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 present studies have examined the effects of 1-beta-D-arabinofuranosylcytosine (ara-C) on activation of the transcription factor kappa B (NF-kappa B). The results demonstrate that treatment of human KG-1 myeloid leukemia cells with ara-C is associated with induction of protein binding to the NF-kappa B consensus sequence. NF-kappa B binding was activated at 30 min and reached maximal levels of binding at 1-2 hr of ara-C treatment. The NF-kappa B consensus sequence was ligated to the heterologous thymidine kinase (TK) promoter and the human growth hormone (GH) reporter gene to determine whether ara-C-induced NF-kappa B activity includes an enhancer function. Ara-C treatment had little effect on transient expression of pTKGH in KG-1 cells but increased transcription of the p (NF-kappa B) TKGH vector by 8-fold. The results also demonstrate that ara-C transiently increases NF-kappa B mRNA levels. However, the finding that ara-C-induced binding of NF-kappa B to DNA occurs in the presence of cycloheximide indicates that this agent activates preexisting NF-kappa B protein. These results suggest that ara-C induces a cytoplasmic pathway that transduces signals to the nucleus by activation of NF-kappa B.
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PMID:Activation of the transcription factor kappa B in human KG-1 myeloid leukemia cells treated with 1-beta-D-arabinofuranosylcytosine. 173 23

The early growth response 1 (EGR-1) gene is induced after mitogenic stimulation of diverse cell types. The present work has examined the effects of okadaic acid, an inhibitor of protein phosphatases 1 and 2A, on EGR-1 expression during monocytic differentiation of U-937 myeloid leukemia cells. Treatment of U-937 cells with okadaic acid was associated with transient increases in EGR-1 mRNA levels. These increases were maximal at 6 h and occurred in the absence of de novo protein synthesis. Nuclear run-on assays demonstrated that although EGR-1 transcription is detectable in untreated U-937 cells, this rate is increased 6-fold by okadaic acid. Sequences responsive to okadaic acid-induced signals were determined by deletion analysis of the EGR-1 promoter. The results demonstrate that okadaic acid-induced EGR-1 transcription is dependent on the presence of CC (A/T)6 GG (CArG) motifs. The EGR-1 promoter contains six CArG boxes. However, only the 5'-most distal (first) CArG sequence conferred okadaic acid inducibility. A 40-base pair oligomer corresponding to the first CArG element also conferred okadaic acid inducibility of the minimal thymidine kinase gene promoter. In contrast, there was no inducibility using a similar oligomer containing a mutated CArG box. Finally, binding of nuclear proteins to the first CArG sequence was similar for control and okadaic acid-treated cells. Taken together, these results suggest that okadaic acid activates EGR-1 transcription and that this event is mediated at least in part by a single CArG element.
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PMID:Transcriptional regulation of the early growth response 1 gene in human myeloid leukemia cells by okadaic acid. 838 Oct 16

The RIZ (G3B or MTB-Zf) zinc finger gene is structurally related to the myeloid leukemia gene, MDS1-EVI1, and the transcription repressor/differentiation factor, PRDI-BF1/BLIMP1, through a conserved amino-terminal motif, the PR domain. Similar to MDS1-EVI1, RIZ gene normally produces two protein products that differ by the PR domain. The smaller protein RIZ2 lacks the PR domain of RIZ1 but is otherwise identical to RIZ1. Here we show that RIZ proteins bind to GC-rich or Sp-1-binding elements and repress transcription. Both RIZ1 and RIZ2 repressed the herpes simplex virus thymidine kinase (HSV-TK) promoter, one of the best characterized eukaryotic promoters. Recombinant RIZ1 proteins were able to bind to HSV-TK promoter. This binding was mediated by the GC-rich Sp-1 elements of the promoter and the first three zinc finger motifs of RIZ1. RIZ also encodes a repressor domain that was mapped to the central region of the protein. Fusion of this region to the GAL4 DNA-binding domain generated GAL4 site-dependent transcriptional repressors. We also show that RIZ1 protein can efficiently repress the simian virus 40 (SV40) early promoter, which primarily consists of Sp-1 sites; RIZ2, however, only weakly repressed this promoter, suggesting a role for PR in modulating RIZ protein function. The data have implications for a role of RIZ proteins in the regulation of cellular gene promoters, many of which are characterized by GC-rich elements.
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PMID:Transcriptional repression mediated by the PR domain zinc finger gene RIZ. 933 9

Thymidine phosphorylase (TP) regulates intracellular thymidine metabolism and can enhance the anti-tumor effectiveness of 5'-deoxy-5-fluorouridine (5'-DFUR) by conversion of the pro-drug 5'-DFUR to 5-fluorouracil (5-FU) in tumor tissues. 5'-DFUR is an effective anti-tumor drug in cells expressing high levels of TP. 3'-Azido 3'-deoxythymidine (AZT) is a thymidine analog that has been proven useful in the treatment of acquired immunodefiency syndrome (AIDS). In this study, we found that AZT induces TP expression and enhances the sensitivity of human myeloid leukemia U937 cells to 5'-DFUR. Both the protein level and the activity of TP in U937 cells were elevated for 48h after exposure to AZT (20, 100 or 300muM). AZT enhanced TP promoter activity in a dose-dependent manner. AZT also increased TP mRNA levels in U937 cells as assayed by Real-time reverse-transcription PCR. AZT enhanced the cytotoxic effect of 5'-DFUR on U937 cells. A TP inhibitor, TPI, abrogated the cytotoxic activity of 5'-DFUR, and attenuated the combined cytotoxicity of AZT and 5'-DFUR. These results suggest that AZT enhances the cytotoxic effect of 5'-DFUR on U937 cells by upregulating TP activity in addition to its inhibition of thymidine kinase (TK) activity and reduction of intracellular dTTP pools.
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PMID:Induction of thymidine phosphorylase expression by AZT contributes to enhancement of 5'-DFUR cytotoxicity. 1645 48

Cancer cells are characterized by uncontrolled replication involving loss of control of cyclin dependent kinases (CDKs) and cyclins, and by abolished differentiation. In this study we introduce KGI, which is a nanoparticle with a Quillaja saponin as an active molecule. By the use of RNA array analysis and confirmation at the protein level, we show that KGI affects myeloid leukemia cells (in particular, the U937 monoblast cancer cell) by the following mechanisms: (A) ceasing cell replication via proteasome degradation, (B) down-regulation of key molecules at check points between G1/S and G2/M phases, (C) reduction of thymidine kinase activity, followed by (D) exit to differentiation and production of interleukin-8 (IL-8), eventually leading to apoptosis. Leukemia cell lines (U937 and HL-60 cells) were exposed to KGI for 8 h, after which the drug was removed. The cancer cells did not revert to replication over the following 10 days. Thus our findings suggest that the nanoparticle KGI inhibits proliferation and promotes differentiation in leukemic cells by interfering with the cell cycle process.
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PMID:The nanoparticulate Quillaja saponin KGI exerts anti-proliferative effects by down-regulation of cell cycle molecules in U937 and HL-60 human leukemia cells. 2413 32