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)

Kaposi sarcoma is a common, though not inevitable consequence of AIDS. There is a body of opinion that believes that this sarcoma is derived from lymphatic endothelium, or at least from a failure of vascular endothelium to distinguish between whether it is attempting to be a blood vessel or a lymphatic. While immunodeficiency and its consequences have proved to be the most significant area of research, the general biology of endothelium, and especially angiogenesis, has perhaps been neglected. I predict that the most important new concept in the biology of endothelium is the recognition of mechanico-receptors as a determinant of its behavior. The concept is illustrated by articles from Oxford (Ryan 1989), from Boston, Massachusetts (Ingber & Folkman 1989), and from Moscow (Shirinsky et al 1989). Most authors studying endothelium have concentrated on blood vascular endothelium and ignored the rich lymphatic bed. Since the lymphatic is par excellence a mechanical receptor, this is perhaps surprising. The lymphatic functions by its responsiveness to mechanical forces, it is a fine control for hydrostatic pressure within the interstitium, and morphologically, its flat and attenuated endothelium linked to strong anchoring fibers is biologically exactly the kind of behavior required of a cell that is responsive to mechanical factors. Perhaps the best known mechanical receptor is the stretch receptor in the muscle fiber. The linkage of this receptor to the enzyme protein kinase C has been described. Ryan has also pointed out that protein kinase C may be an important mechanico-receptor in the fibroblast and possibly also universally in all cells, including lymphatic endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Grip and stick and the lymphatics. 221 67

The protein kinase C (PKC) activator phorbol myristate acetate (PMA) was used to upregulate viral replication in a clone of promonocytic cells chronically infected with human immunodeficiency virus (HIV)-1. Induction of virus could be inhibited by the triphenylethylene anti-estrogen tamoxifen at concentrations that had minimal effects on cellular DNA synthetic responses and cell cycle kinetics. This effect correlated with tamoxifen's ability to block PMA-mediated enhancement of HIV-promoter-driven transactivation in cells of monocyte and CD4+ T-lymphocyte lineages. No interference with a primary infection was noted. Tamoxifen's mechanism of action may relate both to its capacity to inhibit PKC and to consensus sequences for gonadal steroid responsive elements in the HIV long terminal repeat, as it was able to partially inhibit another HIV activator, 5-azacytidine, which does not modulate PKC function. The finding that regulation of HIV in a model for low-level chronic or latent infection is amenable to a nonimmunosuppressive steroid antagonist may suggest approaches to pharmacologic intervention early in HIV infection.
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PMID:Effect of tamoxifen on regulation of viral replication and human immunodeficiency virus (HIV) long terminal repeat-directed transcription in cells chronically infected with HIV-1. 229 71

Infection of Molt-3 cells with human immunodeficiency virus-1 (HIV-1) was found to cause a rapid increase in extractable poly(A) polymerase activity, while the activity of poly(A) degrading endoribonuclease IV strongly decreased at the same time. The increase in poly(A) polymerase activity seems not to be due to a change in the actual number of enzyme molecules, but rather to posttranslational enzyme modification, most likely caused by phosphorylation by nuclear protein kinase NI or protein kinase C. Both kinases were found to be able to phosphorylate poly(A) polymerase in vitro [homogeneous enzyme as well as poly(A) polymerase in intact nuclei]. Phosphoamino acid analysis revealed an incorporation of phosphate into serine and, to a lower extent, into threonine residues of the enzyme protein; no phosphotyrosine could be detected. In the nucleus, the poly(A) polymerase and the endoribonuclease IV are bound to the nuclear matrix. The phosphorylation related enhancement of nuclear poly(A) polymerase activity could be abolished by addition of the zinc and copper chelator o-phenanthroline, which inhibited zinc-containing purified poly(A) polymerase and destroyed the poly(A) polymerase containing nuclear matrix structure, resulting in a solubilization of the enzyme.
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PMID:Dramatic increase in poly(A) synthesis after infection of Molt-3 cells with HIV. 234 76

