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

Terminally differentiated cardiac myocytes adapt to mechanical and neurohumoral stress via morphological changes of individual cells accompanied by reactivation of fetal pattern of gene expression. Endothelin-1, a powerful paracrine mediator of myocyte growth, induces similar changes in cultured cardiac myocytes as those seen in hypertrophied heart in vivo. By using rat B-type natriuretic peptide promoter, we identified a novel ETS binding sequence, on which nuclear protein binding is activated in endothelin-1-treated cultured cardiac myocytes. This sequence binds ETS-like gene-1 transcription factor and mediates endothelin-1-specific activation of transcription, but not responses to increased calcium signaling via l-type calcium channels, angiotensin II treatment, or mechanical stretch of myocytes. Interestingly, endothelin-1 activated signaling converges via p38 mitogen-activated protein kinase-dependent mechanism on ETS binding site, whereas this element inhibits extracellular signal-regulated kinase activated transcription. In conclusion, given the fundamental role of the interaction of mitogen-activated protein kinases and ETS factors in regulation of eukaryotic cell differentiation, growth, and oncogenesis, these results provide the unique evidence of a endothelin-1- and mitogen-activated protein kinase-regulated ETS factor pathway for cardiac myocytes.
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PMID:Endothelin-1-specific activation of B-type natriuretic peptide gene via p38 mitogen-activated protein kinase and nuclear ETS factors. 1244 26

Intracellular phosphorylation of cis-4-methylsphingosine was previously shown to result in a metabolically stable compound that accumulates in Swiss 3T3 fibroblasts and mimics the mitogenic effect induced by the short-lived sphingosine metabolite, sphingosine-1-phosphate. In the present study incubation of neuroblastoma B104 cells with cis-4-methylsphingosine (10 microM) also resulted in an intracellular accumulation of its phosphorylated derivative that was, however, associated with the concentration-dependent induction of apoptosis, not observed after treatment with 10 microM of sphingosine-1-phosphate or sphingosine, respectively. In B104 cells, cis-4-methylsphingosine stimulated p38 mitogen-activated protein kinase (p38 MAPK) and simultaneously inhibited extracellular signal-regulated kinase (ERK), whereas sphingosine and sphingosine-1-phosphate only stimulated p38 MAPK without suppression of ERK. Inhibition of cis-4-methylsphingosine phosphorylation reduced both, apoptosis and concurrent regulation of mitogen-activated protein kinases (MAPKs), suggesting that the unusual accumulation of the phosphorylated sphingoid base was responsible for the biological effects. Furthermore, inhibition of p38 MAPK prevented cis-4-methylsphingosine-induced apoptosis, while suppression of the ERK pathway in the presence of sphingosine or sphingosine-1-phosphate resulted in apoptosis, indicating that the simultaneous opposite regulation of the two MAPKs was required for the induction of apoptosis.
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PMID:Cis-4-methylsphingosine phosphate induces apoptosis in neuroblastoma cells by opposite effects on p38 and ERK mitogen-activated protein kinases. 1255 25

