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)

Experiments were designed to identify herpes simplex virus type 2 (HSV-2)-specific functions expressed during stimulation of human embryo fibroblast DNA synthesis. Cultures were partially arrested in DNA synthesis by pretreatment with 5-fluorouracil and maintenance in low-serum (0.2%) medium during virus infection. Results showed that continuous [methyl-(3)H]thymidine uptake into cellular DNA was ninefold greater in HSV-2-infected than in mock-infected cultures measured after 24 h of incubation at 42 degrees C. Shifting mock-infected cultures from low- to high-serum (10%) medium also caused some stimulation, but [methyl-(3)H]thymidine uptake was only twofold greater than in cells maintained with low serum. Plating efficiencies of both HSV-2-infected and mock-infected cells at 42 degrees C were essentially the same and ranged from 37 to 76% between zero time and 72 h of incubation. De novo RNA and protein syntheses were continuously required for HSV-2 stimulation of cellular DNA synthesis. HSV-2 infection markedly enhanced transport, phosphorylation, and rate of incorporation of [methyl-(3)H]thymidine into cellular DNA, starting at 3 h and reaching a maximum by 12 h; after 12 h, these processes gradually declined to low levels. In mock-infected cells these processes remained at low levels throughout the observation period. Pretreatment of cells with interferon or addition of arabinofuranosylthymine at the time of virus infection inhibited stimulation caused by HSV-2. 5-Bromodeoxyuridine density-labeled experiments revealed that HSV-2 stimulates predominantly semiconservative DNA replication and some DNA repair. Stimulation of [methyl-(3)H]thymidine into cellular DNA correlated with detection of virus-specific thymidine kinase activity. In conclusion, HSV-2 stimulation of cellular DNA synthesis appeared to involve at least four virus-specific functions: induction of thymidine transport, HSV-2 thymidine kinase activity, semiconservative replication, and repair of cellular DNA.
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PMID:Herpes simplex virus type 2 functions expressed during stimulation of human cell DNA synthesis. 21 36

Two lines of Friend virus (FV)-transformed mouse spleen cells have been analyzed in respect to their interferon production capacity: neither F4 cells, which liberate infectious FV when kept under tissue culture conditions, nor the thymidine kinase-deficient B8 cells, which do not produce significant amounts of FV, release detectable amounts of autogenous interferon into cell supernatants. However, interferon is produced in these cells in amounts comparable to that in L-929 cells when interferon induction is initiated with UV-inactivated Newcastle disease virus. Conversely poly(I)-poly(C), a potent interferon inducer in L-929 cells, proved ineffective in this capacity in F4 or B8 cells. When erythropoietic differentiation is induced in these cells by dimethyl sulfoxide, no autogenous interferon production occurs, but with NDV-induction a four- to fivefode increase of interferon production is observed. A similar elevation of interferon production is achieved during 5-bromodeoxyuridine stimulation of differentiation in the thymidine kinase-deficient B8 cells. The refractiveness against poly(I)-poly(C) displayed in unstimulated cells is not overcome at any stage of differentiation, indicating major differences of Newcastle disease virus and poly(I)-poly(C) induction mechanisms.
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PMID:Induction of interferon and erythropoietic differentiation in cells transformed by Friend virus. 123 17

A serum-dependent and two serum-independent variants of the Bowes melanoma cell line, RPMI7272, were transfected with plasmids containing a geneticin-resistance (neo) gene transcribed by the HSV thymidine kinase promoter and an SV40 T antigen gene under control of the mouse metallothionein I promoter. T-antigen increased the cloning efficiency of the serum-dependent cell line in soft-agar more than 50-fold, but cloning efficiency of serum-independent lines was not increased. Trypsinization of serum-independent lines required 100 times lower concentrations of trypsin than serum-dependent cells. Human metal-inducible T-antigen-producing (HMT) melanoma cells supported replication of transfected plasmids containing an SV40 origin of replication. Transient expression of interferon or plasminogen activator from such plasmids was 40-fold higher than in untransformed melanoma cells and could be enhanced 30-fold more by stimulation of transcription of the T antigen gene with cadmium chloride. HMT cells can be grown in suspension and thus may represent an attractive alternative to monkey kidney COS cells.
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PMID:Transformation of Bowes melanoma cells with SV40 T antigen. 136 20

The interferon sensitivity of the expression of an influenza-virus hemagglutinin (HA) gene cloned into the thymidine kinase (TK) gene of vaccinia virus was studied in chick embryo fibroblasts (CEF) and Madin-Darby bovine kidney (MDBK) cells. In CEF, the expression of the HA gene is inhibited by pretreatment of cells with homologous interferon. In MDBK cells, on the other hand, expression of the HA is not impaired by pretreatment with human interferon-alpha, and the synthesis of early vaccinia virus enzymes was also unaffected. These results indicate that the interferon sensitivity of HA gene expression is at least in part controlled by flanking regions of vaccinia virus DNA. In this report, we also address the question whether the expression of an influenza virus HA gene and the human histone H1 zero gene under control of a vaccinia virus immediate early promoter is affected in interferon-treated CEF by a post-transcriptional mechanism in the same way as the expression of the viral TK gene. In interferon-treated cells mRNA synthesis specific for all these genes was enhanced. Steady state mRNA levels 6 hr p.i. were, however, lower than the amounts expected from the rate of mRNA synthesis during the first 6 hr p.i., suggesting that part of the viral RNA was degraded. Degradation resistant mRNA accumulated in the interferon-treated cells in an amount comparable to that found in infected CEF. This RNA could be translated into viral protein in a cell-free system. Therefore the degradation of viral mRNA cannot solely be responsible for the inhibition of viral protein synthesis in interferon-treated cells.
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PMID:Expression of authentic vaccinia virus-specific and inserted viral and cellular genes under control of an early vaccinia virus promoter is regulated post-transcriptionally in interferon-treated chick embryo fibroblasts. 137 50

