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)

Sequences located upstream of the transcription initiation site of the Xenopus vitellogenin A2 (vit A2) gene contain a hormone dependent enhancer that confers estrogen control to the heterologous thymidine kinase (tk) promoter. As a minimal functional estrogen responsive element (ERE), we have defined the 13 bp palindrome GGTCACAGTGACC. This ERE binds estrogen receptor preferentially in vitro. Although the ERE shares some structural features with the glucocorticoid responsive element (GRE) it is distinct from this element since it neither binds glucocorticoid receptor in vitro nor does it confer glucocorticoid inducibility to a fusion gene. Point mutations within the ERE decrease its affinity for the estrogen receptor and result in a complete loss of estrogen inducibility.
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PMID:A 13 bp palindrome is a functional estrogen responsive element and interacts specifically with estrogen receptor. 334 May 49

Because biochemical "feminization" of the liver in males is observed with hepatic regeneration and because the hepatic regenerative response in females is greater than that in males, the possibility that antiandrogens might potentiate liver regeneration was investigated. Before 70% hepatectomy, adult male Wistar rats were treated with cimetidine, an antiandrogenic H2 antagonist, at doses up to 10 times greater than those used clinically. Control animals received either the saline vehicle or ranitidine, an H2 antagonist without antiandrogenic properties. Treatment with cimetidine reduced the hepatic cytosolic androgen receptor content compared with ranitidine treatment. Hepatectomy caused a further reduction in androgen receptor activity in all groups. Hepatic cytosolic estrogen receptor activity was comparable in all groups throughout the study. Moreover, the rate of liver growth and the levels of ornithine decarboxylase and thymidine kinase activity induced as part of the regenerative response were similar in all groups. Thus, cimetidine, despite its ability to bind to androgen receptors, and ranitidine, an H2 receptor antagonist without antiandrogen action, do not modulate the hepatic regenerative response to a 70% partial hepatectomy.
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PMID:Effect of an antiandrogenic H2 receptor antagonist on hepatic regeneration in rats. 339 26

The DNA sequences which interact with the estrogen receptor and which mediate the estrogenic regulation of prolactin gene transcription have been investigated by the use of receptor-DNA-binding experiments and gene transfer studies. Nitrocellulose filter binding assays using highly purified estrogen receptor and cloned fragments of the 5'-flanking region of the rat prolactin gene demonstrate that the receptor selectively binds to DNA sequences located between nucleotides -1713 and -1532 with respect to the transcription initiation site. The binding of the estrogen receptor to this region of the prolactin gene was strongly dependent on receptor concentration, suggesting that receptor dimers may be important in DNA binding. These data demonstrate that the selective binding of purified estrogen receptor to specific sequences of the rat prolactin gene is an intrinsic property of the receptor and is not due to the interaction of receptor with other proteins. The role of specific prolactin gene sequences in mediating the estrogenic regulation of prolactin gene transcription was confirmed by the use of prolactin-chloramphenicol acetyltransferase fusion genes. These studies demonstrated that sequences upstream of position -1532 are required for estrogen responsiveness. Furthermore, the region of the prolactin gene at -1713 to -1495 was able to confer estrogen responsiveness on the thymidine kinase promoter. Exonuclease III protection experiments further localized the receptor-binding sequences to positions -1587 to -1563. Comparison of the nucleotide sequence of the region of the prolactin gene which binds the estrogen receptor with the sequence of other estrogen-responsive genes suggested the presence of the conserved sequence [sequence in text], which shows similarity to sequences thought to mediate glucocorticoid receptor effects on transcription.
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PMID:Identification of an estrogen-responsive element from the 5'-flanking region of the rat prolactin gene. 348 34

Cytosols from breast cancers were measured for estrogen receptor (ER) and thymidine kinase (TK) activity. There was no correlation between ER and TK in 137 primary breast cancers studied. The results of TK from 57 metastatic breast cancers were correlated with the response or failure to subsequent hormonal therapy or chemotherapy. TK did not predict the responses to hormonal therapy in 12 patients. Of the 45 patients treated with chemotherapies, 13 of 15 tumors with TK over 80 pmol/mg/min responded (86%), while only 4 of the 30 tumors (13%) with TK below 80 pmol/mg/min responded (p less than 0.001). TK appears to be useful in predicting the responses to chemotherapy.
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PMID:Thymidine kinase as a predictor of response to chemotherapy in advanced breast cancer. 648 23

In medical clinics or experiments, progesterone (P) has been used for treatment of adenomatous hyperplasia or cancer of the endometrium. In the present paper, effects of P in combination with or without estradiol-17 beta (E2) on the estrogen receptor (ER) and thymidine kinase (TK) activity in immature rat uterus are described. P has been reported to interfere with the replenishment of the cytoplasmic ER of the rat uterus. In the present study, no translocation of the cytoplasmic ER to the nucleus was found after the injection of P, whereas P slightly enhanced the wet weight and the TK activity of the uterus. The TK activity increased 20 to 30 times the control level at 30 hours after the injection of E2. However, the enzyme activity induced by E2 was inhibited by P which was approximately 1,000-fold or more dose of E2. This enzyme was separated into isozymes by DEAE-cellulose column chromatography. Induction of the specific TK isozyme, which was induced by E2 in immature rat uterus and closely related to DNA synthesis, was found to be inhibited by P.
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PMID:[Estrogen and progesterone interactions on the estrogen receptor and thymidine kinase in the immature rat uterus]. 715 94

