPAR target genes. For this, an antibody raised against all PPAR subtypes was used. Immunoselected fragments were amplified and sequenced and one of them, ISF5148, was found to bind specifically to PPARs in gel mobility shift, supershift, and competition assays and to exhibit a down transregulation potentiality in transfection experiments under clofibrate (a PPARalpha agonist) treatment. ISF5148 was mapped by BLAST analysis 8.5 kb upstream of the human semaphorin 6B [(HSA)SEMA6B] gene. The latter encodes a member of the semaphorin family of axon guidance molecules. Expression of this gene in human glioblastoma T98G cells was strongly down regulated after treatment with clofibrate or Wy-14,643, two PPARalpha agonists. Our study establishes for the first time that PPAR activators diminish the expression of the human (HSA)SEMA6B gene. These data are relevant to the fact that PPARs are implicated in brain development, neuronal differentiation, and lipid metabolism in the central nervous system. In addition, cross talk between the peroxisome proliferator and retinoic acid pathways is suggested.
...
PMID:The human semaphorin 6B gene is down regulated by PPARs. 1517 67

Glioblastoma is the most common and highly malignant brain tumor. It is also one among the most therapy-resistant human neoplasias. Patients die within a year of diagnosis despite the use of available treatment strategies such as surgery, radiotherapy, and chemotherapy. Thus, there is a critical need to find a novel therapeutic strategy for treating this disease. Here, we have investigated the molecular mechanisms for induction of apoptosis as well as for activation of immune components in human malignant glioblastoma T98G and U87MG cells following treatment with all-trans retinoic acid (ATRA) plus interferon-gamma (IFN-gamma). Treatment of glioblastoma cells with ATRA alone prevented cell proliferation and induced astrocytic differentiation, while IFN-gamma alone induced apoptosis and modulated expression of human leukocyte antigen (HLA) class II molecules such as HLA-DRalpha, HLA-DR complex, invariant chain (Ii), HLA-DM (an important catalyst of the class II-peptide loading), and gamma interferon-inducible lysosomal thiol-reductase (GILT). Interestingly, both T98G and U87MG cells showed more increase in apoptosis with expression of the HLA class II components for an effective immune response following treatment with ATRA plus IFN-gamma than with IFN-gamma alone. Apoptotic mode of cell death was confirmed morphologically by Wright staining and biochemically by measuring an increase in caspase-3 activity. While conversion of tumor cells into HLA class II+/Ii- cells by stimulation with the helper CD4+ T cells is thought to be challenging, this study reports for the first time that treatment of glioblastoma cells with ATRA plus IFN-gamma can simultaneously enhance apoptosis and expression of the HLA class II immune components with a marked suppression of Ii expression. Taken together, this study suggests that induction of apoptosis and immune components of the HLA class II pathway by ATRA plus IFN-gamma may be a promising chemoimmunotherapeutic strategy for treatment of human malignant glioblastoma.
...
PMID:Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells. 1694 22

In this study, we have shown the transcriptional regulation of the human Sia-alpha2,3-Gal-beta1,4-GlcNAc-R:alpha2,8-sialyltransferase (hST8Sia III) induced by retinoic acid (RA), a potent neuronal cell regulator in glioblastoma cell line (U-87MG). The induction of hST8Sia III by RA is regulated at the transcriptional level in a dose- and time-dependent manner, as evidenced by reverse transcription-polymerase chain reaction (RT-PCR). To elucidate the mechanism underlying the regulation of hST8Sia III gene expression in RA-stimulated U-87MG cells, we characterized the promoter region of the hST8Sia III gene. Functional analysis of the 5'-flanking region of the hST8Sia III gene by the transient expression method showed that the -1194 to -816 region, which contains a retinoic acid nucleic receptor (RAR) at -1000 to -982, functions as the RA-inducible promoter in U-87MG cells. Site-directed mutagenesis indicated that the RA binding site at -996 to -991 is crucial for the RA-induced expression of the hST8Sia III in U-87MG cells. In addition, the transcriptional activity of hST8Sia III induced by RA in U-87MG cells was strongly inhibited by SP600125, c-Jun N-terminal Kinase (JNK) inhibitor, as determined by RT-PCR and luciferase assay of hST8Sia III promoter containing the -1194 to -816 regions. These results suggest that RA markedly modulates transcriptional regulation of hST8Sia III gene expression through JNK signal pathway in U-87MG cells.
...
PMID:Transcriptional regulation of the human Sia-alpha2,3-Gal-beta1,4-GlcNAc-R:alpha2,8-sialyltransferase (hST8Sia III) by retinoic acid in human glioblastoma tumor cell line. 1706 99

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors and belong to the nuclear hormone receptor superfamily. They form heterodimers with retinoid X receptor (RXR) and bind to specific PPAR-response elements. To identify novel PPAR target genes, we developed an affinity method to isolate human genomic fragments containing binding sites for PPARs. For this, an antibody raised against all PPAR subtypes was used. Immunoselected fragments were amplified and sequenced. One of them, ISF1029, was mapped by BLAT and BLAST searches on different human chromosomes, downstream of several POTE genes. ISF1029 contained three hexamers strongly related to the AGGTCA motif organized according to a DR0/3 motif. The latter was found to bind to PPARalpha in gel mobility shift and supershift assays and to exhibit a downregulation potentiality in transfection experiments under clofibrate treatment. POTE genes were shown to be highly expressed in human Caco-2 colorectal adenocarcinoma cells and downregulated by fenofibrate and 9-cis-retinoic acid, as attested by RT-PCR assays. Microarray analysis confirmed and extended to the human T98-G glioblastoma cells, the downregulation of several POTE genes expression by Wy-14,643, a potent PPARalpha activator. Our data provide new insights about the pleiotropic action of PPARs.
...
PMID:Immunoselection and characterization of a human genomic PPAR binding fragment located within POTE genes. 1707 Jun 43

A boy showing symptoms of a Turcot-like childhood cancer syndrome together with stigmata of neurofibromatosis type I is reported. His brother suffers from an infantile myofibromatosis, and a sister died of glioblastoma at age 7. Another 7-year-old brother is so far clinically unaffected. The parents are consanguineous. Molecular diagnosis in the index patient revealed a constitutional homozygous mutation of the mismatch repair gene PMS2. The patient was in remission of his glioblastoma (WHO grade IV) after multimodal treatment followed by retinoic acid chemoprevention for 7 years. After discontinuation of retinoic acid medication, he developed a relapse of his brain tumour together with the simultaneous occurrence of three other different HNPCC-related carcinomas. We think that retinoic acid might have provided an effective chemoprevention in this patient with homozygous mismatch repair gene defect. We propose to take a retinoic acid chemoprevention into account in children with proven biallelic PMS2 mismatch repair mutations being at highest risk concerning the development of a malignancy.
...
PMID:Hypothesis: Possible role of retinoic acid therapy in patients with biallelic mismatch repair gene defects. 1738 11

<< Previous 1 2 3 4 5 6 7 8 9 Next >>