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 intraperiplasmic growth rate and cell yield of wild-type Bdellovibrio bacteriovorus 109J, growing on Escherichia coli of normal composition as the substrate, were not markedly inhibited by 10-3 M methotrexate (4-amino-N10-methylpteroylglutamic acid). In contrast, the growth rate and cell yield of the mutant 109Ja, growing axenically in 0.5% yeast extract +0.15% peptone, were strongly inhibited by 10-4 and 10-3 M methotrexate. Thymine, thymidine, and thymidine-5'-monophosphate, in increasing order of effectiveness, partially or completely reversed the inhibition. E. coli depleted of tetrahydrofolate and having an abnormally high protein/deoxyribonucleic acid (DNA) ratio was obtained by growing it in the presence of methotrexate. B. bacteriovourus grew at a normal rate on these depleted E. coli cells but with somewhat reduced cell yield. Mexthotrexate (10-3 M) inhibited intraperiplasmic growth of bdellovibrio on the depleted E. coli somewhat more than it inhibited growth on normal E. coli, but the effects were small compared with inhibition of axenic growth of the mutant. Total bdellovibrio DNA after growth on the depleted E. coli in the presence or absence of methotrexate exceeded the initial quanity of E. coli DNA present. Thymidine-5'-monophosphate (10-3 M) largely reversed the inhibition and increased the amount of net synthesis of DNA. The data are consistent with the prediction that intraperiplasmic growth of B. bacteriovorus should be insensitive to all metabolic inhibitors that act by specifically preventing synthesis of essential monomers. The data also indicate that B. bacteriovorus possesses thymidylate synthetase, thymidine phosphorylase, and thymidine kinase, and has the potential to carry out de novo DNA synthesis from non-DNA precursors during intraperiplasmic growth. The results also suggest that methionyl tRNAfMet is not required for initiation of protein synthesis by B. bacteriovorus.
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PMID:Effects of methotrexate on intraperiplasmic and axenic growth of Bdellovibrio bacteriovorus. 109 May 93

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy.
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PMID:Effect of antiandrogen flutamide on measures of hepatic regeneration in rats. 259 58

Altered steroid responsiveness leads to various pathological conditions and is a particular problem for the treatment of cancers arising in steroid-sensitive cells. To develop cellular model systems for the analysis of the molecular mechanisms mediating altered steroid responses, we have analyzed the inducibility of a steroid-responsive promoter in different cell lines. In vitro constructs containing the mouse mammary tumor virus promoter fused to the herpes simplex virus thymidine kinase gene or the bacterial neo gene were transfected into four different cell lines [Rat-2, CHO chinese hamster ovary cells, F9, and T47D). Thymidine kinase+ clones and neo-resistant clones were selected in the presence of dexamethasone (dex) and/or other steroid hormones. We find that the mouse mammary tumor virus promoter activity is completely dependent on the presence of dex in Rat-2 cells but is constitutively active in CHO cells and is inactive in F9 teratocarcinoma cells in the presence and absence of dex. In the human breast cancer cell line T47D, we observe no response to dex but do observe an inducibility by progesterone. Examination of glucocorticoid receptors in these cell lines showed that Rat-2, CHO, and F9 cells contain sufficient receptors to allow a hormonal response, whereas in T47D cells several glucocorticoid binding activities appear to be present. Our results indicate that the presence of receptor in cells is not always sufficient to allow hormonal activation and that, in some cell lines, like CHO, other factors are present that can substitute for an activated steroid hormone receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Variable responsiveness of hormone-inducible hybrid genes in different cell lines. 285 Nov

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

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p less than 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p less than 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection.
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PMID:Effect of partial portal vein ligation on hepatic regeneration. 315 99

The molecular details of glucocorticoid hormone regulation of expression of the mouse mammary tumor virus (MMTV) proviral gene have been investigated. Cloned proviral DNA was introduced into cultured cells by a gene transfer procedure. DNA acquired by transfection was shown to be expressed in a hormone regulated fashion. The proviral DNA was fragmented and recombined in vitro with an indicator gene to delimit the hormone response sequence. Inducibility of the indicator gene (thymidine kinase gene from Herpes Simplex Virus, tk) was observed upon recombination with the long terminal repeat (LTR) sequence of MMTV. Further delimitation of the LTR DNA demonstrated that 202 nucleotides located 5' of the RNA initiation site are sufficient to confer glucocorticoid regulation. In vitro interaction of LTR DNA with glucocorticoid hormone receptor complex, showed a preferential affinity to the same sequence which mediated hormonal regulation in transfected cells. Evidence for a direct receptor gene interaction in the process of gene induction was gained by the measurement of the kinetics of induction and the use of a glucocorticoid antagonist (RU 486). The induction of the transfected gene is very rapid, independent of simultaneous protein synthesis and requires a functional glucocorticoid receptor hormone complex.
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PMID:Glucocorticoid hormone interactions with cloned proviral DNA of mouse mammary tumor virus. 620 Jul 2

