UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Akt kinase is an important downstream effector of VEGF in primary endothelial cells (EC), promoting angiogenesis by increased cellular survival, motility and tubulogenesis. Akt1 is the founding member of a family of serine threonine kinases thought to have overlapping function. We sought to determine if other Akt family members were also regulated by VEGF in EC. We show that treatment of EC with the angiogenic inducers VEGF or sphingosine-1-phosphate (S1P) results in an increased stabilization of Akt3 mRNA, concurrent with a PI3 kinase-dependent, Akt1-independent increase in both the protein and its phosphorylation. Given the similarity of Akt3 regulation by VEGF and S1P, the sensitivity of VEGF stimulation to the Gi-protein uncoupling reagent, pertussis toxin was tested and shows that VEGF stimulation requires Gi-protein signaling. We show that the VEGF stimulates the expression of Edg3/S1P3 (S1P3) and that expression of this Gi-protein-coupled receptor is both sufficient and necessary for the expression of Akt3. Blockade of a single isoform does not overtly affect cellular function, whereas inhibition of both kinases results in an increase in apoptosis and a down-regulation of cyclin D3. These results suggest a model whereby extracellular cues maintain total Akt kinase levels through the regulation of specific isoform expression providing a fail-safe mechanism to maintain necessary levels of Akt kinase activity.
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PMID:Modulation of total Akt kinase by increased expression of a single isoform: requirement of the sphingosine-1-phosphate receptor, Edg3/S1P3, for the VEGF-dependent expression of Akt3 in primary endothelial cells. 1652 73

The zinc finger transcription factor early growth response-1 (Egr-1, NGFI-A, zif268, Krox 24, TIS8, ZENK) is upregulated immediately in the brain by cortical spreading depression (CSD) and other preconditioning stimuli and thus might participate in regulation of the overall genomic response to preconditioning. In the present study, the induction of expression of Egr-1 and other early growth response family members was characterized in rat primary cortical neuronal cultures. In neuronal cultures in vitro, depolarization or exposure to extracellular glutamate caused a 4-fold increase in egr-1 mRNA while exposure to extracellular ATP caused a 10-fold increase. The presence of mRNA encoding for multiple types of purinergic receptors was confirmed by RT-PCR. A number of nucleotide agonists proved effective in eliciting an increase in egr-1 mRNA. Over a limited range of concentration, the most effective agonists were ATP > ADP > alpha, beta-methylene ATP > UTP > cAMP > UDP > AMP > adenosine. Pertussis toxin, suramin, reactive blue 2, PPADS, DPCPX and inhibitors of Protein Kinase C, Protein Kinase A and PI3 kinase significantly reduced the upregulation of egr-1 by exposure to extracellular ATP. These findings suggest that neuronal metabotropic purinergic receptor activation contributes to the induction of early growth response transcription factors and may provide a target that can be manipulated to increase ischemic tolerance of the brain in vivo.
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PMID:Regulation of expression of early growth response transcription factors in rat primary cortical neurons by extracellular ATP. 1664 94

Although aldosterone influences a variety of cellular processes through nongenomic mechanisms, the significance of nongenomic pathways for aldosterone-induced regulation of epithelial function is not understood. Recently, we demonstrated that aldosterone inhibits transepithelial HCO(3)(-) absorption in the medullary thick ascending limb (MTAL) through a nongenomic pathway. This inhibition is mediated through a direct cellular action of aldosterone to inhibit the apical membrane NHE3 Na(+)/H(+) exchanger. The present study was designed to identify the intracellular signaling pathway(s) responsible for this aldosterone-induced transport regulation. In rat MTALs perfused in vitro, addition of 1 nM aldosterone to the bath decreased HCO(3)(-) absorption by 30%. This inhibition was not mediated by cAMP/PKA and was not prevented by inhibitors of PKC or PI3-K, pertussis toxin, or rapamycin. The inhibition of HCO(3)(-) absorption by aldosterone was largely eliminated by the MEK/ERK inhibitors U-0126 and PD-98059. Aldosterone increased ERK activity 1.8-fold in microdissected MTALs. This ERK activation is rapid (</=5 min) and is blocked by U-0126 or PD-98059 but is unaffected by spironolactone or actinomycin D. Pretreatment with U-0126 to block ERK activation prevented the effect of aldosterone to inhibit apical NHE3. These data demonstrate that aldosterone inhibits NHE3 and HCO(3)(-) absorption in the MTAL through rapid activation of the ERK signaling pathway. The results identify NHE3 as a target for nongenomic regulation by aldosterone and establish a role for ERK in the acute regulation of NHE3 and its epithelial absorptive functions.
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PMID:Aldosterone inhibits apical NHE3 and HCO3- absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb. 1675 29

