Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thapsigargin, which elevates cytosolic calcium levels by inhibiting the sarcoplasmic/endoplasmic reticulum calcium-dependent ATPase, was tested for its ability to degranulate bone marrow-derived mast cells (BMMCs) from src homology 2-containing inositol phosphatase +/+ (SHIP+/+) and SHIP-/- mice. As was found previously with steel factor, thapsigargin stimulated far more degranulation in SHIP-/- than in SHIP+/+ BMMCs, and this was blocked with the phosphatidylinositol-3 (PI-3) kinase inhibitors, LY294002 and wortmannin. In contrast to steel factor, however, this heightened degranulation of SHIP-/- BMMCs was not due to a greater calcium influx into these cells, nor was the thapsigargin-induced calcium influx inhibited by LY294002, suggesting that the heightened thapsigargin-induced degranulation of SHIP-/- BMMCs was due to a PI-3 kinase-regulated step distinct from that regulating calcium entry. An investigation of thapsigargin-stimulated pathways in both cell types revealed that MAPK was heavily but equally phosphorylated. Interestingly, the protein kinase C inhibitor, bisindolylmaleimide (compound 3), totally blocked thapsigargin-induced degranulation in both SHIP+/+ and SHIP-/- BMMCs. As well, thapsigargin stimulated a PI-3 kinase-dependent, transient activation of protein kinase B, and this activation was far greater in SHIP-/- than in SHIP+/+ BMMCs. Consistent with this, thapsigargin was found to be a potent survival factor, following cytokine withdrawal, for both cell types and was more potent with SHIP-/- cells. These studies have both identified an additional PI-3 kinase-dependent step within the mast cell degranulation process, possibly involving 3-phosphoinositide-dependent protein kinase-1 and a diacylglycerol-independent protein kinase C isoform, and shown that the tumor-promoting activity of thapsigargin may be due to its activation of protein kinase B and subsequent promotion of cell survival.
 ...
PMID:Thapsigargin-induced degranulation of mast cells is dependent on transient activation of phosphatidylinositol-3 kinase. 1086 Oct 44

The elevated levels of inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) have been found in the fluid of airways in symptomatic asthmatics. These cytokines have been considered as mitogens to stimulate cell proliferation in tracheal smooth muscle cells (TSMCs). We therefore investigated the effects of TNF-alpha and IL-1beta on cell proliferation and activation of p42/p44 mitogen-activated protein kinase (MAPK) in these cells. TNF-alpha and IL-1beta induced [(3)H]-thymidine incorporation in a time- and concentration-dependent manner. The maximal stimulation of [(3)H]-thymidine incorporation induced by TNF-alpha and IL-1beta was seen 12 h after incubation with these cytokines. In response to TNF-alpha and IL-1beta, p42/p44 MAPK was activated with a concentration-dependent manner in TSMCs. Pretreatment of TSMCs with pertussis toxin did not change DNA synthesis and phosphorylation of MAPK induced by TNF-alpha and IL-1beta. These responses were attenuated by a tyrosine kinase inhibitor herbimycin, a phosphatidyl choline (PC)-phospholipase C (PLC) inhibitor D609, a phosphatidyl inositide (PI)-PLC inhibitor U73122, a protein kinase C inhibitor staurosporine, and removal of Ca(2+) by addition of BAPTA/AM plus EGTA. TNF-alpha- and IL-1beta-induced [(3)H]-thymidine incorporation and phosphorylation of p42/p44 MAPK was completely inhibited by PD98059 (an inhibitor of MEK1/2), indicating that activation of MEK1/2 was required for these responses. These results suggest that the mitogenic effects of TNF-alpha and IL-1beta were mediated through the activation of MEK1/2 and p42/p44 MAPK pathway. TNF-alpha- and IL-1beta-mediated responses were modulated by PLC, Ca(2+), PKC, and tyrosine kinase associated with cell proliferation in TSMCs.
 ...
PMID:Tumour necrosis factor-alpha- and interleukin-1beta-stimulated cell proliferation through activation of mitogen-activated protein kinase in canine tracheal smooth muscle cells. 1086 97

