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)

The Tat protein is a transcriptional activator which is required for efficient human immunodeficiency virus 1 (HIV-1) gene expression Tat stimulates HIV-1 transcriptional elongation by increasing the processivity of RNA polymerase II. To address whether Tat-mediated effects on HIV-1 gene expression are due to modulation in the phosphorylation of the RNA polymerase II C-terminal domain (CTD), we developed a purification protocol to identify cellular kinases that are capable of binding to Tat and hyperphosphorylating the RNA polymerase II CTD. A 600 kDa protein complex with these properties was isolated, and specific components were identified using peptide microsequence analysis. This analysis indicated that proteins comprising the multi-subunit TFIIH complex, in addition to several novel factors, were associated with Tat using both in vitro and in vivo analysis. The Tat-associated kinase bound to the activation domain of Tat, and its ability to hyperphosphorylate RNA polymerase II was markedly stimulated by Tat. Furthermore, the addition of the Tat-associated kinase to in vitro transcription assays stimulated the ability of Tat to activate HIV-1 transcription. These results define a cellular kinase complex whose activity is modulated by Tat to result in activation of HIV-1 trancription.
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PMID:Purification of a Tat-associated kinase reveals a TFIIH complex that modulates HIV-1 transcription. 918 28

A 42 residue artificial peptide that binds to the HIV-1 enhancers has been described previously. The specificity of interaction of the peptide with its target DNA sequence has been demonstrated by a variety of techniques. Naturally occurring regulatory proteins frequently bind to DNA as dimers, thereby increasing the strength and specificity of the interaction, the dimer interface often being provided by a leucine zipper type coiled coil. As a suitable binding site for this kind of system is located to the 5' end of the HIV enhancer region, it was decided to design and synthesize a fusion peptide that not only contained the DNA binding sequence of the original 42 residue peptide but also incorporated a leucine zipper based on that of the GCN4 transcriptional activator, that should, therefore, be capable of dimerizing. The resultant peptide, LZ66, has now been shown to be fully active in band shift and in vitro transcription assays and to exhibit about double the inhibitory activity of the parent 42 residue peptide. Preliminary CD measurements revealed that the peptide has a high alpha-helical content and that it adopts a stable conformation down to the low micromolar peptide concentration range. Sedimentation equilibrium studies confirmed that the principles involved in the design of the peptide are valid and that the peptide is indeed dimeric in solution.
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PMID:An artificial HIV enhancer-binding peptide is dimerized by the addition of a leucine zipper. 918 62

We have recently reported that chicken ovalbumin upstream promoter transcription factor (COUP-TF) activates human immunodeficiency virus type 1 (HIV-1) gene transcription in glial and neuronal cells. Here, we have examined the role of COUP-TF in microglial cells, the major target cells for HIV-1 infection in brain. We show that COUP-TF activates gene expression from both the lymphotropic LAI and the macrophage-tropic JR-FL HIV-1 strains. Although COUP-TF binds to the -352/-320 nuclear receptor responsive element of the long terminal repeat, it functions as a transcriptional activator by acting on the -68/+29 minimal promoter. This region is a direct target of transcription factors Sp1 and Sp3. We report the discovery and features of a physical and functional interplay between COUP-TF and Sp1. Our cotransfection experiments provide evidence for a functional synergism between Sp1 and COUP-TF leading to enhanced transcriptional activity of the HIV-1 long terminal repeat through the Sp1 element. In contrast, Sp3 functions as a repressor of Sp1- or COUP-TF-induced activation. We further demonstrate that COUP-TF and Sp1 are capable of physically interacting, via the DNA-binding domain of COUP-TF, in vitro and in the cell. These findings reveal how the novel interplay of Sp1 and COUP-TF families of transcription factors regulate HIV-1 gene expression.
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PMID:COUP-TF and Sp1 interact and cooperate in the transcriptional activation of the human immunodeficiency virus type 1 long terminal repeat in human microglial cells. 938 68

