Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HOX A genes are induced in a temporal fashion after retinoic acid (RA) treatment in non-N-ras-transformed PA-1 human teratcarcinoma cells. However, In N-ras-transformed PA-1 cells, RA-Induced expression of HOX A genes is delayed. The mRNA for the transcriptional activator AP-2 is overexpressed in these ras-transformed cells, but AP-2 transcriptional activity is inhibited relative to non ras-transformed PA-1 cells. Constitutive expression of AP-2 mimics the effect of ras by transforming cells and inhibiting differentiation in culture. We analyzed 4 kb of the human HOX A4 gene promoter and identified seven putative AP-2-binding sites in the DNA sequence. Transcription assays with variably sized HOX A4 promoter reporter constructs revealed that a 365 bp region of the promoter, -2950 to -3315 relative to the mRNA start, controls RA responsiveness and ras-mediated inhibition of HOX A4 activity. This region contains an AP-2 binding site and a RARE. Elimination of the AP-2 site by site-directed mutagenesis demonstrated that the AP-2 site is involved in RA-mediated transcriptional activation of the human HOX A4 promoter in combination with the RA receptor response element (RARE). In N-ras-transformed cells, low HOX A4 promoter activity results from ras inhibition of AP-2 transactivation.
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PMID:Functional interaction between a RARE and an AP-2 binding site in the regulation of the human HOX A4 gene promoter. 875 21

The effects of retinoic acid on cell proliferation, differentiation and patterning are thought to be mediated by the various retinoic acid receptors. Different receptor types are encoded by distinct genes (alpha, beta, and gamma), whereas various isoforms within each type are encoded by splicing variants resulting from the use of alternative promoters. The only region that differs between isoforms is the N-terminal A region containing a transcriptional activating domain. It has been proposed that these alternative A regions confer distinct activities on the receptors, thus allowing each to mediate specific effects of retinoic acid, but it has been difficult to demonstrate such isoform specificity as most cells express a number of different retinoic acid receptors. In an attempt to test whether different isoforms can mediate distinct biological effects we are focusing on retinoic-acid-dependent growth inhibition of newt limb cells. We have constructed chimaeric receptors in which the retinoic acid binding domain of each of five newt retinoic acid receptors has been replaced with a thyroid hormone (T3) binding domain. These constructs were introduced individually into cells whose growth rate was then measured in the presence of T3. The chimaeric alpha 1 receptor mediated T3-dependent inhibition of proliferation that was comparable to that given by retinoic acid, whereas the alpha 2 isoform had no activity in this assay, nor did the delta 1A, delta 1B and Delta 2 receptors. When the A region was deleted from the alpha 1 chimaera it remained a potent T3-dependent transcriptional activator, but no longer mediated T3-dependent growth inhibition. In contrast, when the A region of alpha 1 was transferred to a delta chimaeric receptor, the resulting molecule was fully active in T3-dependent growth inhibition. This is the first direct evidence for isoform specificity in a biological response to retinoic acid, and demonstrates that the specificity of this response is confined to the A region.
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PMID:Receptor isoform specificity in a cellular response to retinoic acid. 876 94

AP1 is a heterodimeric complex containing products of the Jun and Fos oncogene families. The c-fos and c-jun protooncogenes act as transcriptional activator for numerous cellular genes, and the overexpression of these genes may cause malignant transformation. In this study, to show evidence of a possible inhibition of AP1 transcriptional activity in molecular mechanisms of foodborne molecules, known to be negative modulators of carcinogenesis, we established two rat liver epithelial (REL) cell lines overexpressing either c-fos (43C line) or c-jun (RELcJ1 line) oncoproteins. Contrary to the 43C line, which was spontaneously transformed, the c-jun-transfected REL cells were only transformed in vitro after 12-O-tetra-decanoylphorbol 13-acetate (TPA) exposure. All trans-retinoic acid (RA) abolished the transformation of the 43C line and TPA-treated RELcJ1 cells, suggesting that RA could decrease AP1 activity in these cells despite c-fos or c-jun overexpression. Furthermore, we show for the first time that a flavonoid, quercetin, which is a natural component of vegetables, inhibited only the transformation of the 43C line. The spontaneous transformation of the c-fos-transfected REL cells was associated with the appearance of c-fos/AP1 complexes binding TRE, suggesting that c-fos/AP1 complexes are involved in the antitransforming mechanism of quercetin.
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PMID:Suppression of oncogene-induced transformation by quercetin and retinoic acid in rat liver epithelial cells. 877 34

