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)

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.
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PMID:Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2+/calmodulin. 1127 60

The regulation of the synthesis and secretion of human growth hormone (hGH), its biologic activity, and its therapeutic use are reviewed. Both the production and secretion of GH are stimulated by hypothalamic GH-releasing hormone (GHRH) and by the endogenous GH secretagogue (GHS) ghrelin, a product of the oxyntic cells located within the fundus of the stomach. Ghrelin and GHRH act synergistically to stimulate GH secretion when administered in vivo, but they act additively when incubated with somatotrophs in vitro. Ghrelin is also found within the hypothalamic arcuate nucleus where it may enhance the release of GHRH and impair that of somatostatin (SRIH) thus contributing to its synergism with GHRH; ghrelin is an orexigenic peptide as well as a GHS and appears to play an important role in energy metabolism. SRIH inhibits the secretion but not the synthesis of GH and more effectively that stimulated by GHRH than that by ghrelin. The action of GH is mediated by the GH receptor, a straight chain protein of 620 amino acids with extracellular, transmembrane and cytoplasmic domains. GH has two specific receptor binding sites, (I, II) that bind sequentially to similar acceptor sequences of two GHRs. Activation of the GHR signal transduction pathway begins with attachment of two Janus kinase 2 (JAK2) molecules to the intracellular domains of the GHRs leading to phosphorylation of the tyrosine residues of JAK2 and the GHRs; thereafter the signal transduction and activators of transcription (STAT) and Ras mitogen-activated-protein kinase pathways are enhanced. GHRH, SRIH, and ghrelin act through G-protein coupled receptors (GPCR); GHRH activates adenylyl cyclase, cyclic AMP, and protein kinase A pathways, while ghrelin stimulates phospholipase C activity leading to production of inositol 1,4,5-trisphophate and diacylglycerol, increase in cytosolic calcium levels, and GH release; SRIH acts though an inhibitory GPCR to prevent depolarization of the somatotroph thus blocking GH secretion. GH has long been used to stimulate linear growth in children with GH deficiency (GHD); it has also been demonstrated to be effective in adults with GHD. The availability of large quantities of recombinant hGH has broadly increased the number of children with short stature being treated with this agent--not always with marked effectiveness. Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly. GHRH also enhances linear growth rate effectively in children with GHD but is less effective than hGH. The discovery of peptidyl and non-peptidyl GH secretagogues (that preceded and led to the identification of ghrelin itself) presents yet other agents for stimulation of endogenous GH secretion that have been useful in diagnostic studies for GHD and for its treatment in small groups of subjects. It is likely that hGH and its secretagoguess will become of increasing clinical usefulness in future decades.
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PMID:Clinical pharmacology of human growth hormone and its secretagogues. 1247 95

We previously reported the fusion of the TEL gene to the Syk gene in myelodysplastic syndrome with t(9;12)(q22;p12). TEL-Syk fusion transformed interleukin-3 (IL-3)-dependent murine hematopoietic cell line BaF3 to growth factor independence. Here, we investigate the intracellular signal transduction of the stable transfectants. TEL-Syk fusion protein was associated with the p85 subunit of phosphatidyl inositol 3 kinase (PI3-K) followed by the activation of Akt in the absence of IL-3. Vav, phospholipase C-gamma2 and mitogen-activated protein kinase (MAPK) were also constitutively activated. TEL-Syk also activated the signal transducer and activator of transcription 5 (STAT5) in the absence of Janus kinase 2 activation. None of these kinases were phosphorylated in the BaF3 cells transfected with TELDeltaPNT-Syk in which the oligomerization domain of TEL was deleted. Inhibitor analysis showed that the MAPK pathway was important in TEL-Syk-mediated cell proliferation. The immunofluorescence technique revealed that the TEL-Syk fusion protein was located in the cytoplasm. These data suggest that TEL-Syk fusion protein in the cytoplasm leads to the constitutive activation of PI3-K/Akt, MAPK and STAT5 signal pathways, which are closely involved in IL-3-independent cell proliferation of BaF3 cells.
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PMID:TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways. 1474