The G protein-coupled pheromone receptor neurons (V1R and V2R) of the vomeronasal organ (VNO) are continually replaced throughout the lifetime of the mouse. Moreover, active signalling of V2Rs via the transient receptor potential 2(TRPC2) channel is necessary for regeneration of receptors, as the TRPC2 null mutant mouse showed a 75% reduction of V2Rs by the age of two months. Here we describe V2R mediated signalling in a neuronal line established from vomeronasal stem cells taken from postnatal female mice. Cells were immunoreactive for Galpha(o) and V2R, whereas V1R and Galpha(i) immunoreactivity could not be detected. Biological ligands (dilute urine and its protein fractions) were found to increase proliferation and survival of these neurons. Dilute mouse urine but not artificial urine also induced ERK, Akt and CREB signalling in a dose dependent way. The volatile fraction of male mouse urine alone was without effect while the fraction containing peptides (> 5 kDa) also stimulated ERK and Akt phosphorylation. The ERK, Akt and CREB phosphorylation response was sensitive to pertussis toxin, confirming the involvement of V2R linked Galpha(o). Dilute mouse urine or its high molecular weight protein fraction increased survival and proliferation of these neurons. Hence, urinary pheromones, which signal important social information via mature neurons, also promote survival and proliferation of their regenerating precursors. These data show that regenerating V2Rs respond to urine and the urinary peptides by activation of the Ras-ERK and PI3-Akt pathways, which appear to be important for vomeronasal neural survival and proliferation.
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PMID:Urinary pheromones promote ERK/Akt phosphorylation, regeneration and survival of vomeronasal (V2R) neurons. 1722 82

Novel therapeutic strategies are needed to reverse the loss of endothelial cell (EC) barrier integrity that occurs during inflammatory disease states such as acute lung injury. We previously demonstrated potent EC barrier augmentation in vivo and in vitro by the platelet-derived phospholipid, sphingosine 1-phosphate (S1P) via ligation of the S1P1 receptor. The S1P analogue, FTY720, similarly exerts barrier-protective vascular effects via presumed S1P1 receptor ligation. We examined the role of the S1P1 receptor in sphingolipid-mediated human lung EC barrier enhancement. Both S1P and FTY-induced sustained, dose-dependent barrier enhancement, reflected by increases in transendothelial electrical resistance (TER), which was abolished by pertussis toxin indicating Gi-coupled receptor activation. FTY-mediated increases in TER exhibited significantly delayed onset and intensity relative to the S1P response. Reduction of S1P1R expression (via siRNA) attenuated S1P-induced TER elevations whereas the TER response to FTY was unaffected. Both S1P and FTY rapidly (within 5 min) induced S1P1R accumulation in membrane lipid rafts, but only S1P stimulated S1P1R phosphorylation on threonine residues. Inhibition of PI3 kinase activity attenuated S1P-mediated TER increases but failed to alter FTY-induced TER elevation. Finally, S1P, but not FTY, induced significant myosin light chain phosphorylation and dramatic actin cytoskeletal rearrangement whereas reduced expression of the cytoskeletal effectors, Rac1 and cortactin (via siRNA), attenuated S1P-, but not FTY-induced TER elevations. These results mechanistically characterize pulmonary vascular barrier regulation by FTY720, suggesting a novel barrier-enhancing pathway for modulating vascular permeability.
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PMID:Pulmonary endothelial cell barrier enhancement by FTY720 does not require the S1P1 receptor. 1747 45

