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)

Of 102 patients suffering from prostatic carcinoma, complete data on the serum concentration of 7 tumour markers were available from 90 patients, together with tumour grade, local stage and the presence or absence of skeletal metastases. The serum content of prostatic acid phosphatase, prostate specific antigen, neopterin, thymidine kinase, osteocalcin, C-reactive protein and tissue polypeptide antigen was measured. By means of Cox's regression and multivariate analysis the ability of these variables to predict prognosis, i.e. death from prostatic cancer, was studied. Neopterin appeared to be the most efficient marker, followed by tumour grade, thymidine kinase and prostate specific antigen. No other variable provided information of statistical significance. In multivariate analysis thymidine kinase performed best, followed by neopterin, tumour grade and prostate specific antigen. Several serum tumour markers reflect the biological activity of human prostate cancers and their value should be further explored. They may become useful in the management of individual patients.
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PMID:Tumour markers as prognostic aids in prostatic carcinoma. 169 4

Serum from 102 patients was analysed with regard to its content of prostatic acid phosphatase (PAP), prostate specific antigen (PSA), neopterin, osteocalcin, thymidine kinase, C-reactive protein, and of tissue polypeptide antigen (TPA). The levels were related to the short-term survival (death from cancer within 3 years) and compared by statistical means. A comparison was also made with tumour grade and stage and the presence or not of metastatic lesions. In this study neopterin was found to be most closely related to the clinical course followed by tumour grade, thymidine kinase and PSA. When all these four variables were in the equation no other parameter added any information of statistical significance. The importance of selecting appropriate cut off values ('normal' vs 'elevated') when using the serum marker as a prognostic indicator is also discussed.
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PMID:Serum tumour markers in human prostatic carcinoma. The value of a marker panel for prognostic information. 202 1

The 5' flanking region of the rat osteocalcin gene has been shown to confer responsiveness to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] after transfection of fusion genes into ROS 17/2.8 cells. Deletion analysis has demonstrated that there are at least two domains in this 5' flanking region that contribute to 1,25(OH)2D3 responsiveness; however, only the downstream region is able to confer 1,25(OH)2D3 responsiveness to either the native osteocalcin promoter or to a heterologous viral promoter (herpes simplex virus thymidine kinase). The proximal region responsible for 1,25(OH)2D3 induction of the rat osteocalcin gene lies 458 base pairs upstream from the transcription start site of this gene. A 25-base-pair oligonucleotide corresponding to the sequences in this region is able to confer 1,25(OH)2D3 responsiveness to the thymidine kinase promoter in an orientation-independent fashion. This sequence contains three copies of a short sequence that are homologous to "half-sites" of steroid response elements. Gel-retardation assays using porcine intestinal nuclear extract as a rich source of 1,25(OH)2D3 receptor demonstrated retardation in the migration of probes containing the sequence noted above. A monoclonal antibody directed against the 1,25(OH)2D3 receptor caused further retardation in the migration of these protein-DNA complexes. Therefore, the sequences represented in this oligonucleotide encompass the sequences necessary for binding of the 1,25(OH)2D3 receptor to DNA as well as those sequences necessary for 1,25(OH)2D3 to induce osteocalcin gene transcription.
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PMID:DNA sequences in the rat osteocalcin gene that bind the 1,25-dihydroxyvitamin D3 receptor and confer responsiveness to 1,25-dihydroxyvitamin D3. 215 98

Biochemical markers of multiple myeloma (MM) including beta 2-microglobulin (beta 2MG), C-reactive protein, neopterin, fibronectin, lactate dehydrogenase (LDH), thymidine kinase, connective tissue components, osteocalcin, amylase, etc. are reviewed. To date, no reliable biochemical markers have been reported for the diagnosis of MM. beta 2MG and LDH are widely used to predict the prognosis of the patients with MM. The value of other parameters is however, controversial. The cytochemical diagnosis of MM, using acid phosphatase, beta-glucronidase and lysozyme are also mentioned. Furthermore, the significance of the assay of various hormones, ammonia, cobalamin and electrolytes in MM are discussed.
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PMID:[Biochemical markers of multiple myeloma]. 769 95

