Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two benzodiazepine compounds, [7-chloro-5-(2-pyrryl)-3H-1,4 benzodiazapin-2-(H)-one] (Ro5-3335) and [7-chloro-5-(1H-pyrrol-2-yl)-3H-benzo[e] [1,4] diazepin-2-yl]- methylamine (Ro24-7429), inhibit human immunodeficiency virus type 1 (HIV-1) replication via a specific effect on the function of the transactivator protein, Tat. To gain further insight into the mechanism of action of these compounds, we have tested their effects in an alternative assay for Tat activation in Xenopus oocytes. In this system, translation of trans-activation response element (TAR)-containing RNA is activated by Tat. Both compounds specifically blocked activation of translation in a dose-dependent fashion, with Ro24-7429 showing the greater potency. In the Xenopus oocyte system, as in mammalian cells, mutation of the TAR loop sequences abolishes Tat action. However, it is possible to obtain TAR-specific, Tat-dependent activation of a target RNA with a mutation in the loop provided that this target is in large excess. This result has been interpreted as indicating that a negative factor has been titrated (M. Braddock, R. Powell, A.D. Blanchard, A.J. Kingsman, and S.M. Kingsman, FASEB J. 7:214-222, 1993). Interestingly Ro24-7429 was unable to inhibit the TAR-specific but loop sequence-independent mode of translational activation. This finding suggests that a specific loop-binding cellular factor may mediate the effects of this inhibitor of Tat action. Consistent with this notion, we could not detect any effect of Ro24-7429 on the efficiency of specific Tat binding to TAR in vitro.
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PMID:Inhibition of human immunodeficiency virus type 1 Tat-dependent activation of translation in Xenopus oocytes by the benzodiazepine Ro24-7429 requires trans-activation response element loop sequences. 825 35

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.
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PMID:Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency. 828 13

The human immunodeficiency virus type 1 transactivator protein, tat, specifically stimulates transcription from the viral long terminal repeat. We used cell-free transcription systems to test whether tat can stimulate transcriptional read-through of an artificial terminator sequence (e.g., a stable RNA stem-loop structure followed by a tract of nine uridine residues) placed downstream of the viral long terminal repeat. In the absence of tat, RNA polymerases are prematurely released from the template at the terminator sequence. Recombinant tat protein purified from Escherichia coli increased the synthesis of full-length transcripts approximately 25-fold and decreased the amount of transcripts ending at the terminator sequence. The reaction is strictly dependent upon the presence of a functional transactivation-responsive region (TAR) sequence. Mutations in the tat binding site on TAR RNA and mutations in the TAR RNA loop block transactivation in vivo. Neither type of mutation is able to respond to tat in vitro. These results strongly suggest that after transcription through the TAR region, tat modifies the transcription complex to increase its elongation capacity.
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PMID:Human immunodeficiency virus type 1 transactivator protein, tat, stimulates transcriptional read-through of distal terminator sequences in vitro. 832 98

The molecular mechanisms regulating human immunodeficiency virus (HIV) persistence in a major cell reservoir such as the macrophage remain unknown. NF-kappa B is a transcription factor involved in the regulation of the HIV long terminal repeat and is selectively activated following HIV infection of human macrophages. Although little information as to what signal transduction pathways mediate NF-kappa B activation in monocytes-macrophages is available, our previous work indicated that classical protein kinase C (PKC) isoenzymes were not involved in the HIV-mediated NF-kappa B activation. In this study, we have focused on atypical PKC isoenzymes. PKC-zeta belongs to this family and is known to be an important step in NF-kappa B activation in other cell systems. Immunoblotting experiments with U937 cells demonstrate that PKC-zeta is present in these cells, and its expression can be downmodulated by antisense oligonucleotides (AO). The HIV-mediated NF-kappa B activation is selectively reduced by AO to PKC-zeta. In addition, cotransfection of a negative dominant molecule of PKC-zeta (PKC-zeta mut) with NF-kappa B-dependent reporter genes selectively inhibits the HIV- but not phorbol myristate acetate- or lipopolysaccharide-mediated activation of NF-kappa B. That PKC-zeta is specific in regulating NF-kappa B is concluded from the inability of PKC-zeta(mut) to interfere with the basal or phorbol myristate acetate-inducible CREB- or AP1-dependent transcriptional activity. Lastly, we demonstrate a selective inhibition of p24 production by HIV-infected human macrophages when treated with AO to PKC-zeta. Altogether, these results suggest that atypical PKC isoenzymes, including PKC-zeta, participate in the signal transduction pathways by which HIV infection results in the activation of NF-kappa B in human monocytic cells and macrophages.
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PMID:Protein kinase C-zeta mediates NF-kappa B activation in human immunodeficiency virus-infected monocytes. 852 29

