Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of human monocyte-derived dendritic cells with the yeast extract zymosan is characterized by a predominant production of IL-10 and a strong induction of cyclooxygenase-2, but the molecular mechanisms underlying this response are only partially understood. To address this issue, the activation of transcription factors that may bind to the il10 proximal promoter was studied. Binding activity to Sp1, Sp3, NF-Y, and cAMP response element (CRE) sites was detected in the nuclear extracts of dendritic cells; however these binding activities were not influenced by zymosan. No binding activity to Stat1, Stat3, and c/EBP sites was detected. Notably, zymosan activated kappaB-binding activity, but inhibition of NF-kappaB was associated with enhanced IL-10 production. In sharp contrast, treatments acting on CREB (CRE binding protein), including 8-Br-cAMP, PGE(2), and inhibitors of PKA, COX, and glycogen-synthase kinase-3beta showed a direct correlation between CREB activation and IL-10 production. Zymosan induced binding of both P-CREB and CREB-binding protein (CBP) to the il10 promoter as judged from chromatin immunoprecipitation assays, whereas negative results were obtained with Ab reactive to Sp1, Sp3, c-Maf, and NF-Y. Zymosan also induced nuclear translocation of the CREB coactivator transducer of regulated CREB activity 2 (TORC2) and interaction of TORC2 with P-CREB coincidental with the association of CREB to the il10 promoter. Altogether, our data show that zymosan induces il10 transcription by a CRE-dependent mechanism that involves autocrine secretion of PGE(2) and a network of interactions of PKA, MAP/ERK, glycogen-synthase kinase-3beta, and calcineurin, which regulate CREB transcriptional activity by binding the coactivators CBP and TORC2 and inhibiting CBP interaction with other transcription factors.
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PMID:The induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the coactivators CREB-binding protein and TORC2 and autocrine PGE2. 1956 45

Ultraviolet B (UVB) irradiation induces skin damage and inflammation. One way to reduce the inflammation is via the use of molecules termed photochemopreventive agents. Sulforaphane (4-methylsulfinylbutyl isothiocyanate, SF), which is found in cruciferous vegetables, is known for its potent physiological properties. This study was designed to evaluate the effect of SF on skin inflammation in vitro and in vivo. In in vitro study using immortalized human keratinocytes (HaCaT), UVB caused marked inflammatory responses [i.e., decrease of HaCaT viability and increase of production of an inflammatory marker interleukin-6 (IL-6)]. SF recovered the cell proliferation and suppressed the IL-6 production. These anti-inflammatory effects of SF were explained by its ability to reduce UVB-induced inflammatory gene expressions [IL-6, IL-1beta and cyclooxgenase-2 (COX-2)]. Because SF seems to have an impact on COX-2 expression, we focused on COX-2 and found that SF reduced UVB-induced COX-2 protein expression. In support of this, PGE(2) released from HaCaT was suppressed by SF. Western blot analysis revealed that SF inhibited p38, ERK and SAPK/JNK activation, indicating that the inhibition of mitogen-activated protein kinases (MAPK) by SF would attenuate the expression of inflammatory mediators (e.g., COX-2), thereby reducing inflammatory responses. Moreover, we conducted skin thickening assay using HR-1 hairless mice and found that UVB-induced skin thickness, COX-2 protein expression and hyperplasia were all suppressed by feeding SF to the mice. These results suggest that SF has a potential use as a compound for protection against UVB-induced skin inflammation.
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PMID:Sulforaphane suppresses ultraviolet B-induced inflammation in HaCaT keratinocytes and HR-1 hairless mice. 1957 49