Among the group of bioactive sphingolipids, sphingosylphosphorylcholine (SPC) has been known to induce both antiproliferative and proliferative effects depending on cell type. In the present investigation we show that SPC (1-10 microM) reduced the proliferation of FRO cells (an anaplastic thyroid carcinoma cell line) in a concentration dependent manner. The effect was pertussis toxin insensitive, and independent of phospholipase C, protein kinase C, p38 kinase, or jun kinase. In addition to inhibiting the migration of FRO cells, application of SPC induced a rapid (<10 min) rounding of the cells, which was dependent on extracellular sodium. However, DAPI staining and caspase-3 analysis could not reveal any apoptotic effects of SPC. Furthermore, when cells treated with SPC for 24h were washed and replated, they continued to grow, albeit somewhat slower than control cells. Flow cytometry analysis revealed a significant increase in the population of cells in the G2-M phase, and a reduction in S phase. SPC reduced the phosphorylation of Akt with about 50% and evoked a substantial decrease in the amount of phosphorylated mitogen-activated protein (MAP) kinase. In cells treated with the PI3 kinase inhibitor wortmannin, both migration and proliferation were inhibited, as well as the amount of phosphorylated MAP kinase. Treatment of the cells with either SPC or wortmannin increased the levels of p21, but decreased that of cyclin B1 and Cdc2. Taken together, SPC is an effective suppressor of thyroid cancer cell proliferation and migration, and this effect is, in part, mediated by inhibition of both the PI3K-Akt and the MAP kinase signalling pathways.
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PMID:Antiproliferative effect of sphingosylphosphorylcholine in thyroid FRO cancer cells mediated by cell cycle arrest in the G2/M phase. 1760 21

CXCL13 is a homeostatic chemokine for lymphocyte homing and positioning within follicles of secondary lymphoid tissues, acting through its cognate receptor, CXCR5. Moreover, the CXCR5-CXCL13 axis plays a unique role in trafficking and homing of B1 cells. Here, we report that chronic lymphocytic leukemia (CLL) B cells express high levels of functional CXCR5. CXCR5 expression levels were similar on CLL B cells and normal CD5+ B cells, and higher compared with normal CD5- B cells, follicular B-helper T cells (T(FH) cells), or neoplastic B cells from other B-cell neoplasias. Stimulation of CLL cells with CXCL13 induces actin polymerization, CXCR5 endocytosis, chemotaxis, and prolonged activation of p44/42 mitogen-activated protein kinases. Anti-CXCR5 antibodies, pertussis toxin, and wortmannin inhibited chemotaxis to CXCL13, demonstrating the importance of Gi proteins and PI3 kinases for CXCR5 signaling. Moreover, CLL patients had significantly higher CXCL13 serum levels than volunteers, and CXCL13 levels correlated with beta2 microglobulin. We detected CXCL13 mRNA expression by nurselike cells, and high levels of CXCL13 protein in supernatants of CLL nurselike cell cultures. By immunohistochemistry, we detected CXCL13+ expression by CD68+ macrophages in situ within CLL lymph nodes. These data suggest that CXCR5 plays a role in CLL cell positioning and cognate interactions between CLL and CXCL13-secreting CD68+ accessory cells in lymphoid tissues.
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PMID:Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. 1765 19

Glycogen synthase kinase-3 (GSK-3) is a multifaceted enzyme involved in development, neurogenesis, and survival at the CNS. We investigated nucleotides signaling to GSK-3 in cerebellar granule neurons and found that the metabotropic agonist 2-methyl-thio-ADP (2MeSADP) was able to induce GSK-3 phosphorylation and inhibition of its catalytic activity. 2MeSADP could be acting through several P2Y-ADP receptors expressed in granule neurons, as RT-PCR expression was found for P2Y(1), P2Y(12), and P2Y(13) receptors, but the pharmacological data fitted well with a Gi-coupled P2Y(13) receptor: the effect was sensitive to pertussis toxin, was unaffected by specific antagonists of P2Y(1) and P2Y(12) receptors, such as 2'-deoxy-N(6)-methyl-adenosine 3',5'-diphosphate and 2-methyl-thio-AMP, respectively, and the EC(50) values for 2MeSADP and ADP were in the same low nanomolar range. 2MeSADP was able to phosphorylate and activate extracellular signal-regulated kinase (ERK)-1,2 and Akt proteins, but its effect on GSK-3 phosphorylation was primarily dependent on the phosphatidyl inositol-3 kinase (PI3-K)/Akt pathway, as it was abolished by the PI3-K inhibitor wortmannin. GSK-3 inactivation by 2MeSADP in granule neurons resulted in nuclear translocation of its substrate beta-catenin, which functions as a transcriptional regulator, this effect being lost with wortmaninn. The present study first describes the coupling of a Gi-coupled P2Y(13)-like receptor to GSK-3 and beta-catenin through PI3-K/Akt signaling.
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PMID:Gi-coupled P2Y-ADP receptor mediates GSK-3 phosphorylation and beta-catenin nuclear translocation in granule neurons. 1798 31