In this study we analyzed the ability of peripheral blood mononuclear cells (PBMC) from hemophilic patients (He) with negative or positive serology for the human immunodeficiency virus (HIV), to increase natural killer (NK) cytotoxicity upon stimulation with physiological and non physiological agents. Purified interleukin-2 (IL-2), the interferon (IFN)-inducer polyinosinic polycytidylic acid (PIC), recombinant alpha- and gamma-IFN and the protein kinase activator phorbol myristate acetate (PMA) were used as stimulatory agents. The NK functional response was correlated with the presence of PBMC bearing phenotypic markers of activated cells (IL-2 receptor, IL-2R) and of different NK cell maturation stages. Our results demonstrate that NK effector cells with slight lytic activity (Leu 7+ CD16-) predominated in HIV+ He patients. On the other hand the occurrence of IL-2R positive cells was similarly high in both HIV+ and HIV- individuals and was probably more related to chronic replacement treatment with Factor VIII or Factor IX concentrates than to HIV infection. The ability to respond to physiological NK regulators such as IL-2 and IFNs, or to the IFN-inducer PIC was impaired in HIV+ He, especially in HIV+ LAS individuals, suggesting that the inability of these cells to increase NK cell activity after appropriate induction was due to an intrinsic defect. Since phosphoinositide turnover and subsequent protein kinase C activation are thought to be part of the physiological mechanism of NK cytotoxicity, we studied the effect of PMA on PBMC from each group of patients. The ability to respond to PMA was lost only in PBMC from HIV+ LAS patients, indicating that impairment of the NK lytic mechanism progresses as the disease gets worse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HIV infection and natural killer cytotoxicity in hemophilic patients. 238 63

We have examined the effect of the protein kinase C (PKC) inhibitor, staurosporine, on tumor necrosis factor (TNF)-induced cytotoxic action and augmentation of human immunodeficiency virus (HIV) expression on the chronically HIV-infected T-cell line, MOLT-4/HIV (HTLV-IIIB strain). Staurosporine enhanced the decrease in the number of viable cells caused by TNF treatment for 3 days (1 ng/ml of TNF, 43% decrease; 1 ng/ml of TNF + 20 nM staurosporine, 94%), whereas the cytotoxic action on that cell line induced by 10 ng/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA), which was known to be an activator of PKC, was partially inhibited by staurosporine. In addition, staurosporine augmented the TNF cytotoxic activity against other cell lines including HIV-uninfected U937 cells(100 ng/ml of TNF, 53% decrease in the number of viable cells; 100 ng/ml of TNF + 5 nM staurosporine, 86%). However, staurosporine did not change the sensitivity of cells to TNF; thus, those insensitive to TNF were not changed to TNF sensitive by staurosporine. Furthermore, staurosporine did not affect the augmentative effect of TNF on HIV expression evaluated by levels of p24 antigen. Moreover, HIV long terminal repeat (LTR)-directed chloramphenicol acetyltransferase assay showed that staurosporine strongly inhibited the TPA-induced activation of HIV LTR, while that caused by TNF was little affected (10 ng/ml of TPA, 98.4% conversion; 10 ng/ml of TPA + 40 nM staurosporine, 22.2%, 1 ng/ml of TNF, 98.5%; 10 ng/ml of TNF + 40 nM staurosporine, 93.9%). These results suggest that TPA and TNF facilitate HIV replication by different pathways and that staurosporine augments TNF cytotoxicity by possible suppression of PKC activity in both HIV-infected and uninfected cells.
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PMID:Augmentation of cytotoxic effect of tumor necrosis factor on human immunodeficiency virus-infected cells by staurosporine, a potent protein kinase C inhibitor. 238 36

The potent protein kinase C inhibitors staurosporine, H-7, and UCN-01 were investigated for their effects on 12-0-tetradecanoylphorbol-13-acetate (TPA)--mediated CD4 down-regulation and on the augmentation of human immunodeficiency virus (HIV) expression. Staurosporine was the most effective TPA inhibitor for both of these actions. Because of its high cytotoxicity, the effect of H-7 on augmentation of HIV expression could not be determined. UCN-01 had no cytotoxic effect, but caused only little inhibition of the augmentation of HIV expression.
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PMID:Comparison of effects of protein kinase C inhibitors on phorbol ester-induced CD4 down-regulation and augmentation of human immunodeficiency virus replication in human T cell lines. 250 37

