Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine-induced C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is an important regulator of leukocyte recruitment to sites of inflammatory challenge. Here, it is demonstrated that the widely distributed contact hapten NiCl(2), like tumor necrosis factor alpha (TNFalpha), induces monocyte-chemoattractant activity in primary human endothelial cells via induction of MCP-1. NiCl(2) rapidly activated mitogen-activated protein (MAP) kinase p38, and inhibition of p38 partially blocked NiCl(2)-induced MCP-1 messenger RNA and protein expression. Both NiCl(2)- and TNFalpha-induced MCP-1 synthesis was sensitive to D609, an inhibitor of phosphatidylcholine-dependent phospholipase C (PC-PLC). NiCl(2)-induced MCP-1 synthesis required activation of NF-kappaB since mutation of NF-kappaB-binding sites in the promoter resulted in complete loss of inducible promoter activity. Consistent with that finding, stimulation with NiCl(2) or TNFalpha activated IkappaB kinase-beta (IKKbeta), and transient transfection of dominant-negative IKKbeta strongly inhibited NiCl(2)- and TNFalpha-induced MCP-1 expression. However, D609 and the specific p38 inhibitor SB202190 did not affect NiCl(2)- and TNFalpha-induced IKKbeta activation, NF-kappaB DNA-binding activity, or transcriptional activity of a Gal4p65 fusion protein. This indicates that p38- and PC-PLC-dependent pathways directly regulate the transcriptional activity of NF-kappaB factors in the transcriptional complex. Consistent with that, inhibition of p38 blocked enhanced transcriptional activity induced by the transcriptional coactivator p300. Thus, it was concluded that at least 3 independent pathways regulate MCP-1 expression in endothelial cells. Its induction requires activation of the IKKbeta/IkappaBalpha/NF-kappaB signaling pathway, resulting in nuclear accumulation of p65 and subsequent recruitment of cofactors. Proper assembly and activity of this transcriptional complex is further modulated by the p38 MAP kinase cascade and a PC-PLC-dependent pathway.
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PMID:Multiple signaling pathways regulate NF-kappaB-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells. 1113 41

We investigated the effect of prostaglandin E2 (PGE2) on the induction of heat shock protein 27 (HSP27) and HSP70, and the mechanism behind the induction in osteoblast-like MC3T3-E1 cells. PGE2 time-dependently increased the level of HSP27 without affecting the level of HSP70. PGE2 stimulated the accumulation of HSP27 dose-dependently in the range between 10 nM and 10 microM. PGE2 stimulated the increase in the level of the mRNA for HSP27. Staurosporine and calphostin C, inhibitors of protein kinase C (PKC), suppressed the PGE2-induced HSP27 accumulation. The effect of PGE2 on HSP27 accumulation was reduced in the PKC down-regulated cells. BAPTA/AM, a chelator of intracellular Ca2+, or TMB-8, an inhibitor of intracellular Ca2+ mobilization, reduced the accumulation of HSP27 induced by PGE2. Dibutyryl cAMP had little effect on the basal level of HSP27. PGE2 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. PD98059 and U-0126, inhibitors of the upstream kinase of p44/p42 MAP kinase, reduced the accumulation of HSP27 induced by PGE2. SB203580, a specific inhibitor of p38 MAP kinase, suppressed the HSP27 accumulation induced by PGE2. U-73122, an inhibitor of phospholipase C, and calphostin C reduced the PGE2-induced phosphorylation of both p44/p42 MAP kinase and p38 MAP kinase. These results indicate that PGE2 stimulates the induction of HSP27 through PKC-dependent activations of both p44/p42 MAP kinase and p38 MAP kinase in osteoblasts.
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PMID:Mechanism of prostaglandin E2-stimulated heat shock protein 27 induction in osteoblast-like MC3T3-E1 cells. 1183 45