The human immunodeficiency virus type 1 transactivator protein, Tat, stimulates transcriptional elongation from the viral long terminal repeat. To test whether Tat associates directly with activated transcription complexes, we have used the lac repressor protein (LacR) to "trap" elongating RNA polymerases. The arrested transcription complexes were purified by binding biotinylated templates to streptaviridin-coated magnetic beads. Transcription complexes were released from the magnetic beads following cleavage of the templates with restriction enzymes and were immunoblotted with antibodies to Tat, LacR and RNA polymerase II. The Tat protein copurified with RNA polymerase bound to wild-type templates but did not copurify with transcription complexes prepared by using templates carrying mutations in the transactivation response element (TAR) RNA. We conclude that Tat and cellular cofactors become attached to the transcription complex during its transit through TAR.
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PMID:Human immunodeficiency virus type-1 Tat is an integral component of the activated transcription-elongation complex. 863 4

The regulation of human immunodeficiency virus type 1 (HIV-1) gene expression is dependent on the transactivator protein Tat and an RNA element extending from the transcription initiation site to +57 known as TAR. TAR forms a stable RNA secondary structure which is critical for high levels of HIV-1 gene expression and efficient viral replication. Using a genetic approach, we isolated HIV-1 mutants in TAR that were competent for high levels of gene expression but yet were markedly defective for viral replication. Single-cycle infections with these viruses demonstrated that they were defective in the initiation of reverse transcription. Additional mutational analysis revealed a variety of other HIV-1 TAR mutants with the same defective phenotype. Thus, in addition to the well-characterized role of the primer binding site, other RNA elements within the HIV-1 genome are also critical in the regulation of reverse transcription. These studies demonstrate that HIV-1 TAR RNA is a key regulator of the reverse transcription and illustrate how a unique RNA structure can modulate diverse regulatory processes in the HIV-1 life cycle crucial for efficient viral replication.
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PMID:A critical role for the TAR element in promoting efficient human immunodeficiency virus type 1 reverse transcription. 864 39

The Tat-responsive region (TAR) element is a critical RNA regulatory element in the human immunodeficiency virus (HIV) long terminal repeat, which is required for activation of gene expression by the transactivator protein Tat. Recently, we demonstrated by gel-retardation analysis that RNA polymerase II binds to TAR RNA and that Tat prevents this binding even when Tat does not bind to TAR RNA. These results suggested that direct interactions between Tat and RNA polymerase II may prevent RNA polymerase II pausing and lead to Tat-mediated increases in transcriptional elongation. To test this possibility, we performed protein interaction studies with RNA polymerase II and both the HIV-1 and the closely related HIV-2 Tat protein. These studies indicated that both the HIV-1 and HIV-2 Tat proteins could specifically interact with RNA polymerase II. Mutagenesis of both HIV-1 and HIV-2 Tat demonstrated that the basic domains of both the HIV-1 and HIV-2 Tat proteins were required for this interaction. Furthermore, "far Western" analysis suggested that the largest subunit of RNA polymerase II was the site for interaction with Tat. The interactions between Tat and RNA polymerase II were of similar magnitude to those detected between RNA polymerase II and the cellular transcription factor RAP30, which stably associates with RNA polymerase II during transcriptional elongation. These studies are consistent with the model that RNA polymerase II is a cellular target for Tat resulting in Tat-mediated increases in transcriptional elongation from the HIV long terminal repeat.
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PMID:Human immunodeficiency virus type 1 and 2 Tat proteins specifically interact with RNA polymerase II. 870 Aug 89