Uterine estrogen receptor (ER) and thymidine kinase (TK) activity were investigated in response to an injection of estradiol (E2) (1.43microgram/100g body weight) in SD-strain immature female rats aged 21 days and spayed-adult rats aged 104 days (14 days after castration). In immature rats, uterine cytosol ER decreased abruptly after the injection of E2 and increased gradually from 4 hours later. On the other hand, nuclear ER increased rapidly and shaped a peak 1 hour after the injection of E2 and decreased gradually afterward. Uterine TK activity began to increase rapidly from 18 hours and shaped a peak 24 hours after the injection of E2 and was reduced to the same level as the controls 48 hours later. No differences in behavior of uterine cytosol and nuclear ER after the injection of E2 between immature and spayed-adult rats were noticed. Although uterine TK activity in immature rats was stimulated 30 times 24 hours after the injection of E2, that of spayed-adult rats increased by only twice. Uterine TK was separated into 3 fractions (A, B and C) by means of a DEAE-cellulose column chromatography. In immature rats, 95% of the great TK activity induced by E2 was involved in fraction A, which was not inhibited by dCTP. In contrast, uterine TK isozymes in spayed-adult rats were at fraction B and C, whose activities were inhibited by dCTP, without relation to the administration of E2. The molecular weight of fraction A was estimated to be approximately 125,000 and that of B was 100,000 by the method of gel filtration on a Sepharose CL-6B column. No differences in uterine ER levels between immature and spayed-adult rats were found, but E2-induced different TK isozymes seem to depend on the stage of uterine growth.
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PMID:[The effects of estradiol on uterine estrogen receptor and thymidine kinase in immature and spayed-adult rats (author's transl)]. 746 Dec 25

We describe a human (h) PRL-producing cell line, SKUT-1B-20, which we isolated as a subclone of a uterine sarcoma cell line. Although this cell line is of uterine origin, it does not use the decidual-specific upstream promoter of the hPRL gene, but transcribes the hPRL gene from the downstream pituitary-type transcription start site, as determined by Northern blot, reverse transcriptase-polymerase chain reaction and primer extension analyses. This is particularly intriguing because SKUT-1B-20 cells lack the transcription factor Pit-1. No Pit-1 messenger RNA was detectable by reverse transcriptase-polymerase chain reaction, and endogenous Pit-1 target genes (GH, PRL, and Pit-1) were refractory to transfected Pit-1 expression vector, whereas in cotransfection experiments, Pit-1 efficiently activated reporter gene fusion constructs carrying 5'-flanking sequences of the human and rat PRL or the mouse Pit-1 genes. By transfecting reporter genes containing 8.7 kilobases of DNA flanking the hPRL pituitary-specific start site (hPRL-8700/Luc) and deletions thereof, we located a Pit-1-independent cis-active region more than 7 kilobases upstream of the start site. The most distal 1650 or 880 base pairs of the hPRL genomic fragment (which extends to -8784 base pairs), when placed directly upstream of the homologous hPRL or the heterologous thymidine kinase promoters, conferred transcriptional activation to those promoters. SKUT-1B-20 cell-specific activation of hPRL-8700/Luc could not be suppressed by the introduction of an inhibitor of protein kinase A (PKA), PKI. This is the first demonstration of pituitary-type PRL gene transcription independent of Pit-1 and activation of the PKA pathway. The SKUT-1B-20 cell line was then used in reconstitution experiments to delineate the role of Pit-1 in modulating the transcriptional effects of phorbol ester, PKA, and estrogen receptor (ER) on the hPRL gene. The low response of hPRL/luciferase fusion genes to phorbol ester was greatly enhanced by cotransfected Pit-1 and was mediated by the proximal region between -250 and -38. The catalytic subunit of PKA, C beta, was able to elicit a moderate induction of hPRL-8700/Luc even in the absence of Pit-1. A potential estrogen response element has been located in the hPRL gene sequence at a position similar to that of the estrogen response element of the rat PRL gene immediately adjacent to the distal enhancer.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pituitary-type transcription of the human prolactin gene in the absence of Pit-1. 747 71

