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:2.3.1.28 (chloramphenicol acetyltransferase)
5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biologic activities of retinoic acid and 3,4-didehydroretinoic acid, two endogenous vitamin A derivatives in various tissues, were compared to their affinities for the nuclear retinoic acid receptors and their ability to induce transcriptional activation. Both retinoids were equipotent inducers of differentiation of F9 teratocarcinoma cells. In a morphologic assay, using reconstructed skin, retinoic acid and 3,4-didehydroretinoic acid inhibited keratinization at a concentration of 100 nM. In cultured keratinocytes, a 50% inhibition of the production of the keratinocyte transglutaminase enzyme was achieved with about 20 nM for both retinoids. The in vitro binding to the nuclear retinoic acid receptors alpha, beta, and gamma showed that retinoic acid and 3,4-didehydroretinoic acid had almost equal affinities for the receptors with Kds ranging from 3 to 47 nM. The transcriptional activation resulting from the addition of the two retinoids to cells co-transfected with alpha, beta, or gamma retinoic acid receptor expression vectors and a retinoic acid responsive element linked to the chloramphenicol acetyltransferase reporter gene was similar. Finally, it was demonstrated that retinoic acid did not metabolize to 3,4-didehydroretinoic acid, and a slow conversion of 3,4-didehydroretinoic acid into retinoic acid was not sufficient to explain the biologic effects produced by the former compound. In conclusion, the present study demonstrates that retinoic acid and 3,4-didehydroretinoic acid have the same activity in several different test systems, but their metabolism differs depending on the cell type used.
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PMID:Biologic activities of retinoic acid and 3,4-didehydroretinoic acid in human keratinocytes are similar and correlate with receptor affinities and transactivation properties. 750 53

Retinoic acid (RA) is widely involved in the control of cell proliferation and differentiation, as well as embryo pattern formation. Transcription of the oncodevelopmental protein, alpha-fetoprotein (AFP), is stimulated by retinoic acid (RA) in neoplastic cells. To study RA regulation of AFP gene expression, the 5'-flanking region of AFP gene was cloned and analyzed. In the present study, transfection of deletion mutants and sequence analysis revealed a retinoid X receptor response element (AFP-RXRE) located at position -139 to -127 of the AFP promoter. Synthetic AFP-RXRE was ligated into a reporter construct with the heterologous promoter and chloramphenicol acetyltransferase (CAT). AFP-RXRE conferred a marked RA responsiveness in the cotransfection with retinoid X receptor (RXR), but not with retinoic acid receptors (RARs). Consistent with these data, only RXR bound to AFP-RXRE with high affinity in the mobility shift assays. Chicken ovalbumin upstream promoter transcription factor (COUP-TF), an orphan member of the steroid/thyroid hormone superfamily, also demonstrated specific binding activity to AFP-RXRE in vitro. In cotransfection assays, COUP-TF dramatically repressed the transactivation of RXR on AFP-RXRE. The mechanism of repression by COUP-TF may involve the mutual occupancy of the AFP-RXRE binding site between RXR and COUP-TF.
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PMID:Transactivation and repression of the alpha-fetoprotein gene promoter by retinoid X receptor and chicken ovalbumin upstream promoter transcription factor. 751 61

Retinoic acid (RA) is known to have potent effects on development and differentiation. alpha-Fetoprotein (AFP), an oncodevelopmental protein, is transcriptionally activated by RA in several cell lines, but little is known about the mechanism of RA regulation of AFP gene expression. In the present study, we have identified a RA response element (RARE) in the 5'-flanking region of the AFP gene. Using deletion mapping, the RARE was located between -6337 to -6266 of the rat AFP 5'-flanking region, which confers RA responsiveness in a heterologous promoter. Further sequence analysis of this cis-acting element demonstrated a RARE direct repeat sequence of AGGTCA and RARE-like motifs at -6327 and -6319, respectively. This far upstream RARE (AFP-RARE1) can specifically bind to both RAR and RXR proteins in gel mobility shift assays. In co-transfections with RAR alpha, beta, gamma and RXR alpha expression vectors, a reporter gene construct consisting of the AFP-RARE1 sequence ligated upstream of the chloramphenicol acetyltransferase (CAT) gene showed strong RA responsiveness to RAR alpha and RXR alpha with 15- and 25-fold increases in CAT activity, respectively. Furthermore, responsiveness of AFP-RARE1 to RA was independent of orientation. These studies present a novel target for RA action by identifying a RARE in the AFP gene.
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PMID:Identification of a retinoic acid response element upstream of the rat alpha-fetoprotein gene. 752 84

