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)

Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating oncogenes. 750 9

The gamma common (gamma c) chain is a partner in several interleukin receptor complexes, including the interleukin-2 receptor (IL-2R), IL-4R, and IL-7R. Mutations in the gamma c gene are associated with X-linked severe combined immunodeficiency (SCID). Using reverse transcriptase-PCR, we examined the level of mRNA-encoding gamma c and its partners in mouse pluripotent hematopoietic stem cells (PHSCs), which repopulate both bone marrow and thymus. We also assayed developing lymphocytes to define which, if any, IL-R complexes are expressed at the earliest stage of T and B lymphocyte maturation. RNA extracted from bone marrow-derived PHSCs did not contain detectable levels of mRNA-encoding IL-7R alpha. However, the most primitive (CD4- CD8-) T cells from the thymus and the most primitive (c-kit+ B220+) B cells from bone marrow contained high levels of IL-7R alpha mRNA. There were no detectable differences between PHSCs and primitive or more mature T and B cells for expression of gamma c mRNA. We conclude that the onset of IL-7R formation occurs at the earliest stage of differentiation of T and B lymphocytes. Our findings are consistent with the hypothesis that the absence of an intact IL-7R (IL-7R alpha and gamma c) may be a critical loss that interrupts lymphopoiesis.
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PMID:Interleukin-7R alpha mRNA expression increases as stem cells differentiate into T and B lymphocyte progenitors. 909 Dec 97

Human papillomavirus type 16 (HPV-16) is strongly associated with the development of cervical cancer. Studies of model systems with animal papillomaviruses have demonstrated the importance of neutralizing antibodies in preventing papillomavirus-associated disease. The assessment of neutralizing antibody responses against HPV-16, previously hampered by the lack of a viral source, was enabled by the recent propagation of an HPV-16 stock in xenografted severe combined immunodeficiency (SCID) mice. HPV-16 infection of an immortalized human keratinocyte cell line was demonstrated by detection of an HPV-16-specific spliced mRNA amplified by reverse transcriptase PCR. Infection was blocked by preincubation of the virus with antiserum generated against HPV-16 virus-like particles (VLPs) composed of the major capsid protein, L1. To examine potential cross-neutralizing activity among the different genital HPV types, rabbit antisera to L1 VLPs corresponding to HPV-6, -11, -18, -31, -33, -35, -39, and -45 were assayed for the ability to block the HPV-16 infection of cultured cells. Antiserum raised against HPV-33 L1 VLPs was the only heterologous antiserum which inhibited HPV-16 infection. Thus, a neutralization assay for HPV-16 may help to characterize the components required to compose a broadly efficacious genital HPV vaccine.
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PMID:In vitro infection and type-restricted antibody-mediated neutralization of authentic human papillomavirus type 16. 944 88

We cloned and sequenced a mouse gene encoding a new type of membrane bound serine protease (epithin) containing a multidomain structure. The initial cDNA clone was found previously in a polymerase chain reaction (PCR)-based subtractive library generated from fetal thymic stromal cells, and the message was shown to be highly expressed in a thymic epithelial nurse cell line. A clone isolated from a severe combined immunodeficiency (SCID) thymus library and extended to its full length at the 5' end with the RACE technique contains an open reading frame of 902 amino acids. Based on the sequence of this clone, the predicted protein structure is a type II membrane protein with a C-terminal serine protease domain linked to the membrane by four low density lipoprotein receptor modules and two CUB domains. High message expression by northern blotting was detected in intestine, kidney, lung, SCID, and Rag-2(-/-) thymus, and 2-deoxyguanosine-treated fetal thymic rudiment, but not in skeletal muscle, liver, heart, testis, and brain. Sorted MHC class II+ and II- fetal thymic stromal cells were positive for expression by reverse transcriptase-PCR, whereas CD45(+) thymocytes were not. The gene was found in chicken and multiple mammalian species under low stringency Southern hybridization conditions. Under high stringency conditions, only a single gene per haploid genome was identified in the mouse. This gene, Prss14 (protease, serine, 14), was mapped to mouse chromosome 9 and is closely linked to the Fli1 (Friend leukemia integration 1) gene.
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PMID:Cloning and chromosomal mapping of a gene isolated from thymic stromal cells encoding a new mouse type II membrane serine protease, epithin, containing four LDL receptor modules and two CUB domains. 1019 18

