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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phorbol ester phorbol myristate acetate (PMA) strongly inhibits human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation; it has been suggested that this inhibitory effect is due to the transient downmodulation of the surface-associated CD4 receptors by PMA (I. H. Chowdhury, Y. Koyanagi, S. Kobayashi, Y. Hamamoto, H. Yoshiyama, T. Yoshida, and N. Yamamoto, Virology 176:126-132, 1990). Surprisingly, PMA treatment of cells expressing truncated (A2.01.CD4.401) and hybrid (A2.01.CD4.CD8) CD4 molecules, which are not downmodulated (P. Bedinger, A. Moriarty, R. C. von Borstel II, N. J. Donovan, K. S. Steimer, and D. R. Littman, Nature [London] 334:162-165, 1988), inhibited their fusion with CD4- (12E1) cells expressing vaccinia virus-encoded HIV-1 envelope glycoprotein (gp120-gp41) and with chronically HIV-1-infected H9 (MN, IIIB, or RF) cells. PMA pretreatment of T (12E1) and non-T (HeLa, U937.3, and Epstein-Barr virus-transformed B) cell lines expressing vaccinia virus-encoded CD4 also blocked fusion with 12E1 cells expressing vaccinia virus-encoded gp120-gp41. Interestingly, pretreatment of the gp120-gp41-expressing 12E1 cells with PMA did not alter their fusion with untreated CD4-expressing cells. Although the inhibitory effect of PMA was rapid and treatment for 1.5 h with 5 ng of PMA per ml was sufficient to reduce fusion by more than 50%, the recovery after treatment was slow and more than 40 h was needed before the cells regained half of their fusion potential. The inhibitory effect of PMA was blocked by staurosporine in a dose-dependent fashion, suggesting that it is mediated by protein kinase C. PMA treatment of A2.01.CD4.401 cells reduced the number of infected cells 6.7-fold, as estimated by a quantitative analysis of the HIV-1 MN infection kinetics, probably by affecting the stage of virus entry into cells. CD26 surface expression was not significantly changed by PMA treatment. We conclude that PMA inhibits the CD4-gp120-gp41-mediated fusion by modulating an accessory component(s), different from CD26, in the target CD4-expressing cells. These findings suggest a novel approach for identification of accessory molecules involved in fusion and may have implications for the development of antiviral agents.
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PMID:The phorbol ester phorbol myristate acetate inhibits human immunodeficiency virus type 1 envelope-mediated fusion by modulating an accessory component(s) in CD4-expressing cells. 790 14

The membrane glycoprotein CD4 is required for optimal antigen-mediated activation of CD4+ T cells restricted by class II molecules of the major histocompatibility complex (MHC). CD4 cross-linking by anti-CD4 antibodies or binding by human immunodeficiency virus (HIV) gp120 has been shown to inhibit antigen-dependent and -independent T cell activation, abrogating T cell proliferation, IL-2 synthesis and the increase in the intracellular calcium concentration. The molecular basis of these opposing phenomena is ill-defined. To characterize further the inhibitory role of the CD4 molecule, we investigated the effects of CD4 ligands on the transcription factors regulating the IL-2 gene enhancer and IL-2 synthesis. We first confirmed that pre-treatment of peripheral human CD4+ T lymphocytes by CD4 ligands, HIV gp120 or anti-CD4 monoclonal antibodies inhibited IL-2 production and cell proliferation, which was normally induced by an anti-CD3 antibody (UCHT1) plus a protein kinase C activator (PMA). Moreover, these CD4 ligands inhibited the proliferation and synthesis of IL-2 induced by activators bypassing membrane events, i.e. PMA and calcium ionophore, pointing to an active signaling pathway triggered by the CD4 molecule. Gp120 and anti-CD4 antibodies induced a specific, significant decrease in the binding activity of NF-AT, NF-kappa B and AP-1, three transcription factors regulating IL-2 gene enhancer activity, as demonstrated by electrophoretic mobility shift assays. Inhibition was similarly observed following cell activation by activators involving membrane events and those bypassing them. These results strongly suggest that the inhibition mediated by cross-linking of the CD4 molecule is at least partly due to negative signal down-regulating the availability of nuclear factors necessary for the regulation of IL-2 gene transcription.
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PMID:Interaction of HIV gp120 and anti-CD4 antibodies with the CD4 molecule on human CD4+ T cells inhibits the binding activity of NF-AT, NF-kappa B and AP-1, three nuclear factors regulating interleukin-2 gene enhancer activity. 795 56

