Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Peptidylglycine alpha-amidating monooxygenase is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. The high expression of peptidylglycine alpha-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of alpha-amidated peptides in tumorigenic growth processes in the brain. After screening of amidated peptides, it was found that human glioblastoma cell lines express high levels of adrenomedullin (AM) mRNA, and that immunoreactive AM is released into the culture medium. AM is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analyzed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendrogliomas. In the present study we also demonstrate the presence of mRNA encoding the putative AM receptors, calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both glioma tissues and glioblastoma cell lines and further show that exogenously added AM can stimulate the growth of these glioblastoma cells in vitro. These findings suggest that AM may function as an autocrine growth factor for glioblastoma cells. One way to test the autocrine hypothesis is to interrupt the function of the endogenously produced AM. Herein, we demonstrate that a polyclonal antibody specific to AM, blocks the binding of the hormone to its cellular receptors and decreases by 33% (P < 0.001) the growth of U87 glioblastoma cells in vitro. Intratumoral administration of the anti-AM antibody resulted in a 70% (P < 0.001) reduction in subcutaneous U87 xenograft weight 21 days after treatment. Furthermore, the density of vessels was decreased in the antibody-treated tumors. These findings support that AM may function as a potent autocrine/paracrine growth factor for human glioblastomas and demonstrate that inhibition of the action of AM (produced by tumor cells) may suppress tumor growth in vivo.
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PMID:Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo. 1194 13

The regulation of matrix metalloproteinase-9 (MMP-9) expression in glioma cells is one of the key processes in tumor invasion through the brain extracellular matrix. Although some studies have demonstrated the implication of classic protein kinase C (PKC) isoforms in the regulation of MMP-9 production by phorbol esters or lipopolysaccharide, the involvement of specific PKC isoforms in the signaling pathways leading to MMP-9 expression by inflammatory cytokines remains unclear. Here we report that the atypical PKC-zeta isoform participates in the induction of MMP-9 expression by interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in rat C6 glioma cells. Indeed, zymography and semi-quantitative reverse transcriptase-PCR analysis showed that pretreatment of C6 cells with PKC-zeta pseudosubstrate abolished MMP-9 activity and gene expression induced by IL-1 or TNF-alpha. Accordingly, IL-1 and TNF-alpha were able to induce PKC-zeta activity, as demonstrated by in vitro kinase assay using immunoprecipitated PKC-zeta. Furthermore, stable C6 clones overexpressing PKC-zeta, but not PKC-epsilon, displayed an up-regulation of MMP-9 constitutive expression as well as an increase of mmp-9 promoter activity. These processes were inhibited by an NF-kappaB-blocking peptide and completely prevented by NF-kappaB-binding site mutation in the mmp-9 promoter. Taken together, these results indicate that PKC-zeta plays a key role in the regulation of MMP-9 expression in C6 glioma cells through NF-kappaB.
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PMID:Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNF-alpha in glioma cells via NF-kappa B. 1213 Jun 32

The regulation of glioma cell proliferation by sphingosine-1-phosphate (S1P) was studied using the human glioblastoma cell line U-373 MG. U-373 MG cells responded mitogenically to nanomolar concentrations of S1P, and express mRNA encoding the S1P receptors S1P1/endothelial differentiation gene (EDG)-1, S1P3/EDG-3 and S1P2/EDG-5. S1P-induced proliferation required extracellular signal-regulated kinase activation and was partially sensitive to pertussis toxin and wortmannin, indicating involvement of a Gi-coupled receptor and phosphatidylinositol 3-kinase. Moreover, S1P1, S1P3 and S1P2 receptors are expressed in the majority of human glioblastomas as determined by reverse transcriptase-polymerase chain reaction analysis. Thus, S1P signaling through EDG receptors may contribute to glioblastoma growth in vivo.
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PMID:Sphingosine-1-phosphate stimulates human glioma cell proliferation through Gi-coupled receptors: role of ERK MAP kinase and phosphatidylinositol 3-kinase beta. 1217 35

