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)

An important aspect of human immunodeficiency virus (HIV-1) infection is the regulation of its expression by nuclear factor kappa B (NF-kappa B) through redox-controlled signal transduction pathways. In this study, we demonstrate that iron chelation by deferoxamine (DFO) protects against the cytotoxic and reactivating effects of hydrogen peroxide (H2O2). These protective effects were observed both in lymphocytic (ACH-2) and promonocytic (U1) cells latently infected by HIV-1. Concomitantly, NF-kappa B activation by H2O2, when followed by gel retardation assay, was decreased in the DFO-treated U1 and ACH-2 cells. This latter DFO-mediated effect was specific, as DFO did not clearly affect AP-1 DNA-binding activity when studied after H2O2-induced stress. More importantly, DFO protected against the H2O2-induced activation of HIV-1 as evidenced by reverse transcriptase activity in the supernatant. DFO also protected against PMA-induced NF-kappa B activation as well as TNF-alpha-induced HIV-1 activation. Furthermore, DFO attenuated the p24 response in PBMC infected with HIV-1 and stimulated with IL-2. These different effects of DFO were obtained at DFO concentrations lower than 5 microM. Other chemically unrelated iron chelators also provided protection against cytotoxicity, NF-kappa B activation, and HIV-1 activation in U1 cells challenged with H2O2.
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PMID:Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. 855 2

Metabolite III (MIII, 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-alpha]pyrazine), a major in vivo metabolite of oltipraz (OLT, 5-pyrazinyl-4-methyl-1,2-dithiole-3-thione), appears to disrupt human immunodeficiency virus type 1 (HIV-1) replication at a point distal to integration of the viral genome into host DNA. We report that MIII (but not OLT) is a nontoxic inhibitor of long terminal repeat (LTR)-driven expression of beta-galactosidase in phorbol-12-myristate-13-acetate (PMA)-stimulated and unstimulated 293.27.2 cells (ED50 = 14 +/- 1 and 41 +/- 4 microM, respectively). Electrophoretic mobility-shift assays (EMSA) reveal that MIII does not significantly reduce the PMA-induced DNA binding activities of NF-kappa B or AP-1. Although the mechanism by which MIII inhibits LTR-driven transcription remains unclear, the antiviral synergism of OLT and MIII in vitro are likely due their independent activities. Whether this translates into antiviral synergy in vivo is being examined by comparing OLT and MIII pharmacokinetics to the pharmacodynamic effects of orally-administered OLT in patients with p24 antigenemia.
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PMID:Inhibition of human immunodeficiency virus type 1 long terminal repeat-driven transcription by an in vivo metabolite of oltipraz: implications for antiretroviral therapy. 862 98

The serine/threonine protein kinase Raf-1 is a component of a conserved intracellular signaling cascade that controls responses to various extracellular stimuli. Transcription from several promoters, including the oncogene-responsive element in the polyomavirus enhancer, the c-fos promoter, as well as other AP-1- and Ets-dependent promoters, can be induced by Raf-1 kinase. Previously, we have shown that activated Raf-1 kinase transactivates the human immunodeficiency virus type 1 (HIV-1) long terminal repeat and have identified the NF-kappaB binding motif as a Raf-1-responsive element (RafRE). We now report that Raf-1 kinase-induced transactivation from the HIV RafRE involves the purine-rich-repeat-binding protein (GABP), which is composed of two distinct subunits (alpha and beta). GABP alpha is an Ets oncogene-related DNA-binding protein, and GABP beta contains four ankyrin-like repeats that have been shown to be essential in protein-protein interactions. In electrophoretic mobility shift assays using nuclear extracts from human Jurkat T cells, a protein-DNA complex which was supershifted with antiserum against GABP alpha and GABP beta was observed. Purified recombinant GABP alpha and beta interact with the HIV RafRE as judged from DNA binding assays. Cotransfection experiments with GABP alpha and beta and Raf-1 kinase demonstrate synergistic transactivation of the HIV-1 promoter. Point mutations in the HIV RafRE abolished the Raf-1 kinase as well as GABP alpha- and beta-induced transactivation. The observed Raf-1-GABP synergism presumably involves phosphorylation of GABP subunits, as treatment of cells with Raf-1 kinase activators serum and 12-O-tetradecanoylphorbol-13-acetate increases phosphorylation of GABP in vivo. However, GABP is not a target of Raf-1 kinase; instead, it is a substrate of mitogen-activated protein kinase (MAPK/ERK), since in vitro phosphorylation of GABP alpha and beta was achieved by the reconstituted protein kinase cascade but not with purified Raf-1 or MEK. These results suggest that Raf-1 kinase- induced activation of the HIV-1 promoter is mediated by the classical cytoplasmic cascade resulting in MAPK/ERK-mediated phosphorylation of GABP alpha and beta. Because the HIV RafRE corresponds to a region within the promoter which is essential for regulation of HIV-1 expression, the data indicate that in addition to NK-kappaB, GABP transcription factors are important for induced expression of HIV.
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PMID:Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter. 864 52

