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)

Expression of the gene encoding the mitochondrial fatty acid. beta-oxidation enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), is regulated among tissues during development and in response to alterations in substrate availability. To identify and characterize cis-acting MCAD gene promoter regulatory elements and corresponding transcription factors, DNA-protein binding studies and mammalian cell transfection analyses were performed with hjman MCAD gene promoter fragments. DNA:protein binding studies with nuclear protein extracts prepared from hepatoma G2 cells, 3T3 fibroblasts, or Y-1 adrenal tumor cells identified three sequences (nuclear receptor response element 1 or NRRE-1, NRRE-2, and NRRE-3) that bind orphan members of the steroid/thyroid nuclear receptor superfamily including chicken ovalbumin upstream promoter transcription factor and steroidogenic factor 1. Sp1 binding sites (A-C) were identified in close proximity to each of the NRREs. NRRE-3 conferred cell line-specific transcriptional repression by interacting with chicken ovalbumin upstream promoter transcription factor or activation via steroidogenic factor 1. In contrast, the Sp1 binding site A behaved as a transcriptional activator in all cell lines examined. We propose that multiple nuclear receptor transcription factors interact with MCAD gene promoter elements to differentially regulate transcription among a variety of cell types.
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PMID:The human medium chain Acyl-CoA dehydrogenase gene promoter consists of a complex arrangement of nuclear receptor response elements and Sp1 binding sites. 759 84

Eukaryotic transcriptional activators have been classified on the basis of the characteristics of their activation domains. Acidic activation domains, such as those in the yeast GAL4 or GNC4 proteins and the herpes simplex virus activator VP16, stimulate RNA polymerase II transcription when introduced into a variety of eukaryotic cells. This species interchangeability demonstrates that the mechanism by which acidic activation domains function is highly conserved in the eukaryotic kingdom. To determine whether such a conservation of function exists for a different class of activation domain, we have tested whether the glutamine-rich activation domains of the human transcriptional activator Sp1 function in the yeast Saccharomyces cerevisiae. We report here that the glutamine-rich domains of Sp1 do not stimulate transcription in S. cerevisiae, even when accompanied by human TATA-box binding protein (TBP) or human-yeast TATA-box binding protein hybrids. Thus, in contrast to the case for acidic activation domains, the mechanism by which glutamine-rich domains stimulate transcription is not conserved between S. cerevisiae and humans.
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PMID:The glutamine-rich activation domains of human Sp1 do not stimulate transcription in Saccharomyces cerevisiae. 782 62

GATA-1 is a cys-2/cys-2 zinc finger transcriptional activator that is required for erythrocyte development in chimeric mice and contributes to the expression of all erythroid genes studied to date, including the erythropoietin receptor, glycophorin B, and porphobilinogen deaminase genes. Transactivation by GATA-1 is mediated by either an amino-terminal acidic domain, R1, or an independent adjacent domain, R2, and may involve the coordinate action of cofactors (NF-E2, EKLF, and Sp1) which bind adjacent cis-elements. To directly assess mechanisms of transactivation, we have developed an efficient cell-free transcription system using recombinant human GATA-1 (rhGATA-1) expressed in SF9 cells. Levels of baculoviral expression of GATA-1 were > or = 200-fold higher than endogenous levels in erythroid K562 cells. Factors from each source were essentially equivalent in molecular weight and DNA binding properties, and highly similar in phosphotryptic peptide composition. Notably, DNA binding was inhibited following treatment with alkaline phosphatase. In both SF9 and K562 cells, GATA-1 occurred largely as heterogeneous multimers, thus complicating its isolation by standard procedures. However, significant purification of this factor (> or = 100-fold; > or = 75% purity) was accomplished via DNA affinity chromatography. In cell-free assays, this rhGATA-1 was shown to be remarkably active in transactivating model erythroid promoters. This work establishes an efficient in vitro system for direct analyses of mechanisms, cofactors, and functional domains of GATA-1 which regulate transcription at defined proximal promoters.
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PMID:In vitro transcription of erythroid promoters using baculoviral-expressed human GATA-1: purification, physicochemistry, and activities. 785 29

