Regulation of thymidine kinase enzyme level in serum-stimulated mouse 3T6 fibroblasts*1

Johnson, Lee F.; Rao, Lakshmi G.; Muench, A J

doi:10.1016/0014-4827(82)90093-3

Cited by 106 publications

(45 citation statements)

References 17 publications

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“…The amount of cytosolic TK1 increased significantly in cells during transition from G1 to S phase [7]. In tumor cells, the expression of TK1 is associated with cell growth control and TK1 get to be phosphorylated when cells are in mitosis state [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The modulation of radiation-induced cell death by genistein in K562 cells: Activation of thymidine kinase 1

et al. 2004

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Ionizing radiation is one of the most effective tools in cancer therapy. In a previous study, we reported that protein tyrosine kinase (PTK) inhibitors modulate the radiation responses in the human chronic myelogenous leukemia (CML) cell line K562. The receptor tyrosine kinase inhibitor, genistein, delayed radiation-induced cell death, while non-recepter tyrosine kinase inhibitor, herbimycin A (HMA) enhances radiation-induced apoptosis. In this study, we focused on the modulation of radiation-induced cell death by genistein and performed PCR-select suppression subtractive hybridization (SSH) to understand its molecular mechanism. We identified human thymidine kinase 1 (TK1), which is cell cycle regulatory gene and confirmed expression of TK1 mRNA by Northern blot analysis. Expression of TK1 mRNA and TK 1 enzymatic activity were parallel in their increase and decrease. TK1 is involved in G1-S phase transition of cell cycle progression. In cell cycle analysis, we showed that radiation induced G2 arrest in K562 cells but it was not able to sustain. However, the addition of genistein to irradiated cells sustained a prolonged G2 arrest up to 120 h. In addition, the expression of cell cycle-related proteins, cyclin A and cyclin B1, provided the evidences of G1/S progression and G2-arrest, and their relationship with TK1 in cells treated with radiation and genistein. These results suggest that the activation of TK1 may be critical to modulate the radiation-induced cell death and cell cycle progression in irradiated K562 cells.

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Section: Introductionmentioning

confidence: 99%

The modulation of radiation-induced cell death by genistein in K562 cells: Activation of thymidine kinase 1

et al. 2004

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“…The regulation of the synthesis of TK is interesting because it is typical of that seen for many enzymes involved in DNA metabolism. TK activity is closely linked to the growth state of the cell, being present in rapidly growing but not in resting cells (13). In synchronized populations of cells, the activity is low in resting or Gl phase cells, but increases dramatically 10 to 20 h after the cells are released from arrest by serum stimulation, in parallel with the onset of DNA synthesis and entry into S phase.…”

mentioning

confidence: 97%

“…In synchronized populations of cells, the activity is low in resting or Gl phase cells, but increases dramatically 10 to 20 h after the cells are released from arrest by serum stimulation, in parallel with the onset of DNA synthesis and entry into S phase. This induction is not absolutely dependent upon DNA synthesis (13), but does require both RNA and protein syntheses, suggesting that induction may be at the level of transcription. TK can also be induced by infection of resting cells with papovaviruses such as simian virus 40 (SV40) and polyoma (16,17), and the viral genes required for this induction are the large T antigens (30).…”

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confidence: 99%

Induction of cellular thymidine kinase occurs at the mRNA level.

Stuart¹,

Ito²,

Stewart³

et al. 1985

Mol. Cell. Biol.

