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)

Both melanocytes and glial cells are derived embryologically from the neural ectoderm. Their malignant transformed counterparts, melanoma and glioma cells, respectively, may share common antigens. Numerous tumor-associated antigens have been identified in melanomas but only a few a gliomas. Using an established reverse transcriptase polymerase chain reaction plus Southern blot assay, we compared the mRNA expression of melanoma-associated antigens (MAAs) of melanomas to brain tumors primarily derived from glial cells. The MAAs studied included tyrosinase (Tyr), tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), gp100, human melanoma antigen-encoding genes 1 and 3 (MAGE-1 and MAGE-3), and melanotransferrin (p97). Glioblastoma multiforme (n = 21), anaplastic astrocytoma (n = 3), ependymoma (n = 2), meningioma (n = 3), oligodendroglioma (n = 1), and melanoma (n = 12) tumor specimens were assayed for MAA mRNA expression. Glioblastoma multiforme, astrocytoma, and melanoma cell lines were also assayed. We observed that individual MAA mRNAs were expressed in these brain tumors and cell lines at varying frequencies. The melanogenesis-pathway-related MAAs Tyr, TRP-1, TRP-2, and gp100 mRNAs were also expressed at different levels in normal brain tissues but at a much lower frequency than in glioblastoma multiforme and melanoma. MAGE-1 and MAGE-3 mRNA were expressed in different types of tumor specimens and cell lines but never in normal brain tissue. Tumor antigen p97 was expressed in all types of tumors and also in normal brain tissues. These studies demonstrate that melanomas and primary brain tumors express common MAAs and could be exploited in patients with malignant glioma by active specific immunotherapy against these common MAAs.
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PMID:Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. 917 5

Human glioma usually shows intrinsic multidrug resistance because of the blood-brain barrier (BBB), in which membrane-associated P-glycoprotein (P-gp), encoded by the human multidrug resistance gene MDR1, plays a role. We studied drug sensitivity to vincristine (VCR), doxorubicin (DOX) and nimustine (ACNU) in both intracerebrally and subcutaneously xenotransplanted human glioma. We examined the levels of MDR1 and murine mdr3 gene expression in the xenografts by reverse transcriptase polymerase chain reaction and the localization of P-gp by immunohistochemistry. Six of seven subcutaneously transplanted xenografts (scX) were sensitive to the above three drugs. In contrast, all three intracerebrally transplanted human glioma xenografts (icX) were resistant to P-gp-mediated drugs VCR and DOX, but were sensitive to the non-P-gp-mediated drug ACNU. Neither icX nor scX showed any MDR1 expression. Intracerebrally transplanted human glioma xenografts showed an increased level of murine mdr3 gene expression, whereas scX showed only faint expression. The localization of P-gp was limited to the stromal vessels in icX by immunohistochemistry, whereas scX expressed no P-gp. Our findings suggest that the P-gp expressed on the stromal vessels in icX is a major contributing factor to multidrug resistance in human glioma in vivo.
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PMID:Murine P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. 927 20

Human T-cell leukemia virus type 1 (HTLV-1) infection is associated with adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis. Inhibition of HTLV-1 transmission is important to prevent the above HTLV-1-associated diseases. We used the antisense oligodeoxynucleotides (oligos) complementary to the first splice junction, rex responsive site, gag, env, tax, rex, and p21 and evaluated the effects on the syncytium formation between HTLV-1 producing human T-cell line, C9/PL cells, and HTLV-1-uninfected human glioma cell line, U251-MG cells. The syncytium formation was significantly inhibited the virion production assayed by antisense oligos to env, tax, gag, p21, and rex, with antisense oligo to env being the most inhibitory. Antisense oligos to env and tax also inhibited reverse transcriptase activity. Antisense oligo to env may have a potential as a preventive measure of HTLV-1 replication and transmission in vivo.
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PMID:Inhibition of human T-cell leukemia virus type 1 replication by antisense env oligodeoxynucleotide. 947 88

