Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance in mammalian cells is often associated with the overproduction of a membrane glycoprotein, P-glycoprotein, that is encoded by mdr genes. Multidrug resistance cell lines selected with either vinblastine, colchicine, or taxol from the drug-sensitive murine macrophage-like cell line J774.2 overexpress the mdr1a and/or mdr1b genes, and overproduce P-glycoprotein. To elucidate the mechanisms of mdr1b gene expression, the mdr1b 5'-flanking sequences have been isolated from a normal mouse liver genomic library and analyzed by gel shift and DNase I footprinting assays. These analyses have demonstrated three nuclear protein binding sites, from -82 to -59 (site 1), from -123 to -101 (site 2), and from -272 to -249 (site 3), which interact with proteins present in nuclear extracts from both sensitive and resistant cells. Although site 1 contains a partially conserved AP-2 consensus sequence, our results indicate that the nuclear protein binding to site 1 is not AP-2 protein. The sequence of site 2 is conserved in the murine mdr1a, human mdr1, and hamster pgp1 promoters. Such conservation suggests that this sequence may have an important role in mdr gene expression. The use of a transient chloramphenicol acetyltransferase expression vector containing the basal promoter for herpes simplex virus thymidine kinase (tkCAT) and either site 1 or site 2 or both revealed that the sequences of sites 1 and 2 enhanced tkCAT activity. DNase I footprinting analyses demonstrated that site 3 is recognized by human AP-1 protein, indicating that the nuclear protein binding to this site is an AP-1-like protein. These observations suggest that mdr1b gene expression is mediated by preexisting transcription factors present in sensitive and resistant cells.
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PMID:Three distinct nuclear protein binding sites in the promoter of the murine multidrug resistance mdr1b gene. 809 13

Drug-resistance in cell lines and in malignant human tumours is associated with dysregulation of several genes including mdr1, MRP1, GST-pi, bcl-2, DNA topoisomerase II alpha and beta, and thymidine kinase I. mRNA expression was evaluated by quantitative RT-PCR coupled with HPLC in three human tumour cell lines and drug-resistant (DR)-sublines. DR sublines from RPMI-8226 and KB cells specifically overexpressed the mdr1 gene without major changes observed in other putative DR-associated genes. In contrast, the DR-H69 cells exhibited a 34-fold overexpression of the MRP gene accompanied by significant down-regulation of both DNA topoisomerase II alpha and bcl-2 mRNA gene expression, by factors of 43 and 13 respectively. These results demonstrate the concomitant down regulation of topoisomerase II alpha and bcl-2 genes in response to DR. Furthermore, differential patterns of gene dysregulations appear to vary depending upon both the drug used to select resistance and cellular origin.
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PMID:Assessment of drug-induced dysregulations among seven resistance-associated genes in human tumour cell lines. 904 17

Gene therapy of oral cancer will require expression of genes by promoters that are both powerful and relatively tumor specific. We compared the level of expression of a reporter gene from promoters of human cytomegalovirus (CMV), SV40 virus, mouse mammary tumor virus (MMTV), human papillomaviruses (HPV) types 16 and 18, and the human multi-drug-resistance gene (mdr1), in several lines of oral cancer cells. In the oral cancer cell line 686LN the rank order of expression levels was: CMV > SV40 > HPV > mdr1 > MMTV. Unlike in previous reports the mdr1 promoter was no more active in two cancer cell lines with mutations in the p53 gene than in two other lines with wild-type p53, and its expression level could not be increased by either doxorubicin or taxol. On the other hand, expression from the MMTV promoter was increased over 10-fold by the presence of 1 microM dexamethasone. Thus, by an appropriate choice of promoter and inducer a wide variety of expression levels, over a 3-log range, could be attained in 686LN cells. The oral cancer-specificity of each promoter was judged by comparing expression in the neuroblastoma line IMR32. The most specific promoters were those from papillomaviruses, which were up to 45 times more active in the oral cancer cells, and the least specific was the CMV promoter. In order to find if an HPV-derived promoter was sufficient to produce expression of a suicide phenotype the 686 promoter was cloned adjacent to the thymidine kinase gene of herpes simplex and the construct was expressed from an adenovirus vector. The vector reduced the growth of 686LN cells over a 5-day period by up to 32% when optimal concentrations of virus and ganciclovir were used. These data will be valuable in the design of new constructs for gene therapy of oral cancer.
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PMID:Strength and specificity of different gene promoters in oral cancer cells. 1074 75

It has been proposed that some host factors may affect the intracellular drug concentration leading to the inability of drug regimens to inhibit human immunodeficiency virus (HIV) replication in cells. Among them, two factors, whose description is the main aim of this review, have been considered during the last years with particular emphasis. They are: i) altered uptake and reduced activation of nucleoside reverse transcriptase inhibitors (NRTIs) in target cells, and ii) efflux of NRTIs and protease inhibitors (PIs) by cellular transporter molecules. In fact, several authors have shown that: changes in the activity of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogs, such as zidovudine, show significantly decreased activity of thymidine kinase compared to untreated HIV-infected persons; NRTI and PIs are substrates for the so-called multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P glycoprotein, and the newly discovered family of multidrug resistance-associated proteins (MRP 1-9) promote the active extracellular efflux of a wide variety of therapeutics and overexpression of some of them lowers intracellular concentration of PIs. In the very near future such mechanisms, called by most authors "cellular drug-resistance", might be taken into account, together with other immunological, virological and behavioral factors, to explain "drug failure" and/or the variability of response in HIV patients undergoing an antiretroviral treatment.
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PMID:Host factors and efficacy of antiretroviral treatment. 1564 66

The multidrug resistance (mdr) mediated by P-glycoprotein (P-gp), the mdr1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a suicide gene therapy approach targeting mdr1 for reversal of P-gp-mediated mdr in the mdr positive K562/A02 cells. To study targeted killing effects of cytosine deaminase (CD)-thymidine kinase (TK) fusion suicide gene on multi-drug resistant leukemia, the CD-TK fusion suicide gene expression vector driven by mdr1 promoter was constructed and transferred into K562 and K562/A02 cells using lipofectintrade mark 2000. RT-PCR was used to demonstrate that there were CD and TK genes expression in K562/A02 cells, but not in K562 cells. MTT analysis showed that, compared with that in K562/CDTK, the survival rate of K562/A02-CDTK cells decreased and at the same time the apoptotic rate increased after treatment with GCV and 5-FC (P < 0.05). In vivo studies showed that the tumor volume in the prodrug treated K562/A02-CDTK groups was significantly less than that in the NS-control and K562-CDTK groups (P < 0.05). These findings show that the CD and TK fusion suicide gene expression driven by mdr1 promoter is effective in killing multidrug resistant K562/A02 cells.
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PMID:Antitumor effects of cytosine deaminase and thymidine kinase fusion suicide gene under the control of mdr1 promoter in mdr1 positive leukemia cells. 1770 92