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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The breakpoints of the translocation t(2;5)(p23;q35) associated with Ki-1-positive anaplastic large cell lymphoma (Ki-1 ALCL) have recently been cloned. They involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase-polymerase chain reaction (RT-PCR) with NPM and ALK primers detects a consistent fusion product in Ki-1 ALCL cases that have the translocation. In the course of a survey of 15 cases of Ki-1 ALCL, we identified a single case with a slightly smaller NPM-ALK RT-PCR product, among 12 cases positive for this fusion RNA. Sequencing of this novel NPM-ALK RT-PCR product showed an in-frame junction of NPM to ALK, 30 bases distal to the usual ALK junction site, but at the usual NPM Junction site. The predicted chimeric protein in this case is thus shorter by 10 amino acids, but the putative ALK catalytic domain remains intact. PCR with ALK primers bracketing the novel fusion point, performed on either cDNA or genomic DNA, yielded the same product, confirming that this novel ALK fusion point was located within an exon. Hybridization analysis of the genomic junction fragment isolated by long-range DNA PCR suggested that the ALK genomic breakpoint was also exonic. Cloning and sequencing of the genomic breakpoint confirmed that the break occurred within the 5' portion of the ALK exon participating in the fusion junction, 28 bases 3' to the normal ALK exon boundary, resulting in the use of a cryptic splice acceptor site two bases distal to the breakpoint. This case demonstrates that, in translocations resulting in chimeric transcripts, genomic breakpoints may rarely lie within an exon, provided that the reading frame is maintained and no domains presumed critical to tumorigenesis are deleted.
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PMID:Molecular variant of the NPM-ALK rearrangement of Ki-1 lymphoma involving a cryptic ALK splice site. 872 82

Biologic responses to peptide calciotropic hormones, such as parathyroid hormone (PTH) and calcitonin, exhibit desensitization. As with most hormones, however, the mechanisms of desensitization are not completely understood. For the beta 2-adrenergic receptor (beta 2AR) system, which is coupled to adenylyl cyclase via the stimulatory guanine nucleotide-binding regulatory (G5) protein, homologous desensitization is mediated in part by a receptor-specific kinase (beta ARK) and a soluble cofactor (beta-arrestin). Recently, this system has been reported to be involved in rapid homologous desensitization of the PTH/parathyroid hormone receptor protein (PTHrP) receptor. We have identified the presence of this system in bone using reverse-transcriptase PCR. Nucleotide sequence of PCR fragments from ROS 17/2.8 cells revealed 100% identity with rat brain beta ARK1 and beta-arrestin 1 sequences. Northern analyses with RNA from ROS 17/2.8, UMR 106-H5 cells, and primary cultures of nontransformed neonatal rat calvariae demonstrated two mRNA species of 4 and 2.6 kilobases (kb) for beta ARK and 7.5 kb for beta-arrestin, comparable to those found in bovine brain. beta ARK-like activity was demonstrated in cytosolic extracts of the UMR 106-H5 cells by assessing phosphorylation of the retinal photoreceptor, rhodopsin, by the extracts. Phosphorylation was enhanced with light-activated rhodopsin and by bovine brain G beta gamma subunits; heparin inhibited phosphorylation. These findings are characteristic of beta ARK. Expression of beta-arrestin in the UMR 106-H5 cells was confirmed by immunoblot. Thus, osteoblastic cells express proteins, beta ARK, and beta-arrestin, which may regulate desensitization of calciotropic hormone receptors.
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PMID:Beta-adrenergic receptor kinase-like activity and beta-arrestin are expressed in osteoblastic cells. 872 79

