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)

Adult rat chromaffin cells in vitro show a large proliferative response to NGF, followed by neuronal differentiation. Infection of replicating chromaffin cells with a retrovirus carrying the Escherichia coli beta-galactosidase (beta-gal) gene demonstrates beta-gal expression in cells that continue to multiply, that differentiate into neurons, and that become static. The effects of NGF on proliferation and differentiation are abolished by the protein kinase inhibitors K252a and staurosporine, and by cholera toxin, an activator of adenylate cyclase. They are diminished, but not abolished, by high concentrations of dexamethasone. Both cholera toxin alone and phorbol myristate acetate (PMA), an activator of protein kinase C, elicit small and inconsistent mitogenic responses. The responses to PMA cannot be shown to be additive with the effects of NGF. NGF is a known mitogen and neuritogen for chromaffin cells from neonatal rats, but has not previously been believed to affect similarly chromaffin cells from adults. The present findings suggest that portions of NGF signaling pathways might continue to be involved in regulating proliferation of adult rat chromaffin cells in vivo, and might be constitutively activated in PC12 cells and other adrenal medullary tumors. They further suggest that rat chromaffin cells might be propagated in vitro to obtain large numbers of sympathetic neurons expressing normal or exogenous genes.
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PMID:Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. 846 33

Infection of human erythrocytes with the malaria parasite Plasmodium falciparum induces many morphological and biochemical changes in the host cell. Host serine/threonine protein kinases could be involved in some of these processes. The aim of this study was to determine the effect of infection on red blood cell protein kinase C (PKC) and establish the importance of this enzyme in parasite growth and sexual stage differentiation. Phorbol myristate acetate (PMA)-induced translocation of erythrocyte PKC activity is impaired in erythrocytes enriched for mature asexual stage infected cells. Western blotting shows that this is due to a relative reduction in membrane PKC protein levels rather than inhibition of enzyme activity and analysis of PKC activity isolated from whole cell lysates by DE52 chromatography suggests that total activatable PKC levels are lower in infected erythrocytes. A reduction in PMA-induced activation is also observed in PKC assays performed in situ. Downregulation of erythrocyte PKC by overnight incubation with PMA before infection causes a significant decrease in the rate of the asexual growth, suggesting that the enzyme, although lost later in infection, may be important in the earlier development of the parasite. By contrast, the lack of PKC had no effect on the production of sexual stage parasites.
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PMID:Modulation of protein kinase C activity in Plasmodium falciparum-infected erythrocytes. 905 62

Infection of humans with Shiga toxin-producing Escherichia coli O157:H7 and Shigella dysenteriae 1 is strongly associated with vascular endothelial cell damage and the development of hemolytic-uremic syndrome. The cytotoxic effect of Shiga toxins on vascular endothelial cells in vitro is enhanced by prior exposure to bacterial lipopolysaccharide (LPS) or either of the host cytokines tumor necrosis factor alpha (TNF) and interleukin-1beta (IL-1). The purpose of this study was to examine individual signal transduction components involved in the sensitization of human umbilical vein endothelial cells (HUVEC) to Shiga toxin 1. The results demonstrate that class I and II protein kinase C (PKC) isozymes are required for sensitization of HUVEC to Shiga toxin by phorbol myristate acetate (PMA) or LPS but not by TNF or IL-1. Thus, the specific competitive inhibitor of class I/II PKC, 1-O-hexadecyl-2-O-methyl-rac-glycerol (AMG), prevented only the action of PMA and LPS on HUVEC. Additional data obtained with ATP binding site inhibitors which affect all PKCs (i.e., classes I, II, and III) suggest that TNF may utilize class III PKC isozymes in the Shiga toxin sensitization of HUVEC. Transcriptional activator NF-kappaB did not appear to be involved in the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA. Thus, the specific serine protease inhibitor L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK) did not inhibit the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA despite its ability to inhibit NF-kappaB activation and the induction of the NF-kappaB-dependent tissue factor gene by these agents. Finally, all-trans retinoic acid partially inhibited the sensitization of HUVEC to Shiga toxin, by unknown mechanisms which also appeared to be independent of NF-kappaB activation. These results indicate that PKC plays a role in the sensitization of HUVEC to Shiga toxin in response to some, but not all, sensitizing agents. In contrast, NF-kappaB activation appears not to be involved in the sensitization of HUVEC to Shiga toxin by LPS, TNF, IL-1, or PMA.
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PMID:Sensitization of human umbilical vein endothelial cells to Shiga toxin: involvement of protein kinase C and NF-kappaB. 923 95

