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)

We have used a herpes virus thymidine kinase (HSV-TK) based metabolic selection system to isolate mutants defective in the interferon gamma mediated induction of the MHC class II promoter. All the mutations act in trans and result in no detectable induction of MHC and invariant chain (Ii) gene expression. Scatchard analysis indicates that the mutants have a normal number of surface IFN gamma receptors with the same affinity constant. The mutants fall into two broad categories. One class of mutants is still able to induce MHC class I, IRF-1, 9-27, 1-8 and GBP genes by IFN gamma. A second class of mutants is defective for the IFN gamma induction of all the genes tested; surprisingly, the IFN alpha/beta induction of MHC class I, 9-27, ISG54 and ISG15 genes is also defective in these mutants, although different members of this class can be discriminated by the response of the GBP and IRF-1 genes to type I interferons. These data demonstrate that the signalling pathways of both type I and type II interferon systems share common signal transduction component(s). These mutants will be useful for the study of IFN gamma regulation of class II genes and Ii chain, and to elucidate molecular components of type I and type II interferon signal transduction.
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PMID:Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s). 131 62

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

Interferon-alpha (IFN alpha) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFN alpha treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFN alpha produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFN alpha did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFN alpha also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFN alpha on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.
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PMID:Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells. 154 Jan 67

Cotransformation with a plasmid containing a thymidine kinase gene (pTK2) and a plasmid encoding human IFN-gamma (pTG11) has been used to establish murine L cell lines expressing human IFN-gamma. The HuIFN-gamma gene was present in 30% of the tk+ cell lines and some of these secreted low levels of IFN into the culture medium. Two of the clones obtained after transformation were selected for detailed analysis. Clone 1-12 constitutively secreted very low levels of HuIFN-gamma in the culture medium. This antiviral activity was characterized by its species specificity and antigenicity as authentic human IFN-gamma In contrast, clone 3-47 produced a HuIFN-gamma activity which could only be detected intracellularly. This clone was resistant to infection both by Vesicular stomatitis (VSV) and Mengo viruses and contained increased levels of enzymes known to be induced by interferon. Our results suggest that clone 3-47 produces a non-secreted HuIFN-gamma like molecule which is able to trigger an antiviral state in the murine cell independent of the interaction with a specific IFN-gamma surface receptor.
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PMID:Expression of extracellular and intracellular human IFN-gamma in mouse L cells transformed with the human IFN-gamma cDNA gene. 242 24

Two methods, the colorimetric method (neutral red dye uptake), and DNA hybridization using a HSV thymidine kinase gene probe (TK) have been used to examine the sensitivity of 84 herpes simplex virus (HSV) type 1 and 2 clinical isolates to two antiviral drugs, acyclovir (ACV) and alpha-interferon (alpha-IFN). Using the colorimetric method, HSV isolates had ED50s ranging from 0.03 +/- 0.02 micrograms/ml to 0.164 +/- 0.03 micrograms/ml for ACV and 6.3 +/- 5.2 IU/ml to 55.0 +/- 11.4 IU/ml for alpha-IFN. With the DNA hybridization method, ED50s ranged from 0.033 +/- 0.012 micrograms/ml to 0.190 +/- 0.031 micrograms/ml for ACV and 8.5 +/- 5.0 IU/ml to 43.5 +/- 6.0 IU/ml for alpha-IFN. Two strains of HSV-1 were found to be resistant to very high concentrations of ACV (greater than 50.0 micrograms/ml). The values obtained by the two methods showed good correlation (r = 0.724, P = 0.002). Furthermore, our results demonstrate that the two methods are reproducible, reliable and the dye uptake assay is suitable for use in a diagnostic virology laboratory.
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PMID:Comparison of two methods in the determination of the sensitivity of 84 herpes simplex virus (HSV) type 1 and 2 clinical isolates to acyclovir and alpha-interferon. 254 87

Human alpha interferons (IFN-a) cause a reorganization of internal cell membranes into tubuloreticular inclusions (TRI). Morphogenesis and cytochemistry indicate a pre-Golgi intracisternal origin from the endoplasmic reticulum. Clinically, TRI formation in human blood mononuclear cells correlates with systemic IFN-a treatment or with endogenous overproduction of IFN-a in viral or autoimmune diseases (e.g., rubella syndrome, AIDS, systemic lupus erythematosus). In vitro, TRI formation can be produced by treatment of Daudi lymphoblasts or vascular endothelial cells with IFN-a, and is blocked by actinomycin-D. In Daudi lymphoblasts or vascular endothelial cell cultures, TRI formation parallels induction of 2'-5' A synthetase, inhibition of thymidine kinase and growth inhibition; however, heavy water treatment of Daudi cells prevented TRI formation while induction of 2'-5' A synthetase and growth inhibition persisted. TRI formation was dissociated from IFN-a antiproliferative activity in a mutant clone of Daudi lymphoblasts. Decreased glycoprotein biosynthesis and increased phospholipid biosynthesis may accompany progressive TRI accumulation.
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PMID:Tubuloreticular reorganization of cytomembranes in cells treated with human alpha interferons--a review. 307 Jul 35