The cement gland is a mucus-secreting organ found at the extreme anterior of frog embryos. It attaches the embryo to a solid support before swimming and feeding begin, and also serves a related sensory function that stops the embryo from moving once it is attached. Cement gland is an extremely useful anterior marker, whose study continues to yield fundamental information concerning vertebrate axial patterning. Cement gland arises from the outer layer of the embryonic ectoderm and, in Xenopus, forms a cone of columnar epithelium. It is the first ectodermal organ to differentiate, beginning to do so by late gastrula. A battery of genes expressed in the developing and mature cement gland serve as useful markers. Cement gland development can be influenced by both stimulatory and inhibitory cell interactions. Stimulatory signals arise from the anterior neural plate, head endoderm, and the dorsal mesoderm. Inhibitory signals are present in the posterior dorsal mesoderm and in ventral ectoderm and mesoderm. Further, signalling between the ectodermal layers may restrict cement gland differentiation to the outer ectodermal cells. Several secreted molecules are able to induce or repress cement gland formation: these include noggin, follistatin, hedgehog, chordin, retinoic acid, embryonic fibroblast growth factor (eFGF), Bone Morphogenetic Protein-4 (BMP-4), and Xwnt-8. Several of these factors alter expression of the homeodomain gene Xotx2, which may be a transcriptional activator of cement gland differentiation genes. The significance of the cell interactions and factors described in positioning cement gland at the front of the embryo is explored.
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PMID:A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning. 885 May 63

Interferon regulatory factors (IRFs) bind to the interferon-stimulated response element (ISRE) and regulate interferon- and virus-mediated gene expression. IRF-1 acts as a transcriptional activator, while IRF-2 acts as a repressor. Here we show that IRF-1 and IRF-2 bind to both cellular TFIIB, a component of the basal transcription machinery, and recombinant TFIIB (rTFIIB) and that this protein-protein interaction facilitates binding of IRFs to the ISRE. A functional interaction between TFIIB and IRF was assessed by a newly established in vitro transcription assay in which recombinant IRF-1 (rIRF-1) stimulated transcription specifically from an ISRE-containing template. With this assay we show that rIRF-1 and rTFIIB cooperatively enhance the ISRE promoter in vitro. We found that the activity of an ISRE-containing promoter was cooperatively enhanced upon cotransfection of TFIIB and IRF-1 cDNAs into P19 embryonal carcinoma cells, further demonstrating functional interactions in vivo. The cooperative enhancement by TFIIB and IRF-1 was independent of the TATA sequence in the ISRE promoter but dependent on the initiator sequence (Inr) and was abolished when P19 cells were induced to differentiate by retinoic acid treatment. In contrast, cotransfection of TFIIB and IRF-1 into NIH 3T3 cells resulted in a dose-dependent repression of promoter activation which occurred in a TATA-dependent manner. Our results indicate the presence of a cell type-specific factor that mediates the functional interaction between IRFs and TFIIB and that acts in conjunction with the requirement of TATA and Inr for promoter activation.
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PMID:Interferon regulatory factors and TFIIB cooperatively regulate interferon-responsive promoter activity in vivo and in vitro. 888 61

A novel potential regulatory pathway of brown adipose tissue (BAT) thermogenesis was recently recognized after identifying retinoic acid (RA) as a transcriptional activator of the uncoupling protein (UCP) gene. Here we provide evidence that the UCP responsiveness to RA in primary cultures of brown adipocytes involves RA receptor alpha (RAR alpha), and show, in the same system and also in CHO cells, that RA down-regulates the steady-state levels of RAR alpha and especially of retinoid X receptor alpha, suggesting autoregulation of the retinoid pathway and therefore supporting the idea of a physiological role for it in controlling the thermogenic capacity of BAT.
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PMID:Retinoic acid modulates retinoid X receptor alpha and retinoic acid receptor alpha levels of cultured brown adipocytes. 910 17

All-trans-4-oxo-retinol, a metabolite of retinol synthesized in mouse embryonal carcinoma F9 cells, is active in inducing differentiation of these cells. It also functions as a ligand of retinoic acid receptors and a transcriptional activator of reporter genes. These findings may dispel the notion that retinoic acids are the only transactivators of retinoid receptor-dependent pathways. However, there are weaknesses that need to be addressed in order to confirm the relevance of this retinol-mediated signaling pathway.
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PMID:A new metabolite of retinol: all-trans-4-oxo-retinol as a receptor activator and differentiation agent. 911 May 64

