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

Several members of the thyroid hormone receptor (TR) family are able to switch from a transcriptional repressor to a transcriptional activator upon binding of their ligand. The oncogene v-erbA is a variant form of the TR unable to bind hormone and thus acts as a constitutive repressor. We demonstrate, using fusion proteins between the DNA-binding domain of the yeast factor GAL4 and the silencing domains of v-erbA and TR beta, that point mutations in three different regions severely affect their repression function. Furthermore, the three regions, each as an inactive fusion protein with the GAL4 DNA-binding domain, restore silencing activity when assembled on the same promoter. These observations define at least three silencing subdomains, SSD1-SSD3, which are involved in the silencing function of v-erbA. We propose a model in which full silencing activity is brought about by the combined interaction of each silencing subdomain with corepressors and/or basal transcription factors.
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PMID:At least three subdomains of v-erbA are involved in its silencing function. 905 83

UV light is a potent stimulus for keratinocytes to release several cytokines. Recently, UV light was shown to inhibit keratinocyte release of IL-7, a growth factor for dendritic epidermal T cells. Since to date IL-7 is the only keratinocyte-derived cytokine down-regulated by UV light, we addressed the molecular mechanisms involved. IFN-gamma treatment of the murine keratinocyte cell line Pam 212 resulted in an up-regulation of IL-7 mRNA, while IL-7 transcripts were suppressed in cells exposed to UV before IFN-gamma. Because IFN-gamma induces IL-7 via activation of an IFN-stimulated response element (ISRE) located in the 5' upstream region of the IL-7 gene, bandshift assays were performed using the ISRE sequence from the IL-7 gene. Nuclear extracts from untreated cells revealed two bands, a slower migrating band identified by supershift analysis as IFN regulatory factor-2 (IRF-2), a transcriptional repressor, and a more rapidly migrating band identified as IRF-1, a transcriptional activator. IFN-gamma significantly induced IRF-1 binding, whereas UV treatment plus IFN-gamma decreased IRF-1 binding, suggesting that UV light suppresses IFN-gamma-induced expression of IL-7 by interfering with IRF-1. Chloramphenicol transferase assay confirmed functional relevance, showing that the minimal promoter sequence for the ISRE explicitly responded to IFN-gamma, which was suppressed by UV irradiation. Northern blot analysis using an IRF-1 cDNA probe revealed that UV light reduced IFN-gamma-induced IRF-1 mRNA. This study demonstrates that UV light can inhibit cytokine activities by interference with transcriptional activators. This newly described ability of UV light may contribute to its immunosuppressive properties.
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PMID:Ultraviolet light suppresses IFN-gamma-induced IL-7 gene expression in murine keratinocytes by interfering with IFN regulatory factors. 916 60

The pathogenic yeast Candida albicans regulates its cellular morphology in response to environmental conditions. Ellipsoidal, single cells (blastospores) predominate in rich media, whereas filaments composed of elongated cells that are attached end-to-end form in response to starvation, serum, and other conditions. The TUP1 gene, which encodes a general transcriptional repressor in Saccharomyces cerevisiae, was isolated from C. albicans and disrupted. The resulting tup1 mutant strain of C. albicans grew exclusively as filaments under all conditions tested. TUP1 was epistatic to the transcriptional activator CPH1, previously found to promote filamentous growth. The results suggest a model where TUP1 represses genes responsible for initiating filamentous growth and this repression is lifted under inducing environmental conditions.
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PMID:Control of filament formation in Candida albicans by the transcriptional repressor TUP1. 934 Jul 47

TFEC is a transcriptional repressor originally identified in rat chondrosarcoma and contains a basic helix-loop-helix and leucine zipper (bHLH/LZ) structure. TFEC shares a closely related bHLH/LZ structure with microphthalmia-associated transcription factor (MITF) and TFE3. In the course of cDNA cloning for a factor structurally related to MITF which is also a regulator for cell differentiation, we have isolated cDNA clones from a THP-1 human monocytic leukemia cell line. These cDNAs encode a protein of 347 amino acids, termed TFECL, a human homolog of a putative rat TFEC isoform. TFECL contains an acidic domain that corresponds to a transcriptional activation domain of TFE3 but its equivalent region is deleted in rat TFEC. We explored a function of TFECL using a melanocyte-specific tyrosinase gene and a ubiquitously expressed heme oxygenase-1 gene, each promoter containing the cis-acting CANNTG motifs. By transient coexpression assays, we showed that TFECL is able to activate or inhibit transcription of a reporter gene linked to either the tyrosinase or the heme oxygenase-1 gene promoter, depending on cell types. These results suggest that TFECL may function as a transcriptional activator under certain conditions.
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PMID:Molecular cloning of cDNA encoding a human TFEC isoform, a newly identified transcriptional regulator. 925 61