Soluble proteins of the human immunodeficiency virus (HIV) might play a significant role in the pathogenesis of HIV infection. The addition of synthetic Tat peptides, but not that of the recombinant Nef or Vif protein, inhibited proliferative responses of CD4+ tetanus antigen-specific, exogenous interleukin-2 (IL-2)-independent T-cell clones in a dose-dependent manner. In addition, Tat peptides inhibited the anti-CD3 monoclonal antibody-induced proliferative responses of both purified CD4+ and CD8+ T cells. Tat did not affect proliferative responses induced by phorbol myristate acetate plus ionomycin. The Tat peptides at the concentrations used (0.1 to 3 micrograms/ml) did not affect the viability of the cells as determined by trypan blue exclusion. Treatment of Tat peptides with polyclonal Tat antibodies abrogated the inhibitory effect of Tat. Soluble Tat proteins secreted by HeLa cells transfected with the tat gene also inhibited antigen-induced proliferation of the T-cell clones. Tat inhibited the anti-CD3 monoclonal antibody-induced IL-2 mRNA expression and IL-2 secretion but did not affect IL-2 receptor alpha-chain mRNA or protein expression on peripheral blood T cells. Finally, treatment of T-cell clones with the Tat peptide did not affect the antigen-induced increase in intracellular calcium, hydrolysis of phosphatidyl inositol to inositol trisphosphate, or translocation of protein kinase C from the cytosol to the membrane. These studies demonstrate that the mechanism of the Tat-mediated inhibition of T-cell functions involves a phospholipase C gamma 1-independent pathway.
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PMID:Human immunodeficiency virus Tat induces functional unresponsiveness in T cells. 798 46

The nef genes of the human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) and the related simian immunodeficiency viruses (SIVs) encode a protein (Nef) whose role in virus replication and cytopathicity remains uncertain. As an attempt to elucidate the function of nef, we characterized the nucleotide and corresponding protein sequences of naturally occurring nef genes obtained from several HIV-1-infected individuals. A consensus Nef sequence was derived and used to identify several features that were highly conserved among the Nef sequences. These features included a nearly invariant myristylation signal, regions of sequence polymorphism and variable duplication, a region with an acidic charge, a (Pxx)4 repeat sequence, and a potential protein kinase C phosphorylation site. Clustering of premature stop codons at position 124 was noted in 6 of the 54 Nef sequences. Further analysis revealed four stretches of residues that were highly conserved not only among the patient-derived HIV-1 Nef sequences, but also among the Nef sequences of HIV-2 and the SIVs, suggesting that Nef proteins expressed by these retroviruses are functionally equivalent. The "Nef-defining" sequences were used to evaluate the sequence alignments of known proteins reported to share sequence similarity with Nef sequences and to conduct additional computer-based searches for similar protein sequences. A gene encoding the consensus Nef sequence was also generated. This gene encodes a full-length Nef protein that should be a valuable tool in further studies of Nef function.
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PMID:Analysis of human immunodeficiency virus type 1 nef gene sequences present in vivo. 804 40

Surface expression of the CD4 glycoprotein molecule is postulated to facilitate antigen recognition through the T cell receptor (TCR) and is itself a receptor for human immunodeficiency virus (HIV)-gp120 glycoprotein. Both antigen-stimulated TCR activation and HIV infectivity can be blocked by whole anti-CD4 antibodies. Although selective modulation of CD4 from the surface by gangliosides (GM1) blocks HIV infectivity, it enhances associated TCR function. Enhanced TCR function has also been observed after intracellular delivery of synthetic CD4 mRNA-antisense oligodeoxynucleotides (ODN) that block de novo synthesis of CD4. These specific CD4 modulations were mechanistically different from one another yet they both selectively removed the CD4 molecule from the T cell surface and enhanced antigen-stimulated function through the TCR. The proposed role of CD4 during TCR function and HIV infectivity was developed, in part, according to decreases following CD4 antagonism by whole antibody or down-modulation of CD4 by phorbol-stimulated protein kinase C activity. Selective CD4 modulations have independently redefined the specific contributions of CD4 surface expression during T cell activation and may establish a role for CD4 receptor subtypes during HIV-1 infection of CD4+ cells.
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PMID:Understanding the CD4 molecule: surface expression and function. 805 86

With T-cell lines constitutively expressing Nef from the SF2 strain of human immunodeficiency virus type 1 (HIV-1SF2) in the form of a hybrid CD8-Nef fusion protein or T-cell lines chronically infected with HIV-1SF2, a cellular serine kinase was found that specifically associates with Nef. Proteins of 62 kDa and 72 kDa, which coimmunoprecipitated with Nef, were phosphorylated in in vitro kinase assays. This Nef-associated serine kinase activity was not blocked by inhibitors of protein kinase C or protein kinase A and was lost when Nef was truncated at amino acid 94 or 99. These findings present evidence that a serine kinase activity is associated with Nef expressed in human T lymphocytes.
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PMID:Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. 810 42

