UNIPROT:P51532 - FACTA Search

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Query: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The t(X;18)(p11.2;q11.2) chromosomal translocation commonly found in synovial sarcomas fuses the SYT gene on chromosome 18 to either of two similar genes, SSX1 or SSX2, on the X chromosome. The SYT protein appears to act as a transcriptional co-activator and the SSX proteins as co-repressors. Here we have investigated the functional domains of the proteins. The SYT protein has a novel conserved 54 amino acid domain at the N-terminus of the protein (the SNH domain) which is found in proteins from a wide variety of species, and a C-terminal domain, rich in glutamine, proline, glycine and tyrosine (the QPGY domain), which contains the transcriptional activator sequences. Deletion of the SNH domain results in a more active transcriptional activator, suggesting that this domain acts as an inhibitor of the activation domain. The C-terminal SSX domain present in SYT-SSX translocation protein contributes a transcriptional repressor domain to the protein. Thus, the fusion protein has transcriptional activating and repressing domains. We demonstrate that the human homologue of the SNF2/Brahama protein BRM co-localizes with SYT and SYT-SSX in nuclear speckles, and also interacts with SYT and SYT-SSX proteins in vitro. This interaction may provide an explanation of how the SYT protein activates gene transcription.
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PMID:Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. 1007 25

The Xenopus homologue of Brachyury, Xbra, is expressed in the presumptive mesoderm of the early gastrula. Induction of Xbra in animal pole tissue by activin occurs only in a narrow window of activin concentrations; if the level of inducer is too high, or too low, the gene is not expressed. Previously, we have suggested that the suppression of Xbra by high concentrations of activin is due to the action of genes such as goosecoid and Mix.1. Here, we examine the roles played by goosecoid and Mix.1 during normal development, first in the control of Xbra expression and then in the formation of the mesendoderm. Consistent with the model outlined above, inhibition of the function of either gene product leads to transient ectopic expression of Xbra. Such embryos later develop dorsoanterior defects and, in the case of interference with Mix.1, additional defects in heart and gut formation. Goosecoid, a transcriptional repressor, appears to act directly on transcription of Xbra. In contrast, Mix.1, which functions as a transcriptional activator, may act on Xbra indirectly, in part through activation of goosecoid.
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PMID:Goosecoid and mix.1 repress Brachyury expression and are required for head formation in Xenopus. 1007 37

Interferon-inducible expression of major histocompatibility class I genes has previously been found to be quantitatively and functionally deficient in neurons compared to other somatic cells or other neural cell types including astrocytes. This deficiency is a key component of neuronal immunoprivilege during viral infections of the CNS. To the contrary, in the present study, induction of functional antiviral state by IFN-beta in neurons compared to astrocytes was found to be highly efficient with respect to both viral replication and protection from cytopathic effects. A candidate antiviral state gene found to be efficiently induced in neurons by IFN-beta was the 2'-5'-oligoadenylate synthetase (OAS) gene. Unlike MHC class I genes, induction of OAS was comparable in neurons and astrocytes indicating differential expression in these neural cell types. Analysis of OAS gene promoter activity indicated that induction of the OAS gene by IFN-beta was dependent on a region containing the interferon stimulated responsive element (ISRE). In contrast, a construct containing the MHC class I-ISRE responsible for induction by IFN-beta in astrocytes was not responsive to IFN-beta in neurons. Therefore, transcription factor binding to the OAS- and MHC-ISREs was analyzed. While the OAS and MHC Class I site bound equal amounts of the transcriptional repressor IRF-2, the OAS-ISRE preferentially interacted with the transcriptional activator ISGF3 in response to IFN-beta. Further, unlike neurons, upregulation of MHC class I genes in astrocytes was related to binding of IRF-1 instead of IRF-2 to the MHC-ISRE. It is proposed that selective activation of anti-viral state genes compared to MHC class I genes by IFN-beta in neurons is mediated by preferential induction and binding of ISGF3 to anti-viral state gene ISREs but not the MHC-ISRE.
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PMID:A mechanism for selective induction of 2'-5' oligoadenylate synthetase, anti-viral state, but not MHC class I genes by interferon-beta in neurons. 1032 80

Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex. An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.
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PMID:MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. 1047 84

