Disease relevance of Tk1

• Mutagenic lesions at the thymidine kinase locus (tk) in mouse lymphoma L5178Y (LY) cells treated with red light and either Photofrin (PF) or chloroaluminum phthalocyanine (AlPc) as the photosensitizer were compared in the relatively photodynamic therapy (PDT)-sensitive strain LY-R16 and the relatively resistant strains LY-S1 and LY-SR1 [1].
• Donor DNA was prepared from three cell lines: (a) mouse cells transfected with UV-inactivated herpes simplex virus (HSV) type 1, or a purified fragment of HSV carrying the TK gene (b) human HeLa cells, and (c( CHO, a cell line derived from Chinese hamster ovaries [2].
• Activity of thymidylate synthetase, thymidine kinase and galactokinase in primary and xenografted human colorectal cancers in relation to their chromosomal patterns [3].
• By means of metaphase chromosomes, the genes for mink thymidine kinase (TK) and hypoxanthine-phosphoribosyltransferase (HPRT) were transferred to mutant mouse cells, LMTK-, A9 (HPRT-) and teratocarcinoma cells, PCC4-aza 1 (HPRT-) [4].
• Mice deficient for cytosolic thymidine kinase gene develop fatal kidney disease [5].

Psychiatry related information on Tk1

• These results, in conjunction with historical cytogenetic data, suggest that a putative growth control locus lies distal to the thymidine kinase (Tk1) gene, near the telomere [6].

High impact information on Tk1

• The insert is composed of two copies of pMK (a metallothionein-thymidine kinase fusion gene) oriented as inverted repeats [7].
• Mouse Ltk- cells were cotransformed with the herpes simplex thymidine kinase gene and total human DNA [8].
• Biochemical transformation of thymidine-kinase-deficient (TK-) mouse L cells is enhanced 20 to 40 fold when microinjected plasmid DNA contains regions of the genomes of Rous sarcoma virus or simian virus 40 in addition to the complete herpes simplex virus tk gene, irrespective of the orientation and location of the enhancer [9].
• Function is retained when the element is moved to the 3' side of the E1A gene in either possible orientation, and the E1A enhancer functions in cis to enhance transformation by the herpesvirus thymidine kinase gene in both mouse and human cells [10].
• This enzyme is inducible by heavy metals, as indicated by assay of thymidine kinase activity following sequential partial hepatectomies with or without cadmium treatment [11].

Chemical compound and disease context of Tk1

• This protection against apoptosis is abrogated by 9-(4-hydroxybutyl)-N2-phenylguanine, a specific inhibitor of herpes simplex virus-1 TK [12].
• Bovine herpesvirus tegument protein VP22 enhances thymidine kinase/ganciclovir suicide gene therapy for neuroblastomas compared to herpes simplex virus VP22 [13].
• Bromate induces loss of heterozygosity in the thymidine kinase gene of L5178Y/Tk(+/-)-3.7.2C mouse lymphoma cells [14].
• There are no toxic effects of 5-fodUrd on cells defective in thymidine kinase or thymidylate synthetase, suggesting that the toxicity may be caused by 5-fodUrd phosphorylation and subsequent inhibition of thymidylate synthetase [15].
• Procarbazine (Natulan) is a potent inducer of gene mutations at the heterozygous tk +/- locus in L5178Y mouse lymphoma cells in the presence of Aroclor-induced rat liver S9 metabolic activation (approximately 10(-3) mutant frequency at 10 micrograms/ml) while exerting a far weaker effect in the absence of S9 [16].

Biological context of Tk1

• DNA isolated from independent TK1-/- mutants was analyzed for loss of heterozygosity (LOH) at the Tk1 locus and two microsatellites, D11Mit48 and D11Nds7 [17].
• From all of these analyses we can conclude that the small colony mutant phenotype is not caused by deletion of both Trp53 and Tk1 [18].
• Inheritance in recombinant inbred (RI) strains of restriction fragment length variants (RFLVs) detected by probes specific for Gaa and Tk-1 showed tight linkage of both to Es-3 on mouse Chromosome (Chr) 11 [19].
• Cells irradiated in the G1 and G2/M phases were most sensitive to the cytotoxic effects of radiation, while cells irradiated in the G2/M phase showed the highest mutant frequency at the thymidine kinase (Tk1) locus [17].
• To determine whether small colonies might, however, include the deletion of both Trp53 and Tk we evaluated, using microsatellite marker analysis, a series of small colony mutants [18].

