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 superoxide anion-generating effect of celecoxib (4-[5-(4-methylpheny)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); SC58633), a selective cyclooxygenase-2 inhibitor, on human neutrophils was evaluated in this study. Celecoxib induced superoxide anion generation in a concentration-dependent manner in human neutrophils. The EC50 value of celecoxib on superoxide anion generation was 15.5+/-2.5 microM. A NADPH oxidase inhibitor, diphenyliodonium (20 microM), and superoxide dismutase (150 U/ml) completely inhibited the free radical generation caused by celecoxib, indicating that the respiratory burst was activated by celecoxib. 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM;10 microM) and staurosporine (200 nM) completely inhibited the superoxide anion release caused by celecoxib, respectively. These data indicated that celecoxib increased superoxide anion release by increasing intracellular calcium and protein kinase C activation. Moreover, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-C)-carbazole (Go-6976; 1 microM) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide, methane sulfate (Ro-31-8220; 0.5 microM), specific inhibitors of conventional protein kinase C isotypes (alpha, beta(I) and beta(II)), significantly inhibited superoxide anion release caused by celecoxib. Rottlerin (5 microM), a protein kinase C delta inhibitor, did not affect the free radical generation caused by celecoxib. Celecoxib caused translocation of protein kinase C alpha, beta(I) and beta(II) from the cytosol to the cellular membrane. 2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one (PD98059; 20 microM) and wortmannin (100 nM) did not decrease the superoxide anion generation caused by celecoxib, indicating that Mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3 kinase) were not involved in the respiratory burst induced by celecoxib. Pertussis toxin (2 microg/ml), a Gi-protein sensitive inhibitor, significantly inhibited superoxide anion release. Moreover, pertussis toxin significantly inhibited intracellular calcium mobilization and protein kinase C alpha, beta(I) and beta(II) translocation from the cytosol to the membrane. Celecoxib increased beta(2)-integrin expression on human neutrophils and this effect was inhibited by BAPTA/AM (10 microM), superoxide dismutase (150 U/ml), genistein (25 microM) and PD98059 (20 microM). This information indicated that intracellular calcium, superoxide anion, tyrosine kinase and MAP kinase are involved in beta(2)-integrin expression. Furthermore, BAPTA/AM, superoxide dismutase and genistein inhibited celecoxib-increased MAP kinase activity, indicating that MAP kinase is a downstream signal for beta(2)-integrin expression. In conclusion, celecoxib stimulates superoxide anion release from human neutrophils by activating pertussis toxin sensitive G-protein. An increase in intracellular calcium and protein kinase C alpha, beta(I) and beta(II) is involved in this process. Celecoxib also regulates beta(2)-integrin expression through superoxide anion release, tyrosine kinase and p42/p44 MAP kinase on human neutrophils.
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PMID:Celecoxib simulates respiratory burst through pertussis toxin-sensitive G-protein, a possible signal for beta 2-integrin expression on human neutrophils. 1472 79

In vivo, ischemia is known to damage the blood-brain barrier (BBB) leading to the development of vasogenic brain edema. Hypoxia-induced vascular endothelial growth factor (VEGF) has been shown to be a key regulator of these permeability changes. However, the signaling pathways that underlie VEGF-induced hyperpermeability are incompletely understood. In this study, we demonstrate that hypoxia- and VEGF-induced permeability changes depend on activation of phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase/Akt (PI3-K/Akt), and protein kinase G (PKG). Inhibition of mitogen-activated protein kinases (MAPK) and of the protein kinase C (PKC) did not affect permeability at all. Paralleling hypoxia- and VEGF-induced permeability changes, localization of the tight junction proteins occludin, zonula occludens-1 (ZO-1), and ZO-2 along the cell membrane changed from a continuous to a more discontinuous expression pattern during hypoxia. In particular, localization of ZO-1 and ZO-2 expression moved from the cell membrane to the cytoplasm and nucleus whereas occludin expression remained at the cell membrane. Inhibition of PLCgamma, PI3-kinase, and PKG abolished these hypoxia-induced changes. These findings demonstrate that hypoxia and VEGF induce permeability through rearrangement of endothelial junctional proteins which involves activation of the PLCgamma and PI3-K/AKT pathway leading to the activation of PKG.
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PMID:Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells. 1475 41