The mechanisms underlying desensitization of serotonin 2A (5-HT(2A)) receptor signaling by antagonists are unclear but may involve changes in gene expression mediated via signal transduction pathways. In cells in culture, olanzapine causes desensitization of 5-HT(2A) receptor signaling and increases the levels of regulators of G protein signaling (RGS) 7 protein dependent on phosphorylation/activation of the Janus kinase 2 (Jak2)/signal transducers and activators of transcription 3 (Stat3) signaling pathway. In the current study, the 5-HT(2A) receptor signaling system in rat frontal cortex was examined following 7 days of daily treatment with 0.5, 2.0 or 10.0 mg/kg i.p. olanzapine. Olanzapine increased phosphorylation of Stat3 in rats treated daily with 10 mg/kg olanzapine and caused a dose-dependent desensitization of 5-HT(2A) receptor-mediated phospholipase C activity. There were dose-dependent increases in the levels of membrane-associated 5-HT(2A) receptor, G(alpha11) and G(alphaq) protein levels but no changes in the G(beta) protein levels. With olanzapine treatment, RGS4 protein levels increase in the membrane-fraction and decrease in the cytosolic fraction by similar amounts suggesting a redistribution of RGS4 protein within neurons. RGS7 protein levels increase in both the membrane and cytosolic fractions in rats treated daily with 10mg/kg olanzapine. The olanzapine-induced increase in Stat3 activity could underlie the increase in RGS7 protein expression in vivo as previously demonstrated in cultured cells. Furthermore, the increases in membrane-associated RGS proteins could play a role in desensitization of signaling by terminating the activated G(alphaq/11) proteins more rapidly.
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PMID:Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex. 1767 5

In order to study the role of the cytokine interleukin-3 (IL-3) and its signaling pathways in erythropoiesis of beta-thalassemia/HbE erythroid progenitor cells, CD34 positive cells were isolated from peripheral blood of patients and healthy subjects. After culturing the cells in the presence or absence of IL-3, cell viability was measured by trypan blue staining and apoptotic cells were analyzed by flow cytometry. After 7 days of culture the highest percent erythroid progenitor cell viability was obtained with cells from healthy subjects, while the lowest percentage was found in those from splenectomized beta-thalassemia/HbE. Viability of beta-thalassemia/HbE erythroid progenitor cells in the presence of IL-3 was higher than that of nonsupplemented cells. In addition, specific inhibitors of protein kinase C (Ro-318220), phospholipase C (U-73122) and Janus kinase 2 (AG-490) were used to investigate the involvement of signaling pathways in erythropoiesis. Percent apoptosis of erythroid progenitor cells from splenectomized beta-thalassemia/HbE subjects treated with RO-318220 was higher than those of nonsplenectomized beta-thalassemia/HbE and healthy subjects. Treatment with U-73122 resulted in enhanced percent apoptotic cells from normal and beta-thalassemia/HbE subjects. All these effects were independent of IL-3 treatment.
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PMID:Role of interleukin-3 and signaling pathways on beta-thalassemia/HbE erythroid progenitor cell in culture. 1804 9

The stromal cell-derived factor-1 (SDF-1)/chemokine C-X-C receptor 4 (CXCR4) axis plays a critical role in homing and engraftment of hematopoietic stem/progenitor cells (HSCs) during bone marrow transplantation. To investigate the transcriptional regulation provided by this axis, we performed the first differential transcriptome profiling of human cord blood CD34(+) cells in response to short-term exposure to SDF-1 and identified a panel of genes with putative homing functions. We demonstrated that CD9, a member of the tetraspanin family of proteins, was expressed in CD34(+)CD38(-/lo) and CD34(+)CD38(+) cells. CD9 levels were enhanced by SDF-1, which simultaneously down-regulated CXCR4 membrane expression. Using specific inhibitors and activators, we demonstrated that CD9 expression was modulated via CXCR4, G-protein, protein kinase C, phospholipase C, extracellular signal-regulated kinase, and Janus kinase 2 signals. Pretreatment of CD34(+) cells with the anti-CD9 monoclonal antibody ALB6 significantly inhibited SDF-1-mediated transendothelial migration and calcium mobilization, whereas adhesion to fibronectin and endothelial cells was enhanced. Pretreatment of CD34(+) cells with ALB6 significantly impaired their homing to bone marrow and spleen of sublethally irradiated NOD/SCID (nonobese diabetic/severe combined immune-deficient) mice. Sorted CD34(+)CD9(-) cells displayed lower bone marrow homing capacity compared with that of total CD34(+) cells. CD9 expression on homed CD34(+) cells was significantly up-regulated in vivo. Our results indicate that CD9 might possess specific functions in HSC homing.
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PMID:The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells. 2161 10