The single-minded gene functions as a master developmental regulator within the midline cell lineage of the embryonic central nervous system of Drosophila melanogaster. Genetic experiments suggest that Single-minded can function as a transcriptional activator. Regions of the Single-minded protein were fused to the DNA binding domain of the mammalian transcription factor Sp1 and shown to activate transcription from a reporter gene linked to Sp1 binding sites. Three independent activation domains were identified in the carboxy terminal region of Single-minded that include areas rich in serine, threonine, glutamine and proline residues. Germ line transformation experiments indicate that the carboxy terminal activation domains, the PAS dimerization domain, and the putative DNA binding basic domain of Single-minded are required for expression of CNS midline genes in vivo. These results define in vivo a functional activation domain within Single-minded and suggest a model in which Single-minded activates transcription through a direct interaction with promoter elements of CNS midline genes.
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PMID:Transcriptional activation domains of the single-minded bHLH protein are required for CNS midline cell development. 801 58

The highly metastatic B16a melanoma has been shown to express higher levels of cathepsin B (CB) mRNA when compared to the less metastatic variants, B16-F1 and B16-F10, and with normal mouse tissues. This increased expression is now shown to be due to increased gene transcription by nuclear run-off assays and measurements of mRNA stability. Transient expression assays, using promoter fragments from the mouse and human CB genes, demonstrated that both promoters were more active in B16a than in the less metastatic melanomas, B16-F1 and B16-F10. The differential gene expression did not depend on the presence of multiple Sp1 sites in both promoters. A Gel shift assay revealed a specific CB promoter binding protein whose levels are correlated with CB expression and the metastatic potential of the three B16 melanoma variants. These results indicate that the increased expression of CB in the B16a melanoma is due to a specific increase in the amount or activity of a transcriptional activator of the CB gene. The ability of the human CB promoter to activate gene expression in B16a melanoma cells suggests similarities in the regulation of CB expression in tumors from humans and mice.
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PMID:Transcriptional regulation of cathepsin B expression in B16 melanomas of varying metastatic potential. 803 44

The p53 tumor suppressor gene product, a sequence-specific DNA-binding protein, has been shown to act as a transcriptional activator and repressor both in vitro and in vivo. Consistent with its role in regulating transcription are recent observations that the N-terminal acidic domain of p53 binds directly to the TATA box-binding protein subunit of the general transcription factor, TF IID. It is now demonstrated that wild-type p53 (wt-p53) inhibits human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-directed chloramphenicol acetyltransferase activity in a cotransfection assay system. Importantly, this effect of wt-p53 on the HIV-1 LTR was also demonstrated by in vitro transcription assays. In addition, the Sp1 sites and the TATA box of the HIV-1 LTR are demonstrated to be the primary sites involved with p53-induced effects on this viral promoter. The upstream elements of the HIV-1 LTR, including the nuclear factor kappa B (NF-kappa B) binding sites, decrease the p53-induced inhibitory effects on viral transcription. In the presence of the HIV-1 TAR sequence and Tat protein, the HIV-1 LTR also becomes less sensitive to wt-p53-induced inhibition. By using a retroviral vector delivery system, mutant forms of p53 genes were expressed in two HIV-1 latently infected cell lines, ACH-2 and U1. In the ACH-2 cell line, which is now demonstrated to contain an endogenous mutant form of p53 (amino acid 248, Arg to Gln), additional mutant p53 proteins did not alter HIV-1 replication. In U1 cells, which completely lack endogenous p53, overexpression of mutant p53 led to an increase in HIV-1 replication. Thus, these data indicate a possible functional role for wt-p53 and mutant p53 proteins in the control of HIV-1 replication patterns and proviral latency.
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PMID:The tumor suppressor protein p53 strongly alters human immunodeficiency virus type 1 replication. 820 5

To gain insight into the regulatory mechanisms of collagen VI synthesis we have characterized the cis-acting elements of the chicken alpha 1(VI) collagen promoter. Footprinting experiments with nuclear extracts from chicken embryos revealed three distinct elements, designated A, B, and C, that were protected from DNase I digestion. The nuclear proteins that interact with the three sites were identified by gel retardation assays in combination with the use of various oligonucleotide competitors as well as specific antibodies raised against well characterized transcription factors. Site A was found to be a target for transcriptional activator AP1, whereas sites B and C were shown to be recognized each by two distinct nuclear proteins which belong to the Sp1 multigene family. To address the question whether the three sites alone are able to direct transcription, a minipromoter construct was created in which the sequences of sites A, B, and C were placed in front of a reporter gene. After transfection into chicken fibroblasts, this construct exhibited a high relative promoter activity when compared to a large genomic fragment containing the basic alpha 1(VI) collagen promoter. Thus, the three sites are sufficient to induce transcription of this gene.
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PMID:Identification of functional elements and reconstitution of the alpha 1(VI) collagen promoter. 827 16