TIS11, a CCCH zinc finger protein, is one of the typical growth factor-inducible nuclear proteins. We found that TIS11 possesses the potential to activate transcription when fused to the GAL4 DNA binding domain and transiently cotransfected into rat pheochromocytoma PC12 cells along with a GAL4-responsive luciferase reporter gene. The study with deletion mutants of TIS11 revealed that the major transactivation region is located at the N-terminal 101 amino acid residues and that the remaining central and C-terminal region had a moderate transactivational activity. In addition, the transactivational activity of TIS11 was found to be significantly reduced by treating the transfectants with phorbol 12-myristate 13-acetate (PMA). PMA-induced inactivation of TIS11 was blocked by calphostin C, a protein kinase C inhibitor, and PD98059, a mitogen-activated protein (MAP) kinase kinase inhibitor. These results suggested that TIS11 functions as a positive transcriptional regulator and that the protein kinase C/MAP kinase signaling cascade is involved in negative regulation of TIS11 by PMA.
 ...
PMID:Transcriptional activation function of zinc finger protein TIS11 and its negative regulation by phorbol ester. 1091 71

We previously reported that activation of mitogen-activated protein kinase (MAPK) is involved in the mitogenic stimulation of normal human melanocytes (NHMC) by endothelin-1 (ET-1). In the present study, we determined signaling mechanisms upstream of MAPK activation that are involved in ET-1 stimulation and their synergism with stem cell factor (SCF). Pretreatment of cultured NHMC with ET(B) receptor antagonists, pertussis toxin, a specific phospholipase C inhibitor (), or a protein kinase C inhibitor (calphostine) blocked a transient tyrosine phosphorylation of MAPK induced by ET-1, whereas the addition of a calcium chelator (BAPTA) failed to inhibit that tyrosine phosphorylation of MAPK. Treatment with ET-1 and SCF together synergistically increased DNA synthesis, which was accompanied by synergism for MAPK phosphorylation. The time course of inositol 1,4,5-trisphosphate formation revealed that there is no difference in the level of inositol 1,4,5-trisphosphate stimulated by ET-1 + SCF or by ET-1 alone. Evaluations of the serine phosphorylation of MEK and Raf-1 activity showed a synergistic effect in SCF + ET-1-treated NHMC. Stimulation with SCF + ET-1 induced a more rapid and stronger tyrosyl phosphorylation of proteins corresponding to p52 and p66 Shc than did stimulation with SCF only, and this was accompanied by a stronger association of tyrosine-phosphorylated Shc with Grb2. Interestingly, a more rapid and marked tyrosine phosphorylation of c-kit was also detected in NHMC-treated with SCF + ET-1 than NHMC treated with SCF only. These data indicate that the synergistic cross-talk between SCF and ET-1 signaling is initiated through the pathway of tyrosine phosphorylation of c-kit, which results in the enhanced formation of the Shc-Grb(2) complex which leads in turn to the synergistic activation of the Ras/Raf-1/MEK/MAP kinase loop.
 ...
PMID:Intracellular signaling mechanisms leading to synergistic effects of endothelin-1 and stem cell factor on proliferation of cultured human melanocytes. Cross-talk via trans-activation of the tyrosine kinase c-kit receptor. 1092 22

Oncostatin M (OSM), a member of the hemopoietic cytokine family, has been implicated in the process of fibrosis and dermal wound healing. As a part of an ongoing study of the mechanisms of fibrosis and dermal wound healing, we have investigated the mechanism of the growth regulation of dermal fibroblasts by OSM. OSM stimulates the mitogenesis of dermal fibroblasts in a dose-dependent manner. This effect was completely blocked by anti-OSM IgG, but not by anti-IL-6 IgG. Furthermore, OSM induction was abolished by genistein, a tyrosine kinase inhibitor, or by PD98059, a specific mitogen-activated protein (MAP) kinase pathway inhibitor, but not by calphostin C, a protein kinase C inhibitor. Immunoblotting analysis using a specific Ab against phosphorylated MAP kinase (Thr202/Tyr204) showed that OSM induces phosphorylation of MAP kinase in dermal fibroblasts. Furthermore, transient transfection of the dominant-negative mutant MAP kinase into dermal fibroblasts abolished the OSM induction. These results strongly suggest that OSM stimulates the growth of dermal fibroblasts via a MAP kinase-dependent pathway.
 ...
PMID:Oncostatin M stimulates the growth of dermal fibroblasts via a mitogen-activated protein kinase-dependent pathway. 1092 1