Feline immunodeficiency virus (FIV) is a member of the genus Lentivirus of the family Retroviridae. FIV can infect T lymphocytes and monocytes/macrophages in vitro and in vivo, and causes an acquired immunodeficiency syndrome-like disease in cats. Several isolates of FIV from geographically distant countries have been molecularly cloned. There is considerable heterogeneity especially in Env gene among the FIV isolates and they can be divided into two or more subgroups. Like other lentiviruses, FIV has a complex genome structure. Gag gene encodes matrix, capsid and nucleocapsid proteins, and Pol gene encodes protease, reverse transcriptase, dUTPase and integrase. The dUTPase is not present in the primate lentiviruses but present in the non-primate lentiviruses. Env gene encodes surface and transmembrane envelope glycoproteins. In addition to the structural and enzymatic proteins, at least three more genes (Vif, ORF A, Rev) are present in FIV. Vif is related to the infectivity of the cell-free viruses. Rev functions in the stability and transport of incompletely spliced viral RNAs from the nucleus to cytoplasm and is indispensable for virus replication. Although the Tat protein of the primate lentiviruses is essential for virus replication, ORF A (putative Tat gene) of FIV is not essential for virus replication in established feline T lymphoblastoid cell lines. However, the ORF A gene product is related to the efficient replication of the virus in primary peripheral blood lymphocytes. In the long terminal repeat (LTR) of FIV, there are many putative binding sites for enhancer/promoter proteins. Among these binding sites, the putative AP-1 site is important for basal promoter activity of the LTR and responsible for the T cell activation signal through protein kinase C, however the site is not required for the virus replication in established feline T lymphoblastoid cell lines. Comparative study of the molecular biology of lentiviruses revealed that the genome structure, splicing pattern and functional enhancer protein-binding sites of FIV are more similar to those of the ruminant lentiviruses than those of the primate lentiviruses.
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PMID:The genome of feline immunodeficiency virus. 812 13

Studies were designed to identify genes induced in fibroblasts after exposure to low-dose neutron radiation but not after gamma rays. Our past work had shown similar modulation of transcripts for alpha-tubulin, beta- and gamma-actins, ornithine decarboxylase and interleukin 1 after exposure to either neutrons or gamma rays. However, differences in the expression of beta-protein kinase C and c-fos genes were observed, with both being induced after exposure to gamma rays but not neutrons. Recently we have identified two genes that are induced after exposure to neutrons but not gamma rays: Rp-8 (a gene associated with apoptosis) and the long terminal repeat (LTR) of the human immunodeficiency virus (HIV). Induction of Rp-8 mRNA was demonstrated in Syrian hamster embryo (SHE) fibroblasts and was found to be induced in cells exposed to neutrons administered at low (0.005 Gy/min) and high dose rate (0.12 Gy/min). No induction of other genes associated with apoptosis such as Rp-2, bcl-2 and Tcl-30 was observed. The induction of transcription from the LTR of HIV was demonstrated in HeLa cells bearing a transfected construct of the chloramphenicol acetyl transferase (CAT) gene driven by the HIV-LTR promoter. Measurements of CAT activity and CAT transcripts after irradiation demonstrated an unresponsiveness to gamma rays over a broad range of doses (0.1-3 Gy). Twofold induction of the HIV-LTR was detected after exposure to neutrons (0.48 Gy) administered at low (0.05 Gy/min) but not high (0.12 Gy/min) dose rates. Ultraviolet-mediated HIV-LTR induction, however, was inhibited by exposure to low-dose-rate neutron irradiation. These results are interesting in light of reports that Rp-8 is induced during apoptosis and that HIV causes apoptosis.
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PMID:Low doses of neutrons induce changes in gene expression. 814 28

Human immunodeficiency virus isolates express a Nef protein with either an alanine or a threonine at amino acid residue 15. The threonine residue is a site for phosphorylation by protein kinase C. Jurkat T cells constitutively expressing the alanine variant of Nef exhibit the ability to downregulate the induction of transcription factors NF-kB and AP-1. In contrast, Jurkat cells with the threonine variant of Nef are at least partially restored in their ability to recruit NF-kB and AP-1.
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PMID:Regulation of human immunodeficiency virus Nef protein by phosphorylation. 817 81

Human immunodeficiency virus 1 (HIV-1) and its purified proteins activate target cell functions. Because protein kinase C (PKC) plays a crucial role in signal transduction and there is a molecular heterogeneity of PKC, we compared the effect of recombinant HIV-1 gp120 and phorbol ester (PMA) on PKC isozymes in monocytic U937 cells, with isozyme-specific antibodies using flow cytometry. All PKC isozymes except PKC-gamma were present in U937 cells. Both PMA and HIV-1 gp120 increased levels of calcium-dependent and -independent PKC isozymes. The most striking change was observed in PKC-zeta isozymes levels. This study for the first time demonstrates that HIV-1 gp120 affects calcium-independent PKC isozymes in U937 cells.
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PMID:Human immunodeficiency virus-1 recombinant gp120 induces changes in protein kinase C isozymes--a preliminary report. 820 85


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