Constitutive overexpression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a key oncogenic event in anaplastic large-cell lymphomas with the characteristic chromosomal aberration t(2;5)(p23;q35). Proteins that interact with ALK tyrosine kinase play important roles in mediating downstream cellular signals, and are potential targets for novel therapies. Using a functional proteomic approach, we determined the identity of proteins that interact with the ALK tyrosine kinase by co-immunoprecipitation with anti-ALK antibody, followed by electrospray ionization and tandem mass spectrometry (MS/MS). A total of 46 proteins were identified as unique to the ALK immunocomplex using monoclonal and polyclonal antibodies, while 11 proteins were identified in the NPM immunocomplex. Previously reported proteins in the ALK signal pathway were identified including PI3-K, Jak2, Jak3, Stat3, Grb2, IRS, and PLCgamma1. More importantly, many proteins previously not recognized to be associated with NPM-ALK, but with potential NPM-ALK interacting protein domains, were identified. These include adaptor molecules (SOCS, Rho-GTPase activating protein, RAB35), kinases (MEK kinase 1 and 4, PKC, MLCK, cyclin G-associated kinase, EphA1, JNK kinase, MAP kinase 1), phosphatases (meprin, PTPK, protein phosphatase 2 subunit), and heat shock proteins (Hsp60 precursor). Proteins identified by MS were confirmed by Western blotting and reciprocal immunoprecipitation. This study demonstrates the utility of antibody immunoprecipitation and subsequent peptide identification by tandem mass spectrometry for the elucidation of ALK-binding proteins, and its potential signal transduction pathways.
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PMID:Identification of NPM-ALK interacting proteins by tandem mass spectrometry. 1496 12

Nicotine is an important component in cigarette smoke that can activate the growth-promoting pathways to facilitate the development of lung cancer. However, the intracellular mechanism(s) by which nicotine promotes survival of lung cancer cells remains enigmatic. Bad is a proapoptotic BH3-only member of the Bcl2 family and is expressed in both small cell lung cancer and non-small cell lung cancer cells. Here we report that nicotine potently induces Bad phosphorylation at Ser112, Ser136, and Ser155 in a mechanism involving activation of MAPKs ERK1/2, PI3K/AKT, and PKA in human lung cancer cells. Nicotine-induced multi-site phosphorylation of Bad results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol. Treatment of cells with PKC inhibitor (staurosporine), MEK-specific inhibitor (PD98059), PI3 kinase inhibitor (LY294002), or PKA inhibitor (H89) blocks the nicotine-induced Bad phosphorylation that is associated with enhanced apoptotic cell death. The fact that beta-adrenergic receptor inhibitor (propranolol) blocks nicotine-induced activation of ERK1/2, AKT, PKA, Bad phosphorylation, and cell survival suggests that nicotine-induced Bad phosphorylation may occur through the upstream beta-adrenergic receptors. The fact that specific knockdown of Bad expression by RNA interference using short interfering RNA enhances cell survival and that nicotine has no additional survival effect on these cells suggests that Bad may act as a required target of nicotine. Thus, nicotine-induced survival may occur in a mechanism through multi-site phosphorylation of Bad, which may lead to development of human lung cancer and/or chemoresistance.
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PMID:Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. 1503 18

Mitochondrial transcription factor A (Tfam, previously mtTFA) is a key regulator of mitochondrial DNA (mtDNA) transcription and replication. We have reported that overexpression of nuclear respiratory factor-1 (NRF-1) and high concentration (50 mM) of glucose increased the promoter activity of the rat Tfam in L6 rat skeletal muscle cells. In this study, we investigated the mechanism of high glucose-induced Tfam transactivation. The addition of 50 mM glucose for 24 h increased Tfam promoter activity up to twofold. The glucose-induced Tfam expression was dose-dependent and cell-type specific. Glucose increased the Tfam promoter-driven transactivity in L6 (skeletal muscle), HIT (pancreatic beta-cell), and CHO (ovary) cells, but not in HepG2 (hepatoma), HeLa, and CV1 (kidney) cells. Among various monosaccharides, only glucose and fructose increased the Tfam promoter activity. Oxidative stress might not be involved in glucose-induced Tfam expression since treatment with antioxidants such as vitamin C, vitamin E, probucol, or alpha-lipoic acid did not suppress the induction. None of the inhibitors of protein kinase C, MAP kinase, and PI3 kinase altered the glucose-induced Tfam promoter activity, suggesting that general phosphorylation is involved in its signaling. However, a dominant negative mutant of NRF-1, in which 200 amino acids of C-terminus were truncated, completely suppressed the glucose-induced Tfam induction. It was concluded that high glucose-induced Tfam transcription in L6 cells might be mediated by NRF-1.
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PMID:Regulation of mitochondrial transcription factor A expression by high glucose. 1512 85

