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: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NF-kappa B is a DNA-binding regulatory factor able to control transcription of a number of genes, including human immunodeficiency virus (HIV) genes. In T cells, NF-kappa B is activated upon cellular treatment by phorbol esters and the cytokine tumor necrosis factor alpha (TNF alpha). In the present work, we investigated the molecular events leading to NF-kappa B activation by TNF alpha in a human T cell line (Jurkat) and its subclone JCT6, which presents a deficiency in the PKA transduction pathway. We found that in both cell lines, both phorbol ester and TNF alpha were able to activate NF-kappa B. Phorbol activation was positively modulated by Ca2+ influx while TNF alpha activation was not. Furthermore, while PMA activation was inhibited by the PKC inhibitor staurosporin, the TNF alpha effect was unchanged. TNF alpha did not activate cAMP production and its signal was not modulated by cAMP activators. Moreover, cAMP activators did not activate NF-kappa B in Jurkat cells. Thus, TNF alpha-induced NF-kappa B activation was found to be mediated by none of the major signal-mediating kinases such as protein kinase C (PKC), protein kinase A, or Ca(2+)-regulated kinases. Furthermore, we found that cytoplasmic acidification facilitated NF-kappa B activation by both TNF alpha and PKC, by a mechanism that increases NF-kappa B/I kappa B dissociation without affecting the NF-kappa B translocation step.
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PMID:NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. 165 56

By using human CD4+ lymphoblastoid T cells transiently cotransfected with human immunodeficiency virus (HIV) and cytomegalovirus (CMV), we tested whether modulation of T-cell activation through the protein kinase C (PKC) or the protein kinase A (PKA) pathway synergized with CMV immediate-early (IE) proteins in HIV long terminal repeat (LTR) transactivation. Stimulation with phorbol myristate acetate, tumor necrosis factor, or cross-linked antibodies to CD3 and CD28 resulted in modest enhancement (two- to fourfold) of the activity of a luciferase expression vector under control of the HIV LTR. Cotransfection of a vector expressing the CMV IE1 and IE2 proteins under the control of their own promoter enhanced HIV LTR activity 16- to 49-fold. Combination of any one of the above stimuli and CMV IE expression amplified HIV LTR activity 99- to 624-fold. Stimulation of PKA-dependent pathways with forskolin, 8-bromo cyclic AMP, or prostaglandin E2 had a minimal effect on HIV LTR activity, whereas such stimuli resulted in synergistic amplification in cells cotransfected with CMV IE (three- to fivefold increases over the effects of CMV IE alone). This synergism was independent of the NF-kappa B binding motifs within the HIV LTR. CMV IE2, but not IE1, protein induced HIV transactivation and synergized with signals modulating T-cell activation. The intense synergism observed was superior to the increase in IE protein expression following PKC activation by phorbol myristate acetate. Treatment of cells with PKC inhibitor GF109203X blocked most of the observed synergism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of T-cell activation through protein kinase C- or A-dependent signalling pathways synergistically increases human immunodeficiency virus long terminal repeat induction by cytomegalovirus immediate-early proteins. 165 49

We have developed a unique physiologic model of chronic human immunodeficiency virus type 1 (HIV-1) infection, OM-10.1, clonally derived from infected HL-60 promyelocytes and harboring a single integrated provirus. Unlike other models of chronic infection, OM-10.1 cultures remain CD4+ under normal culture conditions, during which less than 10% of the cells constitutively express HIV-1 proteins. However, when treated with tumor necrosis factor alpha (TNF-alpha), OM-10.1 cultures dramatically increased (greater than 35-fold) HIV-1 expression and rapidly down-modulated surface CD4, as greater than 95% of the cells became HIV-1+. The complete loss of surface CD4 following viral activation was neither associated with apparent cytopathicity nor due to a decline of available CD4 mRNA. There was, however, a temporal association between CD4 down-modulation and the accumulation of intracellular HIV-1 gp 160/120; in addition, intracellular CD4-gp 160 complexes were identifiable in OM-10.1 cell lysates at time points following TNF-alpha induction after surface CD4 was no longer detectable. Surface CD4 expression by OM-10.1 cells returned once viral activation ceased and could be repeatedly oscillated upon HIV-1 reactivation. Furthermore, inhibition of protein kinase activity following maximal TNF-alpha stimulation of OM-10.1 cells quickly returned activated HIV-1 to a state of latency, as evidenced by an accelerated return of surface CD4. These results with the new OM-10.1 cell line demonstrate that CD4 surface expression can be maintained during chronic infection and is critically dependent on the state of viral activation, that CD4-gp 160 intracellular complexing is involved in CD4 down-modulation, and that protein kinase pathways not only function in the primary induction of latent HIV-1 but also are required for maintaining the state of viral activation.
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PMID:Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection. 167 37

