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 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 enzymes of the DNA synthesizing machinery constitute a group of gene products that are generally expressed co-ordinately at the G1/S boundary of the cell cycle. We have investigated how growth factors regulate the steady-state mRNA levels of two of these genes, the PCNA (proliferating cell nuclear antigen)/cyclin and the thymidine kinase genes. To detect the PCNA/cyclin mRNA, we isolated a cDNA clone from a human library. Two different cell lines were used for these studies: BALB/c3T3 cells, which are exquisitely sensitive to growth factors, and ts13 cells, a temperature-sensitive (ts) mutant of the cell cycle, which arrests in G1 at the restrictive temperature. The steady-state levels of the RNAs for these two genes under different growth conditions were also compared with the levels of histone H3 RNA which are good indicators of the fraction of cells in S phase. Both PCNA/cyclin and thymidine kinase genes share two fundamental characteristics, i.e. they are not inducible in a G1-specific ts mutant of the cell cycle at the restrictive temperature and their expression is inhibited by cycloheximide, indicating that unlike early growth-regulated genes, they require the previous expression of other growth-regulated genes. However, the two genes also show differences, the most notable being that PCNA/cyclin is inducible by epidermal growth factor alone, while thymidine kinase is not.
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PMID:Regulation of the proliferating cell nuclear antigen cyclin and thymidine kinase mRNA levels by growth factors. 289 75

Proliferating cells characteristically undergo programmed (i.e. apoptotic) death if their progression through the cell cycle is sufficiently perturbed. To determine whether androgen ablation-induced programmed death of prostatic glandular cells involves apoptosis triggered by recruitment of nonproliferating cells into a perturbed cell cycle, rat ventral prostates were assessed temporally after castration for several stereotypical molecular stigmata of entry into the proliferative cell cycle. Northern blot analysis was used to assess levels of transcripts from genes characteristically activated 1) during the transition from quiescence (G(0)) into G1 of the proliferative cell cycle (cyclin-D1 and cyclin-C), 2) during the transition from G1 to S (cyclin-E, cdk2, thymidine kinase, and H4-histone), and 3) during progression through S (cyclin-A). Although levels of each of these transcripts increased as expected in prostatic glandular epithelial cells stimulated to proliferate by the administration of exogenous androgen to previously castrated rats, levels of the same transcripts decreased in prostatic glandular cells induced to undergo apoptosis after androgen withdrawal. Northern and Western blot analyses also demonstrated that there was no increase in prostatic p53 messenger RNA or protein content per cell after androgen ablation. Likewise, after castration, there was no enhanced prostatic expression of the WAF1/CIP1 gene, a gene whose expression is known to be induced in both a p53-dependent and -independent manner during recruitment from G0 into G1. In addition, androgen ablation-induced apoptosis of prostatic glandular cells was not accompanied by retinoblastoma protein phosphorylation, which is characteristic of progression into late G1. Nuclear run-on assays demonstrated that there was no increase in the prostatic rate of transcription of the c-myc and c-fos genes after castration. These results demonstrate that prostatic glandular cells undergo programmed death in G(0) without recruitment into the G1 phase of a defective cell cycle, and that an increase in p53 protein or its function is not involved in this death process.
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PMID:Androgen ablation-induced programmed death of prostatic glandular cells does not involve recruitment into a defective cell cycle or p53 induction. 772 Jun 36

This study investigates whether insulin (a differentiation factor for lens epithelial cells) acts as a survival factor. In the absence of insulin, 6-day embryonic chicken lens epithelial explants undergo apoptosis as shown by changes in cell morphology, DNA fragmentation, and loss of trypan blue exclusion. Insulin inhibits these changes and promotes survival of the cells. Aurintricarboxylic acid suppresses the apoptosis of lens explants. In contrast to 6-day embryonic explants, 19-day embryonic explants survive in the absence of insulin, presumably due to an endogenous survival factor. To explore the mechanism of the action of insulin as a survival factor for 6-day embryonic lens explants, we compared the pattern of cell cycle markers (c-fos, c-jun, c-myc, p53, histone H3, thymidine kinase, and cyclin B) in both apoptotic and differentiating lens explants. In the presence of insulin, the expression of c-fos and c-jun was down-regulated after an initial induction. Expression of these genes was also induced in the absence of insulin, but mRNA levels remained elevated as the cells underwent apoptosis. In contrast, expression of c-myc, p53, histone H3, thymidine kinase, and cyclin B showed only minor differences in differentiating and apoptotic cells. Since c-fos and c-jun have been shown to play a role in apoptosis in other cell types, the ability of insulin to regulate expression of these genes may be central to its ability to act as a survival factor for lens epithelial cells.
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PMID:Insulin regulates expression of c-fos and c-jun and suppresses apoptosis of lens epithelial cells. 854 23