The HIV Tat protein, primarily characterized as a transcriptional activator of the viral long terminal repeat (LTR), is also a potent repressor of major histocompatibility complex (MHC) class I transcription. In the present study, we demonstrate that these two functional activities are distinct and mediated by discrete, but overlapping, structural domains of Tat. Tat repressor activity depends on C-terminal sequences, whereas transactivation depends on N-terminal sequences; both functions require core sequences. The repressor activity requires a domain encompassing the region encoded by the second exon of the Tat gene, beginning at amino acid 73, with a C-terminal limit between amino acids 80 and 83. Tat repressor function also depends on the presence of a lysine at position 41, located within the core of the protein. Tat repressor activity is independent of two N-terminal domains essential for transactivation: the acidic segment and the cysteine-rich region. Conversely, Tat transactivation is independent of the second exon-encoded region of Tat. As further support for this novel model of separable Tat functions, we show that in murine fibroblasts, Tat represses class I promoter activity, but does not transactivate the HIV LTR. We propose that distinct structural domains mediate the two functionally distinct activities associated with the Tat protein.
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PMID:HIV Tat protein requirements for transactivation and repression of transcription are separable. 943 53

In the process of homology modelling of the 3-dimensional structure of alleles of the human histocompatibility protein HLA-DQ, we discovered that its RGD tripeptide (beta 167-169) forms part of a loop. A search through protein sequence data bases, revealed this cell adhesion motif in 67 integral plasma membrane proteins (in 48 extracellularly, and in the remaining 19 intracellularly), which are bona fide receptors, and none of them has thus far been considered as a cell adhesion protein. The 3-dimensional structure of one of these, the rat neonatal Fc receptor, is known and its extracellular RGD sequence is in an adhesion-like loop, a fact that went unnoticed in the original papers. In a few other cases, e.g. rat and mouse growth hormone receptor, and mouse CD40 ligand, homology modelling by ourselves and others reveals that the said sequences are part of a loop, in similarity to all RGD sequences found in proteins with established adhesion function and known 3-dimensional structure. Likewise, inspection of all known protein 3-dimensional structures containing an RGD sequence, and not having a documented cell adhesion function (total of 65 separate entries) shows that such sequence is mostly (52/65 or 80% of cases) part of a loop. We therefore call attention to these surprising findings, discuss the possible cell adhesion role of these receptor proteins, and draw an analogy from the two well characterised examples, that of soluble IGF binding protein 1 and the transcriptional activator protein Tat of HIV, where their RGD sequences have been shown by site-directed mutagenesis to participate in cell-adhesion interactions, without prior knowledge of the location of the tripeptide, or the 3-dimensional structure of the respective protein.
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PMID:RGD sequences in several receptor proteins: novel cell adhesion function of receptors? 951 16

Vpr, one of the accessory gene products of the human immunodeficiency virus-1 (HIV-1) genome, exhibits diverse biological characteristics. Vpr functions as a transcriptional activator of HIV and heterologous promoters. It is capable of arresting cells in cell cycle progression and plays a crucial role in the infection of macrophages. Despite the wealth of information available on the biological aspects of Vpr, the structure of Vpr remains poorly understood. To gain insight into the structure-function relationship of Vpr, peptides corresponding to putative helical regions of Vpr were synthesized and their structures determined by circular dichroism (CD) spectroscopy. The CD studies confirmed the predicted helical structures of these peptides. Based on the data, a hypothetical model for the structure of Vpr was proposed which displays an anti-parallel alpha-helix core structure reminiscent of a helix-loop-helix motif. These findings are consistent with the results from mutational studies of Vpr and provide a plausible structural basis to further investigate the multiple functions of Vpr as a viral protein.
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PMID:Structural studies of synthetic peptide fragments derived from the HIV-1 Vpr protein. 953 34

