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 rapidly growing mouse Gaelstein hepatomas 22 and 22a and rat Zajdela hepatoma are characterized both by a high thymidine kinase activity, increased TTP pool and intense 14C-thymidine incorporation into DNA. This is indicative of an intensive thymidylate biosynthesis via a short, "salvage" pathway. The predominance of this pathway for thymidylate is also characteristic for the spleens of normal animals. On the contrast, in rat and mouse thymus, where the TTP pool was the highest of all normal tissues studied, the thymidine kinase activity and thymidine incorporation into DNA were relatively low. The growth of the three hepatomas under study induces involution of tumour carrier thymus, manifested in a decrease of the TTP pool and the rate of labelled thymidine incorporation into DNA, as well as in a 4-fold decrease of the thymidine kinase activity of rat thymus. In the spleen of mice carrying ascite 22a and solid 22 hepatomas an entirely opposite response to the tumour growth was observed, i. e. in the former case the organ weight and all indices of DNA synthesis were sharply reduced, while in the latter case they were substantially enhanced. In the spleen of Zajdela hepatoma carriers the DNA synthesis is suppressed as can be evidenced from the decrease of labelled thymidine incorporation into DNA and of TTP pool; the weight of organ and the thymidine kinase activity, however, exceed the normal level more than 2-fold.
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PMID:[Thymidine kinase activity, intracellular TTP content and DNA synthesis in transplantable hepatomas and lymphoid tissue of the host]. 721 50

The activities of thymidylate synthetase and thymidine kinase were compared in tissues of normal (adult and developing), cortisol-injected, and tumor-bearing rats. The purpose of the study was to determine whether the activities of these two enzymes, which catalyze reactions leading to the same metabolic intermediate, changed proportionately, reciprocally, or independently under different physiological conditions. Both enzymes had high activities in fetal tissues. Thymidine kinase concentrations decreased shortly before or immediately after birth; in several tissues, transient postnatal peaks in thymidine kinase activities appeared within the first 3 weeks after birth. Thymidylate synthetase activities declined gradually after parturition and showed no significant postnatal rises. In sucklings given injections of cortisol, thymidine kinase activities were reduced substantially in eight tissues while thymidlyate synthetase decreased only in lung and thymus of 11-day-old rats. In tumor-bearing rats, thymidine kinase activity increased dramatically in spleen, whereas thymidylate synthetase activities only doubled. In host liver, rises in thymidine kinase activities were not always matched by increases in thymidlyate synthetase. In the tumors, both activities were higher than in most normal adult tissues. Despite the differential sensitivities of the two enzymes to cortisol and tumor bearing, thymidylate synthetase and thymidine kinase were closely correlated in tissues of untreated animals. The Spearman rank correlation coefficient for 112 tissues was 0.895, while the correlation coefficient between the standard scores of the activities was 0.839. The activities of the two enzymes did not appear to be reciprocal or compensatory during normal differentiation or during dedifferentiation associated with tumor bearing, but their potentials for activity were independent of each other.
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PMID:Relative activities of thymidylate synthetase and thymidine kinase in rat tissues. 747 Oct 94

L-beta-Deoxythymidine (L-dT), the optical enantiomer of D-beta-deoxythymidine (D-dT), and L-enantiomers of nucleoside analogs, such as 5-iodo-2'-deoxy-L-uridine (L-IdU) and E-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-BVdU), are not recognized in vitro by human cytosolic thymidine kinase (TK), but are phosphorylated by herpes simplex virus type 1 (HSV-1) TK and inhibit HSV-1 proliferation in infected cells. Here we report that: (i) L-dT is selectively phosphorylated in vivo to L-dTMP by HSV-1 TK and L-dTMP is further phosphorylated to the di- and triphosphate forms by non-stereospecific cellular kinases; (ii) L-dTTP not only inhibits HSV-1 DNA polymerase in vitro, but also human DNA polymerase alpha, gamma, delta and epsilon, human immunodeficiency virus reverse transcriptase (HIV-1 RT), Escherichia coli DNA polymerase 1 and calf thymus terminal transferase, although DNA polymerase beta was resistant; (iii) whereas DNA polymerase beta, gamma, delta and epsilon are unable to utilize L-dTTP as a substrate, the other DNA polymerases clearly incorporate at least one L-dTMP residue, with DNA polymerase alpha and HIV-1 RT able to further elongate the DNA chain by catalyzing the formation of the phosphodiester bond between the incorporated L-dTMP and an incoming L-dTTP; (iv) incorporated L-nucleotides at the 3'-OH terminus make DNA more resistant to 3'-->5' exonucleases. In conclusion, our results suggest a possible mechanism for the inhibition of viral proliferation by L-nucleosides.
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PMID:Stereospecificity of human DNA polymerases alpha, beta, gamma, delta and epsilon, HIV-reverse transcriptase, HSV-1 DNA polymerase, calf thymus terminal transferase and Escherichia coli DNA polymerase I in recognizing D- and L-thymidine 5'-triphosphate as substrate. 754 86