The role of alterations of the MTS1 tumor suppressor gene on chromosome 9p21, which encodes p16, the inhibitor of cyclin-dependent-kinase-4 and 6, in tumorigenesis is not yet clear. Phosphorylation of the retinoblastoma protein by cyclin-dependent kinases 4 and 6 prevents its interaction with the transcription factor E2F, which subsequently promotes the expression of S phase regulated genes, such as thymidine kinase. Although a role of p16 in this regulation has been presumed, there is no proof so far that loss of this tumor suppressor gene really affects E2F-mediated regulations. We investigated the regulation of thymidine kinase in phytohemagglutinin-stimulated normal human lymphocytes and in the p16-negative human acute lymphoblastic leukemia cell lines, MOLT-4 and CEM. Compared to normal lymphocytes, MOLT-4 and CEM cells exhibited an altered cell cycle regulation of thymidine kinase, a much higher intracellular activity of this enzyme, and higher thymidine kinase mRNA expression. Transient expression of p16 in normal human lymphocytes caused arrest in G1, but was without effect on the cell growth of MOLT-4 and CEM cells, although all of them express functional retinoblastoma protein. Nevertheless, in the two leukemia cell lines transient overexpression of p16 reestablished the normal regulation of thymidine kinase, paralleled by an increase of the underphosphorylated form of retinoblastoma protein and decrease of free E2F bound to its motif in the thymidine kinase promoter. We demonstrate that loss of p16 causes upregulation of this DNA precursor pathway enzyme via activation of E2F by a mechanism involving retinoblastoma protein.
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PMID:The role of p16 in the E2F-dependent thymidine kinase regulation. 862 83

Vascular gene transfer may be useful for the treatment of several cardiovascular diseases. It can also be used as an experimental tool to test the effects of various genes in a local vascular compartment. Promising therapeutic effects have been obtained in animal models of restenosis with the transfer of vascular endothelial growth factor, nitric oxide synthase, thymidine kinase, retinoblastoma, growth arrest homeobox gene, cyclin/cyclin-dependent kinase inhibitor (p21), and hirudin genes, and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins. Vascular endothelial growth factor and fibroblast growth factor gene transfers have improved blood flow and capillary development in models of ischaemic limb and myocardium. First experiences of vascular endothelial growth factor gene transfer to human peripheral arteries have also been reported. However, further developments in gene delivery techniques and gene transfer vectors will be required before a full therapeutic potential of gene therapy in cardiovascular diseases can be evaluated.
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PMID:Vascular gene transfer. 918 44

Small DNA viruses (adenoviruses, simian virus 40, or human papillomaviruses) induce S-phase progression but prevent cell division to provide precursors for viral DNA replication. Herpes simplex viruses types 1 or 2 (HSV-1 or HSV-2) contain genes which encode DNA-metabolizing enzymes, for example, ribonucleotide reductase, thymidine kinase and dUTPase, suggesting that S-phase factors are not required for an efficient infection. However, several studies indicated that HSV induces some events that occur during cell-cycle progression. To determine if HSV-2 induces S-phase entry, we examined serum-arrested African green monkey kidney cells (CV-1) after infection. Two hours after infection steady-state levels of the S-phase-specific cyclin, cyclin A, increased. S-phase cyclin-dependent kinase activity (CDK2) was stimulated 10-fold 8 h after infection but decreased at 16 or 24 h after infection. Mitotic CDK activity (CDC2) was not activated after infection, in part due to decreases in CDC2 protein levels and inactivation of enzymatic activity resulting from tyrosine phosphorylation of CDC2. Furthermore, CDK4 activity was not dramatically affected by infection. These studies indicate that HSV-2 infection selectively activates CDK2 after infection but cell-cycle progression does not occur. We hypothesize that infection activates certain components of the cell cycle which enhance viral gene expression and DNA replication.
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PMID:Analysis of cyclin-dependent kinase activity after herpes simplex virus type 2 infection. 940 Sep 86

