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)

The multidrug resistance protein MRP4, a member of the ATP-binding cassette superfamily, confers resistance to purine-based antiretroviral agents. However, the antiviral agent ganciclovir (GCV) has not been shown to be a substrate of MRP4. GCV is important not only in antiviral therapy, but also in the selective killing of tumor cells modified to express herpes simplex virus thymidine kinase (HSV-TK). We therefore tested the effect of MRP4 on the cytotoxicity of GCV, on the ability of GCV to kill cells genetically modified to express HSV-TK, and on the bystander effect in which unmodified target cells are killed by GCV. Cells overexpressing MRP4 had markedly increased resistance to the cytotoxicity of GCV. Although, expression of recombinant HSV-TK increased the intracellular concentration of GCV nucleotide, cells were rescued by the cytoprotective effect of MRP4. In cells that overexpressed MRP4, intracellular accumulation of GCV metabolites was reduced, efflux of these metabolites was increased, and resistance to bystander killing was increased. Therefore, MRP4 can strongly reduce the susceptibility of HSV-TK-expressing cells to GCV, and its overexpression in adjacent cells protects them from bystander cell death. These findings indicate that a nucleotide transporter, such as MRP4, modulates the cellular response to GCV and thus may influence not only the efficacy of antiviral therapy, but also prodrug-based gene therapy, which is critically dependent upon bystander cell killing.
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PMID:Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing. 1210 14

Cisplatin (CDDP) resistance is one of the major impediments in cancer chemotherapy. In an attempt to define this complex mechanism(s) of resistance, we have identified 7 cDNA fragments which are overexpressed in CDDP resistant small cell lung cancer cell line (SR-2) using PCR selected cDNA subtraction. One of these fragments was identical with nucleotide 3657-4042 of MRP4. The other fragments share sequence homology with elongation factor alpha, human placenta villi cDNA, heat shock protein (Hsp70), ribosomal RNA, BNP1 brain specific Na-dependent inorganic phosphate cotransporter and telomeric catalytic subunit. Examination of other MRP members (MRP1, 2, 3, 5, 6) did not show discernable differences in their expression between the parental (SCLC1) and the CDDP-resistant variant (SR-2). Full length MRP4 cDNA was obtained from SCLC1 and SR-2. Both cell lines carry a point mutation at nucleotide 3532 while SR-2 carries two additional mutations at 3228 and 3246. Since MRP4 is known to transport azidiothymidine (AZT) and overexpression of MRP4 confers AZT resistance, we have studied growth inhibitory effects of AZT and [3H]-AZT accumulation. Interestingly, SR-2 is more sensitive to AZT while accumulating lesser amounts of [3H]-AZT. The thymidine kinase activity is similar in both cell lines. Thus, the increased sensitivity to AZT in SR-2 could not be solely due to mutation of MRP4. These findings are most likely due to the inhibitory effects of telomere catalytic subunit by AZT. Thus, certain biochemical changes induced by CDDP can be explored for future treatment to overcome this form of resistance.
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PMID:Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: collateral sensitivity to azidothymidine. 1279 91

The aim of this study was to determine molecular mechanism(s) responsible for the reduced thymidine kinase activity (TK) observed earlier in an arabinosylcytosine (araC) resistant lymphoid cell line (H9-araC cells), which was obtained following continuous cultivation of H9 cells in the presence of 0.5 microM araC. Compared to H9 cells, in H9-araC cells TK1 and TK2 gene expressions were reduced to 17.7% and 2.5%, respectively, and the cellular AZT accumulation was diminished to 35.8%. These cells were also found cross-resistant to azidothymidine (>42-fold). There was no significant difference in the expression of MDR1, MRP4 or TK protein. The lack of correlation between the expressions of TK protein and TK1 and TK2 suggests that post-translational factors may also play a role in the reduced TK activity in H9-araC cells. These findings suggest that araC affects TK expression at the genetic level.
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PMID:Arabinosylcytosine downregulates thymidine kinase and induces cross-resistance to zidovudine in T-lymphoid cells. 1289 60

The p53 protein is mutated in 50% of all human tumors and plays a key role in apoptosis, cell cycle, and the expression of several genes. We investigated if p53 mutations influence the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE). Additionally, we studied some of the underlying mechanisms. GCV sensitivity and BE were studied in a human ovarian carcinoma cell line transfected with an empty vector (A2780/cmv) or a vector containing a p53 hotspot mutation at codon 175 (A2780/m175) or 248 (A2780/m248). In addition, expression levels of two nucleoside analogue transporters, multidrug resistance-related protein 4 and 5 (MRP4/MRP5), were determined. Finally, differences in gap junctional intercellular communication (GJIC) were studied by determining connexin 43 (Cx43) expression and by modulating GJIC with 18-alpha-glycyrrhetinic acid. Our results showed that compared to A2780/cmv, GCV sensitivity was significantly decreased in A2780/m175 and A2780/m248. Additionally, a significant BE (relative increase in cell kill) was found in A2780/cmv and A2780/m248. In contrast, an increased survival was observed in A2780/m175. No MRP4 or MRP5 expression was detected. However, all A2780 cell lines expressed Cx43. Modulating the GJIC significantly decreased the BE in A2780/cmv and A2780/ m248. In conclusion, HSV-tk/GCV-induced BE is influenced by p53 mutations. Differences in GJIC could be one of the underlying mechanisms.
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PMID:Influence of p53 status on the HSV-Tk/GCV-induced bystander effect in a panel of human ovarian carcinoma cell lines. 1605 Jan 36