An artificial HIV enhancer-binding polypeptide has recently been dimerized by covalently linking it to the leucine zipper motif of the yeast transcriptional activator GCN4 (Liu N et al., 1997, Eur Biophys J 25:399-403). Although it seemed that the dimerization of this peptide could be best achieved by the use of the retro sequence of the leucine zipper, this approach was not implemented in the original construct. As the first step toward the synthesis of a basic region-retro leucine zipper HIV enhancer-binding fusion protein, we have now prepared the retro version of the leucine zipper (r-LZ35) and performed initial physicochemical characterization. Circular dichroism and sedimentation equilibrium studies showed that, at concentrations < 100 microM, the retro peptide was an unstructured monomer. At higher concentrations, however, the monomer was in equilibrium with a tetramer and, at 1 mM, the retro peptide was almost fully helical. N-terminal extension of the retro peptide by the tripeptide Cys-Gly-Gly resulted in a 38-residue polypeptide that could be covalently dimerized by forming a disulfide bond between two chains to give the peptide (r-LZ38)2. Even in the low micromolar concentration range peptide (r-LZ38)2 formed a stable, noncovalent, helical dimer as revealed by circular dichroism and sedimentation equilibrium in the presence and absence of guanidinium chloride. (r-LZ38)2 has been crystallized and X-ray structural analysis is under way. The disulfide-crosslinked retro-leucine zipper may lend itself to interesting protein structural studies, including protein design. The present work also highlights the structural and functional potential of retro proteins in general.
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PMID:Synthesis, physicochemical characterization, and crystallization of a putative retro-coiled coil. 960 27

EBNA-2 is the first protein to be detected after infection of primary B lymphocytes by Epstein-Barr virus (EBV) and plays an essential role as transcriptional activator in EBV-induced lymphocyte transformation. We analysed by PCR and sequencing regions of the EBNA-2 type 1 gene from isolates from 13 children with infectious mononucleosis (IM), 6 children with tonsillar hyperplasia (TH), and 9 patients with HIV infection followed longitudinally. We found in all three groups of patients frequent non-silent point mutations at positions 48990, 48991, 49021, 49057, 49083, 49089, 49091, 49113, 49119, 49140, 49156, and a triplet insertion at position 49136. While 4 out of 13 samples from patients with IM showed a mosaic pattern suggesting co-existence of more than 1 substrain of EBNA-2 type 1, none of the samples from TH showed this pattern consistent with substrain selection during clinical latency. No sequence changes were noted over time in samples derived from patients with HIV infection. We conclude that in analogy to the coexistence of several subtypes of EBNA-1 in healthy EBV carriers, samples from IM can harbor more than one subtype of the EBNA-2 type 1 gene.
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PMID:Molecular analysis of critical sequences within the EBNA-2 type 1 gene from Epstein-Barr virus isolates from patients with infectious mononucleosis, tonsillar hyperplasia, and HIV infection. 985 35

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a transcriptional activator that is essential for efficient viral gene expression and replication. Tat increases the level of full-length transcripts from the HIV-1 promoter by dramatically enhancing the elongation efficiency of the RNA polymerase II complexes assembled on this promoter. Tat could potentially activate the transcription machinery during initiation, elongation, or both. We used an immobilized HIV-1 promoter template with a reversible lac repressor (LacR) elongation block inserted downstream to dissect the stages in transcription affected by Tat. Transcription complexes assembled in the absence of Tat and blocked by LacR cannot be activated by incubation with Tat alone. These complexes can, however, be activated if Tat is added in combination with cellular factors. In this system, Tat also promoted the assembly of preinitiation complexes capable of elongating efficiently, suggesting that Tat can associate with transcription complex at an early stage. These data indicate that Tat can activate elongation of RNA polymerase by modifying an already elongating transcription complex. The data also suggest the possibility that Tat can interact with initiation complexes.
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PMID:Human immunodeficiency virus type 1 Tat-dependent activation of an arrested RNA polymerase II elongation complex. 1006 59

HIV-1 trans-activator of transcription (Tat) is an unusual transcriptional activator in being an RNA-binding protein rather than a DNA-binding protein. Recent findings have greatly advanced our understanding of the transcriptional function(s) of this protein. Here we review how Tat interacts with trans-activation responsive RNA and how this interaction contributes to transcription. We discuss the biological implications of recent studies showing an association of Tat with cellular kinases(s) and protein acetylases. Evidence for nontranscriptional activities of the Tat protein is also summarized.
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PMID:Biochemical and functional interactions between HIV-1 Tat protein and TAR RNA. 1032 10


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