The effects of treatment with chemical agents or infection with feline viruses on protein-binding properties of the feline immunodeficiency virus (FIV) long terminal repeat (LTR) were examined by gel-mobility-shift assays using oligonucleotides designed to represent putative AP-1 or ATF motif from the FIV LTR. Infection with FIV led to less nuclear proteins binding to the AP-1 and ATF sites, suggesting that proteins binding to the sites were consumed or suppressed by FIV-replication in FIV-infected cells. Nuclear proteins that bind to the AP-1 or ATF site were examined by using extracts from Crandell feline kidney (CRFK) cells treated with TPA (a phorbol ester; a strong activator of protein kinase C) or forskolin (an inducer of cyclic-AMP), or infection with feline herpesvirus type 1 (FHV-1). Although TPA or forskolin treatment moderately increased the level of both proteins that bound to AP-1 and ATF sites, FHV-1 infection markedly changed the protein-binding patterns of the sites. Furthermore, FHV-1-induced proteins that bind adjacent to the transcriptional initiation site of FIV promoter were also observed in FHV-1-infected CRFK cells, suggesting that the FHV-1-induced-proteins affects the transcription of FIV through the AP-1, ATF and leader sequences.
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PMID:The effects of treatment with chemical agents or infection with feline viruses on protein-binding properties of the feline immunodeficiency virus long terminal repeat. 949 18

Leishmania, a protozoan parasite of macrophages, has been shown to interfere with host cell signal transduction pathways including protein kinase C (PKC)-dependent signaling. Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP, MacMARCKS) are PKC substrates in diverse cell types. MARCKS and MRP are thought to regulate the actin network and thereby participate in cellular responses involving cytoskeletal rearrangement. Because MRP is a major PKC substrate in macrophages, we examined its expression in response to infection by Leishmania. Activation of murine macrophages by cytokines increased MRP expression as determined by Western blot analysis. Infection with Leishmania promastigotes at the time of activation or up to 48 h postactivation strongly decreased MRP levels. Leishmania-dependent MRP depletion was confirmed by [3H]myristate labeling and by immunofluorescence microscopy. All species or strains of Leishmania parasites tested, including lipophosphoglycan-deficient Leishmania major L119, decreased MRP levels. MRP depletion was not obtained with other phagocytic stimuli including zymosan, latex beads, or heat-killed Streptococcus mitis, a Gram-positive bacterium. Experiments with [3H]myristate labeled proteins revealed the appearance of lower molecular weight fragments in Leishmania-infected cells suggesting that MRP depletion may be due to proteolytic degradation.
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PMID:Down-regulation of MARCKS-related protein (MRP) in macrophages infected with Leishmania. 1035 20

Infection of target cells by HIV-1 requires initial binding interactions between the viral envelope glycoprotein gp120, the cell surface protein CD4, and one of the members of the seven-transmembrane G protein-coupled chemokine receptor family. Most primary isolates (R5 strains) use chemokine receptor CCR5, but some primary syncytium-inducing, as well as T cell line-adapted, strains (X4 strains) use the CXCR4 receptor. Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive G(i) proteins and is not required for HIV-1 entry. Here, we show that the PTX holotoxin as well as its binding subunit, B-oligomer, which lacks G(i)-inhibitory activity, blocked entry of R5 but not X4 strains into primary T lymphocytes. Interestingly, B-oligomer inhibited virus production by peripheral blood mononuclear cell cultures infected with either R5 or X4 strains, indicating that it can affect HIV-1 replication at both entry and post-entry levels. T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protein (MIP)-1beta or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and binding of MIP-1beta or HIV-1 to such cells were not impaired. The inhibitory effect of B-oligomer on signaling from CCR5 and on entry of R5 HIV-1 strains was reversed by protein kinase C (PKC) inhibitors, indicating that B-oligomer activity is mediated by signaling events that involve PKC. B-oligomer also blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 in primary T cells, but did not affect cocapping of CXCR4 and CD4 after inoculation of the cultures with X4 HIV-1. These results suggest that the B-oligomer of PTX cross-deactivates CCR5 to impair its function as a coreceptor for HIV-1.
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PMID:The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains. 1047 44

Our laboratory has reported on a biphasic pattern of nuclear factor kappaB (NF-kappaB) activation in cultured human umbilical vein endothelial cells during infection with Rickettsia rickettsii, an obligate, intracellular bacterium, and the etiologic agent of Rocky Mountain spotted fever. Transcriptional activation of the tissue factor (TF) gene during this infection has been shown to involve NF-kappaB. To further understand the signal transduction events underlying these phenomena, we studied the role of protein kinase C (PKC), a ubiquitous family of phospholipid-dependent enzymes implicated in the regulation of a variety of cell signaling pathways. Two inhibitors of PKC, namely, bisindolylmaleimide I hydrochloride (BM-1) and calphostin C, which exhibit different inhibitory properties towards various isozymes of PKC, were used. Infection of cells with R. rickettsii in the presence of BM-1 (50 nM) did not significantly affect NF-kappaB, whereas calphostin C (2.5 microM) completely blocked the early phase of NF-kappaB activation. The late, sustained phase also was not affected by treatment with BM-1. Downregulation of phorbol ester-sensitive PKCs by long-term treatment with phorbol 12-myristate 13-acetate (PMA) did not inhibit NF-kappaB activation. Likewise, this downregulation had no effect on induction of TF activity. The activity of TF was, however, sensitive to BM-1 and calphostin C, whereas expression of TF mRNA was inhibited only by calphostin C. Overall, these results suggest the lack of involvement of classical PKC pathways in R. rickettsii-induced NF-kappaB activation but the possible involvement of a non-PMA-responsive PKC isoform in the posttranscriptional control of TF expression.
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PMID:Involvement of protein kinase C in Rickettsia rickettsii-induced transcriptional activation of the host endothelial cell. 1056 58