1,25 dihydroxyvitamin D3 [1,25(OH)2D3] mediates its biological activities through specific binding to the vitamin D3 receptor (VDR) and subsequent association with vitamin D3 responsive elements (VDRE) in genes modulated by 1,25(OH)2D3. Several novel vitamin D3 compounds (Cmpds) have recently been identified which have 5- to 1000-fold greater abilities to induce differentiation and to inhibit proliferation of HL-60 leukemic blast cells as compared to the parental 1,25(OH)2D3 (code name, Cmpd C). To clarify the mechanism by which five of these vitamin D3 analogs [1,25(OH)2-16ene-D3, (Cmpd HM); 1,25(OH)2-16ene-23yne-D3, (Cmpd V); 1,25(OH)2-16ene-23yne-26,27 F6-D3; 22-Oxa-1,25(OH)2D3; 1,25(OH)2-23yne-D3] mediate their remarkably potent biological activities, we have investigated their abilities in HL-60 cells to transactivate a chloramphenicol acetyl transferase (CAT) reporter gene containing a VDRE from the human osteocalcin gene attached to a thymidine kinase minimal promoter. Also, the abilities of the analogs to enhance the binding of the human recombinant VDR/retinoic X receptor alpha (RXR alpha) heterodimer to the VDRE were examined in gel mobility shift assays. In serumless cultures, a series of potent vitamin D3 analogs had comparable abilities to transactivate the reporter gene as did the biologically less potent 1,25(OH)2D3 (approximately 15-20-fold stimulation in cultures containing 2 x 10(-8)M of vitamin D3 cmpds). Biologically very weak inducers of differentiation of HL-60 [24R,25(OH)2D3; 25(OH)-16ene-23yne-D3] had markedly diminished abilities to induce transactivation. Dose-response studies of Cmpds C, V, HM (10(-7)-10(-11)M) showed that in serumless culture conditions, transactivation of the VDRE-CAT was similar; however, in the presence of serum, Cmpd C at 10(-9)M had 20-fold less activity than analogs V and HM. These results may reflect increased binding of Cmpd C to the D binding protein (DBP) in serum as compared to the lower binding affinities for DBP by Cmpds HM and V. Affinities of the biologically potent analogs for VDR did not parallel their abilities either to transactivate VDRE-CAT or to mediate a biological affect on HL-60 cells. In further studies, gel mobility shift assays showed that VDR alone did not have detectable binding to VDRE; likewise, VDR plus RXR had little binding to VDRE in the absence of ligand. In contrast, biologically active vitamin D3 compounds (Cmpds HM, C, V) in a dose-dependent fashion enhanced the VDR/RXR (retinoid X receptor)-VDRE retarded band.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potent vitamin D3 analogs: their abilities to enhance transactivation and to bind to the vitamin D3 response element. 770 77

1 alpha-25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], together with vitamin D receptor (VDR), directly activates human osteocalcin (hOC) gene expression through a vitamin D-responsive element (VDRE) located in the promoter of the hOC gene. We investigated the effect of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] on the regulation of the hOC gene promoter and compared it with that of 1 alpha,25(OH)2D3. 24R,25(OH)2D3 did not activate the natural promoter in VDR-negative CV-1 cells. 24R,25(OH)2D3, however, induced the activation of this promoter following cotransfection with an hVDR expression vector. In VDR-positive MC3T3-E1 cells, 24R,25(OH)2D3 activated not only the natural hOC promoter but also a chimeric promoter composed of a synthetic hOC VDRE sequence linked to the thymidine kinase promoter. In combination with 1 alpha-25(OH)2D3, 24R,25(OH)2D3 did not exhibit any antagonist activity on the hOC promoter. These results suggest that under conditions of high 24R,25(OH)2D3 levels in vivo, this metabolite of vitamin D3 may activate hOC gene expression through receptor mechanisms identical to that for 1 alpha,25(OH)2D3.
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PMID:Activation of the human osteocalcin gene by 24R,25-dihydroxyvitamin D3 occurs through the vitamin D receptor and the vitamin D-responsive element. 787 65

The osteocalcin (OC) silencer is a unique example of exonic sequences contributing to negative transcriptional control of mammalian gene expression. In this paper we demonstrate, using a reporter transfection assay, that multiple elements reside within the OC +24/+151 domain. Thirty-fold repression is mediated by the +49/+104 fragment, experimentally relocated 3' of the poly(A) signal. Deletion of either the +49/+54 protein-coding sequence or the +98/+104 intronic part of this fragment results in loss of repression activity, suggesting a bipartite organization of the +49/+104 silencer. Of particular interest, we have mapped an antisilencer activity to the ACCCTCTCT motif (+40/+48), found in silencers associated with several other genes. Extension of the +49/+104 silencer to include the +24/+48 and/or the +105/+151 sequences results in increased silencer activity up to 170-fold, suggesting the presence of additional silencer elements within these sequences. The activity of the silencer contained within the +24/+151 OC sequence is directed to the basal promoter and is not dependent on 5' distal enhancer elements, including those that mediate responsiveness of OC transcription to vitamin D. The OC silencer represses the heterologous thymidine kinase promoter and is operative in osseous (normal diploid osteoblasts, ROS 17/2.8 osteosarcoma) as well as HeLa cells. Our results, which suggest the presence of at least five regulatory elements downstream of the OC transcription start site, indicate the complexity of sequences that mediate repression of OC promoter activity.
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PMID:A composite intragenic silencer domain exhibits negative and positive transcriptional control of the bone-specific osteocalcin gene: promoter and cell type requirements. 797 85