Although lysophosphatidic acid (LPA) is known to increase intracellularfree calcium concentration ([Ca(2+)](i)) in different cell types, the effect of LPA on the skeletal muscle cells is not known. The present study was therefore undertaken to examine the effect of LPA on the [Ca(2+)](i) in C2C12 cells. LPA induced a concentration and time dependent increase in [Ca(2+)](i), which was inhibited by VPC12249, VPC 32183 and dioctanoyl glycerol pyrophosphate, LPA1/3 receptor antagonists. Pertussis toxin, a G(i) protein inhibitor, also inhibited the LPA-induced increase in [Ca(2+)](i). Inhibition of tyrosine kinase activities with tyrphostin A9 and genistein also prevented the increase in [Ca(2+)](i) due to LPA. Likewise, wortmannin and LY 294002, phosphatidylinositol 3-kinase (PI3-K) inhibitors, inhibited [Ca(2+)](i) response to LPA. The LPA effect was also attenuated by ethylene glycolbis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), an extracellular Ca(2+) chelator, Ni(2+) and KB-R7943, inhibitors of the Na(+)-Ca(2+) exchanger; the receptor operated Ca(2+) channel (ROC) blockers, 2-aminoethoxydiphenyl borate and SK&F 96365. However, the L-type Ca(2+) channel blockers, verapamil and diltiazem; the store operated Ca(2+) channel blockers, La(3+) and Gd(3+); a sarcoplasmic reticulum calcium pump inhibitor, thapsigargin; an inositol trisphosphate receptor antagonist, xestospongin and a phospholipase C inhibitor, U73122, did not prevent the increase [Ca(2+)](i) due to LPA. Our data suggest that the LPA-induced increase in [Ca(2+)](i) might occur through G(i)-protein coupled LPA(1/3) receptors that may be linked to tyrosine kinase and PI3-K, and may also involve the Na(+)-Ca(2+) exchanger as well as the ROC. In addition, LPA stimulated C2C12 cell proliferation via PI3-K. Thus, LPA may be an important phospholipid in the regulation of [Ca(2+)](i) and growth of skeletal muscle cells.
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PMID:Mechanisms of the lysophosphatidic acid-induced increase in [Ca(2+)](i) in skeletal muscle cells. 1849 35

The extracellular calcium-sensing receptor (CaR) is expressed in various types of endocrine pituitary cell, but the intracellular mechanism this G protein-coupled receptor uses in these cells is not known. In the present study we investigated possible intracellular signal transduction pathway(s) utilized by the CaR of the endocrine melanotrope cells in the intermediate pituitary lobe of the South African-clawed toad Xenopus laevis. For this purpose, the effects of various pharmacological agents on CaR-evoked secretion of radiolabeled secretory peptides from cultured melanotrope cells were assessed. CaR-evoked secretion, induced by the potent CaR agonist L-phenylalanine (L-Phe), could not be inhibited by cholera toxin, nor by NPC-15437 and PMA, indicating that neither G(s)/PKA nor G(q)/PKC pathways are involved. However, pertussis toxin (G(i/o) protein inhibitor), genistein (inhibitor of PTKs), wortmannin/LY-294002 (PI3-K inhibitor) and U-0126 (inhibitor of extracellular signal-regulated kinase, ERK) all substantially inhibited CaR-evoked secretion, indicating that the Xenopus melanotrope cell possesses a PI3-K/MAPK system that plays some role in CaR-signaling. Since no direct effect of L-Phe on ERK phosphorylation could be shown it is concluded that CaR must act primarily through another, still unknown, signaling pathway in Xenopus melanotropes. Our results indicate that the PI3-K/MAPK system has a facilitating effect on CaR-induced secretion, possibly by sensitizing the CaR.
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PMID:Intracellular signal transduction by the extracellular calcium-sensing receptor of Xenopus melanotrope cells. 1850 53

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