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)

G1-specific temperature-sensitive (ts) mutants of the cell cycle arrest in G1 after serum stimulation at the restrictive temperature. Under these conditions, the RNA levels of late growth-regulated genes (such as DNA polymerase alpha, PCNA, thymidine kinase, and core histones) are markedly decreased or even undetectable, while early growth-regulated genes (for instance, c-myc) are normally expressed, and certain promoters are actually super-induced. We have used the human PCNA gene transfected into TK-ts13 cells (a G1-specific ts mutant) to investigate whether the inhibition of gene expression caused by this type of growth inhibition occurs at a transcriptional or post-transcriptional level. Constructs were made in which the 5' and 3' flanking sequences of the human PCNA gene were replaced by the corresponding elements of the SV40 T antigen coding gene. Using these constructs and data from run-on assays and RT-PCR, we conclude that the failure of expression of the PCNA gene in G1-arrested TK-ts13 cells occurs at the transcriptional level.
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PMID:The role of the promoter in the expression of the PCNA gene. 136 Feb 87

The neuroendocrine hormone PRL acts as a progression factor during interleukin-2 (IL2) stimulated lymphocyte proliferation. Since the sequential expression of cell cycle regulated genes occurs during this process, we examined the contribution of IL2 and PRL to specific RNA accumulation. Stimulation of the cloned T cell line L2 with IL2 and PRL induced the sequential expression of interferon regulatory factor-1, c-myc, proliferating cell nuclear antigen, thymidine kinase, cyclin B, and histone H3. Stimulation of L2 cells with PRL alone, however, induced only the expression of interferon regulatory factor-1. Depletion of PRL, through the use of an anti-PRL antiserum, inhibited IL2 driven proliferation and the expression of cyclin B and histone H3. These results demonstrate that PRL may regulate T cell proliferation by enhancing the expression of some genes necessary for entry into S-phase.
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PMID:Requirement for prolactin during cell cycle regulated gene expression in cloned T-lymphocytes. 153 39

The MDA-468 human breast cancer cell line displays the unusual phenomenon of growth inhibition in response to pharmacological concentrations of EGF. This study was initiated with the objective of elucidating the cellular mechanisms involved in EGF-induced growth inhibition. Following EGF treatment the percentage of MDA-468 cells in G1 phase increased, together with a concomitant depletion in S and G2/M phase populations, as revealed by flow cytometry of DNA content. The apparent G1 block in the cell cycle was confirmed by treating the cells with vinblastine. DNA synthesis was reduced to about 35% of that measured in control, untreated cells after 48 h of EGF treatment, as measured by the incorporation of [3H]thymidine. DNA synthesis returned to normal following the removal of EGF from the growth-arrested cells. In order to locate the EGF-induced event responsible for the G1 arrest more precisely, we examined the expression of certain cell cycle-dependent genes by Northern blot analysis. EGF treatment did not alter either the induction of the early G1 marker, c-myc, or the expression of the late G1 markers, proliferating cell nuclear antigen, and thymidine kinase. However, EGF-treated cells revealed down regulation of p53 and histone 3.2 expression, which are expressed at the G1/S boundary and in S phase, respectively. These results indicate that EGF-induced growth inhibition in MDA-468 human breast cancer cells is characterized by a reversible cell cycle block at the G1/S boundary.
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PMID:EGF-dependent growth inhibition in MDA-468 human breast cancer cells is characterized by late G1 arrest and altered gene expression. 167 99

We recently found that inhibition of MYB protein synthesis in human peripheral blood mononuclear cells (PBMC) exposed to human c-myb (designated MYB) antisense oligodeoxynucleotides prevents entry into S phase and cell proliferation. To determine the mechanism(s) by which down-regulation of human c-myb protein (MYB) synthesis interferes with DNA synthesis, we analyzed mRNA levels of DNA polymerase alpha and proliferating cell nuclear antigen (PCNA), transcripts of two genes required for DNA synthesis, in normal and leukemic T lymphocytes exposed to MYB antisense oligodeoxynucleotides. Expression of DNA polymerase alpha was inhibited both in normal T lymphocytes progressing from G0 to S phase and in exponentially growing CCRF-CEM leukemic cells, whereas expression of PCNA was inhibited only in mitogen-stimulated PBMC and remained essentially unaffected in the leukemia T-cell line. The functional link between expression of MYB and DNA polymerase alpha mRNAs was further demonstrated by analyzing DNA polymerase alpha mRNA levels in a temperature-sensitive (ts) fibroblast cell line (TK-ts13; TK is thymidine kinase) constitutively expressing human MYB mRNA driven by the simian virus 40 (SV40) promoter. In the MYB-expressing TK-ts13 cells, DNA polymerase alpha mRNA levels were unaffected following shift to the nonpermissive temperature of 39.6 degrees C, whereas in the parental line, DNA polymerase alpha mRNA levels were readily down-regulated. These findings indicate that the expression of MYB is related to that of DNA polymerase alpha in cells expressing MYB at high levels and suggest that there is a functional link between c-myb and DNA polymerase alpha mRNA expression during cell cycle progression of normal T lymphocytes.
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PMID:Inhibition of T-cell proliferation by a MYB antisense oligomer is accompanied by selective down-regulation of DNA polymerase alpha expression. 169 13