Radioadaptive response is a biological defense mechanism in which low-dose ionizing irradiation elicits cellular resistance to the genotoxic effects of subsequent irradiation. However, its molecular mechanism remains largely unknown. We previously demonstrated that the dose recognition and adaptive response could be mediated by a feedback signaling pathway involving protein kinase C (PKC), p38 mitogen activated protein kinase (p38MAPK) and phospholipase C (PLC). Further, to elucidate the downstream effector pathway, we studied the X-ray-induced adaptive response in cultured mouse and human cells with different genetic background relevant to the DNA damage response pathway, such as deficiencies in TP53, DNA-PKcs, ATM and FANCA genes. The results showed that p53 protein played a key role in the adaptive response while DNA-PKcs, ATM and FANCA were not responsible. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), mimicked the priming irradiation in that the inhibitor alone rendered the cells resistant against the induction of chromosome aberrations and apoptosis by the subsequent X-ray irradiation. The adaptive response, whether it was afforded by low-dose X-rays or wortmannin, occurred in parallel with the reduction of apoptotic cell death by challenging doses. The inhibitor of p38MAPK which blocks the adaptive response did not suppress apoptosis. These observations indicate that the adaptive response and apoptotic cell death constitute a complementary defense system via life-or-death decisions. The p53 has a pivotal role in channeling the radiation-induced DNA double-strand breaks (DSBs) into an adaptive legitimate repair pathway, where the signals are integrated into p53 by a circuitous PKC-p38MAPK-PLC damage sensing pathway, and hence turning off the signals to an alternative pathway to illegitimate repair and apoptosis. A possible molecular mechanism of adaptive response to low-dose ionizing irradiation has been discussed in relation to the repair of DSBs and implicated to the current controversial observations on the expression of adaptive response.
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PMID:DNA damage response pathway in radioadaptive response. 1210 51

The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.
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PMID:Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74. 1524 64

1 In this study, we examined the role of Ca2+ in linking proteinase-activated receptor-2 (PAR2) to the nuclear factor kappa B (NFkappaB) pathway in a skin epithelial cell line NCTC2544 stably expressing PAR2 (clone G). 2 In clone G, PAR2-mediated NFkappaB luciferase reporter activity and NFkappaB DNA-binding activity was reduced by preincubation with BAPTA-AM but not BAPTA. Trypsin stimulation of inhibitory kappa B kinases, IKKalpha and IKKbeta, was also inhibited following pretreatment with BAPTA-AM. 3 BAPTA/AM also prevented PAR2-mediated IKKalpha activation in cultured primary human keratinocytes. 4 The effect of BAPTA-AM was also selective for the IKK/NFkappaB signalling axis; PAR2 coupling to ERK, or p38 MAP kinase was unaffected. 5 Pharmacological inhibition of the Ca2+-dependent regulatory protein calcineurin did not inhibit trypsin-stimulated IKK activity or NFkappaB-DNA binding; however, inhibition of Ca2+-dependent protein kinase C isoforms or InsP3 formation using GF109203X or the phospholipase C inhibitor U73122, respectively, reduced both IKK activity and NFkappaB-DNA binding. 6 Mutation of PAR2 within the C-terminal to produce a mutant receptor, which does not couple to Ca2+ signalling, but is able to activate ERK, abrogated NFkappaB-DNA binding and IKK activity stimulated by trypsin. 7 These results suggest a predominant role for the InsP3/Ca2+ axis in the regulation of IKK signalling and NFkappaB transcriptional activation.
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PMID:The role of intracellular Ca2+ in the regulation of proteinase-activated receptor-2 mediated nuclear factor kappa B signalling in keratinocytes. 1582 58