Previous studies have demonstrated that haptens induce several phenotypic and functional changes of dendritic cells in vivo as well as in vitro. Although recently, the crucial role of p38 mitogen-activated protein kinase has been reported in the activation of dendritic cells by haptens, the signal transduction elements involved in each phenotypic and functional changes that occur in the activation of dendritic cells by haptens remain unknown. Therefore, we examined the role of mitogen-activated protein kinases and nuclear factor-kappaB in the signal transduction of dendritic cells stimulated with two representative haptens, i.e., NiCl2 and 2,4-dinitrochlorobenzene. Human monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene induced the phosphorylation of p38 and stress-activated protein kinase/c-jun N-terminal kinases, whereas NiCl2 induced that of p44/42 extracellular signal-regulated kinases, p38, and stress-activated protein kinase/c-jun N-terminal kinases. In addition, NiCl2 phosphorylated inhibitor kappaB and activated nuclear factor-kappaB. In contrast, primary irritants, e.g., benzalkonium chloride, or sodium lauryl sulfate, did not activate these signal transduction pathways. By using specific inhibitors for extracellular signal-regulated kinases and p38 pathways, PD98059 and SB203580, respectively, we demonstrated that the augmentation of CD86, HLA-DR, and CD83, and the production of interleukin-8 along with its increased mRNA expression by monocyte-derived dendritic cells stimulated with 2,4-dinitrochlorobenzene, and the augmentation of CD83 and the interleukin-12 p40 production by monocyte-derived dendritic cells stimulated with NiCl2, were suppressed by SB203580, whereas PD98059 suppressed the production of interleukin-1beta and tumor necrosis factor-alpha, together with their increased mRNA expression by monocyte-derived dendritic cells treated with NiCl2. On the other hand, in spite of the activation of nuclear factor-kappaB by monocyte-derived dendritic cells stimulated with NiCl2, nuclear factor-kappaB inhibitor did not significantly affect the phenotypic and functional changes in the activation of monocyte-derived dendritic cells. These data indicate that NiCl2 and 2,4-dinitrochlorobenzene stimulate different signal transduction pathways in monocyte-derived dendritic cells, and subsequently induce different phenotypic and functional changes in them.
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PMID:p38 Mitogen-activated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl2 and 2,4-dinitrochlorobenzene. 1260 67

The p38 family of mitogen-activated protein kinases includes p38 alpha (SAPK2a, CSBP), p38 beta (SAPK2b), p38 delta (SAPK4), and p38 gamma (SAPK3/ERK6). p38 alpha and p38 beta are widely expressed p38 isoforms that are involved in regulation of cell proliferation, differentiation, development, and response to stress. Relatively less is known regarding the function of the p38 delta isoform. In this review, we discuss the role of the p38 alpha, p38 beta, and p38 gamma isoforms and then present recent findings that define a role for p38 delta as a regulator of differentiation-dependent gene expression in keratinocytes.
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PMID:p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. 1271 88

P2Y2 receptor up-regulation and activation induces intimal hyperplasia and monocyte/macrophage infiltration in the collared rabbit carotid artery model of vascular injury, suggesting a potential role for P2Y2 receptors in monocyte recruitment by vascular endothelium. In this study, we addressed the hypothesis that activation of P2Y2 receptors by extracellular nucleotides modulates the expression of adhesion molecules on vascular endothelial cells that are important for monocyte recruitment. Results indicated that the equipotent P2Y2 receptor agonists UTP or ATP (1-100 microm) stimulated the expression of vascular cell adhesion molecule-1 (VCAM-1) in human coronary artery endothelial cells (HCAEC) in a time- and dose-dependent manner. P2Y2 antisense oligonucleotides inhibited VCAM-1 expression induced by UTP but not by tumor necrosis factor-alpha. Furthermore, UTP induced VCAM-1 expression in human 1321N1 astrocytoma cell transfectants expressing the recombinant P2Y2 receptor, whereas vector-transfected control cells did not respond to UTP. The effect of UTP on VCAM-1 expression in HCAEC was prevented by depletion of intracellular calcium stores with thapsigargin or by inhibition of p38 mitogen-activated protein kinase or Rho kinase, but was not affected by inhibitors of the mitogen-activated protein/extracellular signal-regulated kinase pathway (i.e. MEK1/2). Consistent with a role for VCAM-1 in the recruitment of monocytes, UTP or ATP increased the adherence of monocytic U937 cells to HCAEC, an effect that was inhibited by anti-VCAM-1 antibodies. These findings suggest a novel role for the P2Y2 receptor in the p38- and Rho kinase-dependent expression of VCAM-1 that mediates the recruitment of monocytes by vascular endothelium associated with the development of atherosclerosis.
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PMID:The P2Y2 nucleotide receptor mediates UTP-induced vascular cell adhesion molecule-1 expression in coronary artery endothelial cells. 1271 97

