Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen, nafoxidine, and clomiphene (1 x 10(-5) M) cause 5- to 15-fold increases in transient expression of plasmids transfected into rat somatomammotrophic pituitary tumor cell lines. To be effective, the antiestrogen must be present during the calcium phosphate transfection though it does not enhance the nuclear uptake or stability of transfected plasmid. The effect occurs with mammalian (rat growth hormone, mouse metallothionein I) or viral (thymidine kinase, Rous sarcoma virus) promoters and is inhibited by prior exposure of cells to high concentrations of estradiol but not glucocorticoid, progesterone or testosterone. Cis-tamoxifen, a conformation with much lower affinity for the estrogen receptor, has only one-fifth the effect of tamoxifen. Neither estradiol nor diethylstilbestrol have similar effects. Tamoxifen also increases endogenous rat growth hormone mRNA in these pituitary tumor cell lines. Transient expression in a number of other cell lines (JEG-3, COS-7, PC-12) is unaffected by tamoxifen suggesting the effect may be cell-type specific though MCF-7 cells are slightly responsive. The mechanism for the potent stimulation of gene transcription by these agents is not apparent but may be relevant to the mechanism of action of these agents as estrogen antagonists in vivo.
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PMID:Antiestrogens stimulate expression of transiently transfected and endogenous genes in rat pituitary tumor cell lines. 181 97

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per se determines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli.
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PMID:Effect of tamoxifen on hepatic regeneration in male rats. 291 Jun 79

The action of estradiol-17 beta (E2) on thymidine kinase (TK) activity was studied in uteri from immature female rats. It was demonstrated that a single injection of E2 highly stimulated the enzyme activity which reached its maximum level 24 h after hormone administration. Physiological amounts of E2 were efficient and changes in TK activity were observed exclusively in uterus and liver. A single injection of Tamoxifen produced the same effect as E2 but repeated administration resulted in the complete inhibition of enzyme activity. Using antibiotics it was demonstrated that E2 induced the synthesis of new enzyme molecules rather than an increase in enzyme activity. This statement was corroborated by the fact that after hormone administration the increase in TK activity was preceded by an increase in RNA-polymerase activity and followed by that in DNA-polymerase alpha activity. Moreover, the separation of TK isoenzymes on DEAE-Sephadex and the use of d-CTP as inhibitor of the adult isozyme suggested that E2 induced the "fetal" form of the enzyme. In addition, it was demonstrated that TK activity in uteri from ovariectomized adult female rats was enhanced by E2 administration, and that the increase was due to the stimulation of the fetal isoenzyme. It was suggested that TK could be used as a marker of the action of estrogens and antiestrogens in target organs.
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PMID:Stimulation by estradiol-17 beta of thymidine kinase activity in the rat uterus. 651 60

The effect of 17 beta-estradiol on cytoplasmic thymidine kinase activity was studied in MCF-7, a human breast cancer cell line in culture which responds to estrogens with an increase in the rate of growth. Levels of 17 beta-estradiol which maximally stimulate [3H]thymidine incorporation into DNA also maximally stimulate thymidine kinase activity. The Vmax for thymidine increased while the Km was not affected by estrogen stimulation when performed on nonpurified enzyme. Tamoxifen, an antiestrogen, decreased the specific activity of the enzyme. To further study its hormonal regulation, cytoplasmic thymidine kinase was purified greater than 2000-fold by affinity column chromatography. The purified preparation migrated in one band to a pI of 8.5 on an isoelectric focusing gel. The purified thymidine kinase was further characterized by examining its molecular weight, pH optimum, heat stability, utilization of phosphate donors, inhibition by nucleotides, and the effect of pyrimidine nucleoside analogs.
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PMID:Purification and properties of estrogen-responsive cytoplasmic thymidine kinase from human breast cancer. 744 7

We find that tamoxifen is a potent activator of estrogen receptor (ER)- mediated induction of promoters regulated by AP-1 sites including the human collagenase gene promoter and constructs in which an AP-1 site is fused to the herpes thymidine kinase promoter. This contrasts with the inability of tamoxifen to activate otherwise identical promoters bearing classical estrogen response elements. Tamoxifen agonism at AP-1 sites is cell type specific, occurring in cell lines of uterine, but not of breast, origin. It thus parallels tamoxifen agonism in vivo. AP-1 proteins such as Jun or Jun/Fos are needed for tamoxifen stimulation, and tamoxifen increases the transcriptional efficiency of these proteins even when they are provided at optimal amounts. The DNA binding domain (DBD) of ER is required for tamoxifen activation at AP-1 sites. In contrast, estrogen activation is partially independent of this domain. This suggests the existence of two pathways of ER action at AP-1: an alpha (DBD-dependent) pathway activated by tamoxifen, and a beta (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates the beta, but not the alpha, pathway. We discuss models for the two pathways and the possibility that the AP-1 pathway is a major route by which ER affects target tissue growth and differentiation in vivo.
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PMID:Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. 765 88

Tamoxifen (1.0 microM) was found to inhibit the expression of a thymidine kinase (TK) promoter-reporter gene, lacking an estrogen response element (ERE), in transiently transfected BeWo cells, suggesting that inhibition of TK promoter activity was linked to secondary estrogen-dependent effects on BeWo cell function. Estradiol (0.05-0.45 microM) stimulated BeWo cell proliferation and increased the percentage of S-phase cells. Tamoxifen (1.35-4.05 microM) inhibited BeWo cell growth and antagonized the stimulatory actions of 0.15 microM estradiol. Reverse transcription-polymerase chain reaction and Western analyses confirmed the presence of estrogen receptor (ER) transcripts and the 67-kD ER in BeWo cells. The BeWo cell ER binds to an ERE consensus sequence and the ER-ERE complex is supershifted by antibodies directed against the ER. We conclude that BeWo cells express a functional ER that is important for the control of BeWo cell proliferation, suggesting a potential role for estrogens in mediating placental trophoblast growth and development.
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PMID:Estrogen receptor expression and growth-promoting function in human choriocarcinoma cells. 930 38

We investigated the effects of tamoxifen on the growth of 7,12-dimethylbenz(a)anthracene induced rat mammary tumors, the activity of thymidylate synthetase and thymidine kinase (key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis), and also their gene expression. The effects on immunohistochemistry using bromodeoxyuridine in the tumors and bone mineral density of the femur in rats were also studied. Chronic administration of tamoxifen markedly reduced the expression of thymidylate synthetase mRNA, followed by a reduction in enzyme activity and S-phase cells in the mammary tumors, and significantly enhanced the bone mineral density. Tamoxifen not only attenuated bone loss in aging but also enhanced bone volume in mammary tumor-bearing rats in which tumor growth was suppressed via both the de novo and salvage pathways for pyrimidine nucleotide synthesis.
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PMID:Effects of tamoxifen on mammary tumors and bone in 7,12-dimethylbenz-(a)anthracene-treated rats. 961 34