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:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of alpha-interferon (alpha-IFN) on spontaneous or induced proliferation of isolated peripheral blood mononuclear cells from 5 hairy cell leukemia patients was studied. alpha-IFN inhibited the low spontaneous proliferation of B-ly7 positive hairy cells (HCs) and also the proliferation induced by tumour necrosis factor (TNF). Interleukin-2 did not affect HCs, but induced CD4 positive T cells to proliferate, an effect which alpha-IFN antagonized. The stimulatory effect of TNF on the growth of HCs proved to be reversible and was partially blocked with either anti-TNF receptor or anti-lymphotoxin antibodies. Cellular or secreted thymidine kinase levels reflected the proliferative state of HCs in response to different in vitro treatments, as confirmed by thymidine incorporation and cell cycle studies.
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PMID:alpha-Interferon inhibits spontaneous and induced DNA synthesis in hairy cell leukemia. 147 34

Transfection of deleted forms of the human interleukin 2 receptor alpha subunit (IL-2R alpha; also called CD25 or Tac antigen) gene (IL2RA) promoter revealed a requirement for sequences 3' of base -317 for phytohemagglutinin- and phorbol 12-myristate 13-acetate (PMA)-induced promoter activation in CD4+ Jurkat T cells. In contrast, sequences 3' of base -271 were sufficient for promoter induction in CD4-/CD8- YT-1 T cells or Jurkat cells expressing the transactivator protein (tat-I) of human T-cell lymphotropic virus type I (HTLV-I). Gel retardation assays revealed that nuclear extracts from induced, but not uninduced, Jurkat and YT-1 cells mediated the formation of two specific DNA-protein complexes with oligonucleotides spanning the region of the IL2RA promoter from position -291 to -245, which contains two imperfect direct repeats (IDRs). Consistent with the different 5' sequence requirements for promoter activation in Jurkat and YT-1 cells, oligonucleotides corresponding to the region from -267 to -243 (downstream IDR and flanking region) formed only one complex with induced Jurkat extracts but two complexes with induced YT-1 extracts. Oligonucleotides containing the region of the IL2RA promoter from -293 to -270 (upstream IDR and flanking region) failed to bind protein in either cell type. In further support of the biological significance of these DNA-protein interactions, the IL2RA oligonucleotide from -291 to -245 proved to be sufficient in either orientation to confer PMA inducibility to the mitogen-insensitive thymidine kinase gene promoter in Jurkat cells. Together, these findings suggest that the interaction of inducible DNA binding proteins with the IL2RA promoter between bases -291 and -245 plays an important role in mitogen-induced changes in the transcriptional activity of this receptor gene. Furthermore, the requisite 5' sequences appear to differ in T cells depending upon the nature of the activation signal and perhaps the stage of cellular maturation.
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PMID:Regulation of interleukin 2 receptor alpha subunit (Tac or CD25 antigen) gene expression: binding of inducible nuclear proteins to discrete promoter sequences correlates with transcriptional activation. 313 14

Subsets of CD4 T cells are defined by the cytokines that they produce; these cytokines determine the effector function of these cells. Cloned CD4 T cells fall into two subsets, producing either interferon-gamma (IFN gamma) or interleukin-4 (IL-4) in combination with other cytokines, and are called Th1 and Th2 cells, respectively. The lineage relationship between naive T cells and effector Th1- and Th2-type cells is unclear. We generated transgenic mice in which IL-4-producing cells express herpes simplex virus 1 thymidine kinase and are eliminated by ganciclovir (GANC). Activation of transgenic T cells in the presence of GANC eliminates IL-4 and IFN gamma production, showing that IL-4- and IFN gamma-producing cells express or have expressed IL-4. These results show that effector cells producing either IL-4 or IFN gamma have a common precursor, which expresses the IL-4 gene.
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PMID:The relationship of IL-4- and IFN gamma-producing T cells studied by lineage ablation of IL-4-producing cells. 790 80

