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)

Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation. The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha-lipoic acid, prior to the stimulation of cells was found to inhibit NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be effective in AIDS therapeutics.
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PMID:Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. 148 76

The transcriptional activator protein (Tax) from human T-cell leukemia virus type 1 was expressed in yeast using several different promoters in several strains: In all instances, expression of Tax resulted in very strong aggregation of the yeast cells. This phenotype appears to be identical by all criteria tested to the flocculation phenotype of the dominant mutation flo 1. Of most significance, mutations in Tax that affect transactivation of the IL-2R alpha regulatory sequences, but retain their ability to activate the viral long terminal repeat also fail to yield the aggregation phenotype. Based on these findings, expression of Tax in yeast may prove to be a simple primordial system for examining the regulatory mechanisms and cellular functions involved in regulation of gene expression.
AIDS Res Hum Retroviruses 1990 Nov
PMID:Expression of the HTLV-I tax transactivator in yeast: correlation between phenotypic alterations and tax function in higher eukaryotes. 207 11

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

Three human T-lymphotropic viruses have been isolated and characterized in the past 5 years. The ability to culture target cells with T-cell growth factor and sensitive detection systems for the virally encoded polymerase reverse transcriptase permitted isolation of HTLV-I, which is strongly linked to the cause of adult T-cell leukemia and associated with other lymphoid malignancies in endemic areas. The same techniques, using a permissive human tumor cell line, allowed the isolation and characterization of HTLV-III/lymphadenopathy-associated virus, which is implicated as the primary cause of the acquired immunodeficiency syndrome (AIDS). This virus shares some features with HTLV-I and HTLV-II, such as additional genes not found in most retroviruses. One gene codes for a transcriptional activator protein and may be a feature of a larger group of related retroviruses. The clear identification of the primary cause of AIDS has resulted in the development of specific immunologic reagents, preventive and therapeutic proposals, and comprehensive identification of the clinical diseases associated with this virus.
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PMID:A human T-lymphotropic retrovirus (HTLV-III) as the cause of the acquired immunodeficiency syndrome. 299 99

A T-lymphotropic retrovirus with cytopathic but not immortalizing activity has been isolated repeatedly from patients with acquired immune deficiency (AIDS) or lymphadenopathy syndrome (LAS) and successfully transmitted to a T-cell line (HT) for continuous production. Seroepidemiology data and the OKT4 tropism and cytopathogenicity of this virus indicate it is the etiological agent of AIDS. We have cloned HTLV-III genomes using three approaches: (1) cDNA clones were obtained from a cDNA plasmid library constructed from RNA of purified virions using oligo (dT) primers; (2) unintegrated provirus clones were obtained from Hirt supernatants of acutely infected H9 cells using virus from H9/HTLV-III; (3) clones of integrated provirus with flanking cellular sequences were obtained from a genomic DNA library of H9/HTLV-III. Analyses of these clones show that the HTLV-III genome is similar in size to those of HTLV-I and HTLV-II and contains a gene that functions as a transcriptional activator. Different isolates of HTLV-III display greater polymorphism than different isolates of HTLV-I among each other, possibly due to the highly replicative nature of HTLV-III. Viral sequences could be detected in fresh lymph node tissues of some AIDS patients, but even in the positive samples the number of infected cells is small (less than 1%). In both fresh tissues that are positive for viral sequences and HTLV-III infected cell lines, a substantial amount of unintegrated viral DNA is present in addition to integrated provirus. This is an unusual finding for retroviruses but may be significant in the cytopathicity of HTLV-III as has been proposed for some avain retroviruses.
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PMID:Molecular characterization of human T-lymphotropic leukemia virus type III associated with the acquired immunodeficiency syndrome. 610 Jun 46

The correlation between virus induced NF-kappa B DNA binding activity and interferon gene expression was examined in the myelomonoblastic PLB-985 cell line. Previous studies have shown that chronic HIV-1 infection of PLB-985 cells (PLB-IIIB) leads to the selection of cells with a more differentiated monocytic phenotype and with constitutive NF-kappa B DNA-binding activity. In this report we demonstrate that the kinetics of HIV-1 and Sendai virus infection of PLB-985 cells directly correlates with induction of NF-kappa B DNA binding activity. Based on UV cross-linking and immunoprecipitation analysis, p50, the strong transcriptional activator p65 and c-Rel represent the major constituents of this NF-kappa B DNA-binding activity. We also demonstrate an alteration in the kinetics of type I IFN gene transcription following secondary Sendai virus infection of PLB-IIIB cells compared to PLB-985. The results of our studies suggest that HIV infected individuals may respond differently to secondary viral or bacterial infections by augmenting the synthesis of NF-kappa B regulated immune response modifiers, which could alter the onset or progression of AIDS.
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PMID:Virus induction of NF-kappa B/Rel proteins and type I interferon gene expression in myelomonoblastic cells. 815 86