We describe the mutagenesis of the IRSI-US5 region of the human cytomegalovirus genome, demonstrating the potential of the E. coli guanosine phosphoribosyl transferase (gpt) gene as a selectable marker for insertion and deletion mutagenesis of high passage (AD169, Towne) as well as low passage (Toledo) strains of virus. Despite evidence suggesting that the US3 gene product may play a regulatory role, disruption of this gene with a gpt insert had no effect on growth of any of these strains of virus in resting or dividing human fibroblasts, or in human thymus plus liver implants in SCID-hu mice. Transcripts of the gpt gene, under control of the herpes simplex virus thymidine kinase promoter adjacent to the US3 enhancer in the viral genome, accumulated with delayed early (beta) kinetics. Mutants with deletions in the IRS1 and US3-US5 regions were isolated by back-selection against gpt with the drug 6-thioguanine by growing virus in human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyl transferase deficient) skin fibroblasts immortalized with human papillomavirus oncogenes. Thus, we demonstrate a dependable method for insertion and deletion mutagenesis that can be applied to any region of the viral genome.
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PMID:Selectable insertion and deletion mutagenesis of the human cytomegalovirus genome using the Escherichia coli guanosine phosphoribosyl transferase (gpt) gene. 756 52

Three isomers of trifluoromethylaniline (TFMA) were investigated for their possible different toxic effects on the hematopoietic system in male Wistar rats. The effects of isomeric 2-, 3- and 4-TFMA were compared with those of aniline, the prototypic drug. Strong leukocytosis manifested by considerable increase in the number of all respective white blood elements was observed in the peripheral blood 1 day after the administration of 4-TFMA. In contrast, erythropoiesis, as ascertained by erythrocyte count and hemoglobin concentration, was inhibited by 4-TFMA. The determination of the ED50 revealed lymphocytes to be the most responsive elements towards 4-TFMA administration. Besides hyperemic and proliferative splenomegaly the histological changes in maturation of immunocompetent cells following the 4-TFMA administration were found also in thymus. In accord with an enhanced incorporation of [3H]thymidine, the specific activity of thymidine kinase (TdK) in spleen was increased after a single dose of 4-TFMA. Activities of the catabolic enzymes adenosine deaminase (ADA) and inosine phosphorylase (IP) decreased in both organs with the exception of IP activity in thymus. The effects evoked by the 3-TFMA isomer were regularly less pronounced, and 2-TFMA was nearly inactive.
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PMID:Effects of trifluoromethylaniline isomers on enzyme activities in lymphatic organs and hematology of the rat. 794 May 66

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

Dendritic cells (DC) are professional Ag-presenting cells that play a major role in T cell-mediated immune responses and in thymocyte differentiation. To better analyze their physiological importance, we sought to generate transgenic mice presenting a conditional DC deficiency. We used a strategy based on the cell-specific expression of a suicide gene. The DC-targeted expression is obtained using HIV regulatory sequences; indirect evidence has suggested that these sequences control a preferential expression in DC. The suicide gene is the herpes simplex virus type 1 thymidine kinase (HSV1-TK) which allows conditional ablation of dividing HSV1-TK-expressing cells by converting nucleoside analogs such as ganciclovir (GCV) into toxic molecules. We generated transgenic mice expressing an HSV1-TK gene transcribed from HIV regulatory sequences. A low but significant HSV1-TK expression was observed in mature DC and DC precursors grown from granulocyte-macrophage colony-stimulating factor-supplemented bone marrow cultures. These HSV1-TK-expressing DC precursors are specifically killed by GCV. We next treated transgenic mice with GCV, and obtained a specific ablation of DC in spleen and thymus. Ninety percent of spleen DC could be depleted within a week, indicating a turnover rate of approximately 15% per day. Interestingly, this DC depletion always correlated with a major thymic atrophy and disappearance of CD4+CD8+ thymocytes. This animal model should help to assess the physiological role of DC in the immune response and in thymocyte differentiation. It should also help to appreciate the consequences of DC dysfunction in pathological situations, such as HIV-infection or allograft rejection.
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PMID:Conditional ablation of dendritic cells in transgenic mice. 828 35