Neisseria gonorrhoeae WS1 is a spontaneous pyocin (a bacteriocin produced by Pseudomonas aeruginosa)-resistant mutant of N. gonorrhoeae FA19 that produces a truncated lipooligosaccharide (LOS) and is non-transformable. The LOS-specific mutation in WS1 was moved into a transformable background by transforming FA19 with chromosomal DNA from WS1 (generating strain JWS-1). A clone (pJCL2) capable of restoring JWS-1 to wild-type LOS expression, as detected by its acquisition of reactivity with monoclonal antibodies and by its complemented sodium dodecyl sulfate-polyacrylamide gel electrophoresis profile, was isolated. Sequential unidirectional deletion and DNA sequence analysis of pJCL2 identified an open reading frame, designated lsi-7, that could complement the defect in JWS-1. Homology searches against various databases indicated that lsi-7 bad homology with several Escherichia coli genes involved in the phosphorylation of sugars. lsi-7 is adjacent to the lsi-6 gene, another gene involved in LOS biosynthesis. Complementation studies using Salmonella typhimurium lipopolysaccharide mutants showed lsi-6 and lsi-7 to be gonococcal homologs of S. typhimurium rfaD and rfaE, respectively. Reverse transcriptase PCR analysis demonstrated that lsi-6 and lsi-7 are part of the same transcriptional unit.
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PMID:Cloning, complementation, and characterization of an rfaE homolog from Neisseria gonorrhoeae. 875 86

The breakpoints of the translocation t(2;5)(p23;q35) associated with Ki-1-positive anaplastic large-cell lymphoma (Ki-1 ALCL) involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase-polymerase chain reaction (RT-PCR) using NPM and ALK primers detects a consistent fusion product in Ki-1 ALCL cases with the translocation, resulting from genomic breakpoints within the same respective introns of NPM and ALK. To examine the feasibility of long-range DNA PCR with the same exonic NPM and ALK primers for the detection of the genomic NPM-ALK rearrangement, we examined 20 cases of Ki-1 ALCL previously characterized by NPM-ALK RT-PCR. Ten cases were positive for the NPM-ALK fusion RNA and 10 were negative. We first confirmed that both the NPM and ALK normal introns are relatively short, approximately 1 and 2 kb, respectively, suggesting that the largest possible size for the chimeric NPM-ALK intron would be about 3 kb. All 10 cases positive by RT-PCR were also positive by long-range DNA PCR. The DNA PCR products ranged, as expected, from the sizes of the normal introns, between 0.5 and 2.5 kb. All 10 RT-PCR-negative cases were also negative by long-range DNA PCR, and control templates for RT-PCR and long-range DNA PCR were successfully amplified. Thus, we have shown that the introns involved by the NPM-ALK rearrangement seen in some Ki-1 lymphomas are relatively short, making the genomic rearrangement amenable to reliable detection by long-range DNA PCR. Furthermore, the variability observed in the sizes of chimeric introns in evidence against clustering of the genomic breakpoints within these introns.
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PMID:Detection of the NPM-ALK genomic rearrangement of Ki-1 lymphoma and isolation of the involved NPM and ALK introns. 886 27

The herpes simplex virus thymidine kinase gene (HSV-TK) in combination with ganciclovir (GCV), is currently being used in gene therapy-based clinical trials for cancer treatment. Its therapeutic effect is based on a "bystander effect" whereby HSV-TK gene-modified tumor cells are toxic to nearby unmodified tumor cells when exposed to the antiviral drug GCV. We have recently hypothesized that the in vivo mechanism of this bystander effect is due to alterations in the tumor microenvironment in response to release of cytokines and an infiltration of leukocytes after treatment with HSV-TK gene-modified tumor cells and GCV, which results in tumor regression. Expression of B7, a recently identified costimulatory molecule that is important for T-cell stimulation, has been shown to be modulated by stimulatory cytokines interferon-gamma, tumor necrosis factor-alpha, and inhibited by interleukin-10. In the present study, we investigated whether the cytokines released after HSV-TK and GCV treatment could include the expression of the costimulatory molecules B7-1 and B7-2 and the adhesion molecule (ICAM)-1 in the tumor. Furthermore, we investigated whether this altered environment affected the antitumor properties of host lymphocytes. An in vitro model was developed to establish the effects of HSV-TK gene-modified tumor cells and GCV on tumor infiltrating cells. The murine macrophage cell line (IC21) was exposed to either supernatants or cell lysates collected from a mixture of HSV-TK-transduced (KBALB-STK) and non-transduced (KBALB) murine fibrosarcoma tumor cells previously exposed to GCV (experimental). Immunohistochemical analysis showed a significant expression (P < .0001) of B7-1 and B7-2 post exposure of IC21 cells to either supernatant or lysate. In contrast, the level of expression in IC21 cells exposed to the control lysate or supernatant remained unchanged for B7-1 and B7-2. In vivo analysis for B7-1 and B7-2 expression by immunohistochemistry in tumor tissues from experimental mice receiving HSV-TK gene-modified tumor cells and GCV treatment showed a significant expression of B7.1 (35%, P < .0001) and B7.2 (38.2%, P < .0001) on tumor-infiltrating mononuclear cells. In contrast, tumor-bearing control animals showed low levels of B7-2 expression (5.8%), whereas B7-1 was undetectable, as confirmed by reverse-transcriptase polymerase chain reaction. In addition, a significant up-regulation of ICAM expression (50%) on tumor tissues was observed in the experimental group (P = .0317) as compared with the control group (25%). Furthermore, T cells isolated from experimental mice showed a significant in vitro proliferative response (p = .0202) when exposed to syngeneic tumor cells as compared with the control group. These data demonstrated that the use of HSV-TK gene-modified tumor cells and GCV as a suicide gene in the treatment of an intraperitoneal tumor resulted in the expression of the B7 costimulatory molecules and ICAM-1 adhesion molecule and enhanced proliferative response of host T cells. These findings help to understand the mechanism of tumor cell killing in vivo using HSV-TK gene-modified tumor cells.
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PMID:Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene. 898 40