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

The duck histone H5 and human H1 zero were inserted into the thymidine kinase (TK) gene of vaccinia virus and the interferon sensitivity of their expression under the control of the viral TK and P7.5 promoters in chick embryo fibroblasts (CEF) was compared to the interferon sensitivity of vaccinia virus WR specific TK induction. Expression and transport of these histones to the nucleus in CEF infected with the appropriate vaccinia virus recombinants could be detected with antisera raised against chick histone H5. In CEF cultivated for 3 days, interferon treatment that completely inhibited TK synthesis had no or only a marginal inhibitory effect on the expression of the histone genes. Inhibition of the expression of the histones could be detected under conditions of increased interferon sensitivity in aged CEF. The magnitude of inhibition was, however, less pronounced than the inhibition of viral TK synthesis. These data indicate that flanking vaccinia virus DNA regions confer interferon sensitivity to the expression of these histone genes, but that they contain structural information that partially exempts their expression from the inhibitory activity of the interferon-induced regulatory system.
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PMID:Regulation of histone H5 and H1 zero gene expression under the control of vaccinia virus-specific sequences in interferon-treated chick embryo fibroblasts. 170 69

Acyclovir (ACV)-resistant herpes simplex virus type 2 (HSV-2) was isolated from a patient with acquired immunodeficiency syndrome after long-term but intermittent ACV therapy. These thymidine kinase-defective isolates were sensitive in vitro to foscarnet. While combined therapy with ACV and interferon produced only partial clinical improvement, the in vitro effect of this combination against an ACV-resistant isolate from the patient was strongly synergistic. A short course (10-12 days) of intravenous foscarnet controlled severe ulceration, and clinical improvement lasted 6 months. After recurrence and further courses of foscarnet, however, the patient responded poorly, and subsequent HSV isolates were resistant to both ACV and foscarnet and hypersensitive to aphidicolin.
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PMID:Altered sensitivity to antiviral drugs of herpes simplex virus isolates from a patient with the acquired immunodeficiency syndrome. 216 40

Latent herpes simplex virus type 1 (HSV-1) infection was induced in human embryonic lung cells in vitro by using a combination of viral replication inhibitors and elevated temperature. Under reactivating conditions (superinfection by human cytomegalovirus or temperature manipulation), a nonantiviral thymidine kinase inhibitor (L-653,180) was found to suppress or delay reactivation of HSV-1 from latently infected human embryonic lung cells. L-653,180 alone or in combination with interferon was ineffective as a primary or acute viral replication inhibitor and was unable to induce latent HSV-1 infection in cell culture. These data suggest that initial or acute virus replication and replication resulting from reactivation from latency are separate events.
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PMID:Suppression of herpes simplex virus type 1 reactivation from latency by (+-)-9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) in vitro. 217 23

The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells. The IDO activity is induced strongly in many cell types by IFN-gamma but rather poorly by IFN-alpha or -beta. A genomic DNA clone containing part of the transcribed region of the IDO gene and approximately 13 kilobases (kb) of the 5'-upstream DNA sequence was isolated and analyzed. An approximately 1.4-kb fragment of this clone, containing 329 nucleotides of the transcribed sequence and approximately 1.1 kb of the 5'-upstream sequence, when ligated to chloramphenicol acetyltransferase (CAT) structural gene made its expression inducible by IFN-gamma, but this construct responded poorly, if at all, to IFN-alpha 2. Deletion constructs derived from this plasmid narrowed down the IFN-gamma-responsive region to a 151-nucleotide segment (-495/-344) which also contained a 14-nucleotide sequence (GGTTTCAGTTTTCC) highly homologous to the IFN(alpha)-stimulated response element (ISRE) that has been found so far in all cellular genes inducible with IFN-alpha or -beta. Expression of CAT activity was stimulated by IFN-gamma more effectively than by IFN-alpha 2 when a 155-nucleotide fragment (-495/-340) containing the 151-nucleotide segment required for IFN-gamma response was inserted before herpes simplex virus thymidine kinase promoter linked to CAT structural gene. The results indicate that despite the presence of an ISRE, the control region of the IDO gene can distinguish between IFN-gamma and IFN-alpha. This may account for the differential activation of IDO gene expression by IFN-gamma as against IFN-alpha or -beta in intact cells, and suggests that the response of ISRE to IFN-alpha or -beta may be governed by other features in the upstream control region of this gene.
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PMID:Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alpha. 217 56

Cells lacking thymidine kinase (tk) have been reported to fail to respond to the action of interferon (IFN). While some laboratories have confirmed this observation, others have failed to do so. We studied the effect of IFN on four freshly isolated tk- lines of mouse L cells infected with mengovirus. In all cases, normal antiviral activity was induced. The antiproliferative activity of IFN was studied using the parental L cell line, a tk- derivative, and a tk- (tk+) subline into which the tk gene of herpes simplex virus was introduced. All three lines had a doubling time of about 20 h. In all cases, 2,000 U/ml of IFN increased this time to about 50 h. In contrast to the above results, an IFN-sensitive mutant of mengovirus (is-1) grew much better in protected tk- cells than in protected normal cells. This phenomenon appears to be dependent on the fact that tk- cells were routinely maintained in medium containing 5-bromodeoxyuridine (BUDR). In the absence of this drug, the virus behaved normally. The implications of this observation are discussed.
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PMID:Growth of wild-type and interferon-sensitive mengovirus in tk- L cells. 240 92


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