Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peptide hormone somatostatin exhibits antiproliferative activity by interacting with the G protein-coupled sst2 or sst5 receptor types. We show here that somatostatin at the human recombinant sst4 receptor induced a concentration-dependent increase in proliferation (EC50 20 nM) with a maximal response 5-fold greater than that produced by its synthetic analog, L-362,855. Analysis of the phosphorylation status of extracellular signal-regulated kinase (ERK)1 and ERK2 showed temporal differences in the changes evoked by the agonists. Phosphorylation induced by somatostatin (100 nM) peaked 10 min after the application and produced a response that continued for at least 4 h. In contrast, L-362,855 (1 microM) showed transient phosphorylation that had declined to basal levels by 1 h. However, both agonists induced rapid and sustained tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) which was pertussis toxin-insensitive. Serine phosphorylation of STAT3 was only apparent after somatostatin treatment and was abolished by pertussis toxin or PD 98059, together with the associated increases in proliferation. Mitogen-activated protein/ERK kinase-1 inhibition also decreased the time interval over which somatostatin-induced ERK phosphorylation was observed (<2 h). We conclude that the difference in the magnitude of the proliferative response evoked by the two agonists at the sst4 receptor can be accounted for by their differential ability to phosphorylate STAT3 on serine residues and supports the concept that selective signaling can be achieved through pharmacological diversity.
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PMID:Activated G protein-coupled receptor induces tyrosine phosphorylation of STAT3 and agonist-selective serine phosphorylation via sustained stimulation of mitogen-activated protein kinase. Resultant effects on cell proliferation. 1034 3

Monocyte chemotactic protein 1 (MCP-1), which is synthesized by vascular cells, is a chemoattractant for monocytes and has been implicated in a wide range of acute and chronic inflammatory processes characterized by monocyte infiltration, including atherosclerosis. However, it is unclear whether MCP-1 is able to modulate vascular smooth muscle cell (VSMC) proliferation. We assessed the effect of MCP-1 on VSMC proliferation and its interaction with serotonin (5-HT), a mitogen for VSMCs. Growth-arrested VSMCs were stimulated with different concentrations of MCP-1 (25-200 ng/ml) and 5-HT (5 and 50 microM) in serum-free medium. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. 5-HT at concentrations of 5 and 50 microM significantly stimulated DNA synthesis by 1.8- and 2.1-fold over the control value, respectively (p < 0.0001). However, MCP-1 at the concentrations tested did not have any significant effect on DNA synthesis. Even though MCP-1 (50 ng/ml) by itself is not mitogenic, when added to 5-HT, it significantly amplified the mitogenic effect of 5-HT compared with that of 5-HT alone (p < 0.0001). The 5-HT2A receptor antagonist sarpogrelate (10 microM) and its major metabolite M-1 (0.1 microM), pertussis toxin (10 ng/ml), Src family protein tyrosine kinase (PTK) inhibitor PP2 (1 microM), protein kinase C (PKC) inhibitor Ro31-8220 (0.1 microM) and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 microM) significantly inhibited the mitogenic effect of 5-HT and its interaction with MCP-1. Anti-MCP-1 antibody (2 microg/ml) and the Janus kinase 2 (JAK2) inhibitor AG490 (10 microM) significantly inhibited the interaction of MCP-1 with 5-HT. Further, the amplified mitogenic effect of 5-HT with MCP-1 was completely reversed by the combined use of sarpogrelate with anti-MCP-1 antibody. Our results suggest that MCP-1 amplifies the mitogenic effect of 5-HT on VSMCs. The mitogenic effect of 5-HT may be mediated by the G protein-Src family PTK-PKC-MAPK pathway. The activation of the JAK2/signal transducer and activator of transcription 3 pathway by MCP-1 in addition to the MAPK pathway by 5-HT may explain the potentiating effect of MCP-1 on 5-HT-induced mitogenesis.
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PMID:Monocyte chemotactic protein 1 amplifies serotonin-induced vascular smooth muscle cell proliferation. 1145 5