Activation of transcription by the promoter-specific factor Sp1 requires coactivators that are tightly associated with the TATA-box-binding protein (TBP) in the TFIID complex. Recent work has shown that the two glutamine-rich activation domains of Sp1, A and B, can interact with at least one component of this complex, the TBP-associated factor dTAFII110. Here we report the mapping of a region of Sp1 with alternating glutamine and hydrophobic residues which is required for the interaction with dTAFII110 and is important for mediating transcriptional activation. Substitution of bulky hydrophobic residues within this region decreased both interaction with dTAFII110 and transcriptional activation in Drosophila cells. In contrast, mutation of glutamine residues in this region had no effect. Thus, the strength of the Sp1-TAF interaction correlates with the potency of Sp1 as a transcriptional activator, indicating that this activator-TAF interaction is an important part of the mechanism of transcriptional activation. Sequence comparison of three activation domains shown to bind dTAFII110 suggests that different activators that utilize dTAFII110 as a coactivator may share common sequence features that we have determined to be important for the Sp1-dTAFII110 interaction.
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PMID:A glutamine-rich hydrophobic patch in transcription factor Sp1 contacts the dTAFII110 component of the Drosophila TFIID complex and mediates transcriptional activation. 827 63

We have previously shown that the Tat protein of the human immunodeficiency virus type 1 (HIV-1) is a modular transcriptional activator that can be targeted upstream of either a synthetic promoter or the intact HIV promoter to activate transcription. This activation was shown to be largely dependent on the presence of consensus binding sites for the cellular transcription factor Sp1. Since the use of heterologous promoters may provide further insight into Tat-mediated transactivation, we have analyzed the transactivation of the thymidine kinase promoter of herpes simplex virus by Tat and by the acidic transcriptional transactivator VP16. The effects of mutations of defined upstream promoter elements show that Tat transactivation is dependent on Sp1 binding sites in a site-specific manner. In contrast, transactivation by the acidic transactivator VP16 is completely independent of any of the defined promoter elements upstream of the TATA box. These results suggest that Tat and the classically defined modular acidic transcriptional activators have different modes of transactivation. In addition, the substitution of the HIV-1 TATA box for the thymidine kinase TATA box substantially increases Tat transactivation, indicating that Tat transactivation may also ultimately involve TATA box-associated cellular transcription factors.
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PMID:Activation of a heterologous promoter by human immunodeficiency virus type 1 Tat requires Sp1 and is distinct from the mode of activation by acidic transcriptional activators. 841 86

Herpes simplex virus type 1 infected cell polypeptide 4 (HSV-1 ICP4) is a multifunctional phosphoprotein that is essential for viral infection. It is both a repressor and an activator of viral gene expression depending upon the promoter. ICP4 represses transcription from its own promoter. In the present study, we used general transcription factors from HeLa cell nuclear extracts, recombinant TATA binding protein (TBP) and TFIIB, and the transcriptional activator Sp1 to reconstitute in vitro transcription for the ICP4 promoter and to examine the effects of purified ICP4 on transcription. ICP4 was able to effectively repress Sp1-induced transcription from ICP4 promoter templates that contain one or multiple Sp1 binding sites. The observed inhibition required the ICP4 binding site that spans the transcription initiation site. ICP4 did not inhibit basal transcription as inferred by its inability to inhibit transcription when (i) Sp1 was not included in transcription reactions, (ii) the templates contained no Sp1 binding sites, and (iii) TBP was used in place of TFIID in the reactions. The in vitro observations were consistent with the behavior of the same constructs expressed in cells from the herpes simplex virus type 1 genome. DNase I footprinting experiments revealed that ICP4 could co-occupy the ICP4 promoter region with TBP-TFIIB, indicating that ICP4 does not necessarily exclude these factors from binding to the TATA region. The data suggest that the repressive effects of ICP4 observed in this study result from ICP4 interfering with the interactions contributing to Sp1-induced transcription.
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PMID:Herpes simplex virus infected cell polypeptide 4 preferentially represses Sp1-activated over basal transcription from its own promoter. 841 35


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