In humans, the biological response to progesterone is mediated by two forms of the progesterone receptor (hPR-A; 94kDa and hPR-B; 114kDa). These two isoforms are transcribed from distinct, estrogen-inducible promoters within a single-copy progesterone receptor (PR) gene; the only difference between them is that the first 164 amino acids of hPR-B are absent in hPR-A. In most cell lines, hPR-A functions as a transcriptional repressor of progesterone-responsive promoters, whereas hPR-B functions as a transcriptional activator of the same genes. The observation, made in the early 1990s, that shorter isoforms of some transcriptional activators can act as transrepressors of the transcriptional activity of the larger isoforms, initiated a line of investigation that led to the discovery that hPR-A is a strong transrepressor of hPR-B activity. Interestingly, hPR-A also functions as a transdominant repressor of the transcriptional activity of the estrogen, glucocorticoid, androgen, and mineralocorticoid receptors. A specific inhibitory domain (ID) within hPR-A responsible for this activity has been mapped to the extreme amino terminus of the receptor. Interestingly, although this inhibitory domain is contained within both PR isoforms, its activity is manifest only in the context of hPR-A. The identification of a discrete inhibitory region within hPR-A, whose activity was masked in the context of hPR-B, suggests that these two receptor isoforms may interact with different proteins (transcription factors, co-activators, co-repressors) within the cell. In support of this hypothesis, we have recently observed that the co-repressor SMRT (silencing mediator of retinoid and thyroid receptors) interacts much more tightly with hPR-A than with hPR-B. This important finding led to the initial conclusion that the ability of hPR-A to repress hPR-B transcriptional activity could occur as a consequence of hPR-B/A heterodimerization, where the presence of SMRT in the complex could prevent transcriptional activation. The observation, however, that hPR-A also inhibits human estrogen receptor (hER) transcriptional activity, a receptor with which hPR-A is not able to heterodimerize, suggests that there must be additional complexity. This chapter outlines what is known about the mechanism of action of hPR-A and hPR-B and how this knowledge has enhanced our understanding of PR pharmacology.
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PMID:The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. 1054 81

The paired-homeodomain transcription factor PAX4 is expressed in the developing pancreas and along with PAX6 is required for normal development of the endocrine cells. In the absence of PAX4, the numbers of insulin-producing beta cells and somatostatin-producing delta cells are drastically reduced, while the numbers of glucagon-producing alpha cells are increased. To gain insight into PAX4 function, we cloned a full-length Pax4 cDNA from a beta-cell cDNA library and identified a bipartite consensus DNA binding sequence consisting of a homeodomain binding site separated from a paired domain binding site by 15 nucleotides. The paired half of this consensus sequence has similarities to the PAX6 paired domain consensus binding site, and the two proteins bind to common sequences in several islet genes, although with different relative affinities. When expressed in an alpha-cell line, PAX4 represses transcription through the glucagon or insulin promoters or through an isolated PAX4 binding site. This repression is not simply due to competition with the PAX6 transcriptional activator for the same binding site, since PAX4 fused to the unrelated yeast GAL4 DNA binding domain also represses transcription through the GAL4 binding site in the alpha-cell line and to a lesser degree in beta-cell lines and NIH 3T3 cells. Repressor activity maps to more than one domain within the molecule, although the homeodomain and carboxyl terminus give the strongest repression. PAX4 transcriptional regulation apparently plays a role only early in islet development, since Pax4 mRNA as determined by reverse transcriptase PCR peaks at embryonic day 13.5 in the fetal mouse pancreas and is undetectable in adult islets. In summary, PAX4 can function as a transcriptional repressor and is expressed early in pancreatic development, which may allow it to suppress alpha-cell differentiation and permit beta-cell differentiation.
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PMID:Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. 1056 52

VHL is the causative gene for both von Hippel-Lindau (VHL) disease and sporadic clear-cell renal cancer. We showed earlier that VHL downregulates vascular endothelial growth factor transcription by directly binding and inhibiting the transcriptional activator Sp1. We have now mapped the VHL Sp1-binding domain to amino acids 96-122. The 96-122 domain is disproportionately affected by substitution mutations, which interfere with the VHL-Sp1 interaction. Deletion of the 96-122 domain prevents VHL effects on Sp1 DNA binding and on VHL target gene expression, indicating the domain contributes importantly to VHL tumor suppressor activity. Nevertheless, prevention of the VHL-Sp1 interaction only partially abrogates VHL's transcriptional repressor activity, supporting the existence of VHL transcriptional effectors in addition to Sp1. VHL also directly interacts with the Sp1 zinc fingers and self-associates via the 96-122 domain, which furthermore suggest the domain may bind other metalloproteins and contribute to VHL dominant-negative effects.
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PMID:An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association. 1058 Nov 62