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP38) regulate anterior pituitary cell secretion and proliferation. In the somatolactotrope GH4C1 cell line, these effects are mediated through the type-II-like PACAP receptor (VPAC2) coupled to the cAMP pathway. In this study, the control of the extracellularly responsive kinases (ERKs) by VIP and PACAP38 was investigated in GH4C1 cells. VIP and PACAP38 increased ERK1 and ERK2 phosphorylation and were equipotent stimulators of both kinases. ERK activation was mimicked by cholera toxin, forskolin and 8bromo-cAMP. VIP and PACAP38 activation of ERK2 was blocked by the protein kinase A inhibitor H89, whereas the protein kinase C inhibitor GF109203X, or prior PMA-induced depletion of the protein kinases C, failed to inhibit VIP and PACAP38 activation of ERK2. In contrast, thyrotropin-releasing hormone (TRH) elicited ERK activation by a PKC-dependent process. ERK activation by VIP or PACAP38 and TRH were additive and both sensitive to the MEK inhibitors PD98059 and U0126. In parallel, U0126 reduced prolactin (PRL) mRNA levels induced by VIP. These results demonstrate for the first time that VIP and PACAP38 activate ERK in GH4C1 cells. Cyclic AMP increase is sufficient to elicit ERK activation in these cells and thus likely to represent the transduction pathway underlying VIP- and PACAP38-dependent ERK activation. This mechanism seems to be involved in VIP-induced PRL gene regulation.
 ...
PMID:Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptides stimulate mitogen-activated protein kinase in the pituitary cell line GH4C1 by a 3',5'-cyclic adenosine monophosphate pathway. 1094 Jul 38

Platelet-activating factor receptor (PAFR) has been identified in B cell lines and primary human B cells, but the regulation of PAFR during B cell activation has not been completely elucidated. In the present study, we have investigated the effects of B cell activation on PAFR binding parameters, PAFR mRNA and PAF-triggered intracellular calcium mobilization. The human B lymphoid cell line LA350 was shown to exhibit high levels of PAFR (48,550 +/- 4,310 sites/cell) as determined by radio-ligand binding assay with PAFR antagonist [3H]WEB2086. Treatment with phorbol 12,13-dibutyrate caused a biphasic reduction of PAFR binding. The early phase was inhibited by the protein kinase C inhibitor bisindolylmaleimide I (BIM), whereas the late phase was not blocked by BIM, protein tyrosine kinase inhibitor genistein, or the mitogen-activated protein kinase/extracellular signal-related kinase inhibitor PD98059. However, staurosporine, a broad-spectrum protein kinase inhibitor, completely inhibited the late phase down-regulation. Ionomycin also decreased [3H]WEB2086 binding sites, whereas the combination of PDB and ionomycin induced a greater reduction than either agent alone. Cross-linking of B cell receptor by anti-IgM Ab also induced down-regulation of PAFR, which was abolished by genistein or PD98059, but not by BIM or staurosporine. The decrease in surface PAFR number was closely paralleled by the reduction in PAFR mRNA both in LA350 cells and human tonsillar B cells, and was associated with decreased response to PAF indicated by decreased intracellular calcium mobilization. These data show that multiple signaling pathways are involved in down-regulating PAFR expression during B cell activation and development.
 ...
PMID:Activation via multiple signaling pathways induces down-regulation of platelet-activating factor receptors on human B lymphocytes. 1094 67

Although originally synthesized as an anti-estrogen, tamoxifen (Tam) was found to be able to inhibit proliferation of estrogen receptor (ER)-negative cancer cells in vitro. However, the molecular basis of such ER-independent growth inhibition is largely unknown. We have previously demonstrated that Tam induces p21WAF1 and p27KIP1 expression in human lung cancer cells which lack ER-alpha and -beta. We found that Tam induced p21WAF1 expression via transcriptional activation. In order to determine the molecular mechanism responsible for p21WAF1 induction by Tam, we performed a deletion analysis on the p21WAF1 promoter. The minimal region in the p21WAF1 promoter required for Tam-activated induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. Our results showed that transcription factor Sp1 and Sp3 bound to this GC-rich region and mutation of Sp1-binding sites dramatically attenuated Tam-induced p21WAF1 promoter activity. We also tried to elucidate the signaling pathway that mediated the activation of p21WAF1 by Tam. Inhibition of mitogen-activated protein kinase pathways did not block Tam-induced p21WAF1. Similarly, protein kinase C inhibitor calphostin C could not suppress Tam-induced p21WAF1. Conversely, pretreatment of a specific protein kinase A inhibitor H89 significantly attenuated the induction of p21WAF1 by Tam. Furthermore, PKA activators forskolin and dibutyryl-cAMP activated p21WAFI promoter activity and increased p21wAF1 protein level in lung cancer cells. Taken together, these results demonstrate that Tam activates the p21WAF1 promoter via Sp1-binding sites and suggest that PKA may be involved in the induction of p21wAF1 by Tam in ER-negative lung cancer cells.
 ...
PMID:Induction of p21WAF1 expression via Sp1-binding sites by tamoxifen in estrogen receptor-negative lung cancer cells. 1094 31