A xenograft model of the human disease Langerhans cell histiocytosis (LCH) was investigated with severe combined immunodeficiency (SCID) mice. Transplantation of human LCH biopsy material into SCID mice resulted in the generation of mouse tumors resembling lymphomas. A thymoma cell line (ThyE1M6) was generated from one of these mice and found to display significant levels of Mg2+-dependent reverse transcriptase activity. Electron microscopy revealed particles with type D retroviral morphology budding from ThyE1M6 cells at a high frequency, whereas control cultures were negative. Reverse transcription-PCR of virion RNA with degenerate primers for conserved regions of various mouse, human, and primate retroviruses amplified novel sequences related to primate type D retroviruses, murine intracisternal A particles, Jaagsiekte sheep retrovirus, and murine long interspersed nuclear elements but not other retroviral classes. We demonstrate that these sequences represent a novel group of endogenous retroviruses expressed at low levels in mice but expressed at high levels in the ThyE1M6 cell line. Furthermore, we propose that the activation of endogenous retroviral elements may be associated with a high incidence of thymomas in SCID mice.
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PMID:Novel endogenous type D retroviral particles expressed at high levels in a SCID mouse thymic lymphoma. 1023 25

The AC133 is a novel antigen selectively expressed on primitive CD34bright stem cells and is a valuable marker for the selection of long-term culture-initiating cells (LTC-ICs) and severe combined immunodeficiency (SCID)-repopulating cells. Human placental cord blood (HPCB) is a rich source of CD34+AC133+ cells. Since AC133 antibody is likely to be used as an alternative to CD34 for the selection of stem cells in transplant and gene therapy situations, we examined the susceptibility of HPCB-isolated CD34+AC133+ stem cells to infection with free and cell-associated HIV-1 in vitro. Freshly isolated HPCB CD34+AC133+ stem cells were not susceptible to HIV-1 infection as determined by PCR and reverse transcriptase assays. Inoculation with HIV-1 did not affect the viability and clonogenic ability of HPCB CD34+AC133+ cells. Although the highly purified HPCB CD34+AC133+ stem cells contained mRNA for CD4 and CXCR4 receptors, CD4 and CXCR4 proteins were not expressed on these cells. Similarly, CCR5 protein, the major macrophage-tropic HIV-1 coreceptor, was not expressed in freshly isolated HPCB CD34+AC133+ stem cells, although the transcript for CCR5 was identified in these cells. Expression of CD4, CXCR4, and CCR5 receptor proteins on the progeny derived from HPCB CD34+AC133+ stem cells was detected and correlated with susceptibility to HIV-1 infection in vitro. These findings suggest that freshly isolated HPCB CD34+AC133+ stem cells are not susceptible to HIV-1 infection and may not be a viral reservoir. These data have important implications for the use of AC133 antibody as a means of enriching for primitive hematopoietic stem cells from placental cord blood and in the design of stem cell or progenitor cell-based gene therapeutic strategies for perinatal HIV-1 infection.
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PMID:Human immunodeficiency virus infection of human placental cord blood CD34+AC133+ stem cells and their progeny. 1058 Apr 5

The cytoplasmic spleen tyrosine kinase (SYK) is a key regulator of signal transduction events, apoptosis and orderly cell cycle progression in B-lineage lymphoid cells. Although SYK has not been linked to a human disease, defective expression of the closely related T-cell tyrosine kinase ZAP-70 has been associated with severe combined immunodeficiency. Childhood CD19(+)CD10(-) pro-B cell acute lymphoblastic leukemia (ALL) is thought to originate from B-cell precursors with a maturational arrest at the pro-B cell stage and it is associated with poor prognosis. Since lethally irradiated mice reconstituted with SYK-deficient fetal liver-derived lymphohematopoietic progenitor cells show a block in B-cell ontogeny at the pro-B to pre-B cell transition, we examined the SYK expression profiles of primary leukemic cells from children with pro-B cell ALL. Here we report that leukemic cells from pediatric CD19(+)CD10(-) pro-B cell ALL patients (but not leukemic cells from patients with CD19(+)CD10(+) common pre-pre-B cell ALL) have markedly reduced SYK activity. Sequencing of the reverse transcriptase-polymerase chain reaction (RT-PCR) products of the Syk mRNA in these pro-B leukemia cells revealed profoundly aberrant coding sequences with deletions or insertions. These mRNA species encode abnormal SYK proteins with a missing or truncated catalytic kinase domain. In contrast to pro-B leukemia cells, pre-pre-B leukemia cells from children with CD19(+)CD10(+) common B-lineage ALL and EBV-transformed B-cell lines from healthy volunteers expressed wild-type Syk coding sequences. Examination of the genomic structure of the Syk gene by inter-exonic PCR and genomic cloning demonstrated that the deletions and insertions in the abnormal mRNA species of pro-B leukemia cells are caused by aberrant splicing resulting in either mis-splicing, exon skipping or inclusion of alternative exons, consistent with an abnormal posttranscriptional regulation of alternative splicing of Syk pre-mRNA. Our findings link for the first time specific molecular defects involving the Syk gene to an immunophenotypically distinct category of childhood ALL. To our knowledge, this is the first discovery of a specific tyrosine kinase deficiency in a human hematologic malignancy.
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PMID:Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia. 1149 25

