Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human pluripotential embryonic teratocarcinoma cells differentially expressed gene activity controlled by the human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) long terminal repeats (LTRs) when differentiation was induced by the morphogen all-trans retinoic acid. The alterations occurred after commitment and before the appearance of the multiple cell types characteristic of these pluripotential cells. After commitment, gene activity controlled by the HIV-1 LTR markedly increased, whereas that controlled by the HTLV-I LTR decreased. Steady-state mRNA levels and nuclear run-on transcription indicated that the increased HIV-1-directed activity during differentiation occurred posttranscriptionally, whereas the decreased HTLV-I activity was at the transcriptional level. Phorbol esters did not cause commitment but strongly enhanced expression by both viral LTRs at the transcriptional level. A specific inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, indicated that the enhanced activity involved the activation of protein kinase(s) C; altered cyclic nucleotide metabolism was apparently not involved. Differentiating cells gradually lost the ability to respond to phorbol ester stimulation. Experiments with a deletion mutant of the HIV-1 LTR suggested that this was due to imposition of negative regulation during differentiation that was not reversed by phorbol ester induction. Cycloheximide, with or without phorbol ester, slightly stimulated HIV-1-directed activity at the transcriptional level and massively increased the amounts of steady-state mRNA by posttranscriptional superinduction. It appeared, however, that new nuclear protein synthesis was required for maximal transcriptional stimulation by phorbol esters. Thus, changing cellular regulatory mechanisms influenced human retrovirus expression during human embryonic cell differentiation.
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PMID:Regulation of expression driven by human immunodeficiency virus type 1 and human T-cell leukemia virus type I long terminal repeats in pluripotential human embryonic cells. 283 1

Replication of human immunodeficiency virus type 1 requires the functional expression in trans of the virally encoded rev gene product (previously called art/trs). Here we demonstrate that this protein can be metabolically labeled with 32Pi. The phosphate receptor in the rev protein is shown to be exclusively serine. Treatment of rev-expressing cells with phorbol ester, a specific activator of protein kinase C, led to significant but transient enhancement of the level of rev phosphorylation. These results indicate that the rev protein is posttranslationally modified in vivo and suggest that the level of this modification is subject to modulation by extracellular stimuli.
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PMID:Phosphorylation of the rev gene product of human immunodeficiency virus type 1. 284 91

In the present work we have used monoclonal antibodies (mAb) as probes to attempt a dissection of the mechanisms underlying the immunodeficiency subsequent to bone marrow transplantation (BMT). To this end we have studied 19 allogeneic BMT recipients, analyzing the proliferative response of peripheral blood mononuclear cells (PBMC) after activation with either phytohemagglutinin (PHA), anti-CD3 or anti-CD2 mAb. All patients presented normal proportions of CD2+ and CD3+ lymphocytes, as assessed by flow cytometry. Our results indicated that in most cases both CD2 and CD3-mediated activation pathways were inefficient to trigger normal T cell proliferation. The addition of exogenous interleukin 2 (IL2) did not restore in most cases the proliferative response, pointing out that additional defects contribute to the hyporesponsiveness. This was more evident in the group of patients studied during the first 6 months. To further dissect the T cell defect we analyzed the effect of a phorbol ester (phorbol myristate acetate, PMA), which activates protein kinase C, on the anti-CD3-induced response. Our data showed that PMA synergized with anti-CD3 similarly to exogenous IL2, and restored the proliferative response only in certain cases. The expression of IL2 receptors (CD25) as assessed by cytofluorimetry, after either PHA or anti-CD3 and PMA stimulation, was shown to be depressed, and the addition of IL2 did not restore it. Finally, we observed that the early increase of intracytoplasmic Ca2+ after anti-CD3 stimulation was comparable to that detected in normal PBMC. Altogether these results indicate that a diminished CD25 expression is associated with the T cell defect, and cannot apparently be attributed to an inability of the CD3 molecule to transduce early activation signals thus suggesting that either protein kinase C itself or an as yet undefined metabolic step preceding IL2 receptor expression is abnormal in variable proportions of T cells after BMT, and constitutes another manifestation of this complex immunodeficiency.
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PMID:Defective interleukin 2 receptor expression is associated with the T cell disfunction subsequent to bone marrow transplantation. 311 80