We have examined the roles of AP-1, AP-3-like, DBF1, and Sp1 binding sites, which are located downstream of the human immunodeficiency virus type 1 (HIV-1) promoter, in regulating basal transcriptional activity directed by the integrated viral long terminal repeat (LTR). Point mutations affecting all four of these elements functionally inactivated the HIV-1 LTR when it was constrained in a chromatin configuration. Analyses of the chromatin structures of the transcriptionally active wild-type and inactive mutated HIV-1 promoters revealed several differences. In the active promoter, the 3' half of the U3 region, including the basal promoter, the enhancer, and the putative upstream regulatory sequences are situated within a nuclease-hypersensitive region. However, the far upstream U3 region appears to be packaged into a nuclease-resistant nucleosomal structure, whereas the R, U5, and gag leader sequences are associated with a region of altered chromatin that is sensitive to restriction endonucleases. In the inactive template, only the basal promoter and enhancer element remain sensitive to nucleases, and the adjacent upstream and downstream regions are incorporated into nuclease-resistant nucleosomal structures. Taken together, these results indicate that the chromatin structure of the integrated HIV-1 LTR plays a critical role in modulating basal transcriptional activity.
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PMID:cis-acting sequences located downstream of the human immunodeficiency virus type 1 promoter affect its chromatin structure and transcriptional activity. 864 7

Fluid shear stress activates the expression of immediate early (IE) genes in vascular endothelial cells. The transcriptional regulation can be mediated through the shear stress-sensitive cis-acting elements at the 5' promoter regions of various IE genes such as the monocyte chemotactic protein-1 (MCP-1) gene. We linked wild-type and mutated MCP-1 promoters to the reporter gene luciferase and used such constructs to investigate the role of the phorbol ester TPA responsive element (TRE) in the shear-induced MCP-1 gene expression in vascular endothelial cells. Functional analysis showed that TGACTCC (a divergent TRE) located at nt -54 to -60 is necessary for shear-inducibility in bovine aortic endothelial cells (BAEC). The induction of the wild-type MCP-1 promoter construct by shear stress was attenuated by pretreating the cells with 1 microM dexamethasone or 1 microM retinoic acid 12 h before the shear stress experiments. The induction by shear stress reduced from 13-fold in the untreated cells to 7- and 3-folds in the dexamethasone- and retinoic acid-treated cells, respectively. These results demonstrate that the glucocorticoid receptor and retinoic acid receptor may interfere with the shear stress-activated AP-1/TRE. The reporter activity of HIV(LTR), which is a plasmid construct of the long terminal repeats of the human immunodeficiency virus and contains a kappa B enhancer element, was also activated by shear stress. The results of our investigations indicate that the shear stress-induced IE gene expression can be mediated through multiple cis-elements.
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PMID:Multiple cis-elements mediate shear stress-induced gene expression. 866 85

