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)

Polysaccharides extracted from human tubercle bacilli (specific substance of Maruyama) have been clinically applied in patients with malignant diseases in Japan and other countries. It is known that increased colorectal carcinogenesis occurs in patients with ulcerative colitis. The repeated mucosal necrosis-regeneration sequence in chronic ulcerative colitis induced with 3 % dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane-pretreated mice. Simultaneously multiple injections with the polysaccharides reduced the increases in thymidylate synthase and thymidine kinase activities and a number of bromodeoxyuridine-incorporated S-phase cells in colorectal tissues resulted in the reduction of tumorous regions with high-grade dysplasia.
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PMID:Polysaccharides extracted from human tubercle bacilli (specific substance of Maruyama) reduces carcinogenesis in murine ulcerative colitis. 1120 61

Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest.
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PMID:Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor. 1122 43

The aim of the present work was to gain insight into a putative anticancer effect of dietary vitamin D3 (cholecalciferol) in a rat model of colon carcinogenesis. Male rats were assigned to three different dietary groups. The dietary regimens were based on a standard murine-defined diet (AIN-76A) or a stress diet containing 20% fat, reduced Ca2+ concentration, a high phosphorus-to-Ca2+ ratio, and either low or high vitamin D3 content. Colorectal cancer was induced by administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Blood Ca2+, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and 25-hydroxyvitamin D3 [25(OH)D3] levels were measured in DMH-treated rats and in respective weight- and age-matched dietary control groups. Colonic epithelial proliferation was assessed by determining thymidine kinase (TK) activity, bromodeoxyuridine (BrdUrd) incorporation into crypt cell DNA, and the mean labeling index along the colonic crypt continuum. Maintenance of rats on the stress diet either unmodified or supplemented with vitamin D3 in the absence of carcinogen treatment provoked a time-dependent rise in colonic TK activity and hyperproliferation of colonic epithelium. DMH treatment of rats maintained on the standard diet caused a marked increase in the proliferative indexes of colonic epithelium and in expansion of the crypt proliferative compartment. TK activity and the crypt mitotic zone were significantly augmented in the animal group fed the stress diet. Supplementary vitamin D3 abrogated the stress diet-enhanced colonic responses to the carcinogenic insult. Colon tumor multiplicity was fourfold higher in animals fed the stress diet than in animals maintained on a standard diet. The marked rise in colonic tumor multiplicity and adenocarcinoma incidence in rats fed the stress diet was obliterated by supplemental dietary vitamin D3. Cumulatively, the present results indicate that dietary vitamin D3 impedes the neoplastic process in murine large intestine and strengthen the view that inappropriate changes in dietary components and micronutrients are contributory determinants of colorectal cancer.
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PMID:A protective role of dietary vitamin D3 in rat colon carcinogenesis. 1134 Oct 47

Many models of carcinogenesis posit that multiple genetic events are required for a normal cell to become cancerous. As the mutation rate of a single gene is in the range of 10(-8) to 10(-5) per cell division, a central question remains, how does a single cell acquire multiple mutations? One hypothesis, originally articulated by Loeb [10], proposed that some mutations may not be isolated events, but are associated with a mutator phenotype that leads to the occurrence of additional mutations elsewhere in the cellular genome. To test this hypothesis, we utilized a human lymphoblastoid cell line (WTK1) that is known to be hypermutable at the autosomal thymidine kinase (TK) locus. We isolated 139 independent clones which were selected for new TK mutations that arose either spontaneously or as the result of a single X-ray exposure of 1.5Gy. These clones were examined for second-site alterations in several microsatellite loci scattered throughout the genome using polymerase chain reaction (PCR) amplification followed by both denaturing gel electrophoresis and single-stranded conformational polymorphism (SSCP) analysis. Of these clones, 21 exhibited second-site mutations primarily involving loss of heterozygosity, 17 arose from irradiated cells whereas the remaining four arose from non-irradiated cells. We further examined the 17 clones which exhibited alterations specifically at the D16S265 locus; alterations at this site were associated with an enhanced frequency of mutations at other loci in the same region of chromosome 16q, but were not associated with additional mutations at other sites in the genome. Furthermore, new mutations arose in loci on 16q when these clones were propagated for 6 months in culture. Overall, these results support the hypothesis that radiation can induce a type of genetic instability which may facilitate the occurrence of multiple mutations throughout the genome in a small population of exposed cells. Furthermore, some cells may possess localized regions in the genome which are highly sensitive to the induction of instability.
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PMID:X-ray induction of microsatellite instability at autosomal loci in human lymphoblastoid WTK1 cells. 1140 74