The calbindin D9k (CaBP9k) gene is under strict estrogen control in the rat uterus. This tissue contains two CaBP9k messenger RNA (mRNA) species. We have used primer extension analysis, reverse transcriptase associated with polymerase chain reaction, and RNase H digestion to show that these two mRNA species have the same structural features, including 5'- and 3'-ends, and poly(A) tail length. Our results suggest that the difference in electrophoretic mobilities of the two mRNA species might be due to interaction with another factor. We also analyzed the imperfect estrogen-responsive element (ERE) present on the first 5'-splice site of the rat CaBP9k gene. The oligonucleotide corresponding to the CaBP9k ERE was cloned in the plasmid pBLCAT2 (where the thymidine kinase promoter governs the expression of the chloramphenicol acetyl transferase gene) and transfected into MCF7 cells. This CaBP9k ERE was found to be a hormone-inducible enhancer that worked in an orientation-independent manner on a heterologous promoter and was functional at physiological hormone concentrations. One CaBP9k ERE conferred only weak (about 2-fold) estrogen induction, but two EREs cloned in tandem were strongly synergistic (14- to 16-fold). The CaBP9k ERE also bound to the partially purified estrogen receptor (ER) and to ER expressed in COS cells by gel shift assay. Methylation interference showed that all the guanine residues in both half-sites of the CaBP9k ERE were protected by ER binding. Thus, ER binds to the CaBP9k ERE in a way similar to other EREs. The gel shift assay results indicate that the strong synergistic effect of two EREs cloned in tandem is not due to cooperative binding between the two elements. As the CaBP9k gene is under strong estrogenic control in the uterus in vivo, the imperfect CaBP9k ERE may cooperate with another trans-acting factor to become fully efficient.
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PMID:Calbindin-D9k gene expression in the uterus: study of the two messenger ribonucleic acid species and analysis of an imperfect estrogen-responsive element. 750 2

We find that stimulation of the protein kinase A (PKA) signaling pathway in MCF-7 human breast cancer cells changes the agonist/antagonist activity of tamoxifen and related antiestrogens; it activates or enhances their estrogen agonist activity and reduces their ability to antagonize the effects of estradiol (E2). In MCF-7 human breast cancer cells which contain high levels of endogenous estrogen receptor (ER), the antiestrogen trans-hydroxy-tamoxifen (TOT) fails to stimulate transcription of the estrogen-responsive promoter-reporter constructs estrogen response element (ERE)-TATA-chloramphenicol acetyl transferase (CAT), (ERE)2-TATA-CAT, and pS2-CAT. However, when cells are treated with isobutyl methylxanthine plus cholera toxin (which increases intracellular cAMP approximately 10-fold), or with 8-bromo-cAMP, or are transfected with expression vectors for the PKA catalytic subunits, the transcriptional activity of the antiestrogen-ER complex is now increased, to levels 20-75% that of E2, and TOT also becomes much less effective in antagonizing the stimulation of transcription by E2. Although this alteration in the agonist and antagonist activity of TOT is observed with three promoter-reporter constructs, containing a simple TATA promoter or a more complex, pS2 promoter, elevation of cAMP did not enhance the transcription by either TOT or E2 of the reporter plasmid ERE-thymidine kinase-CAT. Thus, this phenomenon is promoter specific. The maximal stimulatory effects of isobutylmethylxanthine plus cholera toxin and PKA catalytic subunits on TOT and E2 transcriptional enhancement were not additive, consistent with the hypothesis that they are both acting via stimulation of the same signal transduction pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alteration in the agonist/antagonist balance of antiestrogens by activation of protein kinase A signaling pathways in breast cancer cells: antiestrogen selectivity and promoter dependence. 751 3

Estrogen therapy has been reported to cause multiple alterations in hemostasis and to increase blood levels of several procoagulants, including Hageman factor [factor XII (FXII)]. Liver FXII gene expression has been investigated in ovariectomized rats, treated or not with 17 beta-estradiol. A 6-fold stimulation of FXII gene transcription was observed in treated compared to untreated animals, indicating that 17 beta-estradiol is able to induce FXII gene expression in vivo. We have recently shown that human FXII promoter contains an imperfect palindrome, 5'-GGGCAnnnTGACC-3', at position -43/-31 resembling the consensus estrogen-responsive element (ERE). Portions of different length of the FXII promoter were fused to the chloramphenicol acetyltransferase (CAT) coding sequence and transiently cotransfected with human estrogen receptor (ER) into NIH3T3 and HepG2 cells in the presence or absence of 17 beta-estradiol. A 230-base pair fragment of FXII promoter, spanning nucleotides - 181/49, conferred a strong estrogen responsiveness to the CAT reporter gene, suggesting that a functional ERE resides in this region. Cognate receptors, such as those for thyroid hormone or retinoic acid, did not stimulate CAT activity. Gel mobility assays demonstrated a specific interaction between ER and the 230-bp FXII promoter fragment containing the putative ERE palindrome. Similar results were obtained when an oligonucleotide spanning the consensus ERE was used; the complex between ER and FXII promoter sequences was supershifted after the addition of an anti-ER monoclonal antibody. Insertion of FXII-ERE into the heterologous thymidine kinase promoter conferred a strong estrogen responsiveness that was abolished by mutations of the 5'-half of the palindrome. These results represent the first demonstration at the molecular level of the regulation of a blood coagulation factor gene by 17 beta-estradiol as well as the first identification of a functional ERE within this class of genes.
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PMID:Molecular basis of estrogen regulation of Hageman factor XII gene expression. 758 44


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