Current models of T cell activation implicate increases in intracellular free Ca2+ concentration and activation of the Ca2+ and phospholipid dependent enzyme protein kinase C (PKC) as important early events leading to interleukin 2 (IL-2) production, interleukin 2 receptor (IL-2R) expression, and subsequent cell proliferation. The present study examined the age-related defect in T cell proliferation to determine if signals that activate PKC and increase intracytosolic free Ca2+ concentration might be defective. Using phorbol myristate acetate (PMA), which directly activates PKC, and Ca2+ ionophore A23187, which increases intracellular cytoplasmic free Ca2+ concentration, the induction of IL-2 secretion, IL-2R expression and cell proliferation were studied. The results demonstrate that following stimulation with PMA and A23187, purified T cells from elderly subjects demonstrate low levels of IL-2 production, IL-2R expression and cell proliferation. Exogenous purified human IL-2 did not fully correct the low proliferative responses of T cells from old donors, however, did markedly boost the response. While it appears that the inability of T cells to express IL-2R and respond to IL-2, along with a lower endogenous IL-2 production are limiting factors in cell proliferation, the inability of PMA and A23187 to correct this defect suggests that the early phases of signal transduction per se are probably not a primary cause of the immunodeficiency seen in ageing.
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PMID:Impaired phorbol ester and calcium ionophore induced proliferation of T cells from old humans. 312 7

The molecular mechanism(s) by which human immunodeficiency virus (HIV-1) injures a T-cell line was studied. A pathological role for viral env proteins, which are inserted into the plasma membrane, has been previously demonstrated for HIV as well as other retroviruses which are cytopathic. We therefore initiated studies examining whether perturbations of the cell membrane or membrane-associated biochemical events may be occurring in cells acutely infected with HIV and whether such perturbations, if present, may be responsible for cytopathology. A human T-cell line (ERIC), which is sensitive to the cytopathic effects of HIVs, was infected with HTLV-IIIB and its membrane permeability to cations and its lipid metabolism were studied coincident with the peak expression of viral p24 and with the first sign of cytopathology (slowing of cell division) 72 to 96 hr after infection. It was found that the rate of influx of Ca2+ into the cell increased over that of uninfected cells and that phospholipid synthesis, primarily phosphatidylcholine, became depressed. Diacylglycerol, which serves both as an intermediate for synthesis of phospholipids and as a second-messenger for lymphocyte activation, was also greatly reduced. However, triglyceride synthesis was enhanced, indicating that not all lipid metabolic pathways were being shut down. This decreased membrane-synthetic ability and reduced second-messenger for cell division are likely to be important causes of HIV-1 cytopathology in ERIC cells. This hypothesis was supported by our finding that HIV cytopathology of ERIC cells could be partially prevented by treatment with compounds (diacylglyceride or PMA and transiently by oleic acid) which either replenish diacylglycerol in the infected cell and/or activate protein kinase C or phosphocholine cytidyltransferase, the latter being the rate-limiting step in synthesis of the major structural phospholipid in most cells.
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PMID:Human immunodeficiency virus (HIV-1) cytotoxicity: perturbation of the cell membrane and depression of phospholipid synthesis. 312

Interleukin-2 (IL-2) is a chemically defined lymphokine (LK) available as mixed human (LK) preparations, as partially purified lymphoblastoid IL-2, or as recombinant human IL-2. Each has different actions dependent on companion LKs showing synergistic interaction (e.g., IL-1 and gamma-interferon (gamma-IFN]). IL-2 acts to expand activated T cells; to activate natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytolytic T cells (CTL); to regulate T-cell ontogeny via actions on prothymocytes and immature T cells; and to induce gamma-IFN and activate tumoricidal macrophages. IL-2 acts via specific cell surface receptors on protein kinase C and cyclic GMP-related mechanisms. While stable, its in vivo half-life is short and its persistence is important for it to induce a response. Toxicities include an influenzia-like syndrome, anemia, eosinophilia, and fluid accumulation. In vivo actions include augmentation of cytotoxic responses at high doses, T-cell adjuvant actions, and T-cell restorative actions at midrange doses and at low doses with companion LKs. Antitumor responses in man and animals occur, but irregularly. They are maximized by the concomitant use of LAK cells, cytoreductive therapy, antisuppressor cell therapy, and regional or persistent administration. IL-2 offers hope for more effective therapy of cancer and a variety of immunodeficiency diseases involving IL-2 defects, including AIDS, viral infections, and autoimmune diseases.
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PMID:Recent advances in the preclinical and clinical immunopharmacology of interleukin-2: emphasis on IL-2 as an immunorestorative agent. 314 Oct 54

