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)

The macrophage colony-stimulating factor (M-CSF) is required for the growth and differentiation of mononuclear phagocytes. Previous studies have demonstrated that tumor necrosis factor (TNF) induces transcription of the M-CSF gene in human myeloid cells. The present work examined the effects of TNF on cis-acting elements in the M-CSF promoter. Deleted forms of the M-CSF promoter were linked to the chloramphenicol acetyltransferase (CAT) gene and transfected by electroporation into HL-60 promyelocytic leukemia cells. The results demonstrate that an enhancer responsive to TNF stimulation is located between positions -406 and -344 upstream to the transcription start site. The fragment from positions -419 to -304 was cloned 5' to the heterologous thymidine kinase (TK) promoter and linked to the CAT gene. Both orientations of this fragment enhanced TK-promoter activity in TNF-treated HL-60 cells. The results of gel mobility shift assays with the -419 to -304 fragment demonstrate binding of a constitutive nuclear protein. A TNF-inducible protein also bound to this fragment and resulted in a different mobility pattern. Binding of the TNF-induced nuclear protein to the -419 to -304 fragment was inhibited by an oligonucleotide containing the nuclear factor-kappa B (NF-kappa B) consensus sequence. DNA footprinting demonstrated protection of an NF-kappa B binding site at positions -377 to -368. Methylation interference assays showed that the TNF-induced protein made contact points with guanine residues in the same NF-kappa B sequence. Taken together, the findings provide evidence for involvement of an NF-kappa B-like factor in transcriptional regulation of the M-CSF gene.
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PMID:Involvement of a nuclear factor-kappa B-like protein in induction of the macrophage colony-stimulating factor gene by tumor necrosis factor. 191 81

The receptor for the macrophage colony-stimulating factor (or colony-stimulating factor 1 [CSF-1]) is expressed from different promoters in monocytic cells and placental trophoblasts. We have demonstrated that the monocyte-specific expression of the CSF-1 receptor is regulated at the level of transcription by a tissue-specific promoter whose activity is stimulated by the monocyte/B-cell-specific transcription factor PU.1 (D.-E. Zhang, C.J. Hetherington, H.-M. Chen, and D.G. Tenen, Mol. Cell. Biol. 14:373-381, 1994). Here we report that the tissue specificity of this promoter is also mediated by sequences in a region II (bp -88 to -59), which lies 10 bp upstream from the PU.1-binding site. When analyzed by DNase footprinting, region II was protected preferentially in monocytic cells. Electrophoretic mobility shift assays confirmed that region II interacts specifically with nuclear proteins from monocytic cells. Two gel shift complexes (Mono A and Mono B) were formed with separate sequence elements within this region. Competition and supershift experiments indicate that Mono B contains a member of the polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) family, which includes the AML1 gene product, while Mono A is a distinct complex preferentially expressed in monocytic cells. Promoter constructs with mutations in these sequence elements were no longer expressed specifically in monocytes. Furthermore, multimerized region II sequence elements enhanced the activity of a heterologous thymidine kinase promoter in monocytic cells but not other cell types tested. These results indicate that the monocyte/B-cell-specific transcription factor PU.1 and the Mono A and Mono B protein complexes act in concert to regulate monocyte-specific transcription of the CSF-1 receptor.
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PMID:Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1). 796 46

The effectiveness of combination therapy using a suicide gene and cytokine genes for the treatment of metastatic colon carcinoma in the mouse liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus thymidine kinase gene(tk) exhibited substantial regression, although all treated animals suffered from subsequent relapses. Although cotreatment with a mouse interleukin 2 (mIL-2)-containing adenoviral vector induced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor relapse or distant metastases. In this study, mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A fraction of the animals treated with tk + mIL-2 + mGM-CSF developed long-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced further by subsequent "vaccination" with mIL-2-expressing parental tumor cells. The results indicate that local expression of GM-CSF in the hepatic tumors and prolonged mIL-2 expression are necessary to generate persistent antitumor immunity that is essential for the prevention of tumor recurrence and long-term animal survival.
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PMID:Combination suicide and cytokine gene therapy for hepatic metastases of colon carcinoma: sustained antitumor immunity prolongs animal survival. 870 21