In McA-RH 8994 rat hepatoma cells, all-trans-retinoic acid (t-RA) induces expression of the alpha-fetoprotein (AFP) and albumin genes and results in a phenotype similar to differentiated fetal hepatocytes. The present study elucidated the mechanism involved in AFP gene regulation mediated by retinoic acid. Northern blot analyses demonstrated that 9-cis-retinoic acid (c-RA), a ligand for retinoid x receptors (RXRs), also induced expression of the AFP gene in McA-RH 8994 cells. The induction was time- and dose-dependent. Northern blots and transfection assays using the 7.3 kb full-length regulatory region of the AFP gene demonstrated that c-RA was more effective than t-RA in regulating expression of the AFP gene. At 10(-7) M, c-RA increased AFP mRNA 5-fold and chloramphenicol acetyltransferase (CAT) activity 2.5-fold. In contrast, t-RA at a concentration of 10(-7) M exerted no significant effect; 10(-6) to 10(-5) M t-RA was needed to affect AFP gene expression. These data suggested that activation of RXRs is essential for the regulation of the AFP gene. Co-transfection experiments revealed that over-expression of RXR alpha in McA-RH 8994 cells further enhanced the CAT activity induced by c-RA. In addition, c-RA did not alter the half-life of AFP mRNA. Thus, RXR alpha may play a crucial role in transcriptional regulation of the AFP gene and in controlling hepatocyte phenotype.
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PMID:9-cis-retinoic acid is more effective than all-trans-retinoic acid in upregulating expression of the alpha-fetoprotein gene. 753 13

We report the first evidence that differential transcriptional regulation of human chromogranin A (CHGA) gene expression occurs during in vitro treatment of tumorigenic neuroblastoma (NB) cells with retinoic acid (5 microM) and/or dibutyryl-cAMP (1 mM). The CHGA gene encodes a tissue specific protein restricted to cells of the diffuse neuroendocrine system, but also widely expressed among NB tumours. We previously reported that CHGA as well as other neuroendocrine markers are modulated during NB differentiation in vitro. To investigate, at the molecular level, the mechanisms leading to NB tumour cell differentiation during the treatment with biologically active compounds, we sequenced and functionally characterised 2169 bp of a genomic DNA clone encompassing the 5' flanking region of the human CHGA gene. Computer-assisted analysis of the sequence revealed the presence of a cAMP responsive element at positions -56 to -49, and Sp1 binding sites at positions -181 to -176 and -216 to -210. Two novel 9 bp motifs, located at position -462 to -454 and -91 to -83 of the CHGA promoter were identified in the regulatory regions of two other neuroendocrine genes encoding for tyrosine hydroxylase and neuropeptide Y. In addition, in the first 1000 bp of the untranslated 5' region, we found the presence of several putative DNA binding sites of bHLH molecules, a protein family regulating tissue specific differentiation. Transient transfection experiments of chloramphenicol acetyltransferase (CAT) deletion constructs, showed the presence of an active promoter within the first 455 bp upstream from the start site. This region conferred tissue specific expression to a CAT reporter gene. In addition, the transcriptional activity of this fragment was modulated during the induction of differentiation of NB cells treated by retinoic acid and/or dibutyryl-cAMP. These observations provide preliminary data regarding CHGA transcriptional regulation in NB cells, and indicate that retinoic acid and cAMP activate distinct, apparently competitive, transcriptional pathways during NB cell differentiation. The molecular characterisation of the mechanisms regulating CHGA expression in tumour and normal neuroendocrine tissue could lead to the identification of novel molecules potentially relevant for future gene therapy of NB tumours.
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PMID:Retinoic acid and cAMP differentially regulate human chromogranin A promoter activity during differentiation of neuroblastoma cells. 757 43

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

All-trans-retinoic acid (ATRA) has been shown to be one of the most potent chemical inducers of human neuroblastoma differentiation. The recent discovery that the stereoisomer of ATRA, 9-cis-retinoic acid (9-cis-RA), binds to both the retinoic acid and retinoid X series of receptors prompted us to evaluate the ability of this compound to promote differentiation of this cell type. Using the LA-N-5 cell line, we have now determined that 9-cis-RA can induce the differentiation of human neuroblastoma cells as evidenced by dose-dependent inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity, and reduction of N-myc mRNA expression. In comparing the effects of 9-cis-RA to ATRA, we found that while both compounds induced qualitatively similar cholinergic (versus adrenergic) features in LA-N-5 cells, 9-cis-RA was 5-to-10-fold more potent than ATRA in its antiproliferative and differentiation activity. These results were supported by transient transfection experiments utilizing chloramphenicol acetyltransferase (CAT) plasmid constructs containing a retinoic acid responsive regulatory element which showed a 2-to-3-fold increase in reporter gene activity induced with 9-cis-RA over that seen with ATRA at pharmacologically relevant retinoid concentrations (> 10(-8) M). Furthermore, we have determined that 9-cis-RA can significantly enhance mRNA levels of the nuclear retinoic acid receptors alpha and beta in LA-N-5 cells. Taken together, these findings have established the ability of 9-cis-RA to induce neuroblastoma differentiation and suggest that this retinoic acid isomer may have better therapeutic characteristics than ATRA.
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PMID:Enhanced potency of 9-cis versus all-trans-retinoic acid to induce the differentiation of human neuroblastoma cells. 758 96