Elevated levels of prostaglandins such as PGE(2) in inflamed gingiva play a significant role in the tissue destruction caused by periodontitis, partly by targeting local fibroblasts. Only very few studies have shown that PGE(2) inhibits the proliferation of a gingival fibroblast (GF) cell line, and we expanded this research by using primary human GFs (hGFs) and looking into the mechanisms of the PGE(2) effect. GFs derived from healthy human gingiva were treated with PGE(2) and proliferation was assessed by measuring cell number and DNA synthesis and potential signaling pathways were investigated using selective activators or inhibitors. PGE(2) inhibited the proliferation of hGFs dose-dependently. The effect was mimicked by forskolin (adenylate cyclase stimulator) and augmented by IBMX (a cAMP-breakdown inhibitor), pointing to involvement of cAMP. Indeed, PGE(2) and forskolin induced cAMP generation in these cells. Using selective EP receptor agonists we found that the anti-proliferative effect of PGE(2) is mediated via the EP(2) receptor (which is coupled to adenylate cyclase activation). We also found that the effect of PGE(2) involved activation of Epac (exchange protein directly activated by cAMP), an intracellular cAMP sensor, and not PKA. While serum increased the amount of phospho-ERK in hGFs by approximately 300%, PGE(2) decreased it by approximately 50%. Finally, the PGE(2) effect does not require endogenous production of prostaglandins since it was not abrogated by two COX-inhibitors. In conclusion, in human gingival fibroblasts PGE(2) activates the EP(2)-cAMP-Epac pathway, reducing ERK phosphorylation and inhibiting proliferation. This effect could hamper periodontal healing and provide further insights into the pathogenesis of inflammatory periodontal disease.
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PMID:Prostaglandin E2 inhibits the proliferation of human gingival fibroblasts via the EP2 receptor and Epac. 1958 88

A pleiotropic hormone, leptin, secreted into saliva by the acinar cells of salivary glands is an important mediator of the processes of oral mucosal defense. Here, we report on the role of epidermal growth factor receptor (EGFR) transactivation in the signaling events that mediate leptin protection of sublingual salivary gland acinar cells against ethanol cytotoxicity. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR protein tyrosine kinase and cytosolic phospholipase A(2) (cPLA(2)) activity, and characterized by a marked increase in matrix metalloproteinase MMP-9 and arachidonic acid (AA) release, and PGE(2) generation. The loss in countering capacity of leptin against ethanol cytotoxicity was attained with JAK inhibitor AG490, Src inhibitor PP2, and EGFR inhibitor AG1478, as well as ERK inhibitor PD98059. Moreover, the agents evoked also the inhibition in leptin-induced up-regulation in cPLA(2) activity, AA release, and PGE(2) generation. The changes caused by leptin in EGFR phosphorylation, MMP-9, and cPLA(2) activation were susceptible to suppression by metalloprotease inhibitor GM6001, but the production of MMP-9 was not affected by EGFR inhibitor AG1478 or PKC inhibitor Ro318220. These findings point to the involvement of MMP-9 in the event of leptin-induced EGFR transactivation that results in the signaling cascade leading to cPLA(2) activation and up-regulation in PGE(2) generation, thus providing new insights into the mechanism of oral mucosal protection against ethanol toxicity.
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PMID:Role of epidermal growth factor receptor transactivation in the activation of cytosolic phospholipase A(2) in leptin protection of salivary gland acinar cells against ethanol cytotoxicity. 1961 45

It is well known that pro-inflammatory mediators like nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) contribute to the courses of many inflammatory diseases. In the present study, the authors investigated the anti-inflammatory effects of pseudocoptisine, a quaternary alkaloid with a benzylisoquinoline skeleton, which was isolated from the tubers of Corydalis turtschaninovii by examining its inhibitory effects on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. Pseudocoptisine caused dose-dependent reductions in the levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) at both protein and mRNA levels and concomitant decreases in PGE(2) and NO production. In addition, it was found that pseudocoptisine suppressed the production and mRNA expressions of inflammatory cytokines, such as, TNF-alpha and IL-6. Furthermore, molecular data revealed that pseudocoptisine inhibited the LPS-stimulated DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB). Moreover, this effect was accompanied by decreases in the phosphorylation of inhibitory kappaB (IkappaB)-alpha and in the subsequent blocking of p65 subunit of NF-kappaB translocation to the nucleus. In addition, pseudocoptisine dose-dependently inhibited the phosphorylations of ERK and p38. Taken together, these results suggest that pseudocoptisine reduces levels of the pro-inflammatory mediators, such as, iNOS, COX-2, TNF-alpha, and IL-6 through the inhibition of NF-kappaB activation via the suppression of ERK and p38 phosphorylation in RAW 264.7 cells. These findings reveal in part the molecular basis for the anti-inflammatory properties of pseudocoptisine.
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PMID:Quaternary alkaloid, pseudocoptisine isolated from tubers of Corydalis turtschaninovi inhibits LPS-induced nitric oxide, PGE(2), and pro-inflammatory cytokines production via the down-regulation of NF-kappaB in RAW 264.7 murine macrophage cells. 1966 43