The mechanism by which neurotensin (NT) promotes the growth of prostate cancer epithelial cells is not yet defined. Here, androgen-independent PC3 cells, which express high levels of the type 1 NT-receptor (NTR1), are used to examine the involvement of epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (ERK, SAPK/JNK and p38), PI3 kinase and PKC in the mitogenic effect of NT. NT dose dependently (0.1-30 nM) enhanced phosphorylation of EGFR, ERK and Akt, reaching maximal levels within 3 min as measured by Western blotting. These effects were associated with an accumulation of EGF-like substance(s) in the medium (assayed by EGFR binding) and a 2-fold increase in DNA synthesis (assayed by [3H]thymidine incorporation). The DNA synthesis enhancement by NT was non-additive with that of EGF. The NT-induced stimulation of EGFR/ERK/Akt phosphorylation and DNA synthesis was inhibited by EGFR-tyrosine kinase inhibitors (AG1478, PD153035), metallo-endopeptidase inhibitor phosphoramidon and by heparin, but not by neutralizing anti-EGF antibody. Thus, transactivation of EGFR by NT involved heparin-binding EGF (HB-EGF or amphiregulin) rather than EGF. The effects of NT on EGFR/ERK/Akt activation and DNA synthesis were attenuated by PLC-inhibitor (U73122), PKC-inhibitors (bisindolylmaleimide, staurosporine, rottlerin), MEK inhibitor (U0126) and PI3 kinase inhibitors (wortmannin, LY 294002). We conclude that NT stimulated mitogenesis in PC3 cells by a PKC-dependent ligand-mediated transactivation of EGFR, which led to stimulation of the Raf-MEK-ERK pathway in a PI3 kinase-dependent manner.
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PMID:Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. 1517 34

Despite considerable knowledge on the regulation of insulin gene transcription, little is known about the post-transcriptional control mechanisms of this gene. We have recently reported glucose- and hypoxia-regulated binding of the polypyrimidine tract-binding protein (PTB) to the pyrimidine-rich sequence of the 3'-untranslated insulin mRNA (ins-PRS), an event which may control insulin mRNA stability. The present aim was to probe for the signaling pathways that control this binding activity. Rat islets were exposed to pharmacological inhibitors against several molecules, previously shown to be involved in glucose signaling. The inhibitors used were; LY 294002 (PI3 kinase), Rp-cAMP triatylamine (the cAMP-dependent protein kinase PKA), bisindolylmaleimide I hydrochloride (PKC), PD 098059 (ERK1/ERK2), SB 203580 (p38/SAPK2a), rapamycin (mTOR) and okadaic acid (PP1/2A). PTB-binding activity to the ins-PRS was then analyzed by elecrophoretic mobility shift assay (EMSA). The glucose-induced PTB-binding was only inhibited by the mTOR inhibitor rapamycin. Rapamycin also reduced glucose-induced insulin mRNA expression. Thus, our results suggest an involvement of mTOR in glucose-induced PTB/ins-PRS binding and insulin mRNA stability.
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PMID:Glucose-induced binding of the polypyrimidine tract-binding protein (PTB) to the 3'-untranslated region of the insulin mRNA (ins-PRS) is inhibited by rapamycin. 1522 89