Melanoma-inhibiting activity/cartilage-derived retinoic acid-sensitive protein, a 11 kDa protein, is mainly expressed in cartilage during embryogenesis, and is related to invasion, metastasis, and immunomodulation of melanoma and glioma cells in vivo and in vitro. Here, we describe an alternative splice product of this gene termed melanoma-inhibiting activity (splice), lacking exon 2 of the original protein. A predicted frameshift by alternate splicing results in a unique C-terminal portion of the protein. Consistent with this, a protein migrating at the predicted molecular weight of the splice form (3.5 kDa) was detected using an N-terminal specific antibody. This band was undetectable when using a C-terminal specific antibody. In addition, we describe the expression pattern of melanoma-inhibiting activity (splice) in different human tumors. Expression was shown in tissue samples of five of six primary melanomas, 11 of 12 primary sites of metastatic melanomas, 10 of 10 systemic metastases of melanomas, four of four central nervous system metastases of melanomas, six of eight primary melanoma cultures, and five of five melanoma cell lines. Only a faint signal was obtained in tissue samples of five of six naevi. Interestingly, seven of eight nonmelanocytic tissue samples and five of seven glioma cell lines showed weak expression of melanoma-inhibiting activity (splice). Approaching first functional aspects, reverse transcriptase-polymerase chain reaction showed weak expression of melanoma-inhibiting activity (splice) in relation to melanoma-inhibiting activity in nonmelanocytic and strong expression in melanocytic cells. Staining with a specific anti-serum raised against a synthetic peptide resembling the amino acid sequence of melanoma-inhibiting activity (splice) showed a more nuclear staining pattern in comparison with melanoma-inhibiting activity. Furthermore, incubation of melanoma and glioma cell cultures with transforming growth factor-beta2 showed inverse regulation of the mRNA of melanoma-inhibiting activity and melanoma-inhibiting activity (splice), both suggesting also a different function within the physiologic role of this unique family of proteins. Melanoma-inhibiting activity (splice) has no homology to any other known protein so far. Whereas the biologic function of melanoma-inhibiting activity (splice) is not clear yet, it might provide a relevant diagnostic and therapeutic tool for malignant melanomas.
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PMID:Cloning and characterization of the expression pattern of a novel splice product MIA (splice) of malignant melanoma-derived growth-inhibiting activity (MIA/CD-RAP) [corrected]. 1223 Apr 96

Pleiotrophin (PTN) is a mitogenic/angiogenic, 15.3 kDa heparin-binding peptide that is found in embryonic or early postnatal, but rarely in adult, tissues. Since developmentally regulated factors often re-appear in malignant cells, we examined PTN expression in human glioma cell lines, cell cultures derived from solid gliomas and glioma sections. PTN mRNA or protein was detected by reverse transcriptase-polymerase chain reaction, immunohistochemistry, western blot or enzyme-linked immunoassay in all WHO III and IV grade gliomas and cells analyzed in vitro or in situ. One WHO II grade glioma investigated was PTN negative. In vitro, PTN was synthesized in perinuclear regions of glioma cells, secreted into the cultivation medium, but its production varied considerably between glioma cells cultivated from different solid gliomas or glioma cell lines. In situ, PTN expression was restricted to distinct parts/cells of the tumour. PTN did not influence the proliferation of glioma cells themselves, but stimulated [3H]thymidine incorporation into DNA of microglial cells. Furthermore, in Boyden chamber assays, PTN showed a strong chemotactic effect on murine BV-2 microglial cells. PTN is supposed to be a paracrine growth/angiogenic factor that is produced by gliomas and contributes to their malignancy by targeting endothelial and microglial cells.
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PMID:Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas. 1242 46

The alpha-ketoisocaproic acid (KIC) is a short branched-chain monocarboxylate, which accumulates in neural cells. It plays an important role in maintaining nitrogen balance in the brain, a process of a great importance for shuttling of glutamine and glutamate between astrocytes and neurons. Higher accumulation of KIC in isolated cerebral cortex neurons at lower external pH, as well as sensitivity of this process to alpha-cyano-4-hydroxycinnamate indicate an involvement of a transporter, belonging to the family of monocarboxylate transporters (MCT).The expression of MCT1 and MCT2 isoforms in the brain cells was studied using reverse transcriptase-polymerase chain reaction (RT-PCR) method. The mRNA coding MCT1 was detected in astrocytes, brain endothelial cells, tumour cells (neuroblastoma and glioma) and in cortex neurons of newborn rats, but not in adult ones. MCT2, which is less abundant isoform than MCT1, was expressed in astrocytes, in brain endothelial cells and at low level in newborn rats' neurons, being absent in neurons from adult brain.The observed sensitivity of KIC accumulation towards SH-groups reagents did not fit to the known characteristics of MCT1 and MCT2. Therefore, the change of MCT expression during brain development, as well as lack of MCT1 and MCT2 in neurons of adults, point to another MCT isoform being involved in alpha-ketoisocaproic acid accumulation. This could be either one of other known MCT isoforms or a new member of family MCT, specific towards branched chain alpha-ketoacids.
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PMID:Expression of monocarboxylic acid transporters (MCT) in brain cells. Implication for branched chain alpha-ketoacids transport in neurons. 1274 73