Phenotypic and genotypic analyses were done on 17 varicella-zoster virus (VZV) isolates recovered from 10 persons with AIDS (mean CD4 cell count, 16.4/mm3) who had chronic VZV lesions. Eleven acyclovir-resistant isolates were recovered from 10 patients after a mean of 20.1 weeks of therapy. Six susceptible isolates were recovered before acyclovir treatment (n = 1), early during therapy (n = 4; mean time, 4.2 weeks), or after discontinuation of acyclovir (n = 1). Acyclovir-resistant VZV isolates were deficient in thymidine kinase (TK) or induced a TK with altered substrate specificity; all isolates were susceptible to foscarnet. Ten of 11 acyclovir-resistant mutants contained tk gene mutations, including single nucleotide substitutions in highly conserved binding sites (n = 2) as well as nucleotide deletions (n = 4) and insertions (n = 4). These findings suggest that multiple, nonuniform mutations within the tk gene are associated with acyclovir-resistant VZV phenotypes.
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PMID:Phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. 801 22

Thy-1 has been used as a cell surface marker for identification of mature T cells, T lymphoid precursors and the hematopoietic stem cell. The developmental program of these cells during hemato/lymphopoiesis is complex because of heterogeneity of the populations and subsequent migration. To study the differentiation of Thy-1 positive cells at precise periods of in vivo development we have used a strategy based on cell specific toxicity. In the transgenic mouse studies presented here, Thy-1 positive cells are ablated by targeting the expression of the conditional toxin Herpes simplex virus 1 thymidine kinase (tk) with Thy-1 transcriptional control elements. We demonstrate the controlled expression of HSV1 tk in Thy-1 expressing cells of adult transgenic mice and the conditional ablation of > 90% of maturing thymocytes. We describe the distinct subpopulations of cells remaining within individual ablated thymuses and show by phenotypic analyses that Thy-1 tk induced ablation enriches for CD4 low and double negative thymocytes. Furthermore, we demonstrate a differential effect of thymus directed ablation on the maturing peripheral T cell compartment at various times in mouse development. This strategy is successful for production of a conditional T lymphocyte deficiency and could be useful in the study of T lineage development and direct in vivo isolation of enriched T precursor cell populations.
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PMID:Thy-1 tk transgenic mice with a conditional lymphocyte deficiency. 810 74

To better understand the requirement for interleukin 2 (IL-2) in specific immune responses, we have established the use of cell ablation to selectively eliminate T cells that produce IL-2. To accomplish this we have generated transgenic mice that express the herpes simplex virus 1-thymidine kinase (HSV-TK) gene under the transcriptional control of the murine IL-2 promoter that renders IL-2-producing cells sensitive to the cytotoxic effects of the antiviral drug ganciclovir (GANC). HSV-TK activity was specifically expressed in activated T cells from transgenic mice. When CD4 T cells from transgenic mice were stimulated with the superantigen staphylococcal enterotoxin A (SEA) in the presence of GANC, proliferation and IL-2 production were almost completely inhibited and the activated CD4+V beta 3+ T cell population, eliminated. Proliferation was not restored by adding IL-2, showing that most proliferating cells are not bystander cells. In contrast, the proliferative response to concanavalin A (Con A) was only partially inhibited by treatment of CD4 T cells with GANC, although the efficiency of eliminating IL-2-producing cells was shown to be comparable with that achieved using SEA. This suggests that a portion of the proliferative response to Con A occurs via an alternative pathway not requiring IL-2 synthesis and release.
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PMID:The selective ablation of interleukin 2-producing cells isolated from transgenic mice. 838 45

Genome-wide DNA hypermethylation induced by 3'-azido-3'-deoxythymidine (AZT) has been suggested to be involved in the development of AZT resistance. We used a CD4 T-lymphoblastoid CEM line and its AZT-resistant MT500 variant with reduced thymidine kinase activity. Evaluation of total DNA methylation, after AZT treatment, failed to show an increase in the 5-methylcytosine level in both parental and AZT-resistant cells. The effect was instead observed at a more specific gene level, on the three HpaII sites present in exon 1 of the human thymidine kinase gene. These results suggest that AZT treatment can induce site-specific hypermethylation, even in the absence of a more general DNA hypermethylating effect.
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PMID:AZT-induced hypermethylation of human thymidine kinase gene in the absence of total DNA hypermethylation. 891 12