Direct delivery of the herpes simplex virus thymidine kinase (HSVtk) gene, in combination with the prodrug ganciclovir (GC), has been used for the treatment of localised, inoperable tumours. Several groups have shown that when rodent tumours are ablated in vivo with suicide genes, anti-tumour immunity can also be generated. Hence, this approach may also be useful in treating disseminated disease. Here we have studied the mechanisms associated with this anti-tumour immunity. In B16 HSVtk+ tumours being killed in vivo with GC treatment, we observed the induction of a pronounced intratumoural infiltrate of macrophages, CD4+ and CD8+ T cells. In addition, using reverse transcriptase polymerase chain reaction, expression of interleukin (IL)-2, IL-12, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and granulocyte/macrophage colony-stimulating factor (GM-CSF) but not IL-4, IL-6 or IL-10, was observed, a profile of cytokine expression which resembles that of a Th1 immune response. To complement these findings, we also investigated the mechanisms by which expression of HSVtk leads to cell death. Our data show that B16/HSVtk+ cells die predominantly by necrosis, rather than apoptosis, on exposure to GC, a process which may be associated with the generation of anti-tumour inflammatory responses. From these data we propose a model for the induction of anti-tumour immunity using suicide genes and discuss the development of improved vectors for gene therapy to augment these effects in vivo.
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PMID:Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression. 913 53

The effects of macrophage (M) and granulocyte (G) colony-stimulating factors (CSFs) on the activity of thymidylate synthase and thymidine kinase, which are involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, were investigated in the hematopoietic cells of rats treated with cyclophasphamide. Thymidine kinase activity, but not that of thymidylate synthase, was markedly enhanced in these cells by M- and G-CSF treatment (p < 0.05 and p < 0.01). G-CSF directly, and M-CSF indirectly stimulate myeloid cells and lead to S-phase predominantly via the salvage pathway for pyrimidine nucleotide synthesis. The present study indicates that these CSFs can be effective inducers of complete remission in acute leukemias when employed together with chemotherapy.
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PMID:Effects of macrophage- and granulocyte-colony stimulating factors on thymidylate synthase and thymidine kinase activity in rat hematopoietic cells. 917 25

Three transcripts from the terminal repeat of the channel catfish virus (CCV; also known as ictalurid herpesvirus 1) genome were mapped by S1 nuclease and primer extension analyses as well as by cDNA sequencing. These transcripts, TR3, TR5/6, and TR6, are encoded by open reading frame (ORF) 3, ORFs 5 and 6, and ORF 6, respectively, and correspond to those previously identified by sequence analysis (A. J. Davison, Virology 186:9-14, 1992). ORF 5 has previously been determined to encode thymidine kinase, but ORF 3 and ORF 6 encode proteins of unknown function. Although all three transcripts accumulate to high levels in cells infected in the presence of cycloheximide, kinetic analysis demonstrates that TR5/6 and TR6 are either early or late transcripts that leak through the cycloheximide block. In addition, two transcripts from the terminal repeat of the CCV genome that were mapped previously and were thought to be immediate-early in character, TR8a/9 and TR9, exhibit kinetics characteristic of early or late transcripts. TR3 is an immediate-early transcript that appears to have a very short half-life. In the 3' untranslated region of TR3, there are three copies of an AU-rich element which has previously been shown to be involved in destabilization of the oncogene c-fos and granulocyte/macrophage colony-stimulating factor mRNAs. mRNA destabilization may represent another mechanism by which herpesviruses regulate the rapid switch in expression from immediate-early genes to early genes during the transition to the early phase of infection.
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PMID:Expression kinetics and mapping of the thymidine kinase transcript and an immediate-early transcript from channel catfish virus. 955 75

The ETS domain transcription factor PU.1 is necessary for the development of monocytes and regulates, in particular, the expression of the monocyte-specific macrophage colony-stimulating factor (M-CSF) receptor, which is critical for monocytic cell survival, proliferation, and differentiation. The bZIP transcription factor c-Jun, which is part of the AP-1 transcription factor complex, is also important for monocytic differentiation, but the monocyte-specific M-CSF receptor promoter has no AP-1 consensus binding sites. We asked the question of whether c-Jun could promote the induction of the M-CSF receptor by collaborating with PU.1. We demonstrate that c-Jun enhances the ability of PU.1 to transactivate the M-CSF receptor promoter as well as a minimal thymidine kinase promoter containing only PU.1 DNA binding sites. c-Jun does not directly bind to the M-CSF receptor promoter but associates via its basic domain with the ETS domain of PU.1. Consistent with our observation that AP-1 binding does not contribute to c-Jun coactivation is the observation that the activation of PU.1 by c-Jun is blocked by overexpression of c-Fos. Phosphorylation of c-Jun by c-Jun NH2-terminal kinase on Ser-63 and -73 does not alter the ability of c-Jun to enhance PU.1 transactivation. Activated Ras enhances the transcriptional activity of PU.1 by up-regulating c-Jun expression without changing the phosphorylation pattern of PU.1. The activation of PU.1 by Ras is blocked by a mutant c-Jun protein lacking the basic domain. The expression of this mutant form of c-Jun also completely blocks 12-O-tetradecanoylphorbol-13-acetate-induced M-CSF receptor promoter activity during monocytic differentiation. We propose therefore that c-Jun acts as a c-Jun NH2-terminal kinase-independent coactivator of PU.1, resulting in M-CSF receptor expression and development of the monocytic lineage.
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PMID:c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. 998 37