Chromosomal translocations resulting in chimaeric transcription factors underlie specific malignancies, but few authentic target genes regulated by these fusion proteins have been identified. Desmoplastic small round-cell tumour (DSRT) is a multiphenotypic primitive tumour characterized by massive reactive fibrosis surrounding nests of tumour cells. The t(11;22)(p13;q12) chromosomal translocation that defines DSRT produces a chimaeric protein containing the potential transactivation domain of the Ewing-sarcoma protein (EWS) fused to zinc fingers 2-4 of the Wilms tumour suppressor and transcriptional repressor WT1 (refs 2,3). By analogy with other EWS fusion products, the EWS-WT1 chimaera may encode a transcriptional activator whose target genes overlap with those repressed by WT1 (ref. 4). To characterize its functional properties, we generated osteosarcoma cell lines with tightly regulated inducible expression of EWS-WT1. Expression of EWS-WT1 induced the expression of endogenous platelet-derived growth factor-A (PDGFA), a potent secreted mitogen and chemoattractant whose promoter contains the many potential WT1-binding sites. Native PDGFA was not regulated by wild-type WT1, indicating a difference in target gene specificity between this tumour suppressor and its oncogenic derivative. PDGFA was expressed within tumour cells in primary DSRT specimens, but it was absent in Wilms tumours expressing WT1 and Ewing sarcomas with an EWS-Fli translocation. We conclude that the oncogenic fusion of EWS to WT1 in DSRT results in the induction of PDGFA, a potent fibroblast growth factor that contributes to the characteristic reactive fibrosis associated with this unique tumour.
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PMID:The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. 935 95

In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR gene; the only difference between them is that the first 164 amino acids of hPR-B (B-upstream sequence) are absent in hPR-A. In most cell lines such as MCF-7 (human breast cancer cells), CV-1 (monkey kidney fibroblasts), and HeLa (human cervical carcinoma cells), hPR-A functions as a transcriptional repressor, whereas hPR-B functions as a transcriptional activator of progesterone-responsive genes. Interestingly, in these cell contexts, hPR-A also acts as a trans-dominant repressor of the transcriptional activity of other steroid hormone receptors. In contrast to hPR-A, which functions predominantly as a ligand-dependent transcriptional repressor, we show in this study that the A isoform of the chicken PR (cPR-A) lacks this trans-dominant repressor function and is a transcriptional activator in all contexts examined. By constructing chimeras between the N-terminal domains of the chicken and human PR, we mapped the trans-dominant repressor function of hPR-A to the first 140 amino acids of the protein. Notably, when this 140-amino acid "repressor" domain is placed onto chicken PR-A, the activity of the latter changes from a transcriptional activator to a repressor. Interestingly, however, this "repressor domain" is necessary, but not sufficient, for trans-repression as it is inactive when it is tethered to a heterologous protein. This suggests that the trans-repression function is comprised not only of the repressor domain of hPR-A but also requires the context of the receptor to function. The identification of a discrete inhibitory region within hPR-A which is transferable to another receptor implies that this region interacts with a set of transcription factors or adaptors that are distinct from those recognized by hPR-B, the identification of which will be required to define the mechanism by which hPR-A modulates steroid hormone receptor transcriptional activity. Thus, although chickens and humans both produce two very similar forms of the progesterone receptor, it is clear from these studies that the mechanism of action of progesterone in these two systems is quite different.
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PMID:Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. 940 67

Dof is a novel family of plant proteins that share a unique and highly conserved DNA binding domain with one C2-C2 zinc finger motif. Although multiple Dof proteins associated with diverse gene promoters have recently been identified in a variety of plants, their physiological functions and regulation remain elusive. In maize, Dof1 (MNB1a) is constitutively expressed in leaves, stems, and roots, whereas the closely related Dof2 is expressed mainly in stems and roots. Here, by using a maize leaf protoplast transient assay, we show that Dof1 is a transcriptional activator, whereas Dof2 can act as a transcriptional repressor. Thus, differential expression of Dof1 and Dof2 may permit leaf-specific gene expression. Interestingly, in vivo analyses showed that although DNA binding activity of Dof1 is regulated by light-dependent development, its transactivation activity and nuclear localization are not. Moreover, in vivo transcription and in vitro electrophoretic mobility shift assays revealed that Dof1 can interact specifically with the maize C4 phosphoenolpyruvate carboxylase gene promoter and enhance its promoter activity, which displays a light-regulated expression pattern matching Dof1 activity. We propose that the evolutionarily conserved Dof proteins can function as transcriptional activators or repressors of tissue-specific and light-regulated gene expression in plants.
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PMID:Involvement of maize Dof zinc finger proteins in tissue-specific and light-regulated gene expression. 947 73