Serum selenium levels were determined cross-sectionally in 57 HIV-infected patients who were classified according to the Centers for Disease Control (CDC) 1993 classification system. Mean serum selenium levels were lower in CDC stage II (58.7 +/- 12.2 micrograms/L; p < 0.01; n = 18) and stage III (47.6 +/- 11.3 micrograms/L; p < 0.01; n = 19) HIV-infected patients, than in healthy subjects (80.6 +/- 9.6 micrograms/L; n = 48) and stage I patients (73.6 +/- 16.5 micrograms/L; n = 20). Serum selenium levels were positively correlated with CD4 count, CD4/8 ratio, hematocrit, and serum albumin (r = 0.42; r = 0.39; r = 0.48; and r = 0.45; p < 0.01, respectively) and inversely with serum levels of thymidine kinase (r = -0.49; p < 0.01; n = 49) and beta 2-microglobulin (r = -0.46; p < 0.001; n = 49). In addition, serum selenium levels in 20 randomly selected AIDS-free individuals (CDC I: n = 10; CDC II: n = 10) were inversely correlated with serum concentrations of interleukin-8 (IL-8) and soluble tumor necrosis factor receptors (sTNFR) types I and II. There was no correlation with serum immuneglobulin A and total serum protein levels. The results show that the progressive deprivation of serum selenium in HIV-infection is associated with loss of CD(4+)-cells and with increased levels of markers of disease progression and inflammatory response.
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PMID:Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection. 915 10

Asthma is characterized by chronic eosinophilic inflammation of the airways, and allergen-specific Th2 lymphocytes are thought to play a major role in the development and maintenance of this type of inflammation in allergic asthma. It is generally accepted that airway dendritic cells (DC) are essential for stimulating naive T cells in a primary immune response to inhaled Ag and for the development of allergic sensitization. We have examined the role of airway DC in stimulating memory T cells in a secondary response to inhaled Ag and the subsequent development of chronic airway inflammation. In our mouse model of asthma, OVA aerosol challenge in OVA-sensitized mice leads to CD4-dependent peribronchial and perivascular eosinophilic inflammation, lung Th2 cytokine production, and systemic IgE production. We have used conditional depletion of airway DC by treatment of thymidine kinase-transgenic mice with the antiviral drug ganciclovir to deplete DC during the secondary exposure to OVA. In sensitized thymidine kinase-transgenic mice, a significant decrease in the number of bronchoalveolar CD4 and CD8 T lymphocytes and B lymphocytes was seen after ganciclovir treatment. In addition, Th2 cytokine-associated eosinophilic airway inflammation was almost completely suppressed. These studies demonstrate for the first time that the DC is essential for presenting inhaled Ag to previously primed Th2 cells in the lung, leading to chronic eosinophilic airway inflammation. Altering the function of airway DC may therefore be an important target for new anti-asthma therapy.
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PMID:Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. 955 20

Dividing cells expressing the Herpes simplex type 1 thymidine kinase (TK) can be killed upon ganciclovir treatment. Likewise, conditional cell knock-out can be obtained in transgenic mice expressing a TK gene placed under the control of tissue-specific regulatory sequences. Such animals provide powerful experimental systems for assessing the functional role of specific cell populations through their time-controlled ablation. However, whatever the regulatory sequences used, a leaky toxic overexpression of TK in testis renders male TK-transgenic mice sterile and prevents the generation of homozygous TK-expressing animals. To solve this problem, we designed a truncated TK variant (delta TK) not expressed in the testis. We generated transgenic mice expressing delta TK under the control of lymphocyte-specific regulatory sequences derived from the CD4 gene. The delta TK protein expressed in T-lymphocytes allowed the conditional ablation of activated T-cells in vitro and in vivo. Importantly, for one transgenic line we could generate fertile homozygous mice harboring a functional delta TK transgene. delta TK should thus dramatically facilitate the development of transgenic mice expressing a conditional suicide gene.
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PMID:Fertile homozygous transgenic mice expressing a functional truncated herpes simplex thymidine kinase delta TK gene. 985 21


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