Human T cell leukemia virus type 1 (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with an autoimmune condition. We examined the sensitivity of HTLV-I-infected T cell lines to Fas-mediated apoptosis, which plays a critical role in the elimination of self-reactive T cells. Among 13 human T-cell lines, all 4 HAM-derived T cell lines and 4 of 6 non-HAM/HTLV-I T cell lines were resistant to apoptosis induced by anti-Fas antibody, whereas only 1 of 3 uninfected cell lines was resistant to apoptosis. The cell lines resistant to apoptosis expressed the viral tax gene and/or the cellular FAP-1 (Fas-associated phosphatase) gene, both of which inhibit Fas-mediated apoptosis in T cell lines. Although Tax is a transcriptional activator of a number of cellular genes, the expression of Tax in a T cell line did not induce the expression of FAP-1, suggesting that these two antiapoptotic proteins independently function in HTLV-I-infected cells. Seven of 10 HTLV-I-infected cell lines, compared with only 1 of 3 virus-negative cell lines, expressed FAP-1. All four HAM cell lines expressed the FAP-1 gene, and its level in these cells was higher than in other T cell lines. Our results suggest that virus-infected T cells escape Fas-mediated immune surveillance by the function of Tax and FAP-1, and this escape may be involved in the autoimmune condition observed in HAM/TSP patients.
AIDS Res Hum Retroviruses 1998 Feb 10
PMID:Expression of FAP-1 (Fas-associated phosphatase) and resistance to Fas-mediated apoptosis in T cell lines derived from human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patients. 949 17

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a lymphotropic virus strongly linked to the development of KS, an endothelial cell neoplasm frequent in persons with AIDS. Reactivation from latency in B cells is thought to be an important antecedent to viral spread to endothelial cells during KS pathogenesis. Earlier experiments have posited a role for the transcriptional activator encoded by KSHV open reading frame 50 (ORF50) in such reactivation, since ectopic overexpression of this protein induces reactivation in latently infected B cells. Here we have explored several aspects of the expression, structure, and function of this protein bearing on this role. The ORF50 gene is expressed very early in lytic reactivation, before several other genes implicated as candidate regulatory genes in related viruses, and its expression can upregulate their promoters in transient assays. The protein is extensively phosphorylated in vivo and bears numerous sites for phosphorylation by protein kinase C, activators of which are potent stimulators of lytic induction. The C terminus of the ORF50 protein contains a domain that can strongly activate transcription when targeted to DNA; deletion of this domain generates an allele that expresses a truncated protein which retains the ability to form multimers with full-length ORF50 and functions as a dominant-negative protein. Expression of this allele in latently infected cells ablates spontaneous reactivation from latency and strikingly suppresses viral replication induced by multiple stimuli, including phorbol ester, ionomycin, and sodium butyrate. These results indicate that the ORF50 gene product plays an essential role in KSHV lytic replication and are consistent with its action as a putative molecular switch controlling the induction of virus from latency.
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PMID:Transcriptional activation by the product of open reading frame 50 of Kaposi's sarcoma-associated herpesvirus is required for lytic viral reactivation in B cells. 1051 43

Human immunodeficiency virus type 1 (HIV-1) is unique in that it encodes its own transcriptional activator Tat, which specifically binds to the viral mRNA sequence TAR (transactivation response) element and activates viral transcription at the step of elongation as well as initiation. We recently reported that fluoroquinoline derivatives inhibited HIV-1 replication most likely by blocking viral transcription. In this report, we investigated the mechanism of action of one such compound 7-(3, 4-dehydro-4-phenyl-1-piperidinyl)-1, 4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carbox ylic acid (K-37). We demonstrated that K-37 inhibited not only Tat but also other RNA-dependent transactivators. No effect was observed with DNA-dependent transactivators such as p65 (NF-kappaB) and Gal4VP16. Moreover, K-37 did not inhibit carboxyl-terminal domain (CTD)-kinase activities of CDK-activating kinase (CAK) and positive transcription elongation factor b (P-TEFb), which are known to be involved in Tat-mediated transactivation at the step of transcriptional elongation. It is suggested that RNA-mediated transactivation may involve a common unknown factor to which K-37 directly interacts. Since K-37 did not appear to block DNA-mediated transactivation and thus did not show strong nonspecific cytotoxicity as reported previously, K-37 and its derivative compounds are considered to be feasible candidates for a novel AIDS therapy.
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PMID:Inhibition of the RNA-dependent transactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37. 1087 84

HIV-1 expresses a multifunctional protein called TAT (trans-acting transcriptional activator), the function of which in vivo is tightly correlated with the incidence of Kaposi's sarcoma in AIDS patients. TAT is angiogenic and apparently binds to receptors specific for vascular endothelial growth factor (VEGF). Amino acids 46-60 of HIV-TAT, known as the basic peptide, have been shown to be responsible for its functional interaction with VEGF receptors. To characterize further the binding properties of this peptide, its coding sequence was fused to the reading frame of bacterial thioredoxin, allowing the production of large amounts of chimaeric polypeptides in bacteria in a biologically active form. Binding of chimaeric proteins to VEGF receptors was studied in vitro in endothelial cell cultures expressing either of the two receptors. Chimaeric thioredoxin proteins carrying the basic domain of TAT bound to both VEGF receptors with affinities similar to those of HIV-TAT or VEGF. Interestingly, these polypeptides competed only partially with VEGF for receptor binding, implying different binding sites for the TAT peptide and VEGF. This suggests that TAT binds VEGF receptors at new sites that might be useful targets for pharmacological intervention during pathological angiogenesis. The thioredoxin/basic-peptide chimaeras are functional agonists that mediate VEGF receptor signalling: (1) they stimulate the growth of endothelial cells; (2) together with basic fibroblast growth factor they cause tube formation of endothelial cells in collagen gels; (3) they induce blood vessel formation on the chicken chorioallantoic membrane; and (4) they activate VEGF receptor kinase and mitogen-activated protein kinase activity.
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PMID:Signalling properties of an HIV-encoded angiogenic peptide mimicking vascular endothelial growth factor activity. 1117 Oct 54


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