The mechanisms by which cytotoxic agents perturb the normal cell biology and cell cycle progression of cancer cells were explored using B16F10 cells genetically modified to express the Herpes Simplex Virus-thymidine kinase gene. Culture in the presence of the nucleoside analogue ganciclovir induced a profound morphological change that required entry of treated cells into S phase and was dependent on prenylated proteins such as those of the rho gene family. Cell cycle arrest occurred in late S phase or G2 phase due to the activation of the G2-M DNA damage checkpoint. This checkpoint control operated at the level of inhibition of the activity of Cdc2/cyclin B and occurred by two mechanisms: (a) p53-mediated up-regulation of p21CIP/WAF1 expression and its association with Cdc2/cyclin B; and (b) prevention of the dephosphorylation of tyrosine 15 of Cdc2. These events occurred in vitro and in vivo, and were shown to mediate bystander killing in this model. The mechanism of cell death seemed to be due to the irreversible cell cycle arrest at the G2-M checkpoint, rather than induction of apoptosis. These data link DNA damage checkpoints with cytoskeletal signaling pathways and the core cell cycle machinery and may represent a general mechanism of cytotoxicity of this class of nucleoside analogues.
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PMID:Irreversible G2-M arrest and cytoskeletal reorganization induced by cytotoxic nucleoside analogues. 973 95

Induced cell cycle delays were among the first described cellular responses to ionizing radiation (IR). To understand the sensitivity and the molecular events involved in the response to low doses of IR and to examine the role of p53 and its downstream effector p21Waf1, we measured changes in expression of genes postulated to be involved in the cellular response to IR. Expression levels were examined in normal human diploid fibroblasts irradiated and maintained in quiescent density-inhibited growth up to 24-48 h after exposure to X-ray doses as low as 0.1-0.3 Gy, which have negligible effects on cell survival. Among 31 genes analyzed, we observed down-regulation in response to IR of the mRNA levels of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIalpha, and RAD51. A similar reduction in the expression levels of these genes occurred when irradiated cells were released from confluence and allowed to proliferate. This was not observed in cells in which p53 function was defective and up-regulation of p21Waf1 levels either did not occur (E6 transfected normal human fibroblasts and Li-Fraumeni fibroblasts) or was delayed (ataxia telangiectasia fibroblasts) after irradiation. Down-regulation was also absent in p21Waf1-null mouse embryo fibroblasts (MEFs) but occurred at a lower level in p53-null MEFs, due to slight increases in p21Waf1 levels by a p53-independent pathway. These findings indicate that the down-regulation of these cell cycle regulated genes in irradiated cells is p53-dependent and involves its effector p21Waf1. Although no down-regulation in the expression of genes involved in G2-M was observed in p53 or in p21Waf1-null MEFs, these cells showed a G2-M delay after irradiation, indicating that the expression levels of these genes does not regulate the G2-M delay.
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PMID:Regulation by ionizing radiation of CDC2, cyclin A, cyclin B, thymidine kinase, topoisomerase IIalpha, and RAD51 expression in normal human diploid fibroblasts is dependent on p53/p21Waf1. 983 Dec 41

Transcriptional activation is important for the elevated expression of human thymidine kinase (hTK) in tumor cells. Here, we used TK(-133/+33)-luciferase reporter gene construct and bandshift assay to study the cis-elements involved in transcriptional activation of the hTK promoter. We found that two CCAAT boxes at -71/-67 and -40/-36 and Sp1 binding site located at -118/-113 were critical for maximal expression of the hTK promoter activity. As Sp1-mediated activation of the hTK promoter was not detectable for the promoter construct with double mutations at two CCAAT boxes, we proposed that NF-Y binding to the hTK promoter sequence is a requisite step for the functional interaction with Sp1. Here, we further showed that the hTK promoter activity was reduced in HeLa cells transfected with p16 or p21, both of which are inhibitors of cyclin-dependent kinases (CDKs). Inhibition of the hTK promoter activity by p16 could be abrogated by overexpression of cyclin A, indicating that the cyclin A activating event is more directly involved in transcriptional activation of the hTK promoter. We thus proposed that NF-Y-mediated activation of the hTK promoter is closely linked to the activation of CDK2/cyclin A pathway.
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PMID:NF-Y-mediated trans-activation of the human thymidine kinase promoter is closely linked to activation of cyclin-dependent kinase. 1050 2


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