Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Positive regulatory element I (PRE-I) is a strong enhancer element essential for expression of the human IL-4 gene. To identify transcription factors binding to PRE-I, we screened a cDNA expression library from Jurkat T cells and isolated a cDNA encoding nuclear factor (NF)-IL6 (also known as C/EBP beta). NF-IL6 mRNA was found in human Jurkat T cells and in the mouse Th2 clone D10, but not in Th1 clone 29. rNF-IL6 expressed in bacteria was shown to specifically bind to PRE-I. PRE-I forms multiple DNA-protein complexes with nuclear extracts from Jurkat cells. Some of these complexes were demonstrated to contain NF-IL6 by using anti-C/EBP beta Abs. Overexpression of NF-IL6 enhanced expression of the chloramphenicol acetyl transferase reporter gene linked to the PRE-I-thymidine kinase or the human IL-4 promoter more than 10-fold in Jurkat cells. Promoter deletion studies revealed two additional NF-IL6 binding sites located at positions -44 to -36 (C/EBP proximal) and -87 to -79 (C/EBP medial), respectively. Our results demonstrate that NF-IL6 is involved in transcriptional activation of the human IL-4 promoter in T cells.
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PMID:Nuclear factor-IL6 activates the human IL-4 promoter in T cells. 759 40

To study the role and the regulation of the photolyase gene in the Medaka (small teleost), we constructed a eukaryotic expression plasmid of the Medaka photolyase gene and introduced it into Medaka cells in vivo and in vivo. The expression plasmid contains a cytomegalovirus enhancer and a thymidine kinase promoter to overexpress the photolyase gene of the Medaka. First, we transfected this construct into cultured Medaka cells and established several lines of transfectant. Every transfectant showed enhanced ability of pyrimidine dimer repair in the presence of fluorescent light. In the transfectant that showed the most enhanced ability of photorepair, the augmented transcription of photolyase gene was observed compared with that of progenitor OL32 cells. In this transfectant, we also observed an enhanced rate of UV survival with 20 min of fluorescent light treatment after irradiation with a 400 J/m2 UV sunlamp. Next, the expression construct was microinjected into the embryos of the Medaka at the one cell stage. Compared with the nontreated counterparts, the overexpression of a photolyase gene was detected in the microinjected embryos, but we failed to detect a significant increase in photo-reactivability of death at the midblastula stage.
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PMID:Overexpression of Medaka (Oryzias latipes) photolyase gene in Medaka cultured cells and early embryos. 862 55

The epidermal growth factor receptor is vital for normal development and plays a role in oncogenesis. The level of activation of this receptor by transforming growth factor-alpha (TGF-alpha) is controlled, in part, by the rate of transcription of the TGF-alpha gene. In the characterization of the proximal TGF-alpha promoter by DNase I footprinting, a 43-base pair element (-88 to -130 relative to the transcription start site), designated TalphaRE I, was found that was specifically protected by nuclear proteins from human mammary carcinoma MDA468 cells. TalphaRE I was essential for the maximal expression of the TGF-alpha gene as indicated by deletion and mutagenesis analyses. TalphaRE I consists of two cis-acting elements, a proximal regulatory element (PRE, -89 to -103) and a distal regulatory element (DRE, -121 to -128). Both elements were able to form specific complexes with protein from MDA468 cell nuclear extracts and are necessary for the full activity of the entire 1.1-kilobase pair TGF-alpha promoter. Competition and antibody studies determined that the DRE contains a binding site for the transcription factor AP-2, while the protein that binds to the PRE has yet to be identified. When linked upstream to the heterologous herpes simplex thymidine kinase promoter, the TalphaRE I enhanced transcription up to 11-fold in MDA468 cells. Cotransfection of an AP-2 expression vector was able to activate transcription from the TalphaREI-TK construct in a DRE-dependent manner. These results further our understanding of how TGF-alpha transcription is regulated.
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PMID:Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene. 916 57