To characterize the expression and localization of interleukin (IL)-1beta in human gliomas, both reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used on surgically excised human gliomas, human malignant glioma xenografts, and human glioblastoma cell lines. The RT-PCR products for IL-1beta mRNA were quantified by computerized image analysis. IL-1beta mRNA was detectable in 30 out of 35 (86%) surgically resected gliomas. An abundant expression of IL-1beta mRNA was often found in the glioblastomas, anaplastic astrocytomas, and pilocytic astrocytomas, but not in other types of gliomas. Quantitatively, in both the grade 2 astrocytomas and the oligodendrogliomas, the IL-1beta mRNA levels were significantly (p < 0.05) lower than those of the grade 3/4 astrocytomas. Immunohistochemically, IL-1beta was localized in the pleomorphic tumor cells of the astrocytic tumors and in macrophages. In contrast to the astrocytic tumors, low and high grade oligodendrogliomas showed no or little expression of IL-1beta antigen. IL-1beta was present less frequently than IL-1alpha and IL-1 receptor type 1 in 4 malignant gliomas transplanted into nude mice by RT-PCR. All 2 cell lines showed IL-1beta expression at both the mRNA and protein levels. It is concluded that in human gliomas, both high-grade astrocytomas and pilocytic astrocytomas often express high IL-1beta production, and that IL-1beta is mainly localized in astrocytic tumor cells and macrophages.
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PMID:Expression of interleukin-1beta mRNA and protein in human gliomas assessed by RT-PCR and immunohistochemistry. 969 Jun 69

In the nervous system serine proteases, like thrombin, are involved in developmental and repair processes, but serve also as extracellular signalling molecules, acting via protease-activated receptors. Cellular responses of glial cells to thrombin are transduced by proteolytic activation of the G protein-coupled thrombin receptor. A second member of the protease-activated receptor family, protease-activated receptor-2, is activated by trypsin. We assessed whether glial cells express protease-activated receptor-2 together with the thrombin receptor. By reverse transcriptase polymerase chain reaction and Ca2+ imaging studies we demonstrate that rat astrocytes and C6 glioma cells functionally express protease-activated receptor-2. Short-term stimulation of the glial cells with thrombin, thrombin receptor agonist peptide, trypsin and protease-activated receptor-2 activating peptide dose-dependently induced a transient rise of [Ca2+]i. In astrocytes omission of extracellular Ca2+ attenuated the amplitude of the [Ca2+]i transient induced by protease-activated receptor-stimulation. The decrease was strongest for the trypsin-evoked response and a reduction comparable in size (40%) was observed by pre-treatment with pertussis toxin. In astrocytes concentration-effect curves reveal that (i) the proteases had a higher potency than the respective receptor-activating peptides to induce a Ca2+ response, (ii) proteolytic activation of the receptors by thrombin or trypsin resulted in a double-sigmoidal concentration-effect curve, whereas non-proteolytic activation by receptor activating peptides resulted in a sigmoidal concentration dependence, and (iii) trypsin evoked a significantly greater Ca2+ response than thrombin. Preceding stimulation with trypsin nearly abolished the subsequent response to thrombin, whereas the trypsin-evoked Ca2+ transient was only slightly attenuated after a prior challenge with thrombin. This is the first study to show that neural cells (glial cells) functionally express both thrombin receptor and protease-activated receptor-2 coupled to the mobilization of intracellular calcium. Since calcium is the premier second messenger mediating adaptive changes within the CNS, these findings emphasize an important physiological function of serine proteases in mammalian brain.
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PMID:Co-existence of two types of [Ca2+]i-inducing protease-activated receptors (PAR-1 and PAR-2) in rat astrocytes and C6 glioma cells. 988 72

The discovery of a novel cytosine nucleoside, beta-D-2', 3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC), as a potent antihuman immunodeficiency virus (HIV) agent led us to synthesize a series of analogues and derivatives of beta-D-D4FC that could be more selective and also possess increased glycosidic bond stability. The synthesized D-D4FC analogues were evaluated for anti-HIV-1 activity, anticancer activity, and cytotoxicity in various cells. The biological data demonstrated that the 5-substitution of beta-D-D4FC with bromine (6c) and iodine (6d) resulted in the loss of antiviral activity, and the alpha-D anomer (7a) of D-D4FC was also devoid of activity. The 5-fluorouracil analogues (6b and 7b) of D-D4FC were less potent and more cytotoxic than the parent compound, whereas the beta-L-D4FU (11) showed both potent anti-HIV-1 activity and cytotoxicity. N4- and 5'-O-acyl derivatives (17, 15a-c) of beta-D-D4FC exhibited comparable antiviral activity to beta-D-D4FC. In contrast, the N4-isopropyl derivative (20) of beta-D-D4FC was not active against HIV-1, even at 100 microM. The carbocyclic analogues (26a,b) of D4FC demonstrated weak activity against HIV-1 and no toxicity in various cells. The triphosphates (27a,b) of the carbocyclic nucleosides demonstrated potent inhibitory activity against recombinant HIV-1 reverse transcriptase at submicromolar concentrations. Of the compounds tested as potential anticancer agents, beta-D-, alpha-D-, and beta-L-D4FU (6b, 7b, 11) showed inhibitory activity against rat glioma and modest activity against human lung carcinoma, lymphoblastoid, and skin melanoma cells.
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PMID:Synthesis and biological evaluation of 2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine (D4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase. 1007 83

