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)

A human monocytic cell line, THP-1, stimulated with 40 nM phorbol myristate acetate (PMA), differentiated to macrophage-like cells, and exhibited increased expression and release of interleukin-1 beta and expression of acetylated low density lipoprotein (ac-LDL) receptors. A selective inhibitor, MDL 29,152 (4-propyl-5-(4-quinolinyl)-2(3H)-oxazolone) was used to show that this induction required activation of protein kinase C. MDL 29,152 acts in the catalytic domain of protein kinase C and is at least 200-fold selective for protein kinase C over cAMP-dependent protein kinase in THP-1 cells. MDL 29,152 (50 microM) reduced levels of interleukin-1 beta mRNA in PMA-stimulated cells by 76% and eliminated detectable interleukin-1 beta in the media. Flow cytometric analysis showed that 48 h after THP-1 activation, approximately 50% of the cells expressed ac-LDL receptors, while in the presence of 100 microM MDL 29,152, less than 5% of the cells expressed receptors. The relationship between THP-1 differentiation and protein kinase C activation was determined by following the expression of the cell surface antigen MO-1. Expression of MO-1 antigen increases as monocytes differentiate to macrophages. After 48 h of phorbol activation, 90% of the THP-1 population was MO-1-positive; less than 16% of the population was MO-1-positive when 100 microM MDL 29,152 was present. By dual analysis, it was found that within the differentiated, MO-1-positive population, only approximately 50% of the cells also expressed ac-LDL receptors. Based on these findings, we conclude that protein kinase C promotes processes important in THP-1 activation and differentiation to macrophage-like cells including interleukin-1 beta expression and secretion, ac-LDL receptor and MO-1 expression.
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PMID:Suppression of interleukin-1 beta and LDL scavenger receptor expression in macrophages by a selective protein kinase C inhibitor. 179 49

We recently demonstrated that the preventive effect of trifluoperazine (a potent inhibitor of calmodulin, protein kinase C, and phospholipase A2) on cholesterol-induced atherogenic activity of smooth muscle cells was mediated through its ability to inhibit smooth muscle cellular DNA synthesis coupled with stimulation of LDL receptor synthesis. The present study addressed the effect of trifluoperazine on cholesterol metabolism of aortic SMCs enriched with cholesterol through the nonreceptor pathway and revealed that (a) TFP caused inhibition of cholesterol synthesis compared with control cells bathed with hypercholesterolemic medium alone. (b) The drug also caused inhibition of free cholesterol and cholesteryl ester accumulation within smooth muscle cells compared to control cells. These results demonstrate that the preventive effect of TFP on atherogenic activity of smooth muscle cells may also be due to its ability to affect the altered/modified cholesterol metabolism of smooth muscle cells exposed to hypercholesterolemic medium in vitro.
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PMID:Effect of trifluoperazine on cholesterol metabolism of smooth muscle cells exposed to hypercholesterolemic medium in vitro. 225 16

The role of tyrosine kinase, protein kinase C, cyclic nucleotide- and Ca(2+)-calmodulin-dependent protein kinase second messenger pathways in the induction of LDL receptor gene expression by hepatocyte growth factor (HGF) was studied in the human hepatoma cell line Hep-G2. Incubation with media containing HGF increased the level of LDL receptor mRNA by 6.5-fold. Co-incubation with HGF and either of two tyrosine kinase inhibitors genistein (2.0-20.0 micrograms/ml) and herbimycin A (0.5-500.0 ng/ml) increased the level of LDL receptor mRNA above that observed with HGF alone by 40-60%. Incubation with HGF in the presence of the calmodulin antagonist W7 (10-30 microM) also super-induced the level of LDL receptor mRNA by nearly 230%. The protein kinase C and A inhibitors chelerythrine (0.1-10.0 microM) and H8 (0.5-5.0 microM), respectively, had no significant effects on the induction of LDL receptor mRNA by HGF. Taken together, these data suggest that tyrosine kinase, protein kinases C and A, and Ca(2+)-calmodulin dependent protein kinase activities are not essential for activation of LDL receptor gene expression in Hep-G2 cells by HGF.
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PMID:Tyrosine kinase inhibitors potentiate the induction of low density lipoprotein receptor gene expression by hepatocyte growth factor. 747 49