Glycyrrhizin (GL) achieved a dose-dependent inhibition of the replication of human immunodeficiency virus type 1 (HIV-1) in MOLT-4 (clone No. 8) cells within the concentration range of 0.075 to 0.6 mM. Within this concentration range, GL also effected a dose-dependent reduction in the protein kinase C (PKC) activity of MOLT-4 (clone No. 8) cells. A well-known PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), also proved inhibitory to HIV-1 replication in MOLT-4 (clone No. 8) cells. PKC inhibition may thus be considered as one of the mechanisms by which GL inhibits HIV-1 replication. In addition, GL may also owe its anti-HIV-1 activity, at least in part, to an interference with virus-cell binding, since the compound at 1.2 mM partially inhibited the adsorption of radiolabeled HIV-1 particles to MT-4 cells. At this concentration GL also suppressed giant cell formation induced by co-culturing MOLT-4 (clone No. 8) cells with MOLT-4/HTLV-IIIB cells, whereas the PKC inhibitor H-7 failed to do so.
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PMID:Mechanism of inhibitory effect of glycyrrhizin on replication of human immunodeficiency virus (HIV). 325 Mar 33

AIDS is an immunoregulatory disorder characterized by depletion of the CD4+, helper/inducer lymphocyte population. The causative agent of this disease is the human immunodeficiency virus, HIV, which infects CD4+ cells and leads to cytopathic effects characterized by syncytia formation and cell death. Recent studies have demonstrated that binding of HIV to its cellular receptor CD4 is necessary for viral entry. We find that binding of HIV to CD4 induces rapid and sustained phosphorylation of CD4 which could involve protein kinase C. HIV-induced CD4 phosphorylation can be blocked by antibody against CD4 and monoclonal antibody against the HIV envelope glycoprotein gp120, indicating that a specific interaction between CD4 and gp120 is required for phosphorylation. Electron microscopy shows that a protein kinase C inhibitor does not impair binding of HIV to CD4+ cells, but causes an apparent accumulation of virus particles at the cell surface, at the same time inhibiting viral infectivity. These results indicate a possible role for HIV-induced CD4 phosphorylation in viral entry and identify a potential target for antiviral therapy.
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PMID:Human immunodeficiency virus induces phosphorylation of its cell surface receptor. 325 91

Activation of the enzyme protein kinase C (PKC) plays an important role in T cell activation. We investigated the phosphorylation of CD2, CD3, CD4, CD5, CD7, CD8, CD28 (Tp44), CD43 (sialophorin, gp115), and LFA-1 after incubation of human PBMC with the (PKC) activator PMA. These proteins were chosen for their role in transmembrane signal transduction (CD2, CD3, CD5, CD28, CD43), cell-cell interaction and adhesion (CD2, CD4, CD8, and LFA-1), or involvement in immunodeficiency states (CD43, CD7). CD5, CD7, CD43, and the alpha-chain of LFA-1 were found to be constitutively phosphorylated. PMA induced rapid hyperphosphorylation of CD5, CD7, and CD43, but not of the LFA-1 alpha-chain, and induced the phosphorylation of CD3, CD4, CD8 and of the LFA-1 beta-chain. PMA did not cause the phosphorylation of CD2 and CD28. PMA-induced phosphorylation was partially inhibited by the PKC inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride. Finally, the T cell activator Con A, which binds to the CD3/TCR complex was shown to induce a profile of protein phosphorylation similar to that observed with PMA. We conclude that PKC-mediated phosphorylation of T cell Ag may represent an important regulatory mechanism that governs the process of T cell activation.
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PMID:Phosphorylation of T cell membrane proteins by activators of protein kinase C. 325 10

It is well established that the activation of T lymphocytes by mitogen/antigen is accompanied by a rise in intracellular free calcium ([Ca2+]i), changes in membrane potential, metabolism of inositol phospholipid, and activation of protein kinase C. These early events of signal transduction culminate in late events of lymphocyte activation, namely, DNA synthesis, lymphokine production, and cellular proliferation. In this study we examined the effect of human immunodeficiency virus (HIV) on changes in membrane potential and [Ca2+]i levels. The membrane potentials were markedly decreased (depolarized) in T cell lines infected with HIV (H9/HTLV IIIb) and did not respond normally to phytohemagglutinin (PHA) or anti-T3 (anti-CD3) monoclonal antibody compared to uninfected H9 cell line. The basal [Ca2+]i levels in H9/HTLV IIIb cells were increased in comparison to those in H9 cells; however, there was very little further increase in [Ca2+]i in H9/HTLV IIIb cells following activation with PHA or anti-T3 monoclonal antibody. This is in contrast to a significant rise in [Ca2+]i in H9 cells following similar stimulation. These data demonstrate abnormalities in the plasma membrane potential and [Ca2+]i levels in chronically infected T cells with HIV. These abnormalities in signal transduction of the T-cell activation pathway could be responsible for T-cell dysfunction in patients with HIV infection.
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PMID:Human immunodeficiency virus-associated changes in signal transduction. 350 Sep 63


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