ATP has been known to act as an extracellular signal and to be involved in various functions of kidney. Renal proximal tubular reabsorption of phosphate (Pi) contributes to the maintenance of phosphate homeostasis, which is regulated by Na+/Pi cotransporter. However, the effects of ATP on Na+/Pi cotransporters were not elucidated in proximal tubule cells (PTCs). Thus, the effects of ATP on Na+/Pi cotransporter and its related signal pathways are examined in the primary cultured renal PTCs. In the present study, ATP inhibited Pi uptake in a time (> 1 h) and dose (>10(-6)M) dependent manner. ATP-induced inhibition of Pi uptake was correlated with the decrease of type II Na+/Pi cotransporter mRNA. ATP-induced inhibition of Pi uptake may be mediated by P2Y receptor activation, since suramin (non-specific P2 receptor antagonist) and RB-2 (P2Y receptor antagonist) blocked it. ATP-induced inhibition of Pi uptake was blocked by neomycin, U73122 (phospholipase C (PLC) inhibitors), bisindolylmaleimide I, H-7, and staurosporine (protein kinase C (PKC) inhibitors), suggesting the role of PLC/PKC pathway. ATP also increased inositol phosphates (IPs) formation and induced PKC translocation from cytosolic fraction to membrane fraction. In addition, ATP-induced inhibition of Pi uptake was blocked by SB 203580 [a p38 mitogen activated protein kinase (MAPK) inhibitor], but not by PD 98059 (a p44/42 MAPK inhibitor). Indeed, ATP induced phosphorylation of p38 MAPK, which was not blocked by PKC inhibitor. In conclusion, ATP inhibited Pi uptake via PLC/PKC as well as p38 MAPK in renal PTCs.
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PMID:Effect of adenosine triphosphate on phosphate uptake in renal proximal tubule cells: involvement of PKC and p38 MAPK. 1588 Apr 45

Human CC chemokine-4 (HCC-4)/CCL16 is a chemoattractant for monocytes and lymphocytes. Although HCC-4 binds to multiple CC chemokine receptors, the receptor-mediated signal transduction pathway induced by HCC-4 has not been characterized. Human osteogenic sarcoma cells stably expressing CCR1 were used to investigate HCC-4-mediated chemotaxis signaling events via CCR1. The chemotactic activity of HCC-4 as well as those of other CCR1-dependent chemokines including MIP-1alpha/CCL3, RANTES/CCL5, and Lkn-1/CCL15 was inhibited by the treatment of pertussis toxin, an inhibitor of Gi/Go protein, U73122, an inhibitor of phospholipase C (PLC), and rottlerin, a specific inhibitor of protein kinase Cdelta (PKCdelta). These results indicate that HCC-4-induced chemotaxis signaling is mediated through Gi/Go protein, PLC, and PKCdelta. SB202190, an inhibitor of p38 mitogen activated protein kinase, only blocked the chemotactic activity of HCC-4, but not those of other CCR1-dependent chemokines. SB202190 inhibited HCC-4-induced chemotaxis in a dose-dependent manner (P < 0.01). HCC-4 induces p38 activation in both a time and dose-dependent manner. However, such p38 activation was not induced by other CCR1-dependent chemokines. To further investigate the differential effect of HCC-4, the Ca2+ mobilization was examined. HCC-4 induced no intracellular Ca2+ flux in contrast to other CCR1-dependent chemokines. These results indicate that HCC-4 transduces signals differently from other CCR1-dependent chemokines and may play different roles in the immune response.
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PMID:Differential CCR1-mediated chemotaxis signaling induced by human CC chemokine HCC-4/CCL16 in HOS cells. 1622 54