Basic fibroblast growth factor (bFGF) has been implicated in the regulation of cell proliferation and cholesterol metabolism. In studies reported herein, we show bFGF increases low density lipoprotein (LDL) binding, uptake, and degradation in arterial smooth muscle cells in a dose-dependent manner. This increase was paralleled by an increase in LDL receptor mRNA steady state levels. To determine if bFGF activated transcription of the LDL receptor gene, we transiently transfected smooth muscle cells with a gene construct consisting of the 5'-upstream promoter region of the DNA from the human LDL receptor gene ligated to a plasmid containing the luciferase gene. We found that bFGF and a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate, significantly induced luciferase activity driven by the LDL receptor promoter, whereas 25-hydroxycholesterol reduced the luciferase activity in bFGF-stimulated cells. These findings show that bFGF and PKC are inducing LDL receptor gene transcription. We also evaluated potential signal transduction pathways induced by bFGF to establish the mechanism(s) leading to the activation of the LDL receptor gene. Activation of the activity of FGF receptor tyrosine kinase in smooth muscle cells by ligand binding resulted in tyrosine phosphorylation of one of the FGF receptors and a 90-kDa-protein as well as increased tyrosine phosphorylation of phospholipase C-gamma. Parallel observations were made in that increased PKC and protein kinase A activities occurred with bFGF as compared with control cells. Inhibitors of receptor tyrosine kinase and other protein kinases significantly reduced transcription and surface expression of LDL receptor. Finally, several key enzymes that are central to the regulation of LDL-cholesteryl ester metabolism were also studied in bFGF-stimulated cells. An increase in acyl-CoA:cholesterol acyltransferase activity and cholesterol esterification was observed with bFGF stimulation, but there was no effect on the lysosomal or cytoplasmic cholesteryl ester hydrolase activities. Our findings suggest potential signal transduction pathways activated by bFGF which play a role in regulating transcription and surface expression of the LDL receptor.
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PMID:Basic fibroblast growth factor-induced low density lipoprotein receptor transcription and surface expression. Signal transduction pathways mediated by the bFGF receptor tyrosine kinase. 751 Jul 5

Non-sterol regulation of low density lipoprotein (LDL) receptor gene expression was examined in a mitogen-responsive human T cell line. Stimulation of the leukemic T cell line Jurkat with the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin rapidly and transiently increased LDL receptor mRNA levels. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin resulted in superinduction of LDL receptor mRNA levels by mitogenic stimulation. The increase in LDL receptor mRNA levels resulted from increased gene transcription rather than stabilization of mRNA half-life. Thus, similar results were obtained when reporter gene expression was assessed in Jurkat cells transfected with LDL receptor promoter constructs and mRNA half-life was not significantly altered by the stimuli. Neither mitogenic induction nor superinduction of LDL receptor mRNA levels in Jurkat cells was prevented by sterol downregulation of LDL receptor gene expression. The protein synthesis inhibitors CHX and anisomycin, but not puromycin, also directly stimulated LDL receptor mRNA levels, suggesting that these compounds could provide a signal required for LDL receptor gene transcription. Taken together, these data indicate that various non-sterol stimuli, including activation of protein kinase C, increases in intracellular calcium, inhibition of protein synthesis, and signals generated by the protein synthesis inhibitors CHX and anisomycin, induce LDL receptor gene expression. Thus, transcription of the LDL receptor gene is not only regulated by ambient sterols but also by a variety of influences that govern the various primary response or immediate early genes. These stimuli may play an important role in normal regulation of LDL receptor gene expression.
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PMID:Non-sterol regulation of low density lipoprotein receptor gene expression in T cells. 785 66

