Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reversible phosphorylation of proteins controlled by protein kinases and protein phosphatases is a major mechanism that regulates a wide variety of cellular processes, such as inflammation. It has been reported that the activity of at least 30% of all proteins can be regulated by phosphorylation in eukaryotic cells. Among these proteins, mitogen-activated protein kinases (MAPK) and several transcription factors play pivotal roles in inflammation. We previously demonstrated that Helicobacter pylori in a Korean isolate (HP99) induced proinflammatory chemokine expression by activating MAPK and transcription factors, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) in gastric epithelial AGS cells. In an attempt to determine the role of phosphorylation-dephosphorylation in HP99-induced inflammation, we analyzed the expression of protein phosphatases, the activation of MAPK and transcription factors, and the production of chemokine MCP-1 in AGS cells stimulated with HP99 (at a bacteria-cell ratio of 300:1) and cultured in the presence or absence of a nonspecific serine-threonine protein phosphatase inhibitor, okadaic acid (OA). Our results showed that HP99 induced the expression of protein phosphatases, PP1 and PP2A in AGS cells as early as 30 min. HP99 induced the activation of MAPK and AP-1, and the production of monocyte chemoattractant protein-1 (MCP-1), which were augmented by pretreatment with 100 nM of OA. Gastric epithelial cells induced the expression of PP1 and PP2A in response to HP99 presumably as a defense mechanism against inflammatory chemokine expression by inhibiting the activation of MAPK and AP-1.
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PMID:Inhibition of serine-threonine protein phosphatases in monocyte chemoattractant protein-1 expression in Helicobacter pylori-stimulated gastric epithelial cells. 1740 35

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.
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PMID:Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. 1742 53

Toll-like receptor ligands (TLRLs) produced by various pathogens activate mitogen-activated protein kinases (MAPKs). While the dependence on p38 MAPK activation for the induction of inflammatory genes by the TLR4L, lipopolysaccharide (LPS), has been well documented, the importance of the p38 pathway in gene regulation by other TLRLs is less well understood. We have focused our analysis on two TLRLs with therapeutic potential, imidazoquinoline S28463 (TLR7L) and CpG DNA (TLR9L), to explore in detail their effects on the regulation of gene expression in macrophages. Here we report that activation of the p38 MAPK/MK2 pathway is crucial for both S28463- and CpG-induced cytokine and chemokine production. We show that the stability of TNF mRNA induced by CpG DNA and S28463 is not dependent on the p38 MAPK/MK2 pathway, in contrast to LPS-induced TNF mRNA. Using a GFP reporter construct under the control of the 3' untranslated region of the TNF gene, we demonstrate that S28463 and CpG DNA-induced MK2 signalling regulates TNF mRNA primarily at the translational level, whereas LPS-induced MK2 signalling regulates both the stability and translational efficiency of TNF mRNA. Overall, these data provide insight into distinct molecular mechanisms of gene expression regulation by different Toll-like receptor ligands.
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PMID:Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands. 1748 13

Alloiococcus otitidis is a newly recognized species of gram-positive bacteria frequently associated with otitis media. Although immunostimulating activity of this organism has been investigated, little is known about the signaling pathways of chemokine/cytokine induction by this organism. We investigated the role of NF-kappaB and mitogen-activated protein (MAP) kinases in chemokine interleukin-8 (IL-8) production by human peripheral blood mononuclear cells (PBMCs) after stimulation with A. otitidis. The organism could induce in vitro IL-8 production in human PBMCs. I kappa B alpha, NF-kappaB, p38 MAP kinase, p44/42 MAP kinase (ERK1/2) became phosphorylated in PBMCs after stimulation with A. otitidis. And, inhibitors of NF-kappaB (caffeic acid phenylethyl ester), p38 (SB 203580), or ERK1/2 (PD 98059) significantly reduced IL-8 induction by the organism. These results were similar to findings in IL-8 induction by Streptococcus pneumoniae, another gram-positive major middle ear pathogen. Our preliminary study suggests that multiple pathways including NF-kappaB, p38, and ERK1/2 were simultaneously activated, and were associated with IL-8 induction by A. otitidis in human PBMCs.
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PMID:Interleukin-8 induction via NF-kappaB, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways in human peripheral blood mononuclear cells by Alloiococcus otitidis. 1762 56