The human ATBF1 cDNA reported previously, now termed ATBF1-B, encodes a 306-kDa protein containing 4 homeodomains and 18 zinc fingers including one pseudo zinc finger motif. Here, we report the isolation of a second ATBF1 cDNA, 12 kilobase pairs long, termed ATBF1-A. The deduced ATBF1-A protein is 404 kDa in size and differs from ATBF1-B by a 920-amino acid extention at the N terminus. Analysis of 5'-genomic sequences showed that the 5'-noncoding sequences specific to ATBF1-A and ATBF1-B transcripts were contained in distinct exons that could splice to a downstream exon common to the ATBF1-A and ATBF1-B mRNAs. The expression of ATBF1-A transcripts increased to high levels when P19 and NT2/D1 cells were treated with retinoic acid to induce neuronal differentiation. Preferential expression of ATBF1-A transcripts was also observed in developing mouse brain. Transient transfection assays showed that the 5.5-kilobase pair sequence upstream of the ATBF1-A-specific exon (exon 2) supported expression of the linked chloramphenicol acetyltransferase gene in neuronal cells derived from P19 cells but not in undifferentiated P19 or in F9 cells, which do not differentiate into neurons. These results showed that ATBF1-A and ATBF1-B transcripts are generated by alternative promoter usage combined with alternative splicing and that the ATBF1-A-specific promoter is activated during neuronal differentiation.
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PMID:Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiation-dependent manner. 759 26

Human cytosolic aldehyde dehydrogenase 1 (ALDH1) plays a role in the biosynthesis of retinoic acid that is a modulator for gene expression and cell differentiation. Northern blot analysis showed that liver tissue, pancreas tissue, hepatoma cells, and genital skin fibroblast cells expressed high levels of ALDH1. Sequence analysis showed that the 5'-flanking region contains a number of putative regulatory elements, such as NF-IL6, HNF-5, GATA binding sites, and putative response elements for interleukin-6, phenobarbital and androgen, in addition to a noncanonical TATA box (ATAAA) and a CCAAT box. Functional characterization of the 5'-regulatory region of the human ALDH1 gene was carried out by a fusion to the chloramphenicol acetyltransferase gene. A construct containing 2.6 kilobase pairs of the 5'-flanking region was efficiently expressed in hepatoma Hep3B cells, but not in erythroleukemic K562 cells or in fibroblast LTK- cells, which do not express ALDH1. Within this region, we define a minimal promoter (-91 to +53) that contains positive regulatory elements. The study using site-directed mutagenesis demonstrated that the CCAAT box region is the major cis-acting element involved in basal ALDH1 promoter activity in Hep3B cells. Gel mobility shift assays showed that NF-Y and other octamer factors bound CCAAT box and an octamer motif sequence, but not GATA site existing in the minimal promoter region. Two additional DNA binding activities associated with the minimal promoter were found in the nuclear extract from Hep3B cells, but not from K562 cells. These results offer the possible molecular mechanism of the cell type-specific expression of ALDH1 gene.
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PMID:The transcriptional regulation of human aldehyde dehydrogenase I gene. The structural and functional analysis of the promoter. 761 57

Effects of human retinoid X receptor alpha (hRXR alpha) and its ligand, 9-cis-retinoic acid, on T3-mediated auto-regulation of hTR beta 1 gene expression were examined using a chloramphenicol acetyltransferase (CAT) reporter system, and a deletional analysis of the promoter. hRXR alpha enhanced T3-dependent CAT induction mediated through the proximal (p) TRE in a ligand (9-cis-retinoic acid) independent manner. In a gel mobility shift assay, hRXR alpha enhanced the binding of hTR beta 1 to the pTRE by the formation of hRXR alpha-hTR beta 1 heterodimers. On the other hand, hRXR alpha and 9-cis-retinoic acid did not show any effects on T3-dependent CAT induction mediated through the distal (d) TRE or the binding of hTR beta 1 to the dTRE. A four hundred-base pair (bp) fragment adjacent upstream of the dTRE showed a T3 independent suppressor effect on the function of the pTRE and dTRE. Thus, this region may be an important regulator of the T3 dependent up-regulation of the TR beta 1 gene expression which is observed only under specific conditions.
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PMID:Transcriptional regulation of human thyroid hormone receptor beta 1 gene expression: effect of human retinoid X receptor and identification of a transcriptional silencer region. 767 40


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