Calpain, a Ca2+-activated cysteine protease, has been implicated in apoptosis of immune cells. Since central nervous system (CNS) is abundant in calpain, the possible involvement of calpain in apoptosis of CNS cells needs to be investigated. We studied calpain expression in rat C6 glioma cells exposed to reactive hydroxyl radical (.OH) [formed via the Fenton reaction (Fe2++H2O2+H+-->Fe3++H2O+.OH)], interferon-gamma (IFN-gamma), and calcium ionophore (A23187). Cell death, cell cycle, calpain expression, and calpain activity were examined. Diverse stimuli induced apoptosis in C6 cells morphologically (chromatin condensation as detected by light microscopy) and biochemically [DNA fragmentation as detected by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay]. Oxidative stress arrested a population of C6 cells at the G2/M phase of cell cycle. The levels of mRNA expression of six genes were analyzed by the reverse transcriptase-polymerase chain reaction (RT-PCR). Diverse stimuli did not alter beta-actin (internal control) expression, but increased calpain expression, and the upregulated bax (pro-apoptotic)/bcl-2 (anti-apoptotic) ratio. There was no significant increase in expression of calpastatin (endogenous calpain inhibitor). Western blot analysis showed an increase in calpain content and degradation of myelin-associated glycoprotein (MAG), a calpain substrate. Pretreatment of C6 cells with calpeptin (a cell-permeable calpain inhibitor) blocked calpain overexpression, MAG degradation, and DNA fragmentation. We conclude that calpain overexpression due to.OH stress, IFN-gamma stimulation, or Ca2+ influx is involved in C6 cell death, which is attenuated by a calpain-specific inhibitor.
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PMID:Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. 1035 May 26

1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS.
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PMID:Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. 1051 Apr 44

The effects of transforming growth factor-alpha (TGF-alpha) on cell growth were studied in human glioma U251 cells transfected with antisense TGF-alpha vectors (pcDNAI.neo). Several antisense clones showed a marked decrease in growth rate in serum-free medium but not in medium containing 10% FBS, compared with those of parental cells and clones from sense or vector transfectants. Antisense clones also produced fewer and smaller colonies in anchorage-independent growth assays. Moreover, there was a reduction in TGF-alpha expression in these antisense clones at both the protein and mRNA levels, as determined by enzyme linked immuno-sorbent assay and reverse transcriptase polymerase chain reaction analysis. A U251 clone transfected by TGF-alpha antisense in a different vector (pMT/Ep) also showed a marked suppression in cell growth and TGF-alpha mRNA level. Finally, transfected clones with either vector system, showed decreased tumorigenicity in nude mice. In summary, a strong correlation between the inhibition of glioma cell growth and TGF-alpha expression was obtained from two different plasmid vectors, indicating that the expression of TGF-alpha could be specifically and effectively down-regulated by TGF-alpha antisense vector, which in turn led to growth inhibition. These studies suggests that TGF-alpha plays an essential role in controlling human glioma cell proliferation and may serve as a potential target for treatment of malignant glioma.
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PMID:Transforming growth factor-alpha antisense vectors can inhibit glioma cell growth. 1053 24

Previously we reported the amplification of the peripheral myelin protein 22 (PMP22) gene in cell lines of human osteogenic and glioma tumors. PMP22 normally is expressed at high levels in Schwann cells of the peripheral nervous system and is suggested to function as a structural protein of the myelin sheath. One of the most common inherited peripheral neuropathies, Charcot-Marie-Tooth Type 1A (CMT1A), is associated with a duplication of a 1.5-Mb DNA region on chromosome 17p11.2 - p12 containing PMP22. On the other hand, PMP22 is identical to gas3, whose expression is induced in growth-arresting NIH3T3-fibroblasts and is thought to play a role in cell proliferation. The precise role of gas3/PMP22 remains to be determined. Here we show that in the tumor cell lines RH30 and SF763 the amplified region including PMP22 comprises the whole 1.5-Mb CMT1A region. We could prove expression of PMP22 by reverse transcriptase-polymerase chain reaction (RT-PCR) and discovered an unusual PMP22 transcript in these tumor cell lines. Western blot analyses resulted in detection of a 22-kDa protein by the PMP22-specific antibody 558/2 and in exclusion of myelin protein zero (MPZ) expression in these cell lines.
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PMID:Expression analysis of the PMP22 gene in glioma and osteogenic sarcoma cell lines. 1056 90


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