Estrogens and estrogenic chemicals can affect several vertebrate non-reproductive functions, the immune response in particular. We have previously shown that in the hemocytes of the marine mollusc Mytilus the natural estrogen 17beta-estradiol (E(2)) can affect the immune function through rapid tyrosine kinase-mediated signalling pathways converging on phosphorylation of both mitogen activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs), whose activation plays a key role in the immune response. In this work the effects of synthetic estrogens (such as DES), estrogenic chemicals (such as Bisphenol A, Nonylphenol), and plant estrogens (genistein) on mussel hemocytes were evaluated. The results demonstrate that all the EDCs tested exert in vitro effects similar to those of E(2) on lysosomal membrane stability, although at concentrations 1000 times higher than those of the natural estrogen. When the effects of DES, BPA, and NP on tyrosine kinase-mediated cell signalling were investigated, estrogenic compounds showed distinct effects on the phosphorylation state of MAPK and STAT members. In particular, only DES, like E(2), induced p38 MAPK phosphorylation, whereas BPA and NP seem to have opposite effects. Moreover, different EDCs significantly decreased the tyrosine phosphorylation state of STAT3 and STAT5, showing a distinct effect with respect to E(2). Experiments with specific kinase inhibitors showed that activation of p38 MAPK, but also of ERK MAPK and PI3-kinase, plays a key role in mediating the effect of DES. On the other hand, the effects of NP were partly mediated by ERK MAPK activation. BPA-induced lysosomal membrane destabilisation was unaffected by either MAPK or PI3-K inhibitors. However, hemocyte pre-treatment with the PKC inhibitor GF109203X prevented the effects of both BPA and NP, this indicating that kinase pathways other than those involving MAPKs are also responsible for mediating the effects of certain EDCs. Overall, the results support the hypothesis that EDCs may rapidly modulate the function of mussel hemocytes through activation of transduction pathways involving different kinase-mediated cascades. Moreover, the effects of EDCs on the phosphorylation state of transcription factor STATs suggest that these compounds may lead to changes in gene expression secondary to modulation of kinase/phosphatases. Our data address to the importance of investigating full range responses to estrogenic chemicals and may help understanding their basic mechanisms of action in ecologically relevant invertebrate species.
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PMID:Environmental estrogens can affect the function of mussel hemocytes through rapid modulation of kinase pathways. 1524 52

Treatment of Beas-2B airway epithelial cells with crocidolite asbestos induced tissue factor (TF) mRNA and TF-dependent procoagulant activity. The mitogen-activated protein kinase (MAPK) inhibitors UO126 and SB203850 decreased TF expression in both naive and crocidolite-treated Beas-2B cells to the same extent. Calphostin, an inhibitor of classical and novel protein kinase C (PKC) isotypes, reduced TF mRNA in both intact and crocidolite-treated Beas-2B cells by about 50%. Conversely, the phosphatidylinositol 3-kinase (PI3 kinase) inhibitor LY294002 and a selective PKCzeta inhibitory peptide decreased TF mRNA expression in asbestos-treated cells to a greater extent than in naive cells, suggesting that signaling via this pathway contributes to asbestos-induced TF expression. These results demonstrate that crocidolite asbestos induces TF expression by Beas-2B cells and suggest that the process involves the PI3 kinase-PKCzeta signaling pathway, representing a newly recognized potential mechanism by which asbestos may contribute to lung remodeling.
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PMID:Asbestos induces tissue factor in Beas-2B cells via PI3 kinase-PKC-mediated signaling. 1537 Dec 28

Novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) is a new member of the gp130 cytokine family. NNT-1/BSF-3 is a second ligand to the tripartite CNTFR complex and activates Jak-STAT, MAPK and PI3/Akt signaling pathways in various cell systems. So far, the known functions of NNT-1/BSF-3 encompass neurotrophic and B cell stimulatory effects, as well as neuroimmunoendocrine modulation of corticotroph function. Gene expression of NNT-1/BSF-3 is stimulated by PKA- and PKC-dependent pathways. Cellular secretion of NNT-1/BSF-3 requires heteromeric complex formation with other factors, e.g. cytokine-like factor-1 (CLF-1) or soluble ciliary neurotrophic factor receptor (sCNTFR). This article reviews the current knowledge on NNT-1/BSF-3 expression, secretion, receptor interaction, signal transduction and physiologic effects of this novel gp130 cytokine. Remark: After preparation of this manuscript, another novel gp130 cytokine named neuropoietin (NP) has been reported and shown to be a ligand of the CNTFR complex.
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PMID:Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)--a novel gp130 cytokine with pleiotropic functions. 1545 Feb 49


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