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs), orphan members of the nuclear receptor superfamily, play a key role in the regulation of organogenesis, neurogenesis, and cellular differentiation during embryogenic development. COUP-TFs are also involved in the regulation of several genes that encode metabolic enzymes. Although COUP-TFs function as potent transcription repressors, there are at least three different molecular mechanisms of activation of gene expression by COUP-TFs. First, as we have previously shown, COUP-TF is required as an accessory factor for the complete induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. This action is mediated by the binding of COUP-TF to the glucocorticoid accessory factor 1 (gAF1) and 3 (gAF3) elements in the phosphoenolpyruvate carboxykinase gene glucocorticoid response unit. In addition, COUP-TF1 binds to DNA elements in certain genes and transactivates directly. Finally, COUP-TF1 serves as a coactivator through DNA-bound hepatic nuclear factor 4. Here we show that the same region of COUP-TFI, located between amino acids 184 and 423, is involved in these three mechanisms of transactivation by COUP-TFI. Furthermore, we show that GRIP1 and SRC-1 potentiate the activity of COUP-TFI and that COUP-TFI associates with these coactivators in vivo using the same region required for transcription activation. Finally, overexpression of GRIP1 or SRC-1 does not convert COUP-TFI from a transcriptional repressor into a transcriptional activator in HeLa cells.
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PMID:Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. 1065 38

We have identified a novel human gene encoding a 59-kDa POZ-AT hook-zinc finger protein (PATZ) that interacts with RNF4, a mediator of androgen receptor activity, and acts as a transcriptional repressor. PATZ cDNA was isolated through a two-hybrid interaction screening using the RING finger protein RNF4 as a bait. In vitro and in vivo interaction between RNF4 and PATZ was demonstrated by protein-protein affinity chromatography and coimmunoprecipitation experiments. Such interaction occurred through a small region of PATZ containing an AT-hook DNA binding domain. Immunofluorescence staining and confocal microscopy showed that PATZ localizes in distinct punctate nuclear regions and colocalizes with RNF4. Functional analysis was performed by cotransfection assays: PATZ acted as a transcriptional repressor, whereas its partner RNF4 behaved as a transcriptional activator. When both proteins were overexpressed a strong repression of the basal transcription was observed, indicating that the association of PATZ with RNF4 switches activation to repression. In addition, RNF4 was also found to associate with HMGI(Y), a chromatin-modeling factor containing AT-hook domains.
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PMID:A novel member of the BTB/POZ family, PATZ, associates with the RNF4 RING finger protein and acts as a transcriptional repressor. 1071 5

The timed destruction of cell cycle regulatory proteins is of key importance in controlling cell cycle progression in eukaryotes. Recently, Skp1 from yeast (Saccharomyces cerevisiae) was shown to play an important role in the ubiquitin-mediated proteolysis of these proteins via the Skp1-Cdc53-F-box (SCF) pathway. Here we describe the fortuitous cloning of cDNAs for two Skp1 homologues from the plant Arabidopsis thaliana on account of their ability to activate reporter gene expression in yeast directed by the cyt-1 element from the promoter of the Agrobacterium tumefaciens T-cyt gene, which is essential for expression of the gene in plants. This element is strikingly similar in sequence to the binding site for the yeast Migl protein, a transcriptional repressor of genes involved in the utilisation of carbohydrates other than glucose. We report that Mig1 protein binds to the cyt-1 element with similar specificity as a previously described plant nuclear protein factor, and that the cyt-1 element is a target for an unknown yeast transcriptional activator when Mig1 itself is inactivated. Interestingly, our data further indicate that A. thaliana Skp1 inactivates Mig1 by destabilising the yeast F-box protein Grr1, which is required for cyclin degradation and is thus involved in control of the cell cycle, and for glucose-regulated gene repression. Our results suggest that the plant counterpart of yeast Skp1 is probably also instrumental in ubiquitin-mediated proteolysis of specific proteins via an SCF-like pathway.
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PMID:Overexpression of Arabidopsis thaliana SKP1 homologues in yeast inactivates the Mig1 repressor by destabilising the F-box protein Grr1. 1077 50

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