Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reducing luminal NaCl concentration in the macula densa region of the nephron stimulates renin secretion, and this response is blocked by a specific inhibitor of cyclooxygenase-2 (COX-2) (Traynor, T. R., Smart, A., Briggs, J. P., and Schnermann, J. (1999) Am. J. Physiol. Renal Physiol. 277, F706-710). To study whether low NaCl activates COX-2 activity or expression we clonally derived a macula densa cell line (MMDD1 cells) from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins. MMDD1 cells express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and showed rapid (86)Rb(+) uptake that was inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. Isosmotic exposure of MMDD1 cells to low NaCl (60 mm) caused a prompt and time-dependent stimulation of prostaglandin E(2) (PGE(2)) release that was prevented by the COX-2 specific inhibitor NS-398 (10 microm). Reducing NaCl to 60 and 6 mm for 16 h increased COX-2 expression in a chloride-dependent fashion. Low NaCl phosphorylated p38 kinase within 30 min and ERK1/2 kinases within 15 min without changing total MAP kinase levels. Low NaCl-stimulated PGE(2) release and COX-2 expression was inhibited by SB 203580 and PD 98059 (10 microm), inhibitors of p38 and ERK kinase pathways. We conclude that low chloride stimulates PGE(2) release and COX-2 expression in MMDD1 cells through activation of MAP kinases.
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PMID:Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. 1098 5

This study investigates the mitogenic effect of the coagulation factor Xa in smooth muscle cells (SMC) from human saphenous vein and the procoagulant activity of these cells. Factor Xa elicited a concentration-dependent increase in [3H]thymidine incorporation. This mitogenic effect of factor Xa was inhibited by DX-9065a and BABCH, indicating the requirement of proteolytic activity of the enzyme. Factor Xa activated the MAP kinases ERK1/2 concentration- and time-dependently. PDGF-neutralizing antibodies neither inhibited the increase in [3H]thymidine incorporation nor ERK-1/2 phosphorylation in factor Xa-stimulated cells, suggesting that factor Xa-induced signaling and mitogenic activity in human venous SMC are independent of PDGF. Exposure of SMC to recalcified plasma resulted in a significant thrombin generation which was inhibited by anti-tissue factor antibody, tissue factor pathway inhibitor, inactivated factor VIIa and DX-9065a. These data indicate that interaction of SMC with the clotting system may contribute to venous graft disease, i.e. thrombus formation and intimal hyperplasia.
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PMID:Factor Xa acts as a PDGF-independent mitogen in human vascular smooth muscle cells. 1101 78

Calcitonin gene-related peptide (CGRP) is a neuropeptide with potent cardiovascular effects, which include positive inotropic and chronotropic actions, systemic vasodilation, and hypotension in animal and human studies. Human neuroblastoma cells (SK-N-MC) have been used as a model system to study the CGRP receptors and downstream signaling pathways. This investigation was undertaken to study the role of CGRP in the activation of mitogen-activated protein kinases. While exposure of these cells to CGRP had no significant effect on ERK-1 or p38 MAP kinases, JNK activity was stimulated by CGRP in a time- and concentration-dependent fashion. CGRP-mediated JNK-activation was inhibited by CGRP receptor antagonist, CGRP8-37, confirming that this is a receptor-mediated event. In addition, pretreatment of the cells with H-89, protein kinase A inhibitor or pertussis toxin greatly attenuated CGRP-mediated JNK activation suggesting the requirement of cAMP-dependent protein kinase activation and involvement of pertussis toxin-sensitive G-protein in CGRP-mediated JNK activation.
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PMID:Involvement of cAMP-dependent protein kinase and pertussis toxin-sensitive G-proteins in CGRP mediated JNK activation in human neuroblastoma cell line. 1102 85