Functional studies were performed on human peripheral blood T lymphocytes stained with goat anti-5'-nucleotidase antibodies and separated into ecto-5'-nucleotidase (ecto-5'-NT)-positive and -negative populations using the FACSTAR fluorescence-activated cell sorter. On the average, ecto-5'-NT+ T cells contained 34 +/- 13% CD4+ and 55 +/- 15% CD8+ cells, whereas ecto-5'-NT-T cells contained 65 +/- 12% CD4+ and 23 +/- 8% CD8+ cells. Staining with anti-5'-NT antibodies did not significantly alter the ability of unseparated T cells to proliferate in response to PHA or PMA, or in a MLR. However, prior incubation with anti-5'-NT antibodies did inhibit the ability of irradiated T cells to provide help for PWM-stimulated Ig synthesis by as much as 55%. In five separate experiments, ecto-5'-NT-T cells demonstrated an equal or better ability to incorporate [3H]TdR after PHA stimulation or in a MLR, as compared with ecto-5'-NT+ T cells. Similarly, ecto-5'-NT- T cells were not diminished in their ability to provide help for autologous B cells in a PWM-driven system. Clearly, the inability of ecto-5'-NT- T cells from patients with a variety of immunodeficiency diseases to function in these assays cannot be explained solely by their lack of ecto-5'-NT activity. In contrast, ecto-5'-NT-positive and -negative T cells showed markedly different dose-response curves for proliferation in response to PMA. Ecto-5'-NT+ T cells responded to lower doses of PMA (1.0 ng/ml) than did ecto-5'-NT- T cells and showed a two- to eight-fold greater rate of [3H]TdR incorporation at 3 to 10 ng of PMA per ml. Ecto-5'-NT+ T cells may have a protein kinase C that is more accessible or more easily activated or may utilize an alternate pathway of activation when stimulated with low concentrations of PMA.
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PMID:Functional characterization of ecto-5'-nucleotidase-positive and -negative human T lymphocytes. 253 56

Previously it was established [Pahwa, S., Pahwa, R., Saxinger, C., Gallo, R. C. & Good, R. A. (1985) Proc. Natl. Acad. Sci. USA 82, 8198] that nonviable preparations of human immunodeficiency virus 1 (HIV-1) abolish the proliferative response of human lymphocytes to phytohemagglutinin A. Now we describe that this effect might be, at least partially, due to an impairment of the function of phospholipase C. It was found that addition of HIV-1 preparation to lymphocytes diminished the stimulation of phosphatidylinositol phosphorylation caused by phytohemagglutinin A. Moreover, this preparation completely abolished the phytohemagglutinin-A-stimulated release of inositol trisphosphate and prevented a translocation of protein kinase C from cytosol to membranes. From this data we conclude that nonviable HIV-1 preparations inhibit the intracellular signalling pathway, leading to a reduced mitogenic response to phytohemagglutinin A, at the level of protein kinase C.
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PMID:Inhibitory effect of nonviable preparations from human immunodeficiency virus 1 on inositol phospholipid metabolism. 254 10

Hypericin and pseudohypericin which have been isolated from plants of the Hypericum family are aromatic polycyclic diones. Daniel Meruelo et. al. have reported that hypericin and pseudohypericin showed potent antiretroviral activity including anti-human immunodeficiency virus (1,2). However, the mechanism of these antiretroviral activities has not been clarified. In the course of screening specific inhibitors of protein kinase C we have found that both compounds specifically inhibit protein kinase C with IC50 values 1.7 micrograms/ml and 15 micrograms/ml, respectively, and show antiproliferative activity against mammalian cells. These data suggest that antiretroviral activity of hypericin and pseudohypericin could be attributable to the inhibition of some phosphorylation involved by protein kinase C during viral infection of cells.
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PMID:Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activity. 255 52

We studied a nine-year-old boy with severe, recurrent infections. The patient was exposed in utero to azathioprine and prednisone. He had autoimmune hemolytic anemia, bronchiectasis, and Hodgkin's disease. The patient's circulating lymphocytes were normal in number and phenotype, but stimulation of the T-cell receptor by antigens, mitogens, and monoclonal antibodies failed to induce interleukin-2-receptor expression, interleukin-2 synthesis, or lymphocyte proliferation. The early biochemical events necessary to initiate lymphocyte activation--accumulation of the second messenger diacylglycerol, activation of the enzyme protein kinase C, and elevation of the free intracellular calcium concentration--failed to occur in this patient's lymphocytes. The defect in the lymphocyte could be corrected in vitro by two agents that bypass the receptor-mediated signal mechanism (the diacylglycerol analogue phorbol and the calcium ionophore ionomycin). Further studies localized the defect in signal transduction to the interaction between cell-surface receptors and the guanine nucleotide-binding protein. We conclude that this patient's immunodeficiency was caused by a defective coupling of surface receptors to signal-transducing proteins in his T lymphocytes, resulting in failure of lymphocyte activation.
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PMID:An immunodeficiency characterized by defective signal transduction in T lymphocytes. 278 45


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