Serum stimulation of arterial smooth muscle cells in culture induces a progression through the cell cycle and cell proliferation. Most genes previously described as cell cycle-dependent in various cell types also demonstrate a cell cycle-dependent expression in arterial smooth muscle cells. As in other cell types, these genes can be classified into three groups according to their mode of expression: "immediate early" genes (c-fos, c-myc, ...), "delayed early" genes (2F1, ...), and "late-G1" genes (proliferating cell nuclear antigen, thymidine kinase, . . .). In addition to these previously described genes, three genes isolated from a cDNA library of stimulated smooth muscle cells have been demonstrated to be cell cycle-dependent: A21, the rat JE gene, and L51 can be classified as "immediate early" genes, while M11 represents a new member of the "delayed early" gene family.
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PMID:Induction of cell cycle-dependent genes during cell cycle progression of arterial smooth muscle cells in culture. 170 78

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

We have isolated a cDNA that encodes the murine CCAAT-binding protein mYB-1. The deduced amino acid sequence shows 95% identity with its presumed human homologue (hYB-1A) which was originally isolated as a protein that binds to the Y box of MHC class II genes. In vitro translated mYB-1 binds to CCAAT boxes of the MHCIIE alpha, HSVTK and mouse PCNA promoters but not to alpha-globin or human thymidine kinase CCAAT boxes. Interestingly, complexes formed between the in vitro translated protein and the various CCAAT boxes display the property of being competed more efficiently with self competitor DNA, regardless of the CCAAT box initially used as a probe. A similar phenomenon was observed in a cell extract of Con-A stimulated murine splenocytes when the same competition assays were performed. These results may reflect the generation of multiple forms of a particular CCAAT-binding protein, such as mYB-1, that display distinct, yet overlapping, DNA binding specificities.
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PMID:Unusual DNA binding characteristics of an in vitro translation product of the CCAAT binding protein mYB-1. 174 Dec 93

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

The proliferating cell nuclear antigen (PCNA) gene codes for a protein that is necessary for cellular DNA synthesis and cell cycle progression. A functional promoter has been identified in the 5' flanking region of the human PCNA gene. An abbreviated promoter (from the capsite to the PvuII restriction site at -395) was found to be equally efficient in directing transcription from a linked reporter, whether placed in the correct or reverse orientation in respect to the coding sequence. The reporter used was a cDNA of human thymidine kinase (TK), and the bidirectionality of the promoter was demonstrated by its ability to confer the TK+ phenotype to TK- ts 13 cells and by the amount of specific message in RNA blots. The PvuII promoter placed between two coding sequences (the TK cDNA and the bacterial gene for neoresistance) is capable of driving transcription simultaneously in both directions. Finally, in blots of RNA from human cells, two transcripts could be detected that hybridized to a sense riboprobe from the 5' flanking region of the human PCNA gene. We conclude that the locus for the human PCNA gene contains a bidirectional promoter producing diverging transcripts.
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PMID:The promoter of the human proliferating cell nuclear antigen (PCNA) gene is bidirectional. 197 Jul 85

We report the sequence of 4264 nucleotides of 5' flanking sequence of the human thymidine kinase gene, a gene that is maximally expressed at the G1/S boundary of the cell cycle. The position of nucleotide sequences which can act as binding sites for trans-acting factors, Sp-1, AP-1/jun, AP-2, OTF-1 and CAAT box factors as well as other potential cis-acting sequences have been mapped. The organization of these cis-acting sequences in the promoter of the human PCNA gene (another gene that is maximally expressed at the G1/S boundary) are shown for comparison. The potential role that these sequences may play in the transcriptional regulation of these genes is discussed.
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PMID:Sequence analysis of the human thymidine kinase gene promoter: comparison with the human PCNA promoter. 198 53


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