Polyphenols are widely distributed in plants and known for antioxidant and anti-inflammatory properties. Areca nut, rich in polyphenols, is the major component of betel quid and we have previously shown that the extract of areca nut can induce oxidative stress in vitro. In this study, we have further pinpointed that areca nut extract (ANE) contains catechin based procyanidins which range from dimers to decamers and polymers; this was carried out by HPLC and electrospray ionization/mass spectrometry (ESI/MS). To quantify their antioxidant potential, oligomeric and polymeric procyanidins of ANE were separated and evaluated using the Trolox equivalent antioxidant capacity (TEAC) assay. The results clearly demonstrated that the antioxidant capacity of the ANE procyanidins increased with the degree of polymerization. The anti-inflammatory potential of ANE was also tested using 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated human oral cancer SAS cells. ANE inhibited TPA-induced cyclooxygenase-2 (COX-2) protein expression at low doses, which correlated with the inhibition of ERK phosphorylation in the SAS cells. Furthermore, feeding rats with ANE at 1 and 10mg/kg/day for 5days significantly repressed carrageenan-induced inflammatory exudates and PGE(2) formation. In conclusion, ANE, which contains catechins based oligomeric and polymeric procyanidins, regulates COX-2 expression in vitro and possess anti-inflammatory potential in vivo.
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PMID:Effects of Areca catechu L. containing procyanidins on cyclooxygenase-2 expression in vitro and in vivo. 1984 Aug 28

Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src / epidermal growth factor (EGF) receptor / p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element-binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-kappaB (NF-kappaB)-related signals in the PAR2-triggered PGE(2) release / COX-2 upregulation in A549 cells. The PAR2-triggered PGE(2) release was clearly blocked by an inhibitor of the NF-kappaB pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-kappaB, an indicator of NF-kappaB activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3-kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-kappaB, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-kappaB pathway is involved in PAR2-triggered PGE(2) formation, but not upregulation of COX-2 that is dependent on activation of ERK/CREB and JNK in addition to p38MAPK.
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PMID:Proteinase-activated receptor-2-triggered prostaglandin E(2) release, but not cyclooxygenase-2 upregulation, requires activation of the phosphatidylinositol 3-kinase/Akt / nuclear factor-kappaB pathway in human alveolar epithelial cells. 1988 Dec 25

