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)

The human immunodeficiency viruses (HIVs) primarily infect CD4+ T lymphocytes, leading eventually to the development of a systemic immune dysfunction termed acquired immunodeficiency syndrome (AIDS). An attractive strategy to combat HIV-mediated pathogenesis would be to eliminate the initial pool of infected cells and thus prevent disease progression. We have engineered a replication-defective, conditionally cytotoxic adenovirus vector, Ad-tk, whose action is dependent on the targeted expression of the herpes simplex virus type 1 thymidine kinase gene (tk), cloned downstream of the HIV-1 long terminal repeat, in human cells expressing the HIV-1 transcriptional activator Tat. Infection of Tat-expressing human HeLa or Jurkat cells with Ad-tk resulted in high-level tk expression, which was not deleterious to the viability of these cells. However, in the presence of the antiherpetic nucleoside analog ganciclovir, Ad-tk infection resulted in a massive reduction in the viability of these Tat-expressing cell lines. As adenoviruses are natural passengers of the human lymphoid system, our results suggest adenovirus vector-based strategies for the targeted expression, under the control of cis-responsive HIV regulatory elements, of cytotoxic agents in HIV-infected cells for the therapy of HIV-mediated pathogenesis.
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PMID:Selective induction of toxicity to human cells expressing human immunodeficiency virus type 1 Tat by a conditionally cytotoxic adenovirus vector. 224 44

In this study we have investigated the role of the N-terminal region of thyroid hormone receptors (TRs) in thyroid hormone (TH)-dependent transactivation of a thymidine kinase promoter containing TH response elements composed either of a direct repeat or an inverted palindrome. Comparison of rat TR beta 1 with TR beta 2 provides an excellent model since they share identical sequences except for their N termini. Our results show that TR beta 2 is an inefficient TH-dependent transcriptional activator. The degree of transactivation corresponds to that observed for the mutant TR delta N beta 1/2, which contains only those sequences common to TR beta 1 and TR beta 2. Thus, TH-dependent activation appears to be associated with two separate domains. The more important region, however, is embedded in the N-terminal domain. Furthermore, the transactivating property of TR alpha 1 was also localized to the N-terminal domain between amino acids 19 and 30. Using a coimmunoprecipitation assay, we show that the differential interaction of the N terminus of TR beta 1 and TR beta 2 with transcription factor IIB correlates with the TR beta 1 activation function. Hence, our results underscore the importance of the N-terminal region of TRs in TH-dependent transactivation and suggest that a transactivating signal is transmitted to the general transcriptional machinery via a direct interaction of the receptor N-terminal region with transcription factor IIB.
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PMID:The N-terminal region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but not beta 2 contains a strong thyroid hormone-dependent transactivation function. 753 21

The equine herpesvirus type 1 (EHV-1) immediate-early (IE) gene product, an ICP4 homolog, is the major regulatory protein encoded by EHV-1 during cytolytic infection. The IE gene product has been demonstrated to induce reporter gene expression directed by both homologous and heterologous viral promoters, including the EHV-1 thymidine kinase (tk) promoter, the herpes simplex virus type 1 (HSV-1) tk and ICP4 promoters, and the simian virus 40 early promoter. In this report, the transcriptional activation domain of the EHV-1 IE gene product was mapped to within an acidic, 87-amino-acid region (amino acids 3 to 89) at the amino-terminus of the IE molecule. It is demonstrated that the IE transcriptional activation domain, when fused to the DNA-binding domain of the yeast transcriptional activator GAL4, can activate gene expression in cell lines derived from at least two different species. Moreover, it is shown that the EHV-1 IR2 gene product (Harty and O'Callaghan, J. Virol. 65, 3829-3838, 1991), a truncated form of the IE polypeptide lacking IE amino acid residues 1-322 (and, therefore lacks the deduced transcriptional activation domain), fails to transactivate the EHV-1 tk promoter, but retains the ability to down-regulate the EHV-1 IE promoter. Fusion of the acidic transcriptional activation domain of the HSV-1 virion protein VP16 to the transactivation-deficient IR2 gene product restored the ability of this truncated IE polypeptide to transactivate the EHV-1 tk promoter. These findings suggest a role for the IR2 protein as a trans-repressor of EHV-1 gene expression.
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PMID:The equine herpesvirus type 1 immediate-early gene product contains an acidic transcriptional activation domain. 803 Feb 39