P2Y(2) receptors, which mediate contractile and mitogenic effects of extracellular nucleotides in vascular smooth muscle cells (VSMCs), are upregulated in the synthetic phenotype of VSMCs and in the neointima after balloon angioplasty, suggesting a role in the development of atherosclerosis. Because released cytokines in atherosclerotic lesions mediate multiple effects on gene transcription in VSMCs, we speculated that cytokines could be involved in the regulation of P2Y(2) receptor expression. Using a competitive reverse transcription-polymerase chain reaction, we detected that interleukin (IL)-1beta induced a time- and dose-dependent upregulation of P2Y(2) receptor mRNA, which was dramatically enhanced when combined with interferon-gamma or tumor necrosis factor-alpha. Lipopolysaccharide also significantly increased the expression of P2Y(2) receptor mRNA. The upregulation of P2Y(2) receptor mRNA was paralleled at the functional level because IL-1beta significantly increased the UTP-stimulated DNA synthesis and the release of intracellular Ca(2+). Actinomycin D completely blocked the upregulation of P2Y(2) receptor mRNA expression by IL-1beta, indicating de novo mRNA synthesis. There was no cAMP accumulation in the cells stimulated with IL-1beta. The cyclooxygenase inhibitor indomethacin and the protein kinase C inhibitor RO-31-8220 inhibited IL-1beta-induced upregulation of P2Y(2) receptor mRNA expression, whereas rapamycin and PD098059 had no effects. Furthermore, neither P38 mitogen-activated protein kinase inhibitor SB20358 alone nor its combination with PD098059 blocked the effect of IL-1beta on the expression of P2Y(2) receptor mRNA. Our results demonstrate that inflammatory mediators upregulate vascular P2Y(2) receptors at the transcriptional and at the functional level through protein kinase C and cyclooxygenase but not cAMP, extracellular signal-regulated kinases 1 and 2, or P38-dependent pathways. This may result in increased growth-stimulatory or contractile effects of extracellular UTP and ATP, which may be of importance in the development of vascular disease.
 ...
PMID:Cytokines induce upregulation of vascular P2Y(2) receptors and increased mitogenic responses to UTP and ATP. 1097 50

The effect of alpha-NeuAc(2-->6)Gal/GalNAc-specific lectin from Sambucus nigra (SNA) on the release of lysozyme from human neutrophils was studied in vitro. Interaction of cells with the lectin was accompanied by dose-dependent release of lysozyme, which was increased in the presence of cytochalasin B. The involvement of intracellular signaling pathways in the lectin-induced degranulation of neutrophils was determined using a panel of specific inhibitors tested at concentrations in the range of 10-100 microM. Aristolochic acid (a phospholipase A2 inhibitor), indomethacin (a cyclooxygenase inhibitor), neomycin sulfate (a phospholipase C inhibitor), trifluoperazine (a calmodulin antagonist/protein kinase C inhibitor), N-ethylmaleimide (a sulfhydryl reagent), and guanosine-5;-O-(2-thiodiphosphate) (a G-protein inhibitor) were found to reduce SNA-induced lysozyme release from neutrophils by 20-45%. The treatment of cells with bisindolylmaleimide (a protein kinase C inhibitor), H-8 (an inhibitor of protein kinases A, C, G and of myosin light chain kinase), PD 98059 (a MAP kinase inhibitor), and (+/-)-methoxyverapamil (a Ca2+-channel blocker) failed to affect the release of lysozyme. These results indicate that only selective intracellular pathways associated with activation of G-proteins and phospholipid metabolism as well as the thiol-dependent signaling systems are apparently involved in the realization of the SNA-induced degranulation response of human neutrophils.
 ...
PMID:Effect of signaling inhibitors on the release of lysozyme from human neutrophils activated by Sambucus nigra agglutinin. 1100 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>