The transcriptional activator retinoic acid (RA) has been shown to influence the early patterning of the vertebrate eye. Models for the establishment of the retinofugal projection postulate gradients of cell-surface markers across the retinal surface that are expressed by ganglion cells and mediate the correct connection of fibers within central target fields. Spatial asymmetries of RA and RA-producing enzymes, as have been found in the eyes of mice and zebrafish, could induce the required asymmetry in gene expression. Here we exploited the large size of the retina of the embryonic chick to analyze the spatial and temporal characteristics of the RA system by HPLC in combination with a reporter cell assay. As in other embryonic vertebrates, the chick retina was found to contain different RA-generating enzymes segregated along the dorsoventral axis. The major RA isomer in both dorsal and ventral retina was all-trans RA, and no 9-cis RA could be detected. This excludes a difference in production of these two isomers as an explanation for the expression of different RA-generating enzymes. At developmental stages embryonic days (E) 4 and 5, the ventral retina contained higher all-trans RA levels than the dorsal retina. After E8, however, the difference disappeared, and in embryos at E9 and older the RA concentration was slightly higher in dorsal than ventral retina.
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PMID:Retinoic acid synthesis in the developing chick retina. 929 90

The ecdysone receptor (EcR) is a member of the large family of nuclear hormone receptors, which are ligand regulated transcription factors. In general, ligand converts these receptors into a transcriptional activator. Some vertebrate nuclear hormone receptors, such as the thyroid hormone and retinoic acid receptors, silence gene expression in the absence of ligand. EcR is involved in fly metamorphosis and is used in vertebrates as an inducible system for expression of transgenes. Here, we show that a Drosophila receptor, the EcR, harbours an autonomous silencing function in its carboxy-terminus. Interestingly, EcR mediates also silencing in vertebrate cells. In concordance with this EcR interacts with the corepressors SMRT and N-CoR, while addition of ligand reduces this interaction. Conversely, the v-erbA oncogene product, a thyroid hormone receptor derivative, mediates silencing in Drosophila cells. Thus, our data suggest the involvement of an evolutionarily conserved mechanism by which nuclear hormone receptors mediate gene silencing in multicellular organisms.
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PMID:EcR interacts with corepressors and harbours an autonomous silencing domain functional in both Drosophila and vertebrate cells. 1036 14

Retinoids signal biological effects through retinoic acid receptors (RAR) and retinoid X receptors (RXR) and their co-regulators. We previously reported that all-trans retinoic acid (RA) triggers terminal differentiation in the human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1), through an RARgamma dependent pathway. RARgamma repression in NT2/D1-R1 cells accounts for RA resistance in this line. This report finds RARgamma repression is due to selective repression of RARgamma but not RARbeta transcription in NT2/D1-R1 cells. The repression is neither due to mutations in RARgamma nor its promoter containing the RA response element. Prior work was confirmed and extended by demonstrating that an RARgamma selective agonist preferentially signals differentiation of NT2/D1 cells, while RARalpha/beta, RARbeta, RXR agonists and an RAR pan-antagonist do not even when NT2/D1 cells are treated with these retinoids at 10 microM dosages. None of these examined retinoids induced differentiation of the RA resistant NT2/D1-R1 cells. In contrast, N-(4-hydroxyphenyl)retinamide (4HPR), a reported transcriptional activator of RARgamma was shown to potently induce growth inhibition and apoptosis in both NT2/D1 and NT2/D1-R1 cells. 4HPR-induced apoptosis was unaffected by co-treatment of both cell lines with equimolar RAR antagonist. Semi-quantitative reverse transcription-polymerase chain reaction (RT - PCR) assays of total RNA from 4HPR-treated NT2/D1 and NT2/D1-R1 cells did not reveal RARgamma induction. Since 4HPR signals in RA-resistant NT2/D1-R1 cells having an RARgamma transcriptional block, these results indicate that 4HPR triggers apoptosis but not differentiation through an RARgamma independent pathway. Taken together, these findings implicate a therapeutic role for 4HPR mediated apoptosis in germ cell tumors even when a maturation block is present.
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PMID:4HPR triggers apoptosis but not differentiation in retinoid sensitive and resistant human embryonal carcinoma cells through an RARgamma independent pathway. 1052 55


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