Disease relevance of Tk1

• We report here that production of herpes simplex virus thymidine kinase (tk) RNA is stimulated as much as 50-fold by the glucocorticoid, dexamethasone, when sequences from a particular region of MTV DNA are fused upstream of the normally constitutive tk promoter region [1].
• They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man [2].
• Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1 [3].
• A thymidine kinase-defective HSV-1 virus, KOS-SB, was used to infect 9L cells in culture, and the viability of the infected cells was compared with that of mock-infected (i.e., uninfected) cells [3].
• At later stages, 17-20 days after implantation of the lymphoma, appreciable amounts of thymidine kinase appeared in the plasma: The units of activity per milliliter were 6.2 in single hosts, 0.79 in parabiotic hosts, and 0.55 in host partners (control less than 0.05) [4].

Psychiatry related information on Tk1

• A thymidine kinase deficient Rat1 derivative (Rat2) was not invasive in vitro but produced invasive and metastatic tumors in vivo with long (9 to 21 weeks) latency periods [5].
• Administration of 17 beta-estradiol benzoate (EB) during the sexually critical period of brain differentiation had no effect on thymidine kinase in either brain structure [6].

High impact information on Tk1

• FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase [2].
• An element centered at position -60 of the c-fos promoter, which encompasses a consensus cAMP response element (CRE), is sufficient to confer cAMP responsiveness to a herpes thymidine kinase/CAT fusion gene [7].
• Re: Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies [8].
• METHODS: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells) [9].
• Linking this 0.5-kb region to a heterologous thymidine kinase (tk) promoter, or linking multimerized ntcp GLEs either upstream of the ntcp minimal promoter (-158 to +47 bp) or the heterologous promoter conferred dose-dependent PRL responsiveness [10].

Chemical compound and disease context of Tk1

• This gene (vv2) is a modified form of the bacterial neomycin resistance gene (neo) linked to the herpes simplex virus thymidine kinase (tk) promoter (plasmid pAG60), to which the original bacterial neo promoter from transposon Tn5 was added back, upstream of the eukaryotic promoter [11].
• Mouse teratocarcinoma cells (OTT6050) deficient for thymidine kinase were fused with rat hepatoma cells ( Fu5AH ) deficient for hypoxanthine phosphoribosyltransferase using inactivated Sendai virus [12].
• An oligonucleotide, corresponding to a portion of the rat growth hormone gene 5'-flanking region that contains a T3 response element, was inserted on the 5' side of the herpes simplex virus thymidine kinase promoter in a chloramphenicol acetyltransferase-expressing plasmid [13].
• The inhibition by methylglyoxal bis(guanylhydrazone) of the induction of thymidine kinase by adenovirus type 5 is probably unrelated to its effects on polyamine biosynthesis [14].
• In this study, we show that ganciclovir treatment of tumors transfected with the herpes simplex thymidine kinase gene causes profound changes in water, metabolites, and macromolecules observable by diffusion spectroscopy [15].

Biological context of Tk1

• The nucleotide sequence of the rat thymidine kinase (tk) gene 5' region was determined and compared to the 5' sequences of the tk gene from mouse, human, hamster and chicken [16].
• Cells sedimenting at higher densities of Ficoll exhibited higher thymidine kinase activity and DNA synthesis, suggestive of active cell division [17].
• To investigate this process we focused on the regulation of two late cell cycle genes, histone and thymidine kinase, in T2 cells and fibroblasts exposed in vitro to varying periods of hyperoxia (95% O2) [18].
• In contrast, the SV40 enhancer gave the same relative increase in tk gene expression in the murine, rat, bovine and human cells tested [19].
• Secondly, the amount of tk-specific RNA and TK enzyme activity transiently expressed after DNA transfection was determined [19].

Anatomical context of Tk1

• DNA synthesis and thymidine kinase activity of rat colon epithelial cells fractionated by discontinuous Ficoll gradient [17].
• Specific enzyme activity (including thymidine kinase) of isolated crypt mucosa was significantly increased 1 month after distal resection [20].
• A clonal cell line (519) was isolated that harbored several permuted herpes simplex virus tk genes [21].
• This form of thymidine kinase has also been described in normal human fetal tissue and a variety of human tumor cells [22].
• 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 [23].

Associations of Tk1 with chemical compounds

• Early studies achieved selective incorporation of the thymidine analog 5-Bromo-2-deoxy-Uridine (BrdU) into mtDNA of thymidine kinase-deficient (TK[-]) cells [24].
• Neither acyclovir, FIAU, nor the herpes thymidine kinase alone is harmful to cells [25].
• Our results indicate that both types of O6-substituted guanines are substantially mutagenic, although the methyl substituent induced a 2-fold higher percentage of transformed Rat4 TK+ colonies than its bulkier benzyl analogue [26].
• Furthermore, the region of the prolactin gene at -1713 to -1495 was able to confer estrogen responsiveness on the thymidine kinase promoter [27].
• When this hybrid gene was transfected into Rat 2 TK- cells, its expression was induced threefold by the glucocorticoid dexamethasone, as assessed by transfection efficiency and RNA blotting analyses [28].

Physical interactions of Tk1

• We have developed a recombinant replication-defective adenovirus in which the TIMP-1 promoter is coupled to the herpes simplex virus thymidine kinase gene rendering activated hepatic stellate cells susceptible to ganciclovir [29].

Regulatory relationships of Tk1

• It induced tyrosine aminotransferase in the liver and repressed thymidine kinase in the thymus very effectively [30].
• Triiodothyronine administration altered both ornithine decarboxylase and thymidine kinase activities suggesting that T3 appears to regulate ornithine decarboxylase activity at post-translational level [31].

Other interactions of Tk1

• A chimeric gene was constructed in which a 620-base pair fragment of the 5'-end of the PEPCK gene (including 547 base pairs of 5'-flanking sequence) was ligated to the herpes simplex virus thymidine kinase (TK) structural gene [32].
• When an expression vector encoding the full length of SHARP-2 was cotransfected with thymidine kinase promoter-luciferase reporter plasmids, with or without E box sequences, into MA-10 cells, the luciferase activity was decreased in an E box-dependent manner [33].
• The increase in IGF-II/Man-6-P receptors coincided with increased activity of thymidine kinase in the distal intestinal segment after the resection [34].
• Adenovirus type 5 induces cellular DNA synthesis and thymidine kinase in quiescent rat cells but does not induce ornithine decarboxylase [14].
• Further analysis revealed that CB1 and CB2 acted synergistically when subcloned upstream of a heterologous, minimal thymidine kinase promoter [35].

Analytical, diagnostic and therapeutic context of Tk1

• At 24 hr after injection of P3HR-1 virus DNA, 90-100% of the injected cells expressed the early antigen complex as observed by immunofluorescence staining; 70-80% of the cells simultaneously incorported [3H]thymidine, indicating that thymidine kinase is expressed after injection of viral DNA [36].
• Four injections of subcoma doses of ammonium acetate, octanoic acid or dimethyl disulfide during the first 24 hr after two-lobe hepatectomy in normal rats markedly depressed DNA synthesis as reflected by liver thymidine kinase activity or the incorporation of tritiated thymidine into hepatic DNA [37].
• Ganciclovir has been successfully used in thymidine kinase gene therapy as treatment for various experimental malignancies [15].
• Maximal thymidine kinase and mitotic index were observed in group 1 animals at 24 hr [38].
• Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography [39].

References