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

p53 is a nuclear phosphoprotein whose function is classified as tumor suppression. Studies have shown that p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53; the other p53 recognition sequences included p53-binding fragments found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). The purpose of this study was to compare the abilities of various p53 recognition sequences to mediate transcription in the presence of endogenously produced wild-type (wt) or mutant p53. Three p53-responsive chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and pMCK) that contain one or two copies of p53 recognition sequences upstream of a herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed. Either a p53-responsive gene or a control reporter gene was transfected into human carcinoma cell lines (having various p53 mutations) either with or without a wt or mutant p53 expression vector. CAT activity was assayed to measure transactivation through the various p53-responsive elements. We showed that pOST2 had a greater ability to mediate transactivation by p53 than either pRGC or pMCK. p53 with a mutation at either codon 175 or 248 was unable to transactivate a reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but not pRGC or pMCK, was able to mediate transactivation in cell lines that produce codon 273-mutant p53. These findings suggest that various sensitivities of the different p53-responsive elements to specific mutant and wt p53s may be an important factor in the role of p53 as a transcriptional activator both under normal physiological conditions and during carcinogenesis.
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PMID:p53 transactivation through various p53-responsive elements. 864 24

MHC class I molecules are normally expressed at very low levels in the brain and their up-regulation in response to cytokines and viral infections has been associated with a number of neurological disorders. Here we demonstrate that the down-regulation of surface class I molecules in differentiated primary rat oligodendrocytes was accompanied by reduced steady-state levels of class I heavy-chain mRNA. Transient expression assays were performed in oligodendrocytes and fibroblasts, using a mouse H-2Kb class I promoter chloramphenicol acetyltransferase plasmid termed pH2KCAT (which contained 5'-flanking sequences from -2033 to +5 bp of the H-2Kb gene relative to the transcriptional start site at +1 bp). These assays showed that H-2Kb promoter activity was reduced in oligodendrocytes but not in class I-expressing fibroblasts. H-2Kb promoter activity was up-regulated in oligodendrocytes co-transfected with a plasmid expression vector encoding the transcriptional activator tax of human T-cell leukaemia virus type I, showing that down-regulation of promoter activity was reversible. Deletion mutant analysis of the H-2Kb promoter revealed the presence of negative regulatory elements that were functional in oligodendrocytes at -1.61 to -1.07 kb and -242 to -190 bp. Deletion of sequences in pH2KCAT encompassing the downstream element totally abolished promoter activity in both oligodendrocytes and fibroblasts, whereas a deletion within the upstream negative regulatory element increased promoter activity specifically in oligodendrocytes. The upstream negative regulatory element also down-regulated a linked heterologous herpes simplex virus thymidine kinase promoter in oligodendrocytes, but not in fibroblasts. Gel retardation assays using overlapping DNA probes that spanned the entire -1.61 to -1.07 kb region revealed the presence of a number of DNA-binding activities that were present in oligodendrocyte, but not in fibroblast nuclear extracts.
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PMID:Transcriptional regulation of MHC class I gene expression in rat oligodendrocytes. 946 4

We have isolated and characterized a cDNA encoding a transcription activating factor for the mouse selenocysteine tRNA (tRNAsec) gene from mouse mammary gland. The full-length cDNA, designated m-Staf, has a 1878-base pair open reading frame encoding 626 amino acids. The predicted amino acid sequence of m-Staf is highly homologous to that of Staf, another selenocysteine tRNA gene transcription activating factor of Xenopus laevis. Like Staf, m-Staf contains seven tandemly repeated zinc fingers and four repeated motifs. Gel shift assays indicated that the recombinant m-Staf specifically bound to the activator element region in the mouse tRNAsec gene. Transient co-transfection experiments in Drosophila Schneider cells, which lack endogenous Staf-like binding activity, showed that m-Staf increased the mouse tRNAsec gene transcription about 15-fold, whereas it stimulated Pol II-dependent thymidine kinase promoter only 2-fold. Northern blot analysis detected the presence of a 3.4-kilobase pair m-Staf transcript, which was widely but differentially expressed in various murine tissues. The binding activity of m-Staf in mouse mammary gland was undetectable during virgin and postlactating periods but increased markedly in parallel with the increase of tRNAsec transcript during the periods of pregnancy and lactation, when the gland undergoes growth and development. These results indicate that m-Staf is a transcriptional activator of the mouse tRNAsec gene and that its binding activity in the mammary gland undergoes developmental alterations.
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PMID:Molecular cloning and characterization of the murine staf cDNA encoding a transcription activating factor for the selenocysteine tRNA gene in mouse mammary gland. 953 33