Changes in the osmolarity of the airway surface fluid have been described to be involved in the pathogenesis of exercise induced asthma, and are suggested as the major cause of the lung disease in cystic fibrosis. In this study, we examined the signaling pathway of hyperosmotic challenge to interleukin-8 (IL-8). Hyperosmolarity (NaCl) caused a time- and concentration-dependent increase in IL-8 expression and secretion in bronchial epithelial cells. These effects could be blocked by antioxidants, such as DMSO, DMTU, DTT, and beta-mercaptoethanol, suggesting an involvement of reactive oxygen intermediates (ROI) in the signal transduction of hyperosmolarity-induced IL-8 synthesis. Since IL-8 is regulated by MAP kinases, we examined the influence of MAP kinase inhibitors on hyperosmolarity-induced IL-8 expression. The results show that this induction is regulated by p38 MAPK and not by ERK1/2. Furthermore, antioxidants blocked the activation of p38 MAPK induced by hyperosmolarity. These results suggest that ROIs are critical for p38 MAPK mediated IL-8 expression by hyperosmolarity.
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PMID:Reactive oxygen intermediates are involved in IL-8 production induced by hyperosmotic stress in human bronchial epithelial cells. 1102 15

Tissue factor (TF) has been shown to be up-regulated in endothelial cells by the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) as well as by the main angiogenic factor VEGF. Since both stimuli induce the transcription factor EGR-1, which is critically involved in TF gene regulation, we used EGR-1-dependent TF induction as a model to identify potential cross-talks between the various signal transduction cascades initiated by VEGF and TNF-alpha. The data show that at the MAP kinase level, VEGF mainly activates ERK1/2 and p38 MAP kinases in human endothelial cells. TNF-alpha is able to activate all three MAP kinase cascades as well as the classical inflammatory IkappaB/NFkappaB pathway. Furthermore, the MEK/ERK module of MAP kinases appears to act as the convergence point of VEGF- and TNF-alpha-initiated signaling cascades, which lead to the activation of EGR-1 and subsequent TF expression, whereas the upstream signals are distinct. We found that induction of TF by VEGF via EGR-1 is strongly PKC dependent. The TNF-alpha-initiated MEK/ERK cascade connected to EGR-1 and TF expression is clearly less sensitive to PKC inhibition. TNF-alpha-mediated activation of MEK/ERK and EGR-1 can be blocked by adenoviral expression of a dominant negative mutant of IKK2, whereas the VEGF signaling pathway is unaffected. Thus, our data demonstrate a new link between the classical inflammatory IKK/IkappaB and the MEK/ERK cascades triggered by TNF-alpha. The additional finding that EGF induces ERK and EGR-1 in a PKC-independent manner and that this signal is not sufficient to up-regulate TF emphasizes the importance of a VEGF-specific signaling pattern for the induction of TF.
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PMID:Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells. 1114 11

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.
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PMID:Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain. 1116 17

Protein kinase C is a family of serine/threonine protein kinases involved in many cellular responses, including cell survival and apoptosis. We have recently found that specific inhibition of the PKCalpha isoform by nucleic acid enzymes induced apoptosis in sensitive cells. Here we show that in PKCalpha DNA enzyme-treated glioma cells the activation of MAP kinases ERK1/2 is inhibited, whereas their total level was not significantly affected by the treatment. Similar results were obtained when the overall activity of the PKC was inhibited by calphostin, a specific inhibitor for PKC. These results would indicate that the ERK1/2 signaling pathway plays an important role in glioma cell survival and that the PKCalpha isoform is the main modulator of this pathway. Furthermore, we show that the ERK1/2 signaling pathway is required for the constitutive expression of the basic fibroblast growth factor, a potent mitogen for glioma cell growth.
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PMID:Protein kinase Calpha isoform regulates the activation of the MAP kinase ERK1/2 in human glioma cells: involvement in cell survival and gene expression. 1117 Aug 40

In G0/G1 cell cycle-arrested Y1 adrenocortical cells FGF2 is a strong mitogen, whereas ACTH39 can be a weak mitogen or a strong anti-mitogenic agent. Phosphorylated ERK1/2-MAP kinases are undetectable by Western and immunocitochemistry assay in G0/G1-arrested Y1 adrenal cells. Cell entry into S phase linearly correlates with migration of phosphorylated ERK to nucleus. FGF2 rapid and strongly triggers transient phosphorylation of ERK1/2, whereas ACTH39 is a poor ERK1/2 activator. But, the MEK1 inhibitor, PD98059 (50microM), inhibits cFos and cyclin D1 induction and DNA synthesis stimulation by both ACTH39 and FGF2, suggesting that ERK1/2 activation mediates the strong and the weak mitogenic effect of, respectively, FGF2 and ACTH39. In addition, ACTH39 antagonizes the FGF2 mitogenic effect keeping untouched ERK1/2 activation, c-Fos and cyclin D1 induction.
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PMID:Role of ERK/MAP kinase in mitogenic interaction between ACTH and FGF2 in mouse Y1 adrenocortical tumor cells. 1119 65