Receptor tyrosine kinases (RTK) play an important role in the signal transduction of normal and malignant cells. There are different families of RTKs which are mainly characterized by differences in the ligang-binding extracellular domains. Axl (or UFO/Ark) is the first member of a new class of RTK with two fibronectin type III domains and two immunoglobulin-like domains present at the extracellular domain. The axl-gene has been isolated by means of gene transfection studies using DNA of patients with chronic myelogeneous leukemia. For a previous and the present study, we used a sensitive reverse-transcriptase polymerase chain reaction assay to detect axl's mRNA in cells from normal and malignant hematopoietic tissue. Axl's mRNA expression was mainly detected in myelo-monocytic cells, whereas much weaker transcription was seen in lymphatic cells and in lymphatic leukemias. In normal bone marrow, axl was heavily transcribed in marrow stromal cells. Further, we analysed Axl protein expression using monoclonal antibody M50 in peripheral stem cell harvests; in most harvests, no co-expression of CD34 and Axl was detected. However, in one patient with AML in complete remission, Axl was co-expressed on 80% of the CD34-positive population. These data show that axl is preferentially expressed in monocytes and stromal cells. Furthermore, a fraction of CD34-positive progenitor cells may express Axl. The exact mechanism for transformation of myeloid progenitor cells through Axl, however, remains to be determined.
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PMID:Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias. 913 Jun 17

T-cell lymphoma in patients infected with HIV is much less common than B-cell lymphoma. We describe two cases of HIV-associated extranodal lymphoma that showed Toutonlike tumor giant cells and mononuclear large lymphoma cells. Both cell types expressed T-cell-associated antigens, including CD3, CD5, CD43, and CD45RO, and were CD4- and CD30-positive and negative for all B-lineage-associated antigens. Both cases showed T-cell receptor gamma chain gene rearrangements using the polymerase chain reaction and were negative for the Epstein-Barr virus by in situ hybridization. Despite the expression of CD30 by the multinucleated cells, both cases were negative for ALK1 by immunohistochemistry and failed to show evidence of the nucleophosmin-anaplastic lymphoma kinase fusion product characteristic of t(2;5) using the reverse-transcriptase polymerase chain reaction. Although rare, CD4-positive, T-cell lymphoma with Toutonlike giant cells may be a distinct type of HIV-associated malignant lymphoma.
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PMID:Peripheral T-cell lymphoma with Toutonlike tumor giant cells associated with HIV infection: report of two cases. 1032 82

Angiogenesis is a complex process that includes recruitment and proliferation of mural cells-smooth muscle cells (SMC) and pericytes. Vascular endothelial growth factor (VEGF) has been shown to play an important role in angiogenesis and is an endothelial cell chemoattractant. In addition, certain VEGF isoforms have been implicated in the normal formation of smooth muscle cell-surrounded arteries. Because VEGF's role as a mural cell chemoattractant had not been explored, we examined the ability of VEGF to influence vascular SMC migration in vitro. A Boyden chamber migration assay demonstrated that VEGF (0-100 ng/ml) caused a dose-dependent migration of SMC. VEGF did not cause proliferation of SMC. Reverse transcriptase-polymerase chain reaction analysis demonstrated the presence of both KDR and flt mRNA, two known VEGF receptors, in SMC cultures. Western blot analysis of SMC lysates confirmed these data, revealing bands migrating at approximately 200 kDa and slightly below 200 kDa consistent with KDR and flt. These observations demonstrate that VEGF receptors are present on SMC, and that VEGF can act as an SMC chemoattractant.
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PMID:Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. 1045 28