The initial modeling and subsequent development of the skeleton is controlled by complex gene-environment interactions. Biomechanical forces may be one of the major epigenetic factors that determine the form and differentiation of skeletal tissues. In order to test the hypothesis that static compressive forces are transduced into molecular signals during early chondrogenesis, we have developed a unique three-dimensional collagen gel cell culture system which is permissive for the proliferation and differentiation of chondrocytes. Mouse embryonic day 10 (E10) limb buds were microdissected and dissociated into cells which were then cultured within a collagen gel matrix and maintained for up to 10 days. Static compressive forces were exerted onto these cultures. The time course for expression pattern and level for cartilage specific markers, type II collagen and aggrecan, and regulators of chondrogenesis, Sox9 and IL-1beta, were analyzed and compared with non-compressed control cultures. Under compressive conditions, histological evaluation showed an apparent acceleration in the rate and extent of chondrogenesis. Quantitatively, there was a significant 2- to 3-fold increase in type II collagen and aggrecan expression beginning at day 5 of culture and the difference was maintained through 10 days of cultures. Compressive force also causes an elevated level of Sox9, a transcriptional activator of type II collagen. In contrast, the expression and accumulation of IL-1beta, a transcriptional repressor of type II collagen was down-regulated. We conclude that static compressive forces promote chondrogenesis in embryonic limb bud mesenchyme, and propose that the signal transduction from a biomechanical stimuli can be mediated by a combination of positive and negative effectors of cartilage specific extracellular matrix macromolecules.
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PMID:Compressive force promotes sox9, type II collagen and aggrecan and inhibits IL-1beta expression resulting in chondrogenesis in mouse embryonic limb bud mesenchymal cells. 964 53

Neuronal differentiation in the vertebrate nervous system is temporally and spatially controlled by mechanisms which are largely unknown. Here we investigate the role of XBF-1, an anterior neural plate-specific winged helix transcription factor, in controlling the pattern of neurogenesis in Xenopus ectoderm. We show that, in the anterior neural plate of normal embryos, prospective neurogenesis is positioned at the anterior boundary of the XBF-1 expression domain. By misexpressing XBF-1 in the posterior neural plate we show that a high dose of XBF-1 has a dual effect; it suppresses endogenous neuronal differentiation in high expressing cells and induces ectopic neuronal differentiation in adjacent cells. In contrast, a low dose of XBF-1 does not suppress but instead, expands the domain of neuronal differentiation in the lateral and ventral sides of the embryo. XBF-1 regulates the expression of XSox3, X-ngnr-1, X-Myt-1 and X-&Dgr;-1 suggesting that it acts early in the cascade leading to neuronal differentiation. A fusion of XBF-1 to a strong repressor domain (EnR) mimics most of the XBF-1 effects suggesting that the wild type XBF-1 is a transcriptional repressor. However, fusion of XBF-1 to a strong activation domain (E1A) specifically suppresses neuronal differentiation suggesting that XBF-1 may also work as a transcriptional activator. Based on these findings, we propose that XBF-1 is involved in positioning neuronal differentiation by virtue of its concentration dependent, dual activity, as a suppressor and an activator of neurogenesis.
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PMID:XBF-1, a winged helix transcription factor with dual activity, has a role in positioning neurogenesis in Xenopus competent ectoderm. 981 73

In Drosophila, signalling by the protein Hedgehog (Hh) alters the activity of the transcription factor Cubitus interruptus (Ci) by inhibiting the proteolysis of full-length Ci (Ci-155) to its shortened Ci-75 form. Ci-75 is found largely in the nucleus and is thought to be a transcriptional repressor, whereas there is evidence to indicate that Ci-155 may be a transcriptional activator. However, Ci-155 is detected only in the cytoplasm, where it is associated with the protein kinase Fused (Fu), with Suppressor of Fused (Su(fu)), and with the microtubule-binding protein Costal-2. It is not clear how Ci-155 might become a nuclear activator. We show here that mutations in Su(fu) cause an increase in the expression of Hh-target genes in a dose-dependent manner while simultaneously reducing Ci-155 concentration by some mechanism other than proteolysis to Ci-75. Conversely, eliminating Fu kinase activity reduces Hh-target gene expression while increasing Ci-155 concentration. We propose that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci-155.
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PMID:Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator. 987 71


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