Anatomical context of Tk1

• Afmid/Tk -deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system [20].
• Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine [21].
• These results indicate that the selection of BrdUrd-resistant lymphocytes from Tk+/- mice may be used for assessing in vivo mutation in an endogenous, autosomal gene [22].
• In order to determine the biological significance of the Tk gene, we created Tk(-/-) knockout (KO) mice through homologous recombination in mouse embryonic stem cells [5].
• The alpha-subunit of the skeletal muscle sodium channel is encoded proximal to Tk-1 on mouse chromosome 11 [23].

Associations of Tk1 with chemical compounds

• The four acrylates evaluated (methyl acrylate, ethyl acrylate, trimethylolpropane triacrylate and tetraethyleneglycol diacrylate) induced almost exclusively small-colony TK mutants and very few if any HGPRT mutants [24].
• The origin of the TK that is expressed in these cells was studied by polyacrylamide gel electrohporesis, isoelectric focusing, or heat stability [2].
• The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity) [21].
• Up-regulation of TK activity after IL-3 readdition is prevented by the protein kinase C (PKC) inhibitor staurosporin, but not by tyrosine kinase inhibitors [25].
• The cloning efficiency of KO lymphocytes was not affected by the toxic thymidine analogues 5-bromo-2'-deoxyuridine (BrdUrd) or trifluorothymidine (TFT), or by BrdUrd in the presence of lymphocytes from Tk+/- animals; however, it was easier to identify clones resistant to BrdUrd than to TFT when Tk+/- cells were present [22].

Physical interactions of Tk1

• Cyclin D1/cdk2 kinase is present in a G1 phase-specific protein complex Yi1 that binds to the mouse thymidine kinase gene promoter [26].
• Cloning of this Sp1 binding element in front of the thymidine kinase (TK) promoter and mutations generated in this site demonstrate its function as a silencer [27].
• The promoter of the murine thymidine kinase gene contains a binding site for transcription factor E2F [28].
• Moreover, transfection of Daudi cells with the polymerized NF-kappaB binding sequence ligated to a thymidine kinase/chloramphenicol acetyltransferase (CAT) reporter plasmid greatly induced CAT activity, but transfection with the polymerized mutated NF-kappaB binding sequence did not [29].

Regulatory relationships of Tk1

• The high proportion of small colony tk -/- mutants induced by procarbazine together with the far weaker mutagenic response at the hemizygous hgprt locus in these same cells is interpreted in terms of a chromosomal or multi-gene mutational mechanism [16].
• IL-3 regulates thymidine kinase activity, suggesting that alterations in dNTP metabolism after IL-3 deprivation could be a relevant event in the commitment of hemopoietic cells to apoptosis [30].
• Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12 [31].
• In contrast, the thymidine kinase (TK-1) promoter is also regulated by E2F3 but independent of TFE3 [32].
• The genes encoding thymidine kinase (Tk-1) and p34cdc2 (cdc2) are regulated with kinetics similar to those observed for changes in the macromolecular state of E2F [33].

Other interactions of Tk1

• The frequency of mutants with LOH at both Tk1 and D11Nds7 with no loss of GLK activity was high in all cell populations: There was no significant difference in the observed frequency of these mutants between the populations [17].
• Loss of P53 heterozygosity is not responsible for the small colony thymidine kinase mutant phenotype in L5178Y mouse lymphoma cells [18].
• Both Scn4a and Tk-1 showed clear linkage to mouse Chr 11 loci previously typed in this backcross, yielding the map order: TrJ-(Re, Hox-2, Krt-1)-Scn4a-Tk-1 [23].
• On the other hand, removal of IL-3 from cultures of BAF3 cells resulted in down-regulation of thymidine kinase activity, rapid imbalance in dNTP levels, and apoptosis [12].
• The mouse-lymphoma mutagenesis assay detects forward mutations at the heterozygous thymidine kinase (tk-1) locus in L5178Y tk+/- 3.7.2C cells [34].

Analytical, diagnostic and therapeutic context of Tk1

• Southern blot analysis revealed that 92% (36/39) of the PDT-induced thymidine kinase (TK-/-) mutants of strains LY-R16 and LY-SR1 lost the entire active tk allele [1].
• We also utilized in situ hybridization to determine that the Trp53 alleles are, in fact, in their normal chromosome 11 location in Tk+/- 3.7.2C mouse lymphoma cells [18].
• A functional Tk gene is not necessary for cells in culture, and a naturally occurring Tk deficient phenotype has not been described in humans or animal models [5].
• Molecular cloning and structural analysis of murine thymidine kinase genomic and cDNA sequences [35].
• The structural organization was determined by restriction mapping, Southern blotting, and heteroduplex analysis of the cloned sequences, in combination with a mouse tk cDNA [35].

References