Heptahelical opioid receptors are implicated in the transcriptional regulation of neuronal development. Here we demonstrated that activation of mu-opioid receptors in human neuroblastoma SH-SY5Y cells led to the activation of signal transducer and activator of transcription 3 (STAT3), a transcription factor central to the regulation of numerous biological processes. The mu-opioid-induced activation of STAT3 is sensitive to receptor was further shown to pertussis toxin treatment and required JAK and Src tyrosine kinases, but not phosphatidylinositol 3-kinase. This mu-opioid-induced response was mediated via the extracellular signal-regulated protein kinase in a Raf-1-independent manner. The present study provides a foundation to explore the importance of STAT3 signaling in the regulation of neuronal growth and differentiation by the mu-opioid receptor.
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PMID:Regulation of STAT3 by mu-opioid receptors in human neuroblastoma SH-SY5Y cells. 1519 68

Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor that modulates the expression of several genes. The activation of STAT3 accompanies tyrosine phosphorylation and its translocation to the nucleus. Formyl peptide receptor like 1 (FPRL1) is an important classical chemoattractant receptor. In this study, we observed that the stimulation of FPRL1 by Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) caused serine phosphorylation but not tyrosine phosphorylation of STAT3 in a pertussis toxin-sensitive manner. Moreover, downstream of FPRL1 stimulation, phospholipase D (PLD) activity was dramatically increased. n-butanol, a well-known phosphatidic acid (PA) acceptor, completely inhibited WKYMVm-induced STAT3 serine phosphorylation. Moreover, the exogenous addition of PA mimicked STAT3 phosphorylation by WKYMVm. We also found that WKYMVm stimulated extracellular signal regulated kinase (ERK), and that ERK activity is required for STAT3 serine phosphorylation. This WKYMVm-induced ERK activation was inhibited by n-butanol, whereas ERK activation was also induced by the addition of exogenous PA. In terms of the functional aspects of the WKYMVm-induced serine phosphorylation of STAT3, we found that hydrogen peroxide-stimulated STAT3 activation was blocked by pretreating WKYMVm. Taken together, we found that WKYMVm stimulated FPRL1, and that this resulted in STAT3 serine phosphorylation via PLD-mediated ERK activation, and that the serine phosphorylation of STAT3 blocked hydrogen peroxide-induced STAT3 activity.
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PMID:Activation of formyl peptide receptor-like 1 by WKYMVm induces serine phosphorylation of STAT3, which inhibits its tyrosine phosphorylation and nuclear translocation induced by hydrogen peroxide. 1532 47

The purpose of this study was to identify the role of phospholipase D (PLD) isozymes in Bcl-2 expression. Overexpression of PLD1 or PLD2 increased Bcl-2 expression and phosphatidic acid (PA), the product of PLDs, also upregulated Bcl-2 expression. Treatment with PA activated the phospholipase A(2) (PLA(2))/G(i)/ERK1/2, RhoA/Rho-associated kinase (ROCK)/p38 MAPK, and Rac1/p38 MAPK pathways. PA-induced phosphorylation of ERK1/2 was attenuated by a PLA(2) inhibitor (mepacrine) and, a G(i) protein inhibitor (pertussis toxin, PTX). On the other hand, p38 MAPK phosphorylation was attenuated by a dominant negative Rac1 and a specific Rho-kinase inhibitor (Y-27632). These results suggest that PLA(2)/G(i) acts at the upstream of ERK1/2, while Rac1 and RhoA/ROCK act upstream of p38 MAPK. We next, tried to determine which transcription factor is involved in PLD-related Bcl-2 expression. When signal transducer and activator of transcription 3 (STAT3) activity was blocked by a STAT3 specific siRNA, PA-induced Bcl-2 expression was remarkably decreased, suggesting that STAT3 is an essential transcription factor linking PLD to Bcl-2 upregulation. Taken together, these findings indicate that PLD acts as an important regulator in Bcl-2 expression by activating STAT3 involving the phosphorylation of Ser727 through the PLA(2)/G(i)/ERK1/2, RhoA/ROCK/p38 MAPK, and Rac1/p38 MAPK pathways.
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PMID:Overexpression of phospholipase D enhances Bcl-2 expression by activating STAT3 through independent activation of ERK and p38MAPK in HeLa cells. 2250 1