1 The polysaccharide from Ganoderma lucidum (PS-G) has been reported to enhance immune responses and to elicit antitumor effects. In our previous study, we found that PS-G efficiently inhibited spontaneously and Fas-enhanced neutrophil apoptosis when cultured in vitro. Since phagocytosis and chemotaxis play essential roles in host defense mediated by neutrophils, it is of great interest to know the effect of PS-G on these two cell functions, and the molecular events leading to these actions. 2 Using latex beads and heat-inactive Escherichia coli serving as particles for neutrophil engulfment, we found that PS-G is able to enhance phagocytic activity of human primary neutrophils and neutrophilic-phenotype cells differentiated from all trans retinoic acid-treated HL-60 cells. 3 Chemotactic assay using Boyden chamber also revealed the ability of PS-G to increase neutrophil migration. 4 Exposure of neutrophils to PS-G time dependently caused increases in protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), Hck, and Lyn activities. 5 Results with specific kinase inhibitors indicate that phagocytic action of PS-G was reduced by the presence of wortmannin (Phosphatidylinositol 3-kinase, PI3K inhibitor), pyrazolpyrimidine 2 (Src-family tyrosine kinase inhibitor), Ro318220 (PKC inhibitor), and SB203580 (p38 MAPK inhibitor), but not by PD98059 (mitogen-activated protein/ERK kinase inhibitor). Moreover, chemotactic action of PS-G requires the activities of PI3K, p38 MAPK, Src tyrosine kinases and PKC. 6 All these results demonstrate the abilities of PS-G to enhance neutrophil function in phagocytosis and chemotaxis, and further provide evidence to strengthen the beneficial remedy of G. lucidum in human to enhance defense system.
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PMID:Signaling mechanisms of enhanced neutrophil phagocytosis and chemotaxis by the polysaccharide purified from Ganoderma lucidum. 1277 Sep 34

Raf/mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)1,2/extracellular signal-regulated kinase1,2 and MKK3,6/p38 mitogen-activated protein kinase pathways play an important role in cellular survival and apoptosis. The results of this study identify novel mechanisms to explain the opposing effects of these pathways in the regulation of apoptosis induction. Our results show that activation of p38 by adenoviral expression of MKK3b or arsenite treatment was followed by rapid dephosphorylation of MEK1,2 and subsequent apoptosis in human skin fibroblasts. Inhibition of p38 activity by SB203580 and adenoviral expression of dominant-negative forms of p38 potently inhibited MEK1,2 dephosphorylation and apoptosis. Strikingly, p38-mediated dephosphorylation of MEK1,2, was not detected in a series of transformed human cell lines. Taken together, we provide evidence for mechanisms unidentified previously that negatively regulates survival signaling during apoptosis induction. In addition, we show that in all transformed cell lines we have studied thus far, the function of this pathway is impaired.
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PMID:p38 Mitogen-activated protein kinase pathway suppresses cell survival by inducing dephosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase1,2. 3194 81

Reactive oxygen species are involved in the activation of several mitogen-activated protein kinases (MAPKs), key-players in the production of several cytokines. Therefore the current study investigated whether N-acetylcysteine (NAC), an antioxidative agent, inhibits the interleukin (IL)-1beta-induced expression and production of eotaxin and monocyte chemotactic protein (MCP)-1 in human airway smooth muscle cells (HASMC). NAC (10 mM) decreased the expression of eotaxin and MCP-1, by 46 +/- 11% (n=7) and 87 +/- 4% (n=6), respectively; the eotaxin release was inhibited by 75 +/- 5% (n=7), whereas the MCP-1 release was decreased by 69 +/- 41% (n=10). NAC (1 mM) also decreased the IL-1beta-induced activation of p38 MAPK. Compared with unstimulated cells, a four-fold increase in 8-isoprostane production in IL-1beta-stimulated HASMC was observed, which could be inhibited by NAC in a concentration-dependent way, with a maximum inhibition of 39 +/- 12%, with 1 mM NAC. The present study demonstrated that N-acetylcysteine inhibits the interleukin-1beta-induced eotaxin and monocyte chemotactic protein 1 expression and production due to a decreased activation of p38 mitogen-activated protein kinase. This study has also shown that N-acetylcysteine decreases the interleukin-1beta-induced production of reactive oxygen species, as suggested by a reduction in the 8-isoprostane production.
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PMID:N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells. 1288 49