A polymerase chain reaction (PCR) assay was developed to detect the thymidine kinase gene of feline herpesvirus 1 (FHV-1) and to study the active and latent carrier state in a group of naturally FHV-1 infected specific pathogen free (SPF) cats. The detection limit of PCR products on ethidium bromide stained gels was 390 fg or about 3 x 10(3) copies of the FHV-1 genome. The PCR was 25% more sensitive than conventional cell culture based virus isolation techniques in detecting FHV-1 in oral/ocular swabs and 100 times more sensitive in detecting virus in cell culture supernatants. Sites of FHV-1 latency in FHV-1 carriers as determined by PCR were mainly tissues of the head, especially the trigeminal ganglia, optic nerves, olfactory bulbs and corneas. Oral fauces, salivary glands, lacrimal glands, cerebellum and conjunctiva were less consistently positive. The cerebral cortex, thymus, trachea, lung, liver, spleen, kidney, and peripheral blood mononuclear cells were consistently negative for FHV-1 genome. The distribution of FHV-1 DNA in the tissues of the head was similar whether or not corticosteroid-induced virus shedding was occurring at the time the tissues were collected. Infectious virus was never recovered from tissue homogenates regardless of the PCR status of the tissues.
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PMID:Detection of active and latent feline herpesvirus 1 infections using the polymerase chain reaction. 839 3

Deoxythymidine kinase (TK; EC 2.7.1.21) activity in the liver has been used as a marker of liver regeneration after partial hepatectomy. In this study we examined TK activity of various organs, plasma and peripheral blood mononuclear cells (PMNC) in 70% partially hepatectomized rats. TK activity of lymph nodes, small intestine, heart, lung, kidney and thymus did not increase significantly during the course of the study, except for spleen at 72 h. On the other hand, PMNC-TK and liver cystosolic TK activity increased in a parallel fashion at all times after partial hepatectomy; they began to increase 12 h after surgery and peaked 48 h post-surgery. Fractionation of PMNC into T cells and B cells revealed that both populations increased and peaked 48 h post-surgery. Plasma TK peaked 12-24 h after surgery, then declined at 36, 48 and 72 h after partial hepatectomy. This change paralleled plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PMNC-TK activity correlated significantly with liver cystosolic TK activity 24 h (r = 0.743; P < 0.05) and 48 h (r = 0.708; P < 0.05) after partial hepatectomy. However, it did not correlate with plasma levels of TK, AST and ALT. The results indicate that in the early stage of liver regeneration PMNC-TK may provide a marker of liver regenerative processes.
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PMID:Rat peripheral mononuclear cell thymidine kinase activity increases during liver regenerative processes after partial hepatectomy. 858 Apr 9

We have developed an in vitro DNA polymerase forward mutation assay using damaged DNA templates that contain the herpes simplex virus type 1 thymidine kinase (HSV-tk) gene. The quantitative method uses complementary strand hybridization to gapped duplex DNA molecules and chloramphenicol selection. This design ensures exclusive analysis of mutations derived from the DNA strand produced during in vitro synthesis. We have examined the accuracy of DNA synthesis catalyzed by calf thymus polymerase alpha-primase, polymerase beta and exonuclease-deficient Klenow polymerase. Using unmodified DNA templates, polymerase beta displays a unique specificity for the loss of two bases in a dinucleotide repeat sequence within the HSV-tk locus. Treatment of the DNA template with N-ethyl-N-nitrosourea resulted in a dose-dependent inhibition of DNA synthesis concomitant with an increased mutation frequency. Similar dose-response curves were measured for the three polymerases examined; thus the identity of the DNA polymerase does not appear to affect the mutagenic potency of ethyl lesions. The HSV-tk system is unique in that damage-induced mutagenesis can be analyzed both quantitatively and qualitatively in human cells, in bacterial cells and in in vitro DNA synthesis reactions at a single target sequence.
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PMID:Development and use of an in vitro HSV-tk forward mutation assay to study eukaryotic DNA polymerase processing of DNA alkyl lesions. 906 Apr 43


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