K(+) channels play an important role in glial cell proliferation and are functionally expressed in glial tumors. Because voltage-gated K(+) channel (Kv) subtypes Kv1.3 and Kv1.5 have been shown to contribute to growth-related properties of normal glia rather specifically, we investigated different human glioma samples for the expression of these channel subtypes using reverse transcriptase-PCR. Kv1.5 expression correlated with glioma entities and malignancy grades, i.e. expression was high in astrocytomas, moderate in oligodendrogliomas, and low in glioblastomas. No such correlation was evident for Kv1.3 expression. This study shows a clear differential expression of Kv1.5 in gliomas according to subtype and malignancy grade. This result corresponds to previous data on the expression of voltage-gated sodium channels in gliomas, which likewise showed a low or absent expression of channel subtypes in high-grade tumors.
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PMID:Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas. 1285 May 41

We studied whether the expression of the Neuropilin (NRP) gene was correlated with clinicopathological features in glioma. We examined the gene expression of vascular endothelial growth factor (VEGF)-A, Flt-1, KDR, NRP1 and NRP2 in 37 gliomas by real time reverse transcriptase PCR (real time RT-PCR) as well as immunohistochemical analysis. The vascular counts of each tumor were evaluated by anti-CD34 antibody. NRP1 mRNA overexpression was significantly higher in neoplastic tissue compared to normal brain tissue samples. The higher grade of glioma overexpressed the NRP1 gene significantly (p=0.0015). The glioma patients with NRP1 overexpression showed a poorer prognosis (p=0.0202) than those without such overexpression. NRP1 was observed in the glioma cells by immunohistochemical analyses. VEGF-A and VEGFR overexpression did not show any correlation with the clinicopathological features, including NRP expression. These results suggest that NRP1 overexpression, rather than VEGF-A or VEGFR, contributes to tumor progression and has clinical significance for glioma.
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PMID:Overexpression of the neuropilin 1 (NRP1) gene correlated with poor prognosis in human glioma. 1516 Sep 92

Glioblastoma multiforme is the most malignant of the primary brain tumors and is almost always fatal. The treatment strategies for this disease have not changed appreciably for many years and most are based on a limited understanding of the biology of the disease. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Adrenomedullin (AM) is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analysed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendriogliomas. The correlation of AM expression to the grade of glioma support the hypothesis that AM may participate in the progression of gliomas. We demonstrate that AM may function as an autocrine/paracrine growth factor for glioblastoma cells. The data demonstrated that the anti-AM antibody significantly suppress the growth of established glioblastoma xenografts. The action of AM is specific and is mediated by the calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2, CRLR/RAMP3). Furthermore, the proangiogenic action of AM on cultured endothelial cells via CRLR/RAMP2 and CRLR/RAMP3 receptors may translate in vivo into enhanced neovascularization and therefore identify AM and its receptors acting as potential new targets for antiangiogenic therapies.
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PMID:[Role of adrenomedullin in glioblastomas growth]. 1588 88

Various in vivo studies demonstrated a migration tendency of neural stem cells (NSCs) toward gliomas, making these cells a potential carrier for delivery of therapeutic genes to disseminated glioma cells. We analyzed which factors determine NSC migration and invasion in vitro. Conditioned media prepared from 10 different human glioma cell lines, as well as 13 different tumor-associated growth factors, were analyzed for their chemotactic effects on murine C17.2 NSCs. The growth factor receptor status was analyzed by reverse transcriptase-polymerase chain reaction. Invasion of NSCs into multicellular tumor spheroids generated from 10 glioma cell lines was quantified. NSCs displayed a heterogeneous migration pattern toward glioma spheroids as well as toward glioma-cell-conditioned medium. Chemotactic migration was stimulated up to fivefold by conditioned medium as compared to controls. In coculture assays, NSC invasion varied from single cell invasion into glioma spheroids to complete dissemination of NSCs into glioma spheroids of different cell lines. Among 13 different growth factors, scatter factor/hepatocyte growth factor (SF/HGF) was the most powerful chemoattractant for NSCs, inducing a 2.5-fold migration stimulation. An antibody against SF/HGF inhibited migratory stimulation induced by conditioned media. NSC migration can be stimulated by various growth factors, similar to glioma cell migration. The extent to which NSCs infiltrate three-dimensional glioma cell aggregates appears to depend on additional factors, which are likely to include cell-to-cell contacts and interaction with extracellular matrix proteins.
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PMID:Neural stem cell migration toward gliomas in vitro. 1621 12


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