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)

Approaches to analysing gene regulation in haematopoietic stem cells are limited by their low concentration and rapid cell death outside of a trophic marrow environment. We have used interleukin 3 (IL3)-dependent cell lines as stem-cell models to investigate gene regulation during signal transduction by growth factors. We report that expression of the bacterial chloramphenicol acetyl transferase reporter gene linked via the weak thymidine kinase promoter to known upstream enhancer regions required for expression of the proliferation-dependent proto-oncogene c-fos occurs almost immediately (within 2 h) after transfection. Expression is stimulated by IL3 or activation of protein kinase C. Our findings indicate that IL3-dependent cell lines possess an extremely rapid transcription mechanism for introduced DNA, which if also present in normal cells may be usefully used to analyse gene regulation during signal transduction leading to growth and differentiation by haematopoietic growth factors.
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PMID:Haematopoietic stem cell lines activate novel enhancer-dependent expression of reporter DNA immediately after transfection by mechanisms involving interleukin 3 and protein kinase C. 162 95

The B-myb cDNA has extensive sequence similarities to the c-myb proto-oncogene, but, at variance with c-myb, it is expressed in cells other than hematopoietic cells. In this paper, we show that (1) B-myb is expressed in mouse, human, and hamster fibroblasts; (2) B-myb mRNA levels are growth-regulated in both fibroblasts and peripheral blood mononuclear cells; (3) by its mode of growth regulation (peak of expression, behavior in G1-specific temperature sensitive (ts) mutants and in the presence of cycloheximide), B-myb can be classified, like c-myb, thymidine kinase, PCNA, and others, as a late growth-regulated gene; (4) B-myb mRNA levels decrease when HL-60 cells are induced to differentiate; and (5) the increase in mRNA levels in serum-stimulated cells is only partially explained by an increase in rate of transcription. The possibility that the B-myb gene may be the equivalent in fibroblasts and epithelial cells of the c-myb proto-oncogene of hematopoietic cells is discussed.
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PMID:Growth regulated expression of B-myb in fibroblasts and hematopoietic cells. 171 94

The ets oncogene superfamily consists of a family of sequence-specific DNA-binding proteins that activate transcription. We have previously identified two new members of the ets oncogene superfamily, namely elk-1 and elk-2. In this report we show that the recombinant elk-1 protein expressed in bacteria, like the c-ets-1 proto-oncogene, binds in a sequence-specific manner to Moloney murine sarcoma virus long terminal repeat, E74 target sequences and the PEA3 motif (polyoma enhancer), but does not bind to PU box sequences. Thus analysis of the DNA-binding specificity of ets-related proteins supports the view that different members show similar DNA-binding specificity, which is a general feature of the homeobox proteins. Our data using the chloramphenicol acetyltransferase gene linked to a thymidine kinase promoter containing multimers of the elk-1 target sequence indicates that elk-1 functions as a transcriptional activator. Interestingly, although elk-1 is the most divergent of all the members of the ets gene family, it shows very close similarities with c-ets-1 in some of its sequence-specific DNA-binding specificities. Here, we propose a new function for the elk-1 gene to act as a transcriptional activator of retroviruses and DNA tumor viruses.
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PMID:A divergent ets-related protein, elk-1, recognizes similar c-ets-1 proto-oncogene target sequences and acts as a transcriptional activator. 174 Nov 66

The nuclear proto-oncogene c-myb is preferentially expressed in lymphohematopoietic cells, in which it plays an important role in the processes of differentiation and proliferation. The mechanism(s) that regulates c-myb expression is not fully understood, although in mouse cells a regulatory mechanism involves a transcriptional block in the first intron. To analyze the contribution of the 5' flanking sequences in regulating the expression of the human c-myb gene, we isolated a genomic clone containing extensive 5' flanking sequences, the first exon, and a large portion of the first intron. Sequence analysis of a subcloned 1.3-kb BamHI insert corresponding to 687 nucleotides of the 5' flanking sequence, the entire first exon, and 300 nucleotides of the first intron revealed the presence of closely spaced putative Myb binding sites within a segment extending from nucleotides -616 to -575 upstream from the cap site. A 165-bp segment containing these putative Myb binding sites was linked to a human thymidine kinase (TK) cDNA driven by a low-activity proliferating cell nuclear antigen promoter and cotransfected into TK- ts13 cells with a plasmid in which a full-length human c-myb cDNA is driven by the early simian virus 40 promoter; Myb inducibility of TK mRNA expression was observed both in transient expression assays and in stable transformants. The highest level of inducibility was detected when the 165-bp fragment was placed 138 bp upstream of the proliferating cell nuclear antigen promoter-TK cDNA reporter unit or 3' of the TK cDNA. Mutation of the putative Myb binding sites greatly reduced c-myb transactivation of TK mRNA expression and specifically reduced the binding of in vitro-translated Myb protein at those sites. Finally, c-myb transactivated TK mRNA expression driven by a segment of the authentic c-myb 5' flanking region containing the Myb binding sites. These data suggest that human c-myb maintains high levels of Myb protein in cells that require this gene product for proliferation and/or differentiation by an autoregulatory mechanism involving Myb binding sites in the 5' flanking region.
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PMID:Positive autoregulation of c-myb expression via Myb binding sites in the 5' flanking region of the human c-myb gene. 194 82