Vascular remodeling in hypertension is associated with cell growth and increased deposition of extracellular matrix components, particularly collagen. Mechanisms underlying these processes are unclear, but MAP kinases, particularly ERK1/2 and p38 MAP kinase, may be important. We studied the role of ERK1/2 and p38 MAP kinase in vascular smooth muscle cell (VSMC) collagen synthesis and growth mediated by angiotensin (Ang) II in spontaneously hypertensive rats (SHR). Cultured mesenteric VSMC from Wistar-Kyoto rats and SHR were used. Phosphorylation of ERK1/2 and p38 MAP kinase were assessed by Western blots with phosphospecific antibodies. Ang II-stimulated DNA and collagen synthesis were determined by measuring incorporation of (3)H-thymidine and (3)H-proline, respectively. mRNA expression of procollagen I and III was determined by reverse transcription-polymerase chain reaction. Ang II increased ERK1/2 and p38 MAP kinase phosphorylation. Responses were augmented in SHR. Effects were inhibited by irbesartan, a selective AT(1) antagonist, but not by PD123319, a selective AT(2) blocker. Ang II stimulated (3)H-thymidine and (3)H-proline incorporation. These actions were enhanced 2- to 3-fold in SHR. PD98059, selective inhibitor of the ERK1/2 pathway, attenuated Ang II-induced growth and collagen effects and normalized responses in SHR. SB212190, a selective p38 MAP kinase inhibitor, did not alter Ang II-elicited DNA synthesis but reduced collagen production and mRNA expression of procollagen I and III in SHR. These data demonstrate that (1) Ang II-mediated activation of p38 and ERK1/2 is increased in SHR, (2) augmented growth responses are generated by ERK1/2-dependent, p38 MAP kinase-independent pathways, and (3) p38 MAP kinase influences Ang II-induced collagen production in SHR but not in Wistar-Kyoto rats. These results indicate differential roles of ERK1/2 and p38 MAP kinase in AT(1)-stimulated VSMC growth and collagen production, which may contribute to vascular remodeling in hypertension.
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PMID:p38 Map kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin II in SHR but not in WKY. 1123 Mar 37

Platelet factor 4 (PF-4) is a CXC-chemokine with strong anti-angiogenic properties. We have shown previously that PF-4 inhibits angiogenesis by associating directly with fibroblast growth factor 2 (FGF-2), inhibiting its dimerization, and blocking FGF-2 binding to endothelial cells. We now have characterized a small peptide domain (PF-447-70) derived from the C-terminus of PF-4, which conserves anti-angiogenic effects of the parent protein. PF-447-70 inhibited internalization of 125I-FGF-2 by endothelial cells in a time-dependent manner. The peptide reduced FGF-2-stimulated cell migration to control levels in wounded monolayers of bovine capillary endothelial cells. PF-447-70 also reduced FGF-2 induced phosphorylation of MAP kinases ERK-1 and ERK-2, which are essential for migration and survival of endothelial cells. In a serum-free ex vivo angiogenesis assay, the peptide blocked microvessel outgrowth by 89%. A single amino acid substitution within PF-447-70 abolished all inhibitory activities. To simulate a real anti-angiogenic treatment situation, we administered PF-447-70 systemically to mice implanted subcutaneously with FGF-2 containing gelatin sponges with the result of sparse, scattered, and immature vessel growth. The small peptide fragment derived from the angio-inhibitory CXC-chemokine PF-4 might be used as a starting point to develop anti-angiogenic designer drugs for angiogenesis-dependent pathologies such as cancer, diabetic retinopathy, and rheumatoid arthritis.
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PMID:A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF-2. 1125 63


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