Preimplantation mouse embryos are particularly sensitive to increased osmolarity within their normal physiological range. The detrimental effects can be alleviated by organic osmolytes such as glycine transported into early embryos, an effect thought to be due to the organic osmolyte replacing a portion of intracellular inorganic ions accumulated during acute cell volume regulation. However, no mechanism of cell volume regulation dependent on inorganic ions has been identified in preimplantation embryos. We found that decreased cell volume rapidly activated Na(+)/H(+) exchange in preimplantation mouse embryos. This activity was likely mediated by the NHE1 (Slc9a1) isoform, since it was blocked by the highly selective NHE1 inhibitor, cariporide, which also inhibited the ability of the 1-cell embryo to maintain cell volume. How NHE1 is activated by decreased cell volume is not generally well understood. Full activation of NHE1 by decreased cell volume in 2-cell mouse embryos required the activity of the tyrosine kinase Janus kinase 2 (Jak2), since NHE1 activation was inhibited by the general tyrosine kinase inhibitor genistein, several selective inhibitors of Jak2, and dominant negative Jak2 expressed in 2-cell embryos. Decreased cell volume furthermore resulted in increased tyrosine phosphorylation of proteins in 2-cell embryos detected both by anti-phosphotyrosine antibody and an antibody directed against active phospho-Jak2. Thus, Jak2 apparently serves as a cell volume sensor in embryos. Evidence from pharmacological inhibitors further indicated that NHE1 activation by decreased cell volume was dependent on calmodulin activity, likely downstream of Jak2, and required active phospholipase C.
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PMID:JAK2 mediates the acute response to decreased cell volume in mouse preimplantation embryos by activating NHE1. 2274 Mar 48

Atractylodin is one of the major constituents of the rhizome of Atractylodes lancea, which is widely used in Korean traditional medicine as a remedy for the treatment of gastritis and gastric ulcers. Despite of a major constituent of widely used botanical to treat inflammatory responses little is known about anti-inflammatory effect of atractylodin in the human mast cell (HMC-1). Hence, we evaluated the effect of atractylodin on the release of IL-6, the involvement of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) and mitogen-activated protein kinases (MAPKs) in phorbol-12-myristate-13-acetate and A23187-induced HMC-1. In addition, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), phospholipase C (PLC) gamma 1, and AKT phosphorylation relevant to NPM-ALK signal pathway were assessed. IL-6 levels in the HMC-1 stimulated by phorbol-12-myristate-13-acetate and A23187 were apparently decreased by the treatment of atractylodin. Concurrently, atractylodin not only inhibited the phosphorylation of NPM-ALK, but also suppressed the phosphorylation of JAK2, STAT3, PLC gamma 1, and AKT. Furthermore, the activated mitogen-activated protein kinases (MAPKs) by phorbol-12-myristate-13-acetate and A23187 were inhibited by atractylodin. These results suggested that atractylodin might have a potential regulatory effect on inflammatory mediator expression through blockade of both the phosphorylation of MAPKs and the NPM-ALK signaling pathway.
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PMID:Atractylodin Inhibits Interleukin-6 by Blocking NPM-ALK Activation and MAPKs in HMC-1. 2779 26