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 gene on chromosome 10 at band p12 (AF10), involved in the t(10;11) translocation in acute myeloid leukemia, has been identified and shown to contain conserved zinc finger and leucine zipper domains. These regions are highly homologous to the equivalent regions on AF17, the gene involved in the t(11;17) translocations. A series of adult, childhood, and infant leukemias with either simple or complex versions of the t(10;11) has been examined by Southern analysis and shown to involve rearrangement to the HRX locus. Reverse transcriptase-polymerase chain reaction from either bone marrow or peripheral blood cells showed that HRX sequence was fused to AF10 sequence in all 8 cases and subsequent sequence analysis showed an in-frame fusion between the HRX and AF10 sequence. A consistent feature of these fusions was the juxtaposition of the leucine dimerization motif of AF10 onto the NH2-terminal region of HRX. The published data suggest that a similar conclusion can be drawn about the t(11;17) translocation, implying a critical role for this motif in the chimaeric HRX protein.
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PMID:The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. 766 54

The chicken extracellular matrix glycoprotein ES/ 130 is necessary for epithelial--mesenchymal transformation in the developing heart and is also expressed in noncardiac chicken tissues such as limb and notochord. We have identified hES, the human homolog of chicken ES/130. Fluorescence in situ hybridization analysis (FISH) localizes hES to human chromosome 20p11.2-p12. FISH analyses of individuals with 20p12 deletions and affected by Alagille syndrome exclude hES as a candidate gene for this disorder. Reverse transcriptase-polymerase chain reaction studies reveal that hES is expressed in both fetal and adult human tissues and that hES expression in the left ventricle is increased in the failing adult heart. Further studies will evaluate how hES mutations may relate to congenital human cardiac and skeletal anomalies as well as cardiac remodeling in the adult.
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PMID:Identification, characterization, and chromosomal localization of the human homolog (hES) of ES/130. 881 7

A t(11;22)(p13;p12) chromosomal translocation, juxtaposing the Wilms' tumor (WT1) and Ewing's sarcoma (EWS) genes, is the cytogenetic hallmark of desmoplastic small round cell tumor (DSRCT), a primitive multiphenotypic sarcoma arising in serosal tissues. Chimeric transcripts generated by this rearrangement encode an aberrant transcription factor that fuses the 5' region of EWS with a 3' WT1 segment. We describe the insertion of a LINE-I DNA mobile genetic element at the genomic breakpoint of a DSRCT chromosomal translocation. A 480 bp heterologous DNA segment with homology to the LINE-I DNA consensus sequence was located between EWS intron 8 and WT1 exon 8 in the productively rearranged allele. Sequence homology corresponded to the LINE-I ORF-2, which encodes a protein with reverse-transcriptase activity. The heterologous inserted fragment was not evident in the germline of normal tissue from the patient, suggesting that transposition occurred in somatic cells, possibly during the process of chromosomal rearrangement. This case represents the first example of LINE-I DNA transposition at the fusion site of a tumor-associated chromosomal rearrangement.
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PMID:LINE-I element insertion at the t(11;22) translocation breakpoint of a desmoplastic small round cell tumor. 907 77

The genome of Japanese iris necrotic ring virus (JINRV) consists of a positive-sense ssRNA of 4014 nucleotides with six major open reading frames (ORFs). A 5'-non-coding region of 31 nucleotides precedes the first initiation codon. Like Carnation mottle virus (CarMV), the 5'-proximal three ORFs encode a 26 kDa protein (p26) and two readthrough proteins, i.e. an 85 kDa putative RNA replicase (p85) and a 99 kDa protein (p99). The central ORF encodes a small 8 kDa protein (p8). The 3'-proximal ORF encodes a 38 kDa capsid protein (p38). Another ORF encoding a 12 kDa protein (p12) overlaps the p99 ORF.JINRV RNA treated with bacterial alkaline phosphatase and tobacco acid pyrophosphatase could not be ligated to an oligoribonucleotide using T4 RNA ligase, indicating that the 5' end of the viral RNA is uncapped. The 3' end is not polyadenylated. Comparison of the genomic organization and the predicted amino acid sequences with those of other viruses confirmed that JINRV should be classified as a member of the genus Carmovirus, family Tombusviridae.
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PMID:The nucleotide sequence and genome organization of Japanese iris necrotic ring virus, a new species in the genus Carmovirus. 1079 30

Benign mesenchymal neoplasms associated with rearrangements of the DNA architectural factor gene HMGIC on chromosome 12 include lipomas, uterine leiomyomata, pulmonary chondroid hamartomas, endometrial polyps, salivary gland pleomorphic adenomas, and breast fibroadenomas. Although HMGIC also has been implicated in the pathobiology of aggressive angiomyxoma of the vulva, the molecular mechanisms pertaining to this neoplasm are unclear. Tissue from a recurrent aggressive angiomyxoma was investigated by cytogenetic and expression analysis for HMGIC and HMGIY. The trypsin-Giemsa-banded karyotype showed a clonal translocation between chromosomes 8 and 12 [46,XX,t(8;12)(p12;q15)]. Fluorescence in situ hybridization (FISH) analysis with whole chromosome paint probes for chromosomes 8 and 12 excluded cryptic involvement of other chromosomes. The chromosome 12 breakpoint was mapped with two-color FISH analysis using cosmid probes at the 5' and 3' termini of HMGIC. Both cosmid probes showed hybridization to the normal chromosome 12 and the der(12) chromosome, indicating that the breakpoint was 3' (telomeric) to the gene. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed HMGIC expression in the tumor, and immunohistochemistry localized HMGIC expression to the tumor's spindle cells. Like numerous benign mesenchymal tumors, this locally aggressive tumor is associated with rearrangements near or within HMGIC, but chimeric gene formation was not required for tumorigenesis. Inappropriate expression of this DNA binding protein, however, may be important in the pathobiology of this tumor. Understanding the pathogenetic mechanism may also be helpful in developing new diagnostic tools for identifying residual disease.
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PMID:Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. 1155 Feb 85

FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell myeloproliferative disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33, FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5' sequences from HERV-K fused in frame to 3' FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts, HERV-K/FGFR1.
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PMID:Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3). 1239 97

The t(10;11)(p12-14;q14-21) is a non-random translocation that results in the fusion of CALM gene on chromosome 11 with AF10 gene on chromosome 10. This translocation is observed in acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma. Here we report a patient with t(10;11) who was diagnosed with AML-M4. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay revealed one type of CALM/AF10 and three types of AF10/CALM fusion transcripts. Sequencing analysis for these RT-PCR products determined the breakpoint in CALM at nucleotide (nt) 1926-1927 and in AF10 at nt 423-424. The latter breakpoint was the same as that identified in three monocytic cell lines carrying t(10;11). After achieving complete remission, the patient developed mediastinal emphysema during the course of consolidation therapy, possibly due to the necrosis of his mediastinal mass. Monocytic leukemias with CALM/AF10 fusion are frequently associated with mediastinal invasion. We need to pay special attention to such a complication, even if the chest X-ray is normal at presentation.
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PMID:Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema. 1255 19

Mouse hepatitis virus (MHV) RNA synthesis is mediated by a viral RNA-dependent RNA polymerase (RdRp) on membrane-bound replication complexes in the host cell cytoplasm. However, it is not known how the putative MHV RdRp (Pol) is targeted to and retained on cellular membranes. In this report, we show that a 100-kDa protein was stably detected by an anti-Pol antiserum as a mature product throughout the virus life cycle. Gradient fractionation and biochemical extraction experiments demonstrated that Pol was not an integral membrane protein but was tightly associated with membranes and coimmunoprecipitated with the replicase proteins 3CLpro, p22, and p12. By immunofluorescence confocal microscopy, Pol colocalized with viral proteins at replication complexes, distinct from sites of virion assembly, over the entire course of infection. To determine if Pol associated with cellular membranes in the absence of other viral factors, the pol domain of gene 1 was cloned and expressed in cells as a fusion with green fluorescent protein, termed Gpol. In Gpol-expressing cells that were infected with MHV, but not in mock-infected cells, Gpol relocalized from a diffuse distribution in the cytoplasm to punctate foci that colocalized with markers for replication complexes. Expression of Gpol deletion mutants established that the conserved enzymatic domains of Pol were dispensable for replication complex association, but a 38-amino-acid domain in the RdRp unique region of Pol was required. This study demonstrates that viral or virus-induced factors are necessary for Pol to associate with membranes of replication complexes, and it identifies a defined region of Pol that may mediate its interactions with those factors.
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PMID:Characterization of the expression, intracellular localization, and replication complex association of the putative mouse hepatitis virus RNA-dependent RNA polymerase. 1297 Apr 36

The RNA-dependent RNA polymerase (RdRp) of SARS coronavirus (SARS-CoV) is essential for viral replication and a potential target for anti-SARS drugs. We report here the cloning, expression, and purification of the N-terminal GST-fused SARS-CoV RdRp and its polymerase catalytic domain in Escherichia coli. During purification, the full-length GST-RdRp was found to cleave into three main fragments: an N-terminal p12 fragment, a middle p30 fragment, and a C-terminal p64 fragment comprising the catalytic domain, presumably due to bacterial proteases. Biochemical assays show that the full-length GST-RdRp has RdRp activity and the p64 and p12 fragments form a complex that exhibits comparable RdRp activity, whereas the GST-p64 protein has no activity, suggesting that the p12 domain is required for polymerase activity possibly via involvement in template-primer binding. Nonnucleoside HIV-1 RT inhibitors are shown to have no evident inhibitory effect on SARS-CoV RdRp activity. This work provides a basis for biochemical and structural studies of SARS-CoV RdRp and for development of anti-SARS drugs.
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PMID:Expression, purification, and characterization of SARS coronavirus RNA polymerase. 1584 May 16

We describe the molecular analysis of chromosomal rearrangements in familial t(3;6)(p12.3;q24.3) and t(3;12)(q13.13;q24.23) associated with the development of conventional renal cell carcinomas (RCC). We mapped the breakpoints by high-density oligo array comparative genomic hybridization of tumor cells in t(3;6) at chromosome 3p12.3 between PDZRN3 and CNTN3; the chromosomal rearrangement at 6q24.3 was mapped within the seventh intron of the STXBP5 gene. In the second case, the break at 3q13.13 was mapped downstream of PVRL3 and the breakpoint at 12q24.23 between HSPB8 and CCDC60, one allele of the latter being deleted. Reverse transcriptase polymerase chain reaction analysis of the PDZRN3, CNTN3, STXBP5, PVRL3, HSPB8, and CCDC60 genes revealed slight variation in the copy number of transcripts, but without correlation to the chromosomal rearrangements in translocation-associated and sporadic conventional RCCs. Loss of heterozygosity at chromosome 3p and mutation of VHL occurred at the same frequency in both familial and sporadic cases. Based on our model of nonhomologous chromatid exchange and the data on molecular studies, we suggest that the germline translocation serves as a rate-limiting step toward tumor development by generating a high number of cells with loss of the derivative chromosome carrying the 3p segment.
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PMID:Molecular analysis of germline t(3;6) and t(3;12) associated with conventional renal cell carcinomas indicates their rate-limiting role and supports the three-hit model of carcinogenesis. 2063 63


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