We have examined the expression of 13 proto-oncogenes in proliferating and terminally differentiated cardiac and skeletal muscle. Total RNA was prepared from intact ventricular cardiac-muscle tissue and from purified ventricular cardiac-muscle cells of neonatal and adult rats and from cultured proliferating and terminally differentiated L6A1 rat skeletal-muscle cells. cDNA probes for histone H4, thymidine kinase, myosin heavy chain and M-creatine kinase were used to assess cellular proliferation and differentiation. Oncogenes c-myc, c-raf, c-erb-A, c-ras-H, c-ski, and c-sis were expressed in both proliferating and differentiated cardiac muscle tissue and cells, whereas c-myb expression was not observed in either. c-src was expressed only in neonatal cardiac muscle tissue and cells. c-fms, c-abl, and c-ras-K were expressed in tissue from both neonatal and adult animals but only in purified cells from neonatal animals. c-fes/fps was expressed only in neonatal cardiac muscles cells. c-fos expression was not observed in cardiac-muscle tissue from either neonatal or adult rats, but surprisingly was abundantly expressed in freshly isolated cardiac-muscle cells from animals of both ages. These results emphasize that biochemical analysis using intact cardiac-muscle tissue may not necessarily reflect muscle-specific cell processes. They also show that the expression of c-fos can be activated by the cell isolation procedure. c-myc, c-ski, c-ras-H, c-ras-K, c-abl, c-raf and c-erb-A were expressed in both proliferating and terminally differentiated skeletal-muscle cells, whereas c-myb, c-fos, c-src and c-fms transcripts were observed only in proliferating cells. c-fes/fps and c-sis were not expressed in dividing or fused skeletal-muscle cells. These results demonstrate unique tissue and cell-specific patterns of proto-oncogene expression and suggest that these genes may be involved with the regulation of cellular proliferation and terminal differentiation in striated muscle.
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PMID:Proto-oncogene expression in proliferating and differentiating cardiac and skeletal muscle. 244 74

Transcription of proto-oncogene fos is induced by elevated levels of intracellular cAMP. We report that human c-fos promoter recombinants transfected into rat pheochromocytoma cells (PC12) and human choriocarcinoma cells (JEG-3) are induced by stimulation of adenylate cyclase and that this induction is diminished considerably in the mutant PC12 cell line A126-1B2, which is deficient in cAMP-dependent protein kinase II. An element centered at position -60 of the c-fos promoter, which encompasses a consensus cAMP response element (CRE), is sufficient to confer cAMP responsiveness to a herpes thymidine kinase/CAT fusion gene. The specific binding of a nuclear protein to the c-fos CRE can be competed by the somatostatin and alpha-chorionic gonadotropin (alpha-CG) promoter regions that contain CREs. Gel mobility shift assays with double-stranded oligonucleotides containing either the wild-type or mutated c-fos CRE sequence have demonstrated that binding occurs only to the wild-type CRE. The nuclear factor binding to the c-fos CRE is likely to be transcription factor CREB (CRE nuclear binding protein), because an affinity-purified 43-kD CREB isolated from PC12 cells binds efficiently in a DNA footprinting assay. Thus, regulation of the c-fos gene transcription appears to involve a mechanism common to many genes that respond to cAMP as a second message leading to cell growth and differentiation.
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PMID:Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. 285 Sep 67

A region upstream from the mouse c-mos proto-oncogene, termed upstream mouse sequence (UMS), prevents expression of mos transforming activity. Previous studies suggested that the UMS prevented transcription readthrough. In this study, we constructed a recombinant DNA clone, pHTS3MS, with the UMS inserted downstream from both the mos gene and a truncated long terminal repeat containing only the U3 enhancer region. In this position UMS did not inhibit mos transforming activity. We examined cells transformed by pHTS3MS for RNA expression. S1 nuclease analysis showed that the UMS provides two polyadenylation signals to mos-containing RNA and nuclear run-on transcription showed that the primary transcripts terminate in UMS. In addition, using portions of the UMS, we found that a 360-bp fragment containing the UMS polyadenylation signals and sites inserted between the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (tk) and its promoter inhibits tk transforming activity by 99% and prevents detectable expression of this construct in transient expression assays. Thus, the UMS must contain signals for polyadenylation and appears to function as a transcription terminator.
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PMID:Sequences upstream from the mouse c-mos oncogene may function as a transcription termination signal. 301 57