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The thymidine kinase (TK) gene has been isolated from human genomic DNA. The gene was passaged twice by transfection of LTK- Thymidine kinase (TK) is an enzyme in the pyrimidine salvage pathway that catalyzes the phosphorylation of thymidine to dTMP. Many mammalian cells, including human HeLa cells, contain both cytoplasmic and mitochondrial forms of the enzyme (3), but the cytoplasmic form alone concerns us here. The regulation of the synthesis of TK is interesting because it is typical of that seen for many enzymes involved in DNA metabolism. TK activity is closely linked to the growth state of the cell, being present in rapidly growing but not in resting cells (13). In synchronized populations of cells, the activity is low in resting or Gl phase cells, but increases dramatically 10 to 20 h after the cells are released from arrest by serum stimulation, in parallel with the onset of DNA synthesis and entry into S phase. This induction is not absolutely dependent upon DNA synthesis (13), but does require both RNA and protein syntheses, suggesting that induction may be at the level of transcription. TK can also be induced by infection of resting cells with papovaviruses such as simian virus 40 (SV40) and polyoma (16,17), and the viral genes required for this induction are the large T antigens (30). Whether viral induction occurs by the same or a different mechanism(s) as serum induction is a question that remains to be answered.The TK gene provides a useful model system for carrying out a molecular analysis of genes that are cell cycle regulated and induced by viral infection. First, TK shows a great increase in activity (10-to 20-fold) after both serum and viral induction. Moreover, TK enzyme assays are both sensitive and easily performed. We can genetically select both for (hypoxanthine-aminopterin-thymidine media) and against (bromodeoxyuridine media) the TK+ phenotype, and many TK-cell lines exist. It has been shown that LTK-cells transfected to a TK+ phenotype with heterologous (human, rat, or hamster) chromosomal DNA containing a functional TK gene exhibit normal cell cycle regulation of the gene (31). Recent experiments with a cloned human gene (5) that the sequences required for cell cycle regulation are closely linked to the gene and function after transfection into TK-cells. Thus, this system should offer the chance to dissect the sequences involved in cell cycle-specific gene regulation.The mechanisms by which the expression of cell cycle-dependent genes is controlled, and by which the papovaviruses override these controls, remain obscure, although many of the initial observations were made more than 15 years ago. To a large extent this is because molecular probes for these genes and their transcripts have not been available. In this paper we report the isolation of both the human chromosomal TK locus and a functional human TK cDNA clone. Isolation of the chromosomal locus has previously been reported by several investigators (5,19,22), and our mapping is essentially in agreement with their data. In a...

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“…The expression of the thymidine kinase (TK) gene in higher eucaryotic cells in culture has been understood since the work of Kit et al (14,15) and Littlefield (26,27) in 1965 to be growth phase dependent, i.e., to be maximal as asynchronously growing cell cultures are plated at low density and divide logarithmically and then minimal as cultures reach stationary confluence and cells withdraw from the cell division cycle (1,5,12). With the development of techniques to prepare synchronously dividing in vitro cell cultures, TK gene expression was shown to be cell-cycle S phase specific, to be scarcely measurable in cultures of G1-phase cells, to rise sharply as DNA synthesis is initiated in S-phase cultures, and then to decline as cell cultures progress through the G2 and M phases of the cell division cycle (4,16,17,30,33,40,41).…”

mentioning

confidence: 99%

Genetic determinants of growth phase-dependent and adenovirus 5-responsive expression of the Chinese hamster thymidine kinase gene are contained within thymidine kinase mRNA sequences.

Lewis¹,

Matkovich²

1986

Mol. Cell. Biol.

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We have constructed a chimeric thymidine kinase (TK) minigene, pHe delta 6Ha, which combines the complete coding and 3' noncoding regions of a Chinese hamster TK cDNA with the promoter region and 5' untranslated region of the TK gene of herpes simplex virus type 1. We have transformed rat 4 cells to Tk+ with this gene and analyzed the pattern of TK gene expression in these transformants under various conditions of in vitro cell culture. We find that TK gene expression in these Tk+ transformants is growth phase dependent, responsive to adenovirus 5 infection, and indistinguishable in character under a variety of cell culture conditions from the pattern of TK gene expression in rat 4 cells transformed to Tk+ with the genomic Chinese hamster TK gene clone lambda HaTK.5. We are led to the conclusion that the genetic elements which mediate growth phase-dependent TK gene expression are contained entirely within the sequences of the mature cytoplasmic hamster TK mRNA.

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Regulation of thymidine kinase enzyme level in serum-stimulated mouse 3T6 fibroblasts*1

Cited by 106 publications

References 17 publications

The modulation of radiation-induced cell death by genistein in K562 cells: Activation of thymidine kinase 1

The modulation of radiation-induced cell death by genistein in K562 cells: Activation of thymidine kinase 1

Induction of cellular thymidine kinase occurs at the mRNA level.

Genetic determinants of growth phase-dependent and adenovirus 5-responsive expression of the Chinese hamster thymidine kinase gene are contained within thymidine kinase mRNA sequences.

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