The mycotoxin aflatoxin B1 (AFB1) is one of the most potent rodent and human liver carcinogens. Upon cytochrome P450-specific metabolism, it induces mutations as well as mitotic recombination events in in vitro systems. We have found that in the lower eukaryote yeast, the recombinagenic activity of AFB1 surpasses its mutagenic activity, and we speculated on possible consequences in terms of the mechanism of liver carcinogenesis. In this study we investigated whether the recombinagenic activity of AFB1 also would be identified in human cells. To address this question, we followed the fate of a heterozygous thymidine kinase (tk) allele in the human lymphoblastoid cell line TK6 upon exposure to AFB1. Individual mutants that had lost tk activity were subjected to loss of heterozygosity analysis of the tk locus and its flanking markers. Fluorescence in situ hybridization analysis on chromosome 17 also was performed. In parallel, a similar analysis was performed on TK6 cells exposed to the alkylating agent N-nitrosomethylurea, a well-known classic point mutagen. Our analysis showed a difference in the molecular mechanism leading to inactivation of the tk allele upon exposure to these two mutagens. In AFB1-exposed cells the fraction of recombination-derived mutants predominated, whereas in N-nitrosomethylurea-exposed cells the fraction of point mutants was higher. Thus, the recombinagenic activity of AFB1 previously identified in a lower eukaryote also was found in the human cell line TK6. Our data support the hypothesis that mitotic recombination represents a central mechanism of action in AFB1-induced liver carcinogenesis.
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PMID:Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell line. 1147 21

Using a cultured human colon cancer cell line (Col 2), a structurally diverse group of chemopreventive agents was evaluated for their potential to induce apoptosis. As a result, 1,4-phenylenebis(methylene)selenocyanate (p-xylylselenocyanate; p-XSC) was found to be active in this process. p-XSC, a synthetic organoselenium compound, has been shown to inhibit tobacco-specific 4-(methylnitrosoamino)-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mouse lung, rat tongue carcinogenesis and colon cancer. Known chemopreventive mechanisms include inhibition of DNA methylation, inhibition of thymidine kinase and reduction of oxidative DNA damage. In order to assess apoptosis induction, the cells were exposed to various concentrations of test substances for 48 hours. Enrichment of mono- and oligonucleosomes in the cytoplasm was monitored as an indication of apoptosis using an ELISA kit. As a result, p-XSC caused dose-dependent enrichment of fragmented nucleosomes. In further studies, p-XSC was found to induce DNA laddering in a dose-dependent manner, while apoptotic cells accumulated in a time-dependent manner up to 96 hours. The apoptotic peaks after treatment of p-XSC were also found as confirmed by the flow cytometric analysis of cell cycle distribution. In an additional study, however, p-XSC-mediated apoptosis was not shown to be dependent on p53 expression. Taken together, these results suggest that induction of apoptosis is one possible mechanism for the cancer chemopreventive activity mediated by p-XSC.
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PMID:Induction of apoptosis by 1,4-phenylenebis(methylene)selenocyanate in cultured human colon cancer cells. 1201 40

Mother-to-child transmission of the human immunodeficiency virus is substantially reduced by prenatal and postnatal treatment with anti-retroviral nucleoside analogues; however, the long-term consequences of these drug interventions are not known. The nucleoside analogue zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) is carcinogenic in mice when administered transplacentally or neonatally, and this may be due to a genotoxic mechanism. Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC), or a combination of the two drugs. B6C3F(1)/Tk+/- mice were treated daily from days 1-8 of age with 200 mg AZT/kg/day, 200 mg 3TC/kg/day, or a mixture of 200 mg AZT + 200 mg 3TC/kg/day (AZT/3TC). One and 2 days after the last dose, bone marrow was collected to assess the induction of micronuclei in polychromatic erythrocytes; 3 weeks following treatment, the induction of mutants was determined in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) and thymidine kinase (Tk) genes of spleen lymphocytes. AZT and AZT/3TC, but not 3TC, caused a significant increase in micronuclei, with the response being greatest one day after the last dose. None of the drugs induced mutations in the Hprt gene, while AZT and AZT/3TC, but not 3TC, caused a significant increase in the Tk mutant frequency. The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity). These data suggest that AZT, but not 3TC, is genotoxic in neonatal mice, and that 3TC does not alter significantly the responses observed with AZT alone.
Carcinogenesis 2002 Sep
PMID:Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine. 1218 83