The steady-state messenger RNA levels of several genes increase when cells are stimulated to proliferate. The transcripts from one such gene, the proto-oncogene c-myc, increase approximately 20-fold shortly after cells are stimulated to proliferate and then decline before the onset of DNA synthesis. It has been inferred from these data that expression of c-myc may be specific to the G1 portion of the cell cycle. Alternatively, this transient increase in c-myc mRNA following the stimulation of quiescent cells could be the result of an activational event that renders the cells competent to enter the cell cycle. To distinguish between these possibilities, we performed experiments to determine whether the amount of c-myc mRNA fluctuates during the cell cycle in cells that are under constant stimulation to proliferate. Although c-myc mRNA does undergo a transient increase within 2 h of serum stimulation of quiescent serum-deprived cells, our results show that the level of c-myc mRNA is constant throughout the cell cycle and does not diminish in density-arrested cells maintained in the presence of serum growth factors. In contrast to c-myc, the mRNA levels of two other genes whose expression has been associated with cellular proliferation do show consistent variations within the cell cycle. Both thymidine kinase (TK) and histone 2b (H2b) mRNA levels increase during S phase in continuously growing cells and decrease when cell replication ceases in density-arrested cultures. Therefore, the transient increase in c-myc transcription following the activation of quiescent cells is not due to the type of cell cycle-dependent regulation characteristic of the TK and H2b genes.
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PMID:Levels of c-myc oncogene mRNA are invariant throughout the cell cycle. 398 4

Genetic changes found in human osteogenic sarcoma cells, including loss of the p53 and Rb tumor suppressor elements and overexpression of the cyclin G1 (CYCG1) proto-oncogene, suggest the potential of gene transfer as a treatment for metastatic disease. In this study, we examined the effects of antisense cyclin G1, in comparison with antisense cyclin D1 (CYCD1) and enforced expression of the universal cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the proliferation of human MG-63 osteosarcoma cells. Retroviral vectors bearing antisense CYCG1 as well as antisense CYCD1 and WAF1/CIP1 (in sense orientation) driven by the Moloney murine leukemia virus long terminal repeat promoter inhibited the growth and/or survival of transduced MG-63 cells in 2-7 day cultures. This represents the first demonstration that cyclin G1 is essential for the survival and/or growth of human osteosarcoma cells. Cytostatic and cytopathic effects were accompanied by a significant increase in the incidence of apoptosis, as determined by immunocytochemical analysis of DNA fragmentation. Furthermore, transduction of MG-63 cells with a retroviral vector bearing the suicide gene, herpes simplex thymidine kinase (HStk), induced cell death on treatment with ganciclovir, exhibiting pronounced bystander effects. Taken together, the data affirm the feasibility of modulating inducible cell cycle control enzymes as a potential gene therapy approach in the clinical management of osteogenic sarcoma.
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PMID:Retroviral vector-mediated gene transfer of antisense cyclin G1 (CYCG1) inhibits proliferation of human osteogenic sarcoma cells. 758 20

Formation and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) was examined in three different genes in mouse L cells: 1) a stably integrated insert (called LTL), consisting of a herpes simplex virus thymidine kinase gene (tk) fused to a hormone inducible promotor (LTR); 2) the constitutively expressed proto-oncogene c-abl; and 3) the inactive immunoglobulin J chain gene. Transcription of the tk gene is induced > 50-fold by dexamethasone. There is a nonuniform distribution of CPDs in LTL DNA irradiated in vitro, being 4-fold higher in the LTR than in the tk gene, indicating the LTR may be damaged preferentially in irradiated cells. Repair of CPDs occurs efficiently in both strands of LTL and is unaffected by hormone induction of tk gene transcription. Transcription of tk mRNA is very sensitive to UV damage and follows single hit kinetics with UV dose. Furthermore, tk mRNA expression rapidly recovers during repair incubation. Transcription-coupled repair occurs in these cells, however, since only the transcribed strand of c-abl is efficiently repaired of CPDs; the non-transcribed strand as well as both strands of the J chain gene are inefficiently repaired. Thus, repair in the LTL construct may reflect a lack of transcription-coupled repair in either the LTR promotor or the LTL insertion region of chromatin.
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PMID:Variations in transcription-repair coupling in mouse cells. 787 42


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