The 5'-flanking region of the rat vitamin D3 24-hydroxylase (P450cc24) gene was examined and a vitamin D-responsive element (VDRE) responsible for the 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) enhancement was identified. Unidirectional deletion analyses of the 5'-flanking region indicated that the region [-167/-102] is involved in vitamin D responsiveness. Further functional analyses showed that the segment [-204/-129] conferred the hormone responsiveness in an orientation-independent manner when it was placed upstream to the heterologous thymidine kinase promoter or the rabbit beta-globin promoter. The segment [-204/-129] contained two direct repeat motifs homologous to other VDREs found in the osteocalcin and osteopontin genes. Synthetic oligonucleotides containing the putative VDRE were used for functional analyses and gel mobility shift assays. The proximal [-151/-137], but not the distal [-169/-155] direct repeat activated the transcription in response to 1,25-(OH)2D3 through the beta-globin promoter. Furthermore, the proximal direct repeat formed a complex with the vitamin D receptor and a nuclear accessory factor(s) from COS cells (or retinoid X receptor) in the presence of 1,25-(OH)2D3. These results indicate that a direct repeat motif, AGGTGAgt-gAGGGCG, located at -151 base pairs upstream in the antisense strand binds to a heterologous dimer consisting of the VDR occupied with 1,25-(OH)2D3 and the nuclear accessory factor and that it plays a critical role in mediating the vitamin D enhancement of the rat P450cc24 gene expression.
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PMID:Identification of a vitamin D-responsive element in the 5'-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. 814 41

We have examined the 5' flanking region of the mouse calbindin-D28k gene and identified a 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-responsive element by deletion mutant analysis of the native promoter as well as by studies with a heterologous thymidine kinase (TK) promoter. The segment between residues -200 and -169 was found to confer a dose-dependent 1,25-(OH)2D3 responsiveness through the TK promoter in Ros 17/2.8 cells as well as in CV-1 cells cotransfected with pAV-hVDR (human vitamin D receptor expression vector). This region contains sequences homologous to the rat osteocalcin vitamin D response element (VDRE). Incubation of this element with nuclear extracts from 1,25-(OH)2D3-treated Ros 17/2.8 cells or from 1,25-(OH)2D3-treated COS cells that had been transfected with pAV-hVDR resulted in a specific protein-DNA interaction. In addition to 1,25-(OH)2D3, sodium butyrate, a differentiating agent, has also been found to modulate expression of calbindin-D28k. Deletion analysis of the mouse calbindin-D28k promoter as well as studies with a heterologous TK promoter resulted in identification of a butyrate-responsive element between -180 and -150 that was found to bind specifically to nuclear factors from butyrate-treated Ros 17/2.8 cells. This butyrate-responsive element may represent a genetic element acted upon by enhancer binding proteins. In summary, the 5' flanking region of the mouse calbindin-D28k gene contains responsive elements that interact with nuclear factors and may mediate, at least in part, the enhanced expression of this gene by 1,25-(OH)2D3 and butyrate.
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PMID:Identification of sequence elements in mouse calbindin-D28k gene that confer 1,25-dihydroxyvitamin D3- and butyrate-inducible responses. 846 15

Previous studies identified several glucocorticoid response elements (GREs) in the 5'-promoter region of the rat osteocalcin (OC) gene by purified receptor binding. The present study addresses functionality of the GRE sequences in the proximal promoter at nucleotide (nt) -16 to -1 downstream of the TATA element together with the GRE half-element in the OC box at nt -86 to -81. This was done by assaying glucocorticoid responsiveness [at 10(-6) M dexamethasone (DEX)], and in combination with 10(-8) M 1,25-dihydroxyvitamin D3, of a series of deleted and mutated OC promoter reporter constructs (OCCAT) in osteoblast-like cells, the ROS 17/2.8 rat osteosarcoma line. Promoter deletion analysis revealed an additional GRE in the distal promoter at nt -697 to -683 that functions to suppress OC transcription. In the absence of this upstream negative GRE (nGRE), the -531 OCCAT construct exhibited enhanced promoter activity in response to DEX (1.8-fold DEX/Control), but further deletion (-348 and -108 OCCAT constructs) restored DEX suppression to OC promoter activity (0.6- and 0.8-fold DEX/Control, respectively). Mutations introduced in both the proximal GRE (nt -16 to -1) and the half-GRE in the OC box, or in the proximal GRE alone, nearly abrogated DEX responsiveness of OC promoter activity. Both distal and proximal GREs specifically bound glucocorticoid receptor present in ROS 17/2.8 nuclear extracts as shown by competition with wild type and mutated oligonucleotides and antibody inhibition of binding. Furthermore, both GREs, independently, conferred DEX-responsive transcriptional repression to the heterologous thymidine kinase basal promoter. We also report that glucocorticoid suppression of 1,25-dihydroxyvitamin D3-stimulated transcription occurs independently of distal or proximal GREs. Taken together, these results demonstrate that in vivo responsiveness of OC to DEX involves the integrative activities of several functional promoter elements.
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PMID:Contributions of distal and proximal promoter elements to glucocorticoid regulation of osteocalcin gene transcription. 859 14


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