Preclinical and clinical evidence shows that cyclooxygenase-2 (Cox-2)-mediated prostaglandin E(2) (PGE(2)) overexpression plays an important role in tumor growth, metastasis, and immunosuppression. It has been shown that expression of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme responsible for PGE(2) inactivation, is suppressed in the majority of cancers, including breast and colon carcinoma. We have developed adenoviral vectors (Ad) encoding the 15-PGDH gene under control of the vascular endothelial growth factor receptor 1 (VEGFR1/flt-1; Adflt-PGDH) and the Cox-2 (Adcox-PGDH) promoters. The purpose of this study was to investigate cytotoxicity in vitro and therapeutic efficacy in vivo of 15-PGDH-mediated cancer therapy. The levels of PGE(2) and VEGF expression were correlated with PGE(2) receptor and Cox-2 and flt-1 expression in cancer cells. The in vitro study showed that Ad-mediated 15-PGDH expression significantly decreased proliferation and migration of cancer cells. Animal breast and colon tumor therapy studies showed that 15-PGDH gene therapy produced a significant delay in 2LMP and LS174T tumor growth. Combined therapy using 15-PGDH and anti-VEGF antibody (bevacizumab) significantly increased inhibition of growth of LS174T tumor xenografts in comparison with agents alone. These results suggest that 15-PGDH-mediated regulation of PGE(2) catabolism in the tumor microenvironment represents a novel approach for therapy of human breast and colon cancer.
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PMID:Experimental cancer therapy using restoration of NAD+ -linked 15-hydroxyprostaglandin dehydrogenase expression. 1988 44

Thiazolidinediones, known as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, may modify prostaglandin formation and exert gastroprotective effects. Since activation of proteinase-activated receptor-1 (PAR1) reveals endogenous prostanoid-dependent gastroprotection, we investigated if two thiazolidinediones, ciglitazone and troglitazone, modulate the prostaglandin E(2) (PGE(2)) release caused by activation of PAR1 in normal rat gastric mucosal epithelial RGM1 cells. Ciglitazone dramatically facilitated the PAR1-triggered PGE(2) production and cyclooxygenase-2 (COX-2) upregulation, although it had no effect by itself. In contrast, troglitazone suppressed the PAR1-triggered PGE(2) production and COX-2 upregulation. Either effect of ciglitazone and troglitazone was resistant to GW9662, a PPARgamma antagonist. The facilitation of the PGE(2) release by ciglitazone was blocked by inhibitors of MEK, p38 MAP kinase (p38MAPK) and PI3-kinase (PI3K), but not JNK. Nonetheless, ciglitazone failed to enhance the PAR1-triggered phosphorylation of ERK and p38MAPK. In conclusion, ciglitazone and troglitazone, exert opposite effects on the PAR1-triggered PGE(2) production and COX-2 upregulation by targeting molecules other than PPARgamma.
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PMID:Opposite effects of two thiazolidinediones, ciglitazone and troglitazone, on proteinase-activated receptor-1-triggered prostaglandin E(2) release. 1995 59

Cyclooxygenase (COX)-2-derived prostaglandin (PG)E(2) controls many aspects of colon cancer development, modulating from apoptosis resistance and cell proliferation to angiogenesis, invasion, and metastasis. Here, we investigated the role of different phospholipases (PL)A(2) in supplying arachidonic acid (AA) for COX-2-dependent PGE(2) generation and signaling pathways involved in activation of colon cancer cells by a physiologically relevant stimulus. To emulate the hypertonic environment found physiologically in colon, the human colon cancer cell line Caco-2 was maintained in hypertonic complete DMEM medium. Human colon cancer cell line Caco-2 exposed to a hypertonic environment responded with marked AA release, COX-2 induction and PGE(2) generation. Selective secretory (s)PLA(2) and calcium-independent (i)PLA(2) inhibitors did not modify PGE(2) generation, while either COX-2 or cytosolic (c)PLA(2) inhibitors completely inhibited PGE(2) generation. cPLA(2)-alpha was responsible for AA supply for PGE(2) generation, but had no role in COX-2 induction. Mitogen-activated protein (MAP) kinases, ERK 1/2, p38, and JNK, participated in the signaling events that lead to PGE(2) generation by modulating AA release, but only ERK 1/2 was involved in COX-2 upregulation. Our results indicate that hypertonic stress activates PGE(2) generation by Caco-2 cells through a mechanism dependent on MAP kinase-regulated AA mobilization, increased cPLA(2)-alpha activity, and COX-2 induction.
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PMID:Hypertonic environment elicits cyclooxygenase-2-driven prostaglandin E2 generation by colon cancer cells: role of cytosolic phospholipase A2-alpha and kinase signaling pathways. 2000 62


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