Thyroid hormone receptor (TR) can act as both a transcriptional activator and a silencer. Optimal activation by TR requires synergism with activator(s) bound to the promoter (promoter proximal activator). It is thought that liganded TR either helps to recruit preinitiation complexes (PIC) to the promoter or activates the PIC already recruited. However, the studies analyzing the TR action on the PIC formation were done in vitro and, therefore, it is not clear how relevant they are to the in vivo TR action. For example, in vivo, the TR can act from distances equal to or greater than a kilobase from the promoter, but such distant effect is not reproducible in vitro. In this study, we used the PIN*POINT (ProteIN POsition Identification with Nuclease Tail) assay to define the molecular mechanism of TR action on transcription from the thymidine kinase promoter in the cellular context. We demonstrate that the recruitment of promoter-proximal activator Sp1, and the components of the basal transcription factors such as TBP, TFIIB, and Cdk7, is enhanced with thyroid hormone activation. Our results suggest that DNA forms a loop with TR-mediated activation to accommodate interactions between the liganded TR complex and the complex formed on the promoter. We also show that Sp1 bound to the promoter is essential for the DNA looping and recruitment of basal transcription factors such as TFIIB and Cdk7 but not for recruitment of TBP. On the basis of these findings, we present a model that illustrates the molecular mechanism of TR-mediated activation in vivo.
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PMID:In vivo transcription factor recruitment during thyroid hormone receptor-mediated activation. 1046 67

Signal transducers and activators of transcription (Stat) are latent transcription factors that participate in cytokine signaling by regulating the expression of early response genes. Our previous studies showed that Stat5 functions not only as a transcriptional activator but also as a transcriptional inhibitor, depending on the target promoter. This report further investigates the mechanism of Stat5b-mediated inhibition and demonstrates that PRL-inducible Stat5b inhibits nuclear factorkappaB (NFkappaB) signaling to both the interferon regulatory factor-1 promoter and to the thymidine kinase promoter containing multimerized NFkappaB elements (NFkappaB-TK). Further, PRL-inducible Stat5b inhibits tumor necrosis factor-alpha signaling presumably by inhibiting endogenous NFkappaB. This Stat5b-mediated inhibitory effect on NFkappaB signaling is independent of Stat5b-DNA interactions but requires the carboxyl terminus of Stat5b as well as Stat5b nuclear translocation and/or accumulation, suggesting that Stat5b is competing for a nuclear factor(s) necessary for NFkappaB-mediated activation of target promoters. Increasing concentrations of the coactivator p300/CBP reverses Stat5b inhibition at both the interferon-regulatory factor-1 and NFkappaB-TK promoters, suggesting that Stat5b may be squelching limiting coactivators via protein-protein interactions as one mechanism of promoter inhibition. These results further substantiate our observation that Stat factors can function as transcriptional inhibitors. Our studies reveal cross-talk between the Stat5b and NFkappaB signal transduction pathways and suggest that Stat5b-mediated inhibition of target promoters occurs at the level of protein-protein interactions and involves competition for limiting coactivators.
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PMID:Stat5b inhibits NFkappaB-mediated signaling. 1062 51

The vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactivation but do not affect constitutive activation by Ets-1. Therefore, in contrast with the actions of vitamin D, activation by Ets-1 is independent of the AF2 domain. Ets-1 also conferred a ligand-independent activation to the estrogen receptor and to peroxisome proliferator-activated receptor alpha. In addition, Ets-1 cooperated with the unliganded receptors to stimulate the activity of reporter constructs containing consensus response elements fused to the thymidine kinase promoter. There is a direct interaction of the receptors with Ets-1 which requires the DNA binding domains of both proteins. Interaction with Ets-1 induces a conformational change in VDR which can be detected by an increased resistance to proteolytic digestion. Furthermore, a retinoid X receptor-VDR heterodimer in which both receptors lack the core C-terminal AF2 domain can recruit coactivators in the presence, but not in the absence, of Ets-1. This suggests that Ets-1 induces a conformational change in the receptor which creates an active interaction surface with coactivators even in the AF2-defective mutants. These results demonstrate the existence of a novel mechanism, alternative to ligand binding, which can convert an unliganded receptor from an inactive state into a competent transcriptional activator.
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PMID:Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors. 1107 80


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