A number of eucaryotic viruses have devised strategies to minimize the deleterious effects on protein synthesis caused by activation of the interferon-induced, double-stranded-RNA-activated protein kinase, P68. In a recent report, we described the down regulation of the P68 protein kinase in cells infected by human immunodeficiency virus type 1 (HIV-1) (S. Roy, M. G. Katze, N. T. Parkin, I. Edery, A. G. Hovanessian, and N. Sonenberg, Science 247:1216-1219, (1990). We now present evidence that such a decrease in amounts of P68 could be essential for HIV-1 replication because of the presence of the Tat-responsive sequence (TAR sequence) present in the 5' untranslated region of HIV-1 mRNAs, which activates the P68 kinase. We found that poly(A)+ mRNAs prepared from HIV-1-infected cells efficiently activated the protein kinase as did mRNAs from stably transformed cell lines constitutively expressing the TAR region. Furthermore, we found that TAR-containing RNAs complexed with purified P68 protein kinase in vitro by two independent assays and could be cross-linked to P68 kinase present in a HeLa cell extract. Experiments using in vitro-synthesized wild-type and mutant TAR RNAs revealed that both the efficient binding to and the activation of P68 kinase were dependent on the TAR RNA stem structure. The TAR-P68 complex could be competed out by a synthetic RNA that bound to and activated the protein kinase but not by a synthetic RNA that bound with low affinity and did not activate P68. The possible biological consequences of a P68-TAR interaction that may include the switch from latent to active virus replication are discussed.
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PMID:The integrity of the stem structure of human immunodeficiency virus type 1 Tat-responsive sequence of RNA is required for interaction with the interferon-induced 68,000-Mr protein kinase. 170 40

Myeloblast cell line K562, when stably transfected with the human genomic c-fes sequence encoding a proto-oncogene tyrosine-protein kinase, acquires the characteristics of more mature granulocytic cells (WS-1 cells) and the ability to undergo differentiation (Yu, G., Smithgall, T. E., and Glazer, R. I. (1989) J. Biol. Chem. 264, 10276-10281). To explore the role of transcription factors in the differentiation process, WS-1 cells were analyzed for the presence of DNA-binding proteins capable of interacting with the 5'-long terminal repeat (LTR) region of human immunodeficiency virus (HIV)-1, that contains the binding sequences for transcription factors Sp1 and NFKB. Southwestern blotting and mobility shift assays revealed the presence of Sp1 in K562 and WS-1 cells. The DNA-binding activity of Sp1 was significantly greater in WS-1 cells than in K562 cells, despite the detection by immuno-blotting of equivalent quantities and degrees of heterogeneity of Sp1 in both cell lines. DNA footprinting of the HIV-1 5'-LTR demonstrated that two of the three Sp1-binding sites and both NFKB binding sequences were protected by nuclear extracts from WS-1 cells, while no protection was afforded by nuclear extracts from K562 cells. Analysis of transcription in vitro by primer extension revealed enhanced initiation of transcription from the HIV-1 5'-LTR by nuclear extracts from WS-1 cells, but not from K562 cells. These data indicate that the response evoked by the c-fes tyrosine-protein kinase leads to enhanced DNA binding activity of Sp1 and NFKB, that results in the activation of transcription from the HIV-1 5'-LTR.
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PMID:Increased DNA binding and transcriptional activity associated with transcription factor Sp1 in K562 cells transfected with the myeloid-specific c-fes tyrosine kinase gene. 187 37

Translational effects of the RNA leader and Tat protein of human immunodeficiency virus type 1 (HIV-1) were investigated in rabbit reticulocyte lysate. Hybrid RNA species with natural or mutated HIV-1 leader fused to human interferon- gamma mRNA were produced in vitro from recombinant plasmids. HIV-1 leader RNA was found to inhibit translation through two mechanisms. A 3-fold trans-inhibition of translation was demonstrated by mixing hybrid HIV-1 leader RNA with indicator interferon mRNA. By comparison, HIV-1 leader caused a 50-fold cis-inhibition in lysate in which two trans-inhibitory factors, double-stranded RNA-dependent protein kinase and (2'-5')oligoadenylate synthetase, were suppressed. In contrast, purified HIV-1 Tat protein produced in Escherichia coli enhanced by 4-fold translation from HIV-1 leader-interferon mRNA but not from interferon mRNA lacking HIV sequences or from total poly(A)+ RNA. Translation of mRNA containing either a single base substitution in the loop of the "trans-acting responsive" sequence (TAR) or an alternative stem-loop in TAR was nevertheless stimulated by Tat. The enhancement of translation by Tat was largely due to relief of cis-inhibition, since the effect was found even in lysate in which double-stranded RNA-dependent protein kinase was inhibited with 2-aminopurine. These results suggest that translation is an important level of control in the replication cycle of HIV-1.
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PMID:Direct evidence for translational regulation by leader RNA and Tat protein of human immunodeficiency virus type 1. 212 Jul 1