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

CC-chemokine ligand 20 (CCL20), a unique chemokine ligand of CC-chemokine receptor 6 (CCR6), play roles in various pathologic conditions. However, the characteristic expression profiles of CCL20 during human tuberculosis (TB) have been largely unknown. The present study analyzed the production and regulatory mechanisms of CCL20 in peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from active pulmonary TB patients and healthy controls (HC). The 30-kDa antigen (Ag) of Mycobacterium tuberculosis actively induced the production of CCL20 by human PBMC and MDM. A comparative analysis revealed that the expression of CCL20 protein was prominently up-regulated in PBMC, MDM, bronchoalveolar lavage fluids (not in sera) from TB patients compared with the corresponding cells or body fluids from HC. Blockade of either tumour necrosis factor-alpha or interferon-gamma, but not interleukin-10, significantly attenuated the CCL20 production. In addition, recombinant CCL20 induced CCR6 expression by CD45RO+ T lymphocytes in a dose-dependent manner. Furthermore, the expression of CCR6 was significantly increased in CD45RO+ T lymphocytes from TB patients, as compared with those from HC. Pharmacological inhibition studies showed that the 30-kDa Ag-induced CCL20 mRNA expression involves mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase 1/2 and p38)- and NF-kappaB-dependent signalling. Collectively, the present study demonstrated that TB patients show the up-regulated expression of CCL20, which is modulated by proinflammatory cytokines, and through MAPK/NF-kappaB-mediated transcriptional mechanisms. The findings suggest important implications of potential roles of CCL20-CCR6 in immunopathogenesis of TB.
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PMID:Expression and regulation of the CC-chemokine ligand 20 during human tuberculosis. 1805 67

Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFkappaB-driven chemokines. However, the signal transduction pathways by which substance P-NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen-activated protein kinases (MAPKs) in substance P-induced synthesis of pro-inflammatory chemokines, monocyte chemoanractant protein-1 (MCP-I), macrophage inflammatory protein-lalpha (MIP-lalpha) and macrophage inflammatory protein-2 (MIP-2), in pancreatic acini. In this study, we observed a time-dependent activation of ERK1/2, c-Jun N-terminal kinase (JNK), NFkappaB and activator protein-1 (AP-1) when pancreatic acini were stimulated with substance P. Moreover, substance P-induced ERK 1/2, JNK, NFkappaB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P-induced activation of ERK 112, JNK, NFkappaB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFkappaB and AP-1 signalling pathways in mouse pancreatic acini.
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PMID:Effect of mitogen-activated protein kinases on chemokine synthesis induced by substance P in mouse pancreatic acinar cells. 1820 3

Phosphatidylinositol-3-OH kinase (PI(3)K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3)K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta was mediated by mTOR through regulation of the transcription factor KLF2. PI(3)K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3)K and mTOR to match metabolism and trafficking.
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PMID:Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. 1842 96

Mycoplasma pneumoniae is an extracellular pathogen, residing on mucosal surfaces of the respiratory and genital tracts. The lack of cell walls in mycoplasmas facilitates the direct contact of the bacterial membrane with the host cell. The cell membrane of mycoplasma is the major inducer of the host pathogenic response. Airway diseases caused by M. pneumoniae include bronchiolitis, bronchitis, and rarely bronchiectasis. In such disorders, neutrophil infiltration of the airways predominates. More recently, M. pneumoniae has been implicated in the pathogenesis of asthma. Epithelial cells play an important role in recruiting inflammatory cells into the airways. Since M. pneumoniae infection of human epithelial cells induces expression of IL-8-a potent activator of neutrophils-we investigated the signaling and transcriptional mechanisms by which mycoplasma membrane induces expression of this chemokine. In BEAS-2B human bronchial epithelial cells, mycoplasma membrane fraction (MMF) increased IL-8 mRNA and protein production. Activation of the transcriptional elements activating protein-1, nuclear factor-interleukin-6, and particularly NF-kappaB are essential for optimal IL-8 production by MMF. The mitogen-activated protein kinases individually played a modest role in MMF-induced IL-8 production. Toll-like receptor-2 did not play a significant role in MMF-induction of IL-8. Antibiotics with microbicidal activity against M. pneumoniae are also known to have anti-inflammatory effects. Whereas clarithromycin, azithromycin, and moxifloxacin individually were able to inhibit TNF-alpha-induction of IL-8, each failed to inhibit MMF-induction of IL-8.
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PMID:Induction of IL-8 by Mycoplasma pneumoniae membrane in BEAS-2B cells. 1848 55

Breast cancer development and breast cancer progression involves the deregulation of growth factors leading to uncontrolled cellular proliferation, invasion and metastasis. Transforming growth factor (TGF)-beta plays a crucial role in breast cancer because it has the potential to act as either a tumor suppressor or a pro-oncogenic chemokine. A cross-communication between the TGF-beta signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-beta signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-beta signaling network as well as TGF-beta functions in breast cancer cells via the G protein-coupled receptor 30 (GPR30). Silencing of GPR30 in MCF-7 cells completely reduced the ability of 17-beta-estradiol (E2) to inhibit the TGF-beta pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-beta signaling only after transfection with GPR30-encoding plasmids. It is most interesting that the antiestrogen fulvestrant (ICI 182,780), which possesses agonistic activity at the GPR30, also diminished TGF-beta signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-beta pathway. Our results indicate that GPR30 induces the stimulation of the mitogen-activated protein kinases (MAPKs), which interferes with the activation of Smad proteins. Inhibition of MAPK activity prevented the ability of E2 from suppressing TGF-beta signaling. These findings are of great clinical relevance, because down-regulation of TGF-beta signaling is associated with the development of breast cancer resistance in response to antiestrogens.
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PMID:17-Beta-estradiol inhibits transforming growth factor-beta signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30. 1876 37


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