Short wavelength (254 nm) ultraviolet light (UVC) radiation was much more potent in activating transcription of human immunodeficiency virus 1 (HIV) reporter genes stably integrated into the genomes of human and monkey cells than ionizing radiation (IR) from a 137Cs source at similarly cytotoxic doses. A similar differential was also observed when c-jun transcription levels were examined. However, these transcription levels do not correlate with activation of nuclear factor (NF)-kappa B and AP-1 measured by band-shift assays, i.e. both types of radiation produce similar increases in NF-kappa B and AP-1 activity, suggesting existence of additional levels of regulation during these responses. Because of the well-established involvement of cytoplasmic signaling pathways in the cellular response to tumor necrosis factor-alpha (TNF-alpha), UVC, and IR using other types of assays, the role of TNF-alpha in the UVC response of HIV and c-jun was investigated in our cell system. We demonstrate that UVC and TNF-alpha activate HIV gene expression in a synergistic fashion, suggesting that it is unlikely that TNF-alpha is involved in UVC activation of HIV transcription in stably transfected HeLa cells. Moreover, maximum TNF-alpha stimulation resulted in one order of magnitude lower levels of HIV expression than that observed after UVC exposure. We also observed an additive effect of UVC and TNF-alpha on c-jun steady-state mRNA levels, suggestive of a partial overlap in activation mechanism of c-jun by UVC and TNF-alpha; yet these responses are distinct to some extent. Our results indicate that the HIV, and to some extent also the c-jun, transcriptional responses to UVC are not the result of TNF-alpha stimulation and subsequent downstream cytoplasmic signaling events in HeLa cells. Additional levels of regulation that do not directly involve the NF-kappa B and AP-1 transcription factors, such as changes in chromatin structure associated with the UV repair process, may also be important for a full transcriptional response of HIV and c-jun to UVC. In addition to the new data, this report also summarizes our current views regarding UVC-induced activations of HIV gene expression in stably transfected cells.
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PMID:Signal transduction and HIV transcriptional activation after exposure to ultraviolet light and other DNA-damaging agents. 876 May 69

To examine the roles of auxiliary genes and the AP-1 binding site in the long terminal repeat of feline immunodeficiency virus (FIV) in vivo, three mutant viruses, which are defective in the vif gene ([delta]vif), ORF-A gene (deltaORF-A), and AP-1 binding site (deltaAP-1), and wild-type virus as a positive control were separately inoculated into three specific-pathogen-free cats. These cats were assessed by measuring the number of proviral DNA copies in peripheral blood mononuclear cells (PBMCs), the CD4/CD8 ratio and antibody responses to FIV for 16 weeks and then examining histological changes at necropsy. Although viral DNAs were detected in PBMCs from all 12 cats to various degrees until 16 weeks postinoculation, no virus was recovered from PBMCs of cats infected with (delta)vif virus during the observation period. However, a very weak antibody response was induced in one cat infected with the (delta)vif virus. In contrast, despite the successful recovery of virus from both groups of cats infected with deltaORF-A and deltaAP-1 virus, antibody responses and decrease in the CD4/CD8 ratio in the groups were milder than those in cats infected with wild-type virus. Furthermore, the numbers of proviral DNA copies in PBMCs from the two groups were not able to reach the level in cats infected with wild-type virus during the observation period. From these results, we conclude that these mutant viruses are still infectious for cats but failed in efficient viral replication and suggest that these auxiliary genes and enhancer element are important or essential to full viral replication kinetics and presumably to full pathogenicity during the early stage of infection in vivo.
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PMID:Roles of the auxiliary genes and AP-1 binding site in the long terminal repeat of feline immunodeficiency virus in the early stage of infection in cats. 897 Sep 75

Under physiological conditions, activation of CD4+ T cells by major histocompatibility complex (MHC)antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell proliferation and interleukin (IL)-2 production in human CD4+ T cells, in an MHC-independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL-2 transcription factors NF-AT, NF-kappaB, and AP-1. AP-1 plays a key role in the regulation of IL-2 transcription, and ERK and JNK activities are necessary for regulating AP-1 at both the transcriptional and the post-transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK) by two CD4 ligands, gp160 the envelope glycoprotein of human immunodeficiency virus (HIV) and an anti-CD4 monoclonal antibody (mAb). Pre-incubation of CD4+ T lymphocytes in the presence of anti-CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12-myristate 13-acetate and ionomycin. In the same conditions, phosphorylation and activation of ERK-2 were also inhibited. Inhibition of both JNK and ERK-2 activities are specific for binding of CD4 ligands to the CD4 molecule. They were not observed in CD8+ T lymphocytes. These results suggest that a specific inhibition of JNK and ERK-2 activities contributes to defective IL-2 production in T lymphocytes pre-incubated with CD4 ligands.
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PMID:gp160 of HIV or anti-CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK-2 activities in human peripheral CD4+ T lymphocytes. 904 10