It has been reported that epidermal growth factor (EGF) and EGF receptor were highly expressed in embryo, suggesting that the EGF system is related to early embryo development in an autocrine and/or paracrine manner. Glucose becomes the preimplantation exogenous energy substrate and enters the blastocyst via glucose transporters. Thus, the effect of EGF on [3H]-2-deoxyglucose (2-DG) uptake and its related signaling pathways were examined in mouse embryonic stem (ES) cells. EGF significantly increased 2-DG uptake in time- and concentration- dependent manner (>12 hr, >10 ng/ ml) and increased mRNA and protein level of glucose transporter 1 (GLUT1) compared to control, respectively. Actinomycin D and cycloheximide completely blocked the effect of EGF on 2-DG uptake. EGF-induced increase of 2-DG uptake was blocked by AG1478 (EGF receptor tyrosine kinase blocker), genistein or herbimycin (tyrosine kinase inhibitors). In addition, EGF effect was blocked by neomycin and U 73122 [phospholipase C (PLC) inhibitors] as well as staurosporine and bisindolylmaleimide I [protein kinase C (PKC) inhibitors]. EGF was also observed to increase inositol phosphates (IPs) formation and activate a PKC translocation from the cytosolic to membrane fraction, suggesting a role of PLC and PKC. SB 203580 [p38 mitogen activated protein kinase (MAPK) inhibitor] or PD 98059 (p44/42 MAPKs inhibitor) blocked EGF-induced increase of 2-DG uptake. EGF also increased phosphorylation of p38 MAPK and p44/42 MAPKs, which was blocked by genistein or bisindolylmaleimide I, respectively. In conclusion, EGF partially increased 2-DG uptake via PKC, p38 MAPK, and p44/42 MAPKs in mouse ES cells.
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PMID:PKC and MAPKs pathways mediate EGF-induced stimulation of 2-deoxyglucose uptake in mouse embryonic stem cells. 1654 31

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon P2X(7) receptor stimulation, for example, microglia release small amounts of TNF, which protect neurons, whereas LPS causes massive TNF release leading to neuroinflammation. Here we report that, in rat primary cultured microglia, nicotine enhances P2X(7) receptor-mediated TNF release, whilst suppressing LPS-induced TNF release but without affecting TNF mRNA expression via activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs). In microglia, nicotine elicited a transient increase in intracellular Ca(2+) levels, which was abolished by specific blockers of alpha7 nAChRs. However, this response was independent of extracellular Ca(2+) and blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP(3) receptor. Repeated experiments showed that currents were not detected in nicotine-stimulated microglia. Moreover, nicotine modulation of LPS-induced TNF release was also blocked by xestospongin C. Upon LPS stimulation, inhibition of TNF release by nicotine was associated with the suppression of JNK and p38 MAP kinase activation, which regulate the post-transcriptional steps of TNF synthesis. In contrast, nicotine did not alter any MAP kinase activation, but enhanced Ca(2+) response in P2X(7) receptor-activated microglia. In conclusion, microglial alpha7 nAChRs might drive a signaling process involving the activation of PLC and Ca(2+) release from intracellular Ca(2+) stores, rather than function as conventional ion channels. This novel alpha7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function.
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PMID:Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. 1665 43

Infection with group B streptococcus (GBS) is the most common cause of early onset neonatal sepsis in many countries, leading to neonatal morbidity and mortality. There is much evidence for a direct involvement of platelets in the pathogenesis of inflammation and sepsis. Several bacteria are known to directly interact with platelets leading to activation and aggregation, a phenomenon also observed with GBS. Here, we demonstrate that GBS rapidly bound to platelets; however, only strains isolated from septic patients bound fibrinogen on their surface and induced platelet thromboxane synthesis, platelet aggregation, and P-selectin (CD62P) expression. In contrast, GBS strains isolated from healthy newborns or healthy pregnant women induced only shape change, but not platelet thromboxane synthesis, platelet aggregation, or CD62P expression. All GBS strains investigated were able to activate FcgammaRIIA receptor signaling pathways including phospholipase C gamma2 (PLCgamma2), as well as calcium/calmodulin-dependent myosin kinase II (CaMKII) and phosphorylation of myosin light chain (MLC). In contrast, protein kinase C (PKC) was exclusively activated by GBS strains isolated from septic patients, and p38 mitogen activated protein kinase (p38 MAP kinase) was preferentially activated by septic GBS strains. Furthermore, stress signaling kinase SEK1/MKK4 and focal adhesion kinase (FAK) were activated by all tested GBS strains in a FcgammaRIIA-independent way. This study demonstrates that septic, but not colonizing, GBS strains bind fibrinogen on their surface, and that septic GBS strains influence platelet function not only via the FcgammaRIIA receptor, but also via pathways distinct from IgG-mediated signalling. These mechanisms lead to platelet aggregation and secretion, thereby possibly modulating the pathophysiologic course of GBS infections.
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PMID:Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades. 1667 76


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