The tat-responsive region (TAR) of the human immunodeficiency virus-1 (HIV-1) exhibits a trans-inhibitory effect on translation in vitro by activating the interferon-induced 68-kilodalton protein kinase (p68 kinase). Productive infection by HIV-1 was shown to result in a significant decrease in the amount of cellular p68 kinase. The steady-state amount of p68 kinase was also reduced in interferon-treated HeLa cell lines stably expressing tat, as compared to the amount of the kinase in interferon-treated control HeLa cells. Thus, the potential translational inhibitory effects of the TAR RNA region mediated by activation of p68 kinase may be downregulated by tat during productive HIV-1 infection.
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PMID:Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product. 218 64

The transient expression of hepatitis B virus (HBV) surface and "eJ" antigens caused by transfection of human hepatoblastoma HepG2 cells with HBV DNA was markedly inhibited by cotransfection with poly(I):poly(C). Cotransfection with poly(I):poly(C) also inhibited the expression of bacterial chloramphenicol acetyltransferase (CAT) gene which was under the control of either the HBV core promoter or the human immunodeficiency virus (HIV-1) long terminal repeat. This inhibition was much more pronounced on the expression of HBV-promoted CAT than HIV-promoted CAT. The uptake of reporter plasmid was not affected by cotransfected poly(I):poly(C). The inhibition was found to be at the steady-state CAT mRNA level and appeared to be specific for HBV and HIV regulatory sequences since CAT expression directed by other viral and cellular regulatory sequences was not inhibited. Cotransfection with a mixture of equal amounts of poly(I) and poly(C) had similar inhibitory effects whereas cotransfection with poly(l) or poly(C) alone, or other double-stranded ribo- or deoxyribonucleotides, did not have such strong effects. The addition of poly(l):poly(C) to the culture medium of cells transfected with these reporter plasmids caused little inhibition. Transfection with poly(l):poly(C) induced a minimal amount of intracellular interferon-alpha in HepG2 cells which may be involved in selective inhibition of HBV-and HIV-1-directed gene expression. 2-Aminopurine, an inhibitor of double-stranded RNA activated protein kinase known to block interferon gene induction by poly(l):poly(C), partially reversed the poly(l):poly(C)-induced inhibitory effect on HBV-CAT expression.
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PMID:Selective inhibition of hepatitis B virus and human immunodeficiency virus sequence-promoted gene expression by cotransfected poly(I):poly(C). 221 31

Transcription from the human immunodeficiency virus type 1 promoter gives rise to short cytoplasmic transcripts of approximately 60 nucleotides as well as to longer mRNAs. These RNAs contain the Tat-responsive region sequence, which is capable of assuming a stem-loop structure and has been implicated in the regulation of both transcription and translation. It has been reported that Tat-responsive region RNA inhibits translation in vitro through activation of an interferon-induced protein kinase, the double-stranded-RNA-activated inhibitor, which phosphorylates eukaryotic initiation factor 2. We show that the activation property is due to double-stranded RNA that often contaminates RNA synthesized in vitro using bacteriophage RNA polymerases. After purification, high concentrations of Tat-responsive region RNA inhibit the activation of double-stranded RNA-activated inhibitor, suggesting that it may serve to protect human immunodeficiency virus type 1 infection from a cellular defense mechanism.
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PMID:Tat-responsive region RNA of human immunodeficiency virus 1 can prevent activation of the double-stranded-RNA-activated protein kinase. 224 37

The G0S19 genes are members of the "small inducible" family of genes, which have similar exon-intron organizations and encode secreted proteins with similar dispositions of cysteine and proline residues. G0S19-1 mRNA is increased shortly after the addition of lectin or cycloheximide to cultured human blood mononuclear cells. The cDNA sequence is homologous to that of a murine gene encoding an inhibitory cytokine (MIP1 alpha/SCI), which decreases hemopoietic stem cell proliferation. The homology extends to the 3' noncoding region, which contains two conserved elements: (i) GGGACTCTTC, a potential transcription factor NF chi B-binding site, and (ii) TTTTGTAATTTATTTT, which is found in some related genes (e.g., that encoding the immediate early protein ornithine decarboxylase). A similar but complementary sequence is present in human immunodeficiency virus. Two of the three human genes that hybridize to G0S19-1 cDNA were sequenced. G0S19-1 has 5' AP1-like recognition elements as found in some other phorbol ester-responsive genes (e.g., c-fos). G0S19-2 has a 5' Alu sequence, but is likely to be expressed because of the conservation of sections of the gene believed to be important for function. The 5' flanks of both genes contain the nucleotide motifs CK-2 and SRE, indicating cytokine-like genes with the potential to respond to growth factors. G0S19-1 is the main G0S19 gene expressed in adult T lymphocytes and may encode a homeostatic negative regulator of the size of cell populations (or subpopulations) which are derived ultimately from marrow stem cells. As such, it is a potential antioncogene.
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PMID:Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation. 227 Nov 20


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