Nerve growth factor (NGF) is known to exert a mitogenic effect on human breast cancer cells through proto-TrkA activation. Reverse transcriptase-PCR analysis of proto-TrkA expression in human breast carcinoma specimens and cell lines revealed trkA transcript in 12 of 14 human breast carcinoma specimens and in all of four cell lines tested. While cytofluorimetric and Western blot analysis indicated proto-TrkA expression in three of the four cell lines, NGF stimulated growth in only two of the three positive cell lines. Inhibition of NGF-induced MAPK activation by an antibody directed against the extracellular domain of TrkA but not by an inhibitor of TrkA phosphorylation demonstrated the requirement of NGF binding but not of proto-TrkA kinase activity for MAPK activation, suggesting the recruitment of another kinase for transmission of the mitogenic signaling. Indeed, NGF induced tyrosine phosphorylation and stimulated kinase activity of p185(HER2), a kinase receptor of the HER family. A TrkA phosphorylation inhibitor did not affect this activation. Moreover, the two receptors were coprecipitated by antibodies directed against proto-TrkA and p185(HER2). Down-modulation of p185(HER2) expression in a breast carcinoma line transfected with a construct containing an anti-p185(HER2) antibody sequence and expressing proto-TrkA impaired NGF-induced MAPK activation and proliferation. Together these data show that in cells expressing low levels of TrkA such as breast carcinoma cells, NGF must recruit other overexpressed receptors such as p185(HER2) in order to generate a biological signal that can induce breast cancer cell growth.
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PMID:Nerve growth factor cooperates with p185(HER2) in activating growth of human breast carcinoma cells. 1068 13

Extracellular ATP can function as a glial trophic factor as well as a neuronal transmitter. In astrocytes, mitogenic signalling by ATP is mediated by metabotropic P(2Y) receptors that are linked to the extracellular signal regulated protein kinase (Erk) cascade, but the types of P(2Y) receptors expressed in astrocytes have not been defined and it is not known whether all P(2Y) receptor subtypes are coupled to Erk by identical or distinct signalling pathways. We found that the P(2Y) receptor agonists ATP, ADP, UTP and 2-methylthioATP (2MeSATP) activated Erk and its upstream activator MAP/Erk kinase (Mek). cRaf-1, the first kinase in the Erk cascade, was activated by 2MeSATP, ADP and UTP but, surprisingly, cRaf-1 was not stimulated by ATP. Furthermore, ATP did not activate B-Raf, the major isoform of Raf in the brain, nor other Mek activators such as Mek kinase 1 (MekK1) and MekK2/3. Reverse transcriptase-polymerase chain reaction (RT - PCR) studies using primer pairs for cloned rat P(2Y) receptors revealed that rat cortical astrocytes express P(2Y(1)), a receptor subtype stimulated by ATP and ADP and their 2MeS analogues, as well as P(2Y(2)) and P(2Y(4)), subtypes in rats for which ATP and UTP are equipotent. Transcripts for P(2Y(6)), a pyrimidine-preferring receptor, were not detected. ATP did not increase cyclic AMP levels, suggesting that P(2Y(11)), an ATP-preferring receptor, is not expressed or is not linked to adenylyl cyclase in rat cortical astrocytes. These signal transduction and RT - PCR experiments reveal differences in the activation of cRaf-1 by P(2Y) receptor agonists that are inconsistent with properties of the P(2Y(1)), P(2Y(2)) and P(2Y(4)) receptors shown to be expressed in astrocytes, i.e. ATP=UTP; ATP=2MeSATP, ADP. This suggests that the properties of the native P(2Y) receptors coupled to the Erk cascade differ from the recombinant P(2Y) receptors or that astrocytes express novel purine-preferring and pyrimidine-preferring receptors coupled to the ERK cascade.
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PMID:P(2Y) purinoceptor subtypes recruit different mek activators in astrocytes. 1069 92


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