Steroid hormones, when complexed to their receptors, recognize and bind specific DNA sequences and subsequently induce increased levels of transcription. The mechanisms of steroid hormone action were analyzed by constructing chimeric DNA molecules from portions of mouse mammary tumor virus envelope and long terminal repeat (LTR) regions ligated to the thymidine kinase (tk) gene of herpes simplex virus. This construction allowed the tk gene to be expressed in a hormone-responsive fashion upon transfection into Ltk- cells. Comparison of transcription data with in vitro binding data showed that hormone-responsive transcription can be directly correlated to the presence of steroid hormone receptor binding sites on the DNA. There are at least two such receptor binding sites in the LTR region, one between -202 and -137 and another between -137 and -50 base pairs from the RNA cap site, as well as a site near the 5' end of the envelope region. These results strengthen the hypothesis that steroid-receptor complexes regulate genes primarily by binding to DNA sites near the promoter region and thereby modulate transcription.
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PMID:Correlation of glucocorticoid receptor binding sites on MMTV proviral DNA with hormone inducible transcription. 631 11

Thyroid hormone receptor (TR) can act as both a transcriptional activator and a silencer. Optimal activation by TR requires synergism with activator(s) bound to the promoter (promoter proximal activator). It is thought that liganded TR either helps to recruit preinitiation complexes (PIC) to the promoter or activates the PIC already recruited. However, the studies analyzing the TR action on the PIC formation were done in vitro and, therefore, it is not clear how relevant they are to the in vivo TR action. For example, in vivo, the TR can act from distances equal to or greater than a kilobase from the promoter, but such distant effect is not reproducible in vitro. In this study, we used the PIN*POINT (ProteIN POsition Identification with Nuclease Tail) assay to define the molecular mechanism of TR action on transcription from the thymidine kinase promoter in the cellular context. We demonstrate that the recruitment of promoter-proximal activator Sp1, and the components of the basal transcription factors such as TBP, TFIIB, and Cdk7, is enhanced with thyroid hormone activation. Our results suggest that DNA forms a loop with TR-mediated activation to accommodate interactions between the liganded TR complex and the complex formed on the promoter. We also show that Sp1 bound to the promoter is essential for the DNA looping and recruitment of basal transcription factors such as TFIIB and Cdk7 but not for recruitment of TBP. On the basis of these findings, we present a model that illustrates the molecular mechanism of TR-mediated activation in vivo.
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PMID:In vivo transcription factor recruitment during thyroid hormone receptor-mediated activation. 1046 67

Thyroid hormone receptor (TR), a ligand-mediated transcription factor, binds to a DNA sequence known as a thyroid-hormone response element (TRE) to activate or repress transcription of target genes. Recently, studies have shown that Ca2+/calmodulin-dependent protein kinases (CaMKs) may be involved in regulating gene transcription via phosphorylation of specific transcription factors, including RORalpha, a retinoic acid-related orphan nuclear hormone receptor. In this light, we examined the effect of CaMK type IV (CaMKIV) and RORalpha, which also shown to influence thyroid hormone action, on TR-mediated transcription using a transient transfection assay. Expression vectors containing TR, vitamin D receptor (VDR), and estrogen receptor (ER) were cotransfected in CV-1 cells with RORalpha and/or constitutively active CaMKIV and thymidine kinase promotor-luciferase reporter vector containing their cognate response elements. When CaMKIV or RORalpha was co-transfected with TR, the T3-induced transcription was significantly augmented compared to that induced by TR alone. When both were co-transfected with TR, T3-induced transcription was augmented additively. In contrast, the augmentation by CaMKIV or ROR on ligand-induced transcription was not detected with VDR and ER. Hence, these results indicate that the augmentation mediated by CaMKIV and RORalpha is specific for TR-mediated transcription on TRE. Our results suggest that CaMKIV, as well as RORalpha, play important roles in TR-mediated transcription on TREs.
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PMID:Augmentation of thyroid hormone receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase type IV. 1083 Mar 18

Retinoid X receptors (RXRs) comprise a family of nuclear retinoid activated transcription factors that are members of the steroid hormone receptor superfamily. RXRs are obligate heterodimerization partners with several other hormone receptor family members, making them critical mediators of a wide range of signaling pathways. Retinoids have been used successfully for the prevention of a number of epithelial cancers, including skin squamous cell carcinoma (SCC). The reduced expression levels of retinoid receptors including RXRalpha, the predominant RXR expressed in skin, is associated with malignancy in skin SCC. In order to study the regulation of RXRalpha in skin SCC carcinogenesis we have previously mapped the majority of the human RXRalpha gene. In the present study we have identified its first exon and promoter region. Exon 1, which contains the translation start site, is located in a highly G+C rich region of the genome at least 58 kb centromeric from exon 2. The promoter region itself is unusually G+C rich (75% G+C in 1200 bp of upstream sequence), has 17 putative SP1 transcription factor binding sites and no TATA or CAAT boxes. Transient transfection experiments with RXRalpha promoter-luciferase reporter constructs in SRB12-p9 skin SCC cells, as well as with PC3 prostate carcinoma cells, revealed that RXRalpha transcription is relatively weak compared to the positive control thymidine kinase (TK) promoter and is stimulated by treatment with all-trans retinoic acid (ATRA), the biologically active form of vitamin A. These results indicate that the RXRalpha gene is transcribed at stable levels, similar to most housekeeping genes, and its transcription is regulated by ATRA. In addition, the 5' untranslated region of RXRalpha is highly G+C rich, resulting in a potentially stable folding pattern, that would place RXRalpha amongst a group of genes that are subject to regulation at the translational level.
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PMID:Identification and characterization of the human retinoid X receptor alpha gene promoter. 1651 99


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