beta-Interferon (beta-IFN) gene expression can be induced by poly(I)-poly(C) or virus, but there is considerable variation in the extent of induction between different cell lines. We characterized two poorly inducible human cell lines, HeLa and 143 thymidine kinase negative (143 tk-), to define cellular factors involved in the activation of the beta-IFN gene. We show that the deficiency in beta-IFN induction in these cells can be complemented by fusion to highly inducible mouse cells. We conclude that the human cells are deficient in a trans-acting factor required for B-IFN gene activation. The level of induction of the beta-IFN gene in HeLa and 143 tk- cells can also be increased by priming with IFN before induction. If IFN priming is carried out in the presence of cycloheximide, a approximately 200-fold increase in induction is observed. We conclude that activation of the beta-IFN gene requires an IFN-inducible factor that is only expressed at low levels in unprimed HeLa and 143 tk- cells.
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PMID:Activation of the human beta-interferon gene requires an interferon-inducible factor. 377 93

A murine model of genital infection with a thymidine kinase-deficient (tk-) strain of herpes simplex virus type 2 (HSV-2) was utilized to examine the development of the local T cell response in the genital mucosa and draining genital lymph nodes (gLN). HSV-specific cytokine-secreting T cells were detected in the gLN 4 days postintravaginal inoculation but not in the urogenital tract or spleen until 5 days postinoculation, suggesting the cellular immune response originates in the gLN. More CD4+ than CD8+ gLN T cells were detected by flow cytometric analysis following primary vaginal inoculation and the majority of HSV-specific gLN T cells detected by ELISPOT were CD4+ and Th1-like based on secretion of IFN gamma and not IL-4 or IL-5. A similar population of HSV-specific memory T cells persisted in the genital tract 2 months following HSV-2 tk- genital inoculation. These data suggest that the urogenital cellular immune response elicited in mice following genital inoculation with HSV-2 tk- is predominantly CD4+ and Th1-like, resembling that observed in humans. The results of this study are important for the rational design of vaccines capable of inducing protective immunity in the genital tract.
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PMID:Analysis of herpes simplex virus-specific T cells in the murine female genital tract following genital infection with herpes simplex virus type 2. 757 18

To elucidate the structural basis responsible for the reduced IFN sensitivity of expression of the histone H1(0) and H5 gene, integrated into the vaccinia virus genome, vaccinia virus thymidine kinase (VV-TK)-histone H1(0)/H5 fusion genes were constructed and translocated into the TK locus of the VV genome. The chimeric genes, consisting of parts of either of the two histone genes and the 5' or 3' half of the TK gene, respectively, were expressed as histone-TK fusion proteins under the control of either the VV-TK promoter or the early sequences of the VV 7.5K promoter. IFN sensitivity of the expression of histone-TK fusion genes was shown to be influenced by the relative length of the histone sequence. Expression of fusion genes containing more than 45% cellular sequence either from the 5' or the 3' part of one of the two histone genes showed clearly reduced IFN sensitivity compared to the expression of VV-TK. On the other hand, by further reducing the relative amount of histone H5 or H1(0) sequence to 32%, the IFN sensitivity of expression of the corresponding fusion gene was drastically enhanced to levels indistinguishable from those of VV-TK.
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PMID:Interferon sensitivity of expression of histone H5/H1(0)-vaccinia thymidine kinase fusion genes expressed by recombinant vaccinia viruses is enhanced by shortening the histone sequence. 769 Apr 99

Glucocorticoids bind to their receptors and trigger the transcriptional activation or repression of target genes by binding to DNA sequences, the glucocorticoid responsive element (GRE). The murine interferon-beta (Mu-IFN beta) gene in L929 cells can be induced by dexamethasone to give both transcription and translation products specific to murine IFN beta. The 3'-noncoding region of the Mu-IFN beta gene was found to contain a GRE very similar to the consensus GRE sequence involved in glucocorticoid-regulated genes. Gel retardation assays showed that the oligonucleotide corresponding to that GRE competed with the MMTV GRE oligonucleotide for glucocorticoid receptor binding and was supershifted by human antiglucocorticoid receptor antibodies. Transiently transfected murine cells (L929) with the GRE-IFN beta 3' sequence inserted upstream of the thymidine kinase promoter and the chloramphenicol acetyl transferase gene treated with dexamethasone with or without the antiglucocorticoid RU486 and their chloramphenicol acetyl transferase activity assayed, show that this GRE is efficient. We conclude that the Mu-IFN beta gene in L929 murine cells can be induced by dexamethasone, and that the hormone effect may be mediated by the 3'-GRE sequence.
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PMID:Induction of interferon-beta gene expression by dexamethasone in murine L929 cells. 777 70


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