Ras expression has been suggested as a marker for tumor aggressiveness of breast cancer,including the degrees of invasion and tumor recurrence.We showed previously that H-ras, but not N-ras, up-regulates matrix metalloproteinase 2 expression and induces invasive phenotype in MCF10A human breast epithelial cells (A. Moon, et al. Int. J. Cancer, 85: 176-181, 2000). In this study, we show that H-ras also promotes cell motility more effectively than N-ras in MCF10A cells. We have investigated H-ras-specific signaling pathway(s) critical for H-ras-mediated cell motility and invasive phenotype. Whereas neither H-ras nor N-ras activated c-Jun NH(2)-terminal kinase 1, both H-ras and N-ras effectively activated extracellular signal-regulated protein kinase (ERK) -1,2. Importantly, prominent activation of p38 mitogen-activated protein kinase was shown only in H-ras-activated cells but not in N-ras-activated MCF10A cells. Functional significance of H-ras-activated p38 in invasiveness and cell motility was evidenced by studies using SB203580, a chemical inhibitor of p38, and a dominant-negative construct of p38. Whereas inhibition of c-Jun NH(2)-terminal kinase 1 activity had no effect on H-ras-induced MCF10A cell invasion and motility, the inhibition of the ERK pathway using a chemical inhibitor PD98059 or dominant-negative mutant of mitogen-activated protein/ERK kinase 1, an activator of ERKs, significantly reduced H-ras-induced invasion and migration. We also provide evidence that p38 and, to a lesser degree, ERKs, are critical for H-ras-mediated up-regulation of matrix metalloproteinase 2. Taken together, the present study shows that H-ras activation of both p38 and ERKs induces cell invasion and motility, whereas N-ras activation of ERKs alone is not sufficient. This study reveals the p38 kinase as a key signaling molecule differentially regulated by H-ras and N-ras, leading to H-ras-specific cell invasive and migrative phenotypes in human breast epithelial cells.
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PMID:p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. 1450 Mar 81

Receptor activator of NF-kappaB ligand (RANKL) is essential for differentiation and function of osteoclasts. The negative signaling pathways downstream of RANKL are not well characterized. By retroviral transduction of RAW264.7 cells with a dominant negative Src homology 2 domain-containing phosphatase-1 (SHP-1)(C453S), we studied the role of tyrosine phosphatase SHP-1 in RANKL-induced osteoclastogenesis. Over-expression of SHP-1(C453S) significantly enhanced the number of tartrate-resistant acid phosphatase-positive multinuclear osteoclast-like cells in response to RANKL in a dose-dependent manner. RANKL induced the recruitment of SHP-1 to a complex containing TNFR-associated factor (TRAF)6. GST pull down experiments indicated that the association of SHP-1 with TRAF6 is mediated by SHP-1 lacking the two Src homology 2 domains. RANKL-stimulated IkappaB-alpha phosphorylation, IkappaB-alpha degradation and DNA binding ability of NF-kappaB were increased after over-expression of SHP-1(C453S). However, RANKL-induced phosphorylation of mitogen-activated protein kinases, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, was unchanged. In addition, SHP-1 regulated RANKL-stimulated tyrosine phosphorylation of p85 subunit of phosphatidylinositol 3 kinase and the phosphorylation of Akt. Increased numbers of osteoclasts contribute to severe osteopenia in Me(v)/Me(v) mice due to mutation of SHP-1. Like RAW264.7 cells expressing SHP-1(C453S), the bone marrow macrophages of Me(v)/Me(v) mice generated much more osteoclast-like cells than that of littermate controls in response to RANKL. Furthermore compared with controls, RANKL induces enhanced association of TRAF6 and RANK in both RAW264.7 cells expressing SHP-1(C453S) and bone marrow macrophages from Me(v)/Me(v) mice. Therefore, SHP-1 plays a role in signals downstream of RANKL by recruitment to the complex containing TRAF6 and these observations may help to understand the mechanism of osteoporosis in Me(v)/Me(v) mice.
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PMID:Receptor activator of NF-kappa B ligand stimulates recruitment of SHP-1 to the complex containing TNFR-associated factor 6 that regulates osteoclastogenesis. 1450 Jun 59


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