Oncostatin M (OM), a 28 kilodalton glycoprotein cytokine, is structurally and functionally related to interleukin 6 and leukemia-inhibitory factor. We reported previously that OM strongly up-regulated low density lipoprotein (LDL) receptors in human liver cells by a tyrosine kinase-mediated mechanism. Now, we demonstrate that the transcription factor Egr-1 is induced by OM. The induction of Egr-1 was time and concentration dependent; maximal inductions of 10-fold occurred by 30 min at concentrations of 10-25 ng/ml and higher. This concentration dependency was identical to those for OM-mediated tyrosine phosphorylation and LDL receptor up-regulation. The Egr-1, tyrosine kinase, and LDL receptor responses were inhibited at similar concentrations of genistein, suggesting that induction of Egr-1 and up-regulation of LDL receptors depended on activation of tyrosine kinase by OM. In contrast, depletion of protein kinase C by preincubation with 4 beta-phorbol 12-myristate 13 alpha-acetate did not affect OM-mediated induction of Egr-1 or up-regulation of LDL receptors, indicating that protein kinase C is not required for the OM action. Other similar cytokines were investigated, and, of these, only interleukin 1 could increase both Egr-1 and LDL receptor activity. The correlation among tyrosine kinase phosphorylation, Egr-1 induction, and LDL receptor regulation suggests that Egr-1 may be a nuclear signal transducer utilized by OM to induce transcription of the LDL receptor gene. In support of this possibility is the discovery of an Egr-1 consensus sequence (GAGGGGGCG) at approximately 330 base pairs upstream from the transcription initiation site of the LDL receptor promoter region.
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PMID:Induction of Egr-1 by oncostatin M precedes up-regulation of low density lipoprotein receptors in HepG2 cells. 839 2

Low density lipoproteins (LDL) and high density lipoproteins (HDL) from serum stimulate signal-transduction pathways and exocytosis in rat alveolar type II cells. Both LDL and HDL stimulated primary cultures of type II cells to secrete phosphatidylcholine (PtdCho), the major phospholipid component of pulmonary surfactant. The effects on secretion were preceded temporally by stimulation of inositol phospholipid catabolism, calcium mobilization, and translocation of protein kinase C from cytosolic to membrane compartments. Heparin, which blocks the binding of ligands to the LDL receptor, completely inhibited the effects of LDL on signal transduction and PtdCho secretion but did not inhibit the effects of HDL. Unilamellar PtdCho liposomes the size of native LDL had no effect on type II cells; however, PtdCho complexes containing either apolipoproteins E or A-I stimulated both signal transduction and PtdCho secretion. LDL receptors were present in type II cell membranes by immunoblotting. In contrast to findings with hepatic membranes, type II cells exhibited two major bands of 130 kDa and 120 kDa and a minor band at 230 kDa that also was present under reducing conditions. These results are consistent with our hypothesis that the LDL-receptor pathway functions in vivo to deliver cholesterol to type II cells and that this process is coupled to surfactant assembly and secretion via signal-transduction pathway(s). HDL elicits similar responses independent of the LDL receptor, suggesting that type II cells may use the selective uptake pathway to obtain cholesterol or that HDL triggers signal transduction by mechanisms unrelated to lipid delivery.
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PMID:Low density lipoprotein- and high density lipoprotein-mediated signal transduction and exocytosis in alveolar type II cells. 848 41

Low- and high-density lipoproteins (LDL and HDL, respectively) stimulate alveolar type II cells to secrete surfactant. Increases in phosphoinositide hydrolysis, cytosolic Ca2+, and membrane-associated protein kinase C activity precede LDL- and HDL-stimulated secretion. We report three lines of evidence supporting the hypothesis that Gi mediates LDL- and HDL-stimulated surfactant secretion and signal transduction in type II cells. First, pertussis toxin (PTX) inhibited secretion stimulated by the apolipoprotein ligands for either the LDL receptor or the HDL binding protein. Second, PTX inhibited protein kinase C activity in cell membranes stimulated by LDL or HDL. Third, treatment of cell membranes with LDL or HDL inhibited PTX-catalyzed labeling of substrates corresponding in molecular mass to Gi alpha. These observations suggest that receptor-mediated activation of Gi is required for LDL- and HDL-stimulated secretion and that LDL and HDL activate Gi. These studies in type II cells are the first to support the hypothesis that Gi mediates the effects of LDL or HDL on important phenotype-specific functions of differentiated cells.
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PMID:Lipoprotein-stimulated surfactant secretion in alveolar type II cells: mediation by heterotrimeric G proteins. 931 99