Infections with Shiga toxin (Stx)-producing bacteria cause bloody diarrhea which may progress to life-threatening complications, including acute renal failure and neurological abnormalities. The precise mechanism of disease progression is unclear, although evidence suggests that the localized production of the host proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 may exacerbate toxin-mediated vascular damage. Purified Stxs have been demonstrated to elicit proinflammatory cytokine synthesis from human peripheral blood mononuclear cells and monocytic cell lines in vitro. To understand toxin-monocyte interactions required for cytokine synthesis, we have treated differentiated THP-1 cells with purified wild-type toxins, enzymatic mutants, or B subunits and measured TNF-alpha production. Our data suggest that A subunit enzymatic activity is essential for cytokine production. THP-1 cells were treated with a series of protein kinase C (PKC), PKA, and protein tyrosine kinase inhibitors to examine the role of intracellular signaling molecules in Stx-mediated cytokine production. Treatment of cells with PKC and tyrosine kinase inhibitors blocked TNF-alpha secretion by Stx-stimulated THP-1 cells. Stx treatment directly activated PKC, which occurred at a point upstream of transcriptional activation of the gene encoding TNF-alpha.
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PMID:Shiga toxin-induced tumor necrosis factor alpha expression: requirement for toxin enzymatic activity and monocyte protein kinase C and protein tyrosine kinases. 1094 42

Interaction of erythropoietin (Epo) with its cell surface receptor activates signal transduction pathways which result in the proliferation and differentiation of erythroid cells. Infection of erythroid cells with the Friend spleen focus-forming virus (SFFV) leads to the interaction of the viral envelope glycoprotein with the Epo receptor and renders these cells Epo independent. We previously reported that SFFV induces Epo independence by constitutively activating components of several Epo signal transduction pathways, including the Jak-Stat and the Raf-1/mitogen-activated protein kinase (MAPK) pathways. To further evaluate the mechanism by which SFFV activates the Raf-1/MAPK pathway, we investigated the effects of SFFV on upstream components of this pathway, and our results indicate that SFFV activates Shc and Grb2 and that this leads to Ras activation. While studies with a dominant-negative Ras indicated that Ras was required for Epo-induced proliferation of normal erythroid cells, the Epo-independent growth of SFFV-infected cells can still occur in the absence of Ras, although at reduced levels. In contrast, protein kinase C (PKC) was shown to be required for the Epo-independent proliferation of SFFV-infected cells. Further studies indicated that PKC, which is thought to be involved in the activation of both Raf-1 and MAPK, was required only for the activation of MAPK, not Raf-1, in SFFV-infected cells. Our results indicate that Ras and PKC define two distinct signals converging on MAPK in both Epo-stimulated and SFFV-infected erythroid cells and that activation of only PKC is sufficient for the Epo-independent proliferation of SFFV-infected cells.
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PMID:Growth factor-independent proliferation of erythroid cells infected with Friend spleen focus-forming virus is protein kinase C dependent but does not require Ras-GTP. 1095 44

Infection of the J774 murine macrophage-derived cell line with Listeria monocytogenes results in several elevations of intracellular calcium during the first 15 min of infection. These appear to result from the actions of secreted bacterial proteins, including phosphatidylinositol-specific phospholipase C (PI-PLC), a broad-range phospholipase C, and listeriolysin O (LLO) (S. J. Wadsworth and H. Goldfine, Infect. Immun. 67:1770-1778, 1999). We have measured hydrolysis of host PI and the activation of host polyphosphoinositide-specific PLC and host phospholipase D (PLD) during infection with wild-type and mutant L. monocytogenes. Elevated hydrolysis of host PI occurred within the first 10 min of infection and was dependent on both bacterial PI-PLC and LLO, both of which were required for the earliest elevations of intracellular calcium in the host cell. A more rapid hydrolysis of host PI was observed at 30 min after infection, at the time when wild-type bacteria have been internalized. Activation of host PLC, also occurred in the first 10 min of infection but was not dependent on the presence of bacterial PI-PLC. Similar observations were made in murine bone marrow-derived macrophages. In J774 cells, activation of host PLD was observed after 20 min of infection and was dependent on bacterial LLO. Mutants in the bacterial phospholipases produced levels of PLD activation similar to those produced by the wild type. Phorbol myristate acetate (PMA) also activated host PLD, while long-term treatment with PMA resulted in loss of the ability of L. monocytogenes to activate host PLD, suggesting an involvement of protein kinase C (PKC) in the activation of PLD. Rottlerin, an inhibitor of PKC delta in J774 cells, also inhibited the activation of PLD, but hispidin, an inhibitor of PKC betaI and betaII, did not. Pretreatment of J774 cells with the PLD inhibitor, 2, 3-diphosphoglycerate partially inhibited escape of the bacteria from the primary phagocytic vacuole.
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PMID:Activation of host phospholipases C and D in macrophages after infection with Listeria monocytogenes. 1099 79


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