It is known that colony stimulating factors (CSFs) stimulate the myeloid cells of bone marrow and splenic cells in rodents. The effects of macrophage (M)-CSF on the activities of thymidylate synthase and thymidine kinase, involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, in haematopoietic cells of bone marrow and spleen were investigated in rats. A single M-CSF injection did not elevate the mRNA expression levels of the enzymes in bone marrow cells 6 h after treatment, but it enhanced the splenic thymidylate synthase mRNA expression. M-CSF stimulated the splenic thymidylate synthase activity without an increase of the peripheral granulocytes. The effect of M-CSF on granulocytes is considered to be weak compared with that of granulocyte (G)-CSF, because of the indirect secretion of endogenous G-CSF from the cells with M-CSF receptors stimulated by exogenous M-CSF. Since M-CSF was able temporarily to lead progenitor cells from long G1-phase into S-phase, M-CSF might accelerate the anticancer effects when used together with anticancer agents.
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PMID:Does macrophage-colony stimulating factor stimulate rat haematopoietic cells? 1076 79

Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present study, we examined the efficacy of adv/tk/GCV gene therapy in a syngeneic BT4C rat malignant glioma model, either as a single administration or given as three injections during three consecutive days. The effect of combined adv-mediated macrophage colony-stimulating factor (MCSF) and adv/tk gene transfer was also studied. BT4C malignant glioma cells were injected into the right corpus callosum of BDIX rats (n=112). Before gene therapy, the presence of tumors was verified by MRI. The rats were divided into eight groups as follows: group I (n=20) received a single adv/tk gene transfer (total dose 4x10(8) pfu) and GCV treatment for 14 days; group II (n=5) received the same gene transfer without GCV; group III (n=28) received three adv/tk injections (total dose 4x10(8) pfu) on three consecutive days and GCV for 14 days; group IV (n=5) received three similar adv/tk injections without GCV medication; group V (n=13) received three adv/MCSF injections (total dose 2x10(8) pfu) on three consecutive days and GCV medication; group VI (n=12) received three adv/tk and adv/MCSF (total dose 6x10(8) pfu) injections on three consecutive days followed by GCV medication; and group VII (n=12) the same treatment without GCV. Group VIII (n=17) consisted of wild-type BT4C malignant glioma tumors without any treatment. Treatment effect and tissue responses were characterized by general histology, immunohistochemistry, MRI, and survival of the study groups. The best treatment effect and survival was found in rats treated with adv/tk gene transfer once a day for three consecutive days (P<.05). No improvement of the treatment effect was seen after the combined adv/tk and adv/MCSF gene transfer compared with the repeated adv/tk gene transfer. The results show that 20% of the rats can be cured (survival >6 months) after optimized adv/tk gene therapy. It is concluded that repeated intratumoral administration of adv/tk is a promising approach for the treatment of malignant glioma tumors in vivo.
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PMID:Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model. 1238 30

We evaluated the antitumor effects of combination gene therapy on CT26 mouse colon cancer cells, using the genes for herpes simplex virus thymidine kinase gene HSV-TK combined with granulocyte macrophage colony-stimulating factor (GM-CSF) compared with HSV-TK alone. Cells, unmodified or retrovirally transduced with HSV-TK or GM-CSF, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSV-TK and GM-CSF were also delivered using different routes (in separate cells vs doubly transfected single cells). Both HSV-TK (with i.p. ganciclovir - GCV - treatment) and GM-CSF genes had independent antitumor effects, and given together they caused significant reduction in tumor volumes compared with the HSV-TK gene alone (P < 0.001). Following GCV treatment, however, the treated/control ratios for tumor volumes were not different between tumors containing either HSV-TK alone or both genes (0.27 vs 0.25, respectively). Thus, the presence of GM-CSF did not increase the bystander effect of HSV-TK. Tumors receiving genes transferred in separate cells tended to be more consistently suppressed after GCV treatment than when both genes were transferred in the same cells, although this was not statistically significant. Thus, combination GM-CSF and HSV-TK gene therapy produced greater therapeutic efficacy than HSV-TK alone, but the bystander effect was not enhanced by GM-CSF.
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PMID:Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model. 1523 2


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