The signaling pathway involved in low density lipoprotein (LDL) receptor gene expression induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated in the human hepatoma HepG2 cell line. Treatment of HepG2 cells with 100 nM TPA resulted in an approximately 20-fold increase in LDL receptor mRNA level, as determined by RT-PCR, which peaked at 2-4 h of treatment and subsequently declined. The protein kinase C (PKC) inhibitors calphostin C and staurosporine prevented TPA-mediated LDL receptor mRNA induction. In contrast, TPA did not affect squalene synthase mRNA expression. Immunoblotting of cell extracts with isozyme-specific PKC antibodies revealed that HepG2 cells expressed PKC alpha, which was mainly cytosolic, and PKC beta, PK epsilon, and PKC zeta, all of which were present in both the cytosolic and particulate fractions. Treatment of HepG2 cells with 100 nM TPA resulted in translocation of cytosolic PKC alpha to the particulate fraction, with a maximum at 30 min-2 h of treatment, but was without effect on the subcellular distribution of the other isozymes. TPA treatment also led to activation of the mitogen-activated protein kinase (MAPK) ERK cascade. The specific MAPK pathway inhibitor PD98059 blocked TPA-induced ERK activation. Furthermore, pretreatment of cells with PD98059 inhibited TPA-induced LDL receptor mRNA induction. Moreover, pretreatment of cells with calphostin C inhibited TPA-mediated ERK activation and LDL receptor mRNA induction in a dose-dependent fashion. Based on a close kinetic correlation between PKC alpha translocation and ERK activation, and the effects of specific inhibitors, these findings suggest that translocation/activation of PKC alpha, and subsequent activation of the Raf-1/MEK/ERK MAPK cascade, represent key events in the transcriptional induction of LDL receptor gene by TPA in HepG2 cells.
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PMID:Phorbol ester-induced low density lipoprotein receptor gene expression in HepG2 cells involves protein kinase C-mediated p42/44 MAP kinase activation. 939 22

LDL is known to increase the sensitivity of human platelets for agonists and to induce aggregation and secretion independently at high concentrations, but its mechanism of action is largely obscure. To clarify how LDL increases platelet sensitivity, cells were incubated in lipoprotein-poor plasma and treated with collagen at a concentration that induced approximately 20% secretion of 14C-serotonin. Preincubation with LDL (30 minutes at 37 degreesC) enhanced secretion in a dose-dependent manner to 60+/-14% at a concentration of 2 g LDL protein/L. Similar stimulation by LDL was seen when secretion was induced by the thrombin receptor-activating peptide. This enhancement was strongly reduced (1) in the presence of monoclonal antibody PAC1 against activated alphaIIbbeta3, a polyclonal antibody against alphaIIb, and in the presence of the fibrinogen peptides GRGDS and HHLGGAKQAGDV; (2) in alphaIIbbeta3-deficient platelets; and (3) after dissociation of alphaIIbbeta3. In contrast, binding of 125I-LDL to normal platelets in the presence of PAC1, anti-alphaIIb, GRGDS, and HHLGGAKQAGDV, and to alphaIIbbeta3-deficient platelets was normal. LDL increased the surface expression of fibrinogen in lipoprotein-poor plasma and fibrinogen-free medium, suggesting that extracellular and granular fibrinogen bind to alphaIIbbeta3 after platelet-LDL interaction. Platelets deficient in fibrinogen (<0.5% of normal) or von Willebrand Factor (<1% of normal) but containing normal amounts of other ligands for alphaIIbbeta3 preserved responsiveness to LDL, indicating that occupancy of alphaIIbbeta3 was not restricted to fibrinogen. Inhibition of protein kinase C (bisindolylmaleimide) diminished fibrinogen binding and sensitization by LDL; inhibition of tyrosine kinases (herbimycin A) left fibrinogen binding unchanged but diminished sensitization by LDL. We conclude that an increased concentration of LDL, such as observed in homozygous familial hypercholesterolemia, sensitizes platelets to stimulation by collagen and thrombin receptor-activating peptide via ligand-induced outside-in signaling through integrin-alphaIIbbeta3.
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PMID:Low-density lipoprotein enhances platelet secretion via integrin-alphaIIbbeta3-mediated signaling. 997 3


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