The incidence of colorectal carcinogenesis is increased in patients with ulcerative colitis. We investigated the effects of repetitive diarrhea on colorectal carcinogenesis in mice singly pretreated by a low-dose of chemical carcinogen. Mucosal changes were investigated in mice pretreated with a single intraperitoneal injection of 8.0 mg/kg body weight of azoxymethane prior to a repetitive oral administration of 3% dextran sulphate sodium to induce chronic diarrhea. Repetitive treatment with dextran sulphate sodium induced a cycle of chronic diarrhea-remission in the colorectum. Five submucosal-invasive adenocarcinomas and 65 high-grade dysplasias were found in 15 mice that underwent azoxymethane-pretreatment with 3 cycles of 3% dextran sulphate sodium-exposure, i.e. colorectal carcinogenesis was observed mainly in the left side of the large intestine within 11 weeks after the initial treatment with carcinogen. Consequently, thymidine kinase was expressed and activated, and an increase in bromodeoxyuridine-immuno-reactive (S-phase) cells was observed in the regenerating mucosa and the colorectum with tumorous lesions. Colorectal carcinogenesis developed with the increasing duration of diarrhea induced by 3% dextran sulphate sodium in mice pretreated by a single injection of a small dosage of azoxymethane during the comparatively short period of this experimental colitis system.
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PMID:The more an ulcerative colitis is repeated, the more the risk of colorectal carcinogenesis is increased in mice. 1255 18

The functional effect of the interaction of E2F1 and hepatitis B virus X protein (HBx) on the promoter of human p53 gene was studied using chloramphenicol acetyl transferase (CAT) assay. E2F1 activated the p53 promoter through E2F1 binding site. As previously reported, HBx repressed the p53 promoter through E-box. When E2F1 was cotransfected with HBx, E2F1 overcame the repressive effect of HBx on the p53 promoter through the E2F1 site. However, in the thymidine kinase (tk) heterologous promoter system with the E2F1 binding sites, cotransfection of E2F1 and HBx showed a strong synergistic activation. An in vitro interaction assay showed that E2F1 and HBx physically bind with each other. Analyses of the interaction domain with the GAL4 fusion protein showed that the pRb-binding domain of E2F1 was necessary for the functional interaction of these two proteins. Taken together, these results imply the functional inhibitory action of E2F1 on the HBV life cycle and HBV-mediated hepatocellular carcinogenesis (HCC). Therefore, the normal or enhanced function of E2F1 gene would be important in controlling the HBx function in HCC.
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PMID:E2F1 activates the human p53 promoter and overcomes the repressive effect of hepatitis B viral X protein (Hbx) on the p53 promoter. 1262 70

Inositol hexaphosphate (IP6) or phytic acid, contained in most mammalian cells, has been shown to have anticancer and anti-cell-proliferative effects in several experimental models of carcinogenesis. We investigated the effect of topical application of IP6 on 7,12-dimethylbenzanthracene (DMBA)-induced complete carcinogenesis and on selective critical events of proliferation, differentiation, or apoptosis after DMBA exposure. IP6 inhibited skin tumor development significantly in a dose-dependent manner. IP6 induced the DMBA-inhibited transglutaminase activity. DNA synthesis, as determined by [3H]thymidine incorporation, was suppressed by IP6 in a dose-dependent manner. IP6 also inhibited thymidine kinase enzyme, which is responsible for [3H]thymidine incorporation into DNA. Our results show that topical application of IP6 inhibits DMBA-induced mouse skin tumor development and that IP6 exerts its tumor inhibitory effect probably by modulating proliferation, differentiation, or apoptosis. It seems that IP6 is an effective and potential chemopreventive agent for management of skin tumorigenesis.
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PMID:Suppression of DMBA-induced mouse skin tumor development by inositol hexaphosphate and its mode of action. 1292 6


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