In determining the biological profiles of various antiprogestins, it is important to assess the hormonal and antihormonal activity, selectivity, and potency of their proximal metabolites. The early metabolism of mifepristone is characterized by rapid demethylation and hydroxylation. Similar initial metabolic pathways have been proposed for CDB-2914 (CDB: Contraceptive Development Branch of NICHD) and CDB-4124, and their putative metabolites have been synthesized. We have examined the functional activities and potencies, in various cell-based assays, and relative binding affinities (RBAs) for progesterone receptors (PR) and glucocorticoid receptors (GR) of the putative mono- and didemethylated metabolites of CDB-2914, CDB-4124, and mifepristone and of the 17alpha-hydroxy and aromatic A-ring derivatives of CDB-2914 and CDB-4124. The binding affinities of the monodemethylated metabolites for rabbit uterine PR and human PR-A and PR-B were similar to those of the parent compounds. Monodemethylated mifepristone bound to rabbit thymic GR with higher affinity than monodemethylated CDB-2914 or CDB-4124. T47D-CO cells were used to assess inhibition of R5020-stimulated endogenous alkaline phosphatase activity and transactivation of the PRE(2)-thymidine kinase (tk)-luciferase (LUC) reporter plasmid in transient transfections. The antiprogestational potency was as follows: mifepristone/CDB-2914/CDB-4124/monodemethylated metabolites (IC(50)'s approximately 10(-9)M) > aromatic A-ring derivatives (IC(50)'s approximately 10(-8)M) > didemethylated/17alpha-hydroxy derivatives (IC(50)'s approximately 10(-7)M). Antiglucocorticoid activity was determined by inhibition of dexamethasone-stimulated transcriptional activity in HepG2 cells. The mono- and didemethylated metabolites of CDB-2914 and CDB-4124 had less antiglucocorticoid activity (IC(50)'s approximately 10(-6)M) than monodemethylated mifepristone (IC(50) approximately 10(-8)M) or the other test compounds. At 10(-6)M in transcription assays, none of these compounds showed progestin agonist activity, whereas mifepristone and its monodemethylated metabolite manifested slight glucocorticoid agonist activity. The reduced antiglucocorticoid activity of monodemethylated CDB-2914 and CDB-4124 was confirmed in vivo by the thymus involution assay in adrenalectomized male rats. The aromatic A-ring derivatives-stimulated transcription of an estrogen-responsive reporter plasmid in MCF-7 and T47D-CO human breast cancer cells but were much less potent than estradiol. Taken together, these data suggest that the proximal metabolites of mifepristone, CDB-2914, and CDB-4124 contribute significantly to the antiprogestational activity of the parent compounds in vivo. Furthermore, the reduced antiglucocorticoid activity of CDB-2914 and CDB-4124 compared to mifepristone in vivo may be due in part to decreased activity of their putative proximal metabolites.
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PMID:In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. 1512 Apr 21

Steroid hormones, especially glucocorticoids, exert physiologic effects on dopaminergic neurotransmission and have been implicated in several dopamine-mediated neuropsychiatric conditions. D(2) dopamine receptor gene expression is regulated by the zinc finger-type nuclear protein GDNF-inducible transcription factor (GIF). In this study, we sought to investigate if steroids could regulate transcription of the GIF gene itself. Transient co-transfection of the D(2) expressing neuroblastoma cell line NB41A3 with GIF promoter-luciferase constructs along with expression vectors for steroid hormone receptors showed that activation of glucocorticoid receptors but not estrogen receptors up-regulates transcription from the GIF promoter 5.0-fold. Progesterone receptors, which share the same consensus DNA recognition sequence as glucocorticoid receptors, also activated the GIF promoter. Serial 5'-deletion mutants of the GIF gene upstream region localized the glucocorticoid-responsive segment between nucleotides -128 and -66 relative to the transcription start site. This region contains a putative glucocorticoid-responsive element/progesterone-responsive element (GRE/PRE). Additionally, this fragment of the GIF gene 5'-upstream region activated the heterologous herpes simplex virus thymidine kinase (TK) promoter, which is known to be glucocorticoid and progesterone responsive. Furthermore, glucocorticoid receptor activation up-regulated endogenous GIF gene mRNA expression in NB41A3 cells. These observations demonstrate a molecular basis for glucocorticoid and progesterone-induced up-regulation of GIF gene transcription and provide a mechanism for the modulation of dopamine-mediated behaviors by these hormones.
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PMID:Activation of the GDNF-inducible transcription factor (GIF) gene promoter by glucocorticoid and progesterone. 1942 58