When transcriptionally active, the human immunodeficiency virus (HIV) promoter contains a nucleosome-free region encompassing both the promoter/enhancer region and a large region (255 nucleotides [nt]) downstream of the transcription start site. We have previously identified new binding sites for transcription factors downstream of the transcription start site (nt 465 to 720): three AP-1 sites (I, II, and III), an AP3-like motif (AP3-L), a downstream binding factor (DBF) site, and juxtaposed Sp1 sites. Here, we show that the DBF site is an interferon-responsive factor (IRF) binding site and that the AP3-L motif binds the T-cell-specific factor NF-AT. Mutations that abolish the binding of each factor to its cognate site are introduced in an infectious HIV-1 molecular clone to study their effect on HIV-1 transcription and replication. Individual mutation of the DBF or AP3-L site as well as the double mutation AP-1(III)/AP3-L did not affect HIV-1 replication compared to that of the wild-type virus. In contrast, proviruses carrying mutations in the Sp1 sites were totally defective in terms of replication. Virus production occurred with slightly delayed kinetics for viruses containing combined mutations in the AP-1(III), AP3-L, and DBF sites and in the AP3-L and DBF-sites, whereas viruses mutated in the AP-1(I,II,III) and AP3-L sites and in the AP-1(I,II,III), AP3-L, and DBF sites exhibited a severely defective replicative phenotype. No RNA-packaging defect could be measured for any of the mutant viruses as determined by quantification of their HIV genomic RNA. Measurement of the transcriptional activity of the HIV-1 promoter after transient transfection of the HIV-1 provirus DNA or of long terminal repeat-luciferase constructs showed a positive correlation between the transcriptional and the replication defects for most mutants.
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PMID:Transcription factor binding sites downstream of the human immunodeficiency virus type 1 transcription start site are important for virus infectivity. 922 6

NF-kappaB and activator protein 1 (AP-1) are dimeric transcription factors involved in transcriptional regulation in many cells, including neurons. We have examined their activity during mouse cerebellum development, a postnatal process starting just after birth and completed by the fourth postnatal (PN) week. The activity of these factors was analyzed by binding of nuclear extracts to a synthetic oligonucleotide representing the kappaB site of human immunodeficiency virus or the AP-1 site of the urokinase promoter. NF-kappaB activity was observed from 7 PN, was restricted to the developing cerebellum, and was not observed in the early postnatal neocortex and hippocampus. On the other hand, AP-1 activity was not found in cerebellum but was present in both neocortex and hippocampus. Moreover, a kappaB-driven transgene was found to be increasingly expressed in the cerebellum from 5 PN to 10 PN but not in the adult. The regulation of NF-kappaB activation in mouse cerebellum was analyzed by intraperitoneal injection of glutamate receptor antagonists to 9 PN mice, which abolished NF-kappaB-binding activity, suggesting an endogenous loop of glutamate receptor activation. Glutamate receptor agonists, on the other hand, induced NF-kappaB nuclear translocation in the cerebellum of 5 PN mice, which is a stage in which NF-kappaB is not yet endogenously activated. This effect was specific for NF-kappaB and not observed for AP-1. In adult mice, NF-kappaB activity was absent in the cerebellum and was not induced by intraperitoneal injection of glutamate receptor agonists. These data show that NF-kappaB is specifically activated during cerebellum development and indicate an important role of glutamate receptors in this process.
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PMID:Glutamate-dependent activation of NF-kappaB during mouse cerebellum development. 923 17


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