A retroviral element (multiple sclerosis-associated retrovirus, MSRV) defining a family of genetically inherited endogenous retroviruses (human endogenous retrovirus type W, HERV-W) has been characterized in cell cultures from patients with multiple sclerosis. Recently, MSRV retroviral particles or the envelope recombinant protein were shown to display superantigen activity in vitro, but no animal model has yet been set up for studying the pathogenicity of this retrovirus. In the present study, the pathogenicity of different sources of MSRV retroviral particles has been evaluated in a hybrid animal model: severe combined immunodeficiency (SCID) mice grafted with human lymphocytes and injected intraperitoneally with MSRV virion or mock controls. MSRV-injected mice presented with acute neurological symptoms and died within 5 to 10 days post injection. Necropsy revealed disseminated and major brain hemorrhages, whereas control animals did not show abnormalities (P <.001). In ill animals, reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed circulating MSRV RNA in serum, whereas overexpression of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma was evidenced in spleen RNA. Neuropathological examination confirmed that hemorrhages occurred prior to death in multifocal areas of brain parenchyma and meninges. Further series addressed the question of immune-mediated pathogenicity, by inoculating virion to SCID mice grafted with total and T lymphocyte-depleted cells in parallel: dramatic and statistically significant reduction in the number of affected mice was observed in T-depleted series (P <.001). This in vivo study suggests that MSRV retroviral particles from MS cultures have potent immunopathogenic properties mediated by T cells compatible with the previously reported superantigen activity in vitro, which appear to be mediated by an overexpression of proinflammatory cytokines.
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PMID:Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. 1258 71

In this series of studies, we determined the potential role of intracellular estrogen receptors (ER), ERalpha and ERbeta, on macrophage function in response to bacterial stimuli. The sex hormone 17beta-estradiol (E(2)) and ER have been shown to modulate inflammatory responses as well as T helper cell type 1 (TH1)/TH2 responses. The mechanisms E(2) and its receptors use to alter these immune functions remain largely unknown. ERalpha and ERbeta possess complex actions in tissues where they are expressed. We have characterized the receptor repertoire of murine dendritic cells and thioglycollate-elicited peritoneal macrophages (PM). Both cell types express mRNA for ERalpha. Neither cell type expressed detectable amounts of ERbeta mRNA, as determined by reverse transcriptase-polymerase chain reaction using exon-specific primers spanning each of the seven intron/exon junctions. Primary macrophages from ERalpha- and ERbeta-deficient severe combined immunodeficiency mice [ERalpha knockout (KO) and ERssKO, respectively] were used to delineate the effects and potential mechanisms via which steroid receptors modulate macrophage function. ERalpha-deficient PM exposed ex vivo to lipopolysaccharide or Mycobacterium avium exhibited significant increases in tumor necrosis factor alpha (TNF-alpha) secretion as well as reduction in bacterial load when compared with wild-type (WT) PM. In contrast, ERbeta-deficient PM possessed no significant difference in TNF-alpha secretion or in bacterial load when compared with WT littermates. These studies suggest that ERalpha, but not ERbeta, modulates murine PM function.
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PMID:Estrogen receptor-alpha deficiency promotes increased TNF-alpha secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro. 1502 Jun 52

The tyrosine kinase inhibitor STI571 is an effective agent for the treatment of chronic myelogenous leukemia (CML). However, a lack of response to STI571 or the recurrence of the disease after a transient initial response is usually seen in patients with advanced stage CML. We have established a novel STI571 (Gleevec/Glivec, imatinib mesylate)-resistant acute myelocytic leukemia cell line (SR-1) from an STI571-resistant blast crisis patient. By flow cytometry, the immunophenotype of SR-1 was found to be compatible with a myeloid lineage (CD13+, CD33+, HLA-DR+, anti-MPO+). Conventional cytogenetics showed a three-way reciprocal translocation involving 7p22, 9q34, and 22q11.2, i.e., a variant Philadelphia chromosome translocation. The BCR/ABL rearrangement was detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. To determine the tumorigenicity of the SR-1 cell line in vivo, cells were injected subcutaneously into severe combined immunodeficiency mice. Four weeks later, tumors had grown and showed the same laboratory findings as in SR-1. Although STI571 resistance is a known treatment complication, in vivo STI571-resistant cell lines have not been fully established. We hope that our SR-1 cell line may be useful in molecular pathogenetic investigations of STI571-resistant CML.
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PMID:Establishment and characterization of an STI571-resistant human myelogenous leukemia cell line, SR-1. 1538 72


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