The human immunodeficiency virus type 1 (HIV-1) regulatory gene, tat, encodes an early transactivator protein (Tat) necessary for virus replication. We have reported that the HIV-1 tat gene can up-regulate interleukin 4 receptors (IL-4R) however, the mechanism of this up-regulation is not understood. We now show that in Raji cells, 125I-labeled IL-4 cross-linked to three proteins of 140, 70, and 63 kDa, which were immunoprecipitated with an antibody to the human IL-4R. Although this level of all three IL-4 binding proteins increased in tat-transfected cells, the binding characteristics of IL-4R on control or mock transfected control and tat-transfected cells remained similar. The exogenous recombinant Tat protein or supernatant of tat transfected Raji cells also up-regulated the expression of the IL-4R on two renal cell carcinoma cell lines in a concentration-dependent manner. The actinomycin D chase experiments revealed that the half-lives of the IL-4R protein (t1/2 3.5 hr) and mRNA transcripts (t1/2 2.5 hr) were similar in both control and tat-transfected cells. In contrast, nuclear run-on experiments revealed that the rate of the IL-4R mRNA transcription increased 3- to 5-fold in Raji-tat compared to Raji cells. These data indicate that the HIV-1 tat gene up-regulates IL-4R expression by increasing the transcription rate rather than posttranscriptional stabilization of either the mRNA or the protein. HIV-tat inducible exogenous tumor necrosis factor (TNF-alpha) did not up-regulate IL-4R and IL-4R inducible activation of signal transducers and activators of transcription (STAT-6) was not observed by Tat even though IL-4R were up-regulated. These results allow us to speculate that HIV-1 tat may interact directly with the IL-4R gene and up-regulate IL-4R transcription.
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PMID:Transcriptional up-regulation of interleukin 4 receptors by human immunodeficiency virus type 1 tat gene. 889 Nov 14

Activating protein-1 (AP-1) binding phorbol ester responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind cFos and junD and transmit protein kinase C (PKC) activation signals to the LTR. Further studies suggested the DSE might also bind AP-1-related proteins of the CREB/ATF family. Since enhanced HIV-1 expression is associated with activation of the cAMP-dependent protein kinase A (PKA) signaling pathway, we determined whether binding of CREB/ATF proteins to the DSE mediate cAMP/PKA activation of the HIV-1 LTR. In the present study. DSE binding complexes in nuclear protein extracta from colonic epithelial cells are shown to contain ATF-1, ATF-2, and CREB and transfection of either an ATF-2 or PKA expressing plasmid transactivated the DSE. Cholera toxin (Ctx), a potent activator of the cAMP/PKA pathway. Increased HIV-1 virus production from a latently infected promonocytic cell line, U1. Ctx increased LTR promoter activity and increased the CREB content of DSE binding complexes. Transfection of U1 cells with a series of mutant LTR reporter constructs demonstrated that the Ctx response was in large part mediated by the DSE. The Ctx response was also mediated by a heterologous promoter containing multiple TRE sites. Nuclear protein extracts from a T-cell line infected by HIV-1 contained higher levels of CREB/ATF proteins and manifested increased CREB/ATF binding activity. Collectively, these results indicate the DSE are TRE-like cAMP responsive elements that bind both AP-1 and CREB/ATF permitting induction of the HIV-1 LTR by both PKC and PKA activation signals.
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PMID:U5 region of the human immunodeficiency virus type 1 long terminal repeat contains TRE-like cAMP-responsive elements that bind both AP-1 and CREB/ATF proteins. 920 Dec 33

The transactivator protein (Tat) of the human immunodeficiency virus (HIV) is a key regulatory protein in the viral replication cycle and belongs to the RNA binding proteins of the arginine-rich motif (ARM) family. Very little is known about their mechanism of RNA recognition. To study the principles of RNA-protein recognition we constructed a system to display HIV-1 Tat on the surface of the filamentous bacteriophage M13. HIV-1 Tat (1-72) and a mutant Tat lacking five cysteine residues were cloned into the pAK phagemid system, which allows fusion of the tat gene to a supershort version of the gene for minor M13 coat protein. Expression of the resulting fusion proteins was shown via western blot analysis. Phages displaying functional Tat could be selected from phages without Tat or with a non-functional Tat variant via binding to biotinylated TAR using streptavidin coated paramagnetic beads. By randomizing certain amino acid positions of Tat and screening of the resulting phage libraries for affinity and specificity, we are now able to study the role and importance of amino acids of HIV-1 Tat for affinity and specificity to TAR RNA.
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PMID:A selection system to study protein-RNA interactions: functional display of HIV-1 Tat protein on filamentous bacteriophage M13. 920 43


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