Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a "second wave" of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IkappaB kinase (IKK) alpha and IKKbeta are distinctly involved in MUC5AC induction via an ERK1-dependent, but IkappaBalpha-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.
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PMID:A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. 1723 23

Hydrogen sulfide (H2S) is now considered an endogenous, gaseous mediator, which has been demonstrated to be involved in many inflammatory states. However, the mechanism of its proinflammatory function remains unknown. In the present study, we used IFN-gamma-primed human monocytic cell line U937 to investigate the effects of H2S in vitro on monocytes. We found that treatment with the H2S donor, sodium hydrosulfide, led to significant increases in the mRNA expression and protein production of TNF-alpha, IL-1beta, and IL-6 in U937 cells. H2S-triggered monocyte activation was confirmed further by the up-regulation of CD11b expression on the cell surface. We also observed that H2S could induce a rapid degradation of IkappaBalpha and subsequent activation of NF-kappaB p65, and this effect was attenuated by Bay 11-7082, a specific inhibitor of NF-kappaB. Furthermore, pretreatment of cells with Bay 11-7082 substantially inhibited the secretion of TNF-alpha, IL-1beta, and IL-6 induced by H2S. We also found that H2S stimulated the phosphorylation and activation of ERK1/2, but not of p38 MAPK and JNK, and pretreatment with PD98059, a selective MEK1 antagonist, could inhibit H2S-induced NF-kappaB activation markedly. Together, our findings suggest for the first time that H2S stimulates the activation of human monocytes with the generation of proinflammatory cytokines, and this response is, at least partially, through the ERK-NF-kappaB signaling pathway.
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PMID:Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway. 1728 97

Acrolein is a highly reactive alpha, beta-unsaturated aldehyde, and a product of lipid peroxidation reactions. Acrolein is also an environmental pollutant and a key component of cigarette smoke, and has been implicated in multiple respiratory diseases. Lung tissue is a primary target for acrolein toxicity in smokers and may lead to chronic lung inflammation and lung cancer. Chronic inflammation, associated with expression of cyclooxygenase-2 (COX-2) and prostaglandins, are predisposing factors for malignancy. In this study, we investigated the induction of COX-2 by acrolein in rat lung epithelial cells and its related signaling cascade. Induction of COX-2 by acrolein was significant at 6 h post-treatment and was dependent upon NFkappaB activation. The activation of NFkappaB by acrolein was induced as a result of degradation of IkappaBalpha over the time of treatment. In addition, the upstream signaling cascade involved Raf-1/ERK activation by acrolein in the COX-2 induction and was inhibited by GW5074 (a Ras/Raf-1/ERK inhibitor), thereby providing evidence for the role of this cascade in this process. The results of these studies offer an explanation for the mechanism of COX-2 induction by acrolein in rat lung epithelial cells.
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PMID:Induction of COX-2 by acrolein in rat lung epithelial cells. 1731 10

beta-Lapachone (LAPA) is a chemotherapeutic agent that can inhibit the expression of nitric oxide (NO) and inducible NO synthase (iNOS) in alveolar macrophages. No other information on the agent's anti-inflammatory activity has been reported. In the present study, we investigated the molecular mechanism of LAPA on lipopolysaccharide (LPS)-induced responses in BV2 microglia. Treatment of LAPA significantly inhibited NO and PGE(2) release in LPS-stimulated BV2 microglia. The inhibition of iNOS and COX-2 was also observed, suggesting the blockage of transcriptional levels. In addition, LAPA attenuated the expression of mRNA and proteins of proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha in a dose-dependent manner. Moreover, LAPA exhibits anti-inflammatory properties by suppressing the NF-kappaB activation by blocking IkappaBalpha degradation and downregulating the ERK, p38 mitogen-activated protein kinase (MAPK) and Akt pathway. The results show that LAPA may be useful as a potential anti-inflammatory agent for attenuating inflammatory diseases.
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PMID:Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. 1732 74

LCY-2-CHO has anti-inflammatory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of anti-inflammatory and inflammatory proteins in cultured rat aortic vascular smooth muscle cells (VSMC). LCY-2-CHO is able to induce heme oxygenase-1 (HO-1) protein expression through a transcriptional action. The HO-1 inducting effect of LCY-2-CHO was inhibited by SB203580, N(G)-nitro-l-arginine methylester (l-NAME), and wortmannin, but was not affected by U0126 or SP600125. In accordance LCY-2-CHO increased protein phosphorylation of p38, Akt, and eNOS. Nrf2 is a transcription factor essential for HO-1 gene induction and we showed that LCY-2-CHO is able to cause Nrf2 nuclear translocation and this action depends on p38, Akt and eNOS. In addition to induce anti-inflammatory HO-1, LCY-2-CHO reduced interleukin-1beta (IL-1beta)-induced inflammatory mediators, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), growth-related oncogene protein-alpha (GRO-alpha), and interleukin-8 (IL-8). Inhibitory effect on IL-1beta-mediated NF-kappaB activation was evidenced by the diminishment of IkappaB kinase (IKK) phosphorylation and IkappaBalpha degradation. In contrast, IL-1beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1beta and LCY-2-CHO displayed the non-additivity. Taken together, given the overall anti-inflammatory properties of LCY-2-CHO in VSMC, in terms to induce HO-1 gene expression and inhibit inflammatory gene expression, these results highlight the therapeutic potential of LCY-2-CHO in atherosclerosis.
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PMID:The anti-inflammatory actions of LCY-2-CHO, a carbazole analogue, in vascular smooth muscle cells. 1749 20

Overexpression of epidermal growth factor (EGF) receptor and constitutive activation of nuclear factor-kappaB (NF-kappaB) are frequently encountered in tumor cells. Although EGF has been shown to induce NF-kappaB activation, the mechanism is poorly understood. EGF activated NF-kappaB DNA binding, induced NF-kappaB reporter activity and the expression of antiapoptotic and cell-proliferative gene products. Interestingly, non-small cell lung adenocarcinoma cell lines (HCC827 and H3255), which exhibit EGFR amplification, showed ligand-independent activation of NF-kappaB. Unlike tumor-necrosis factor (TNF), however, EGF failed to induce IkappaBalpha phosphorylation and ubiquitination and the activation of IkappaBalpha kinase (IKK). Although DN-IKKbeta inhibited TNF-induced NF-kappaB activity, DN-IKKbeta had no effect on EGF-induced NF-kappaB activation, suggesting that EGF-induced NF-kappaB activation is IKK independent. Using dominant-negative plasmids, we also demonstrated the role of TRADD, TRAF2, NIK and Ras in EGF-induced NF-kappaB activation. By using specific antibodies and IkappaBalpha plasmid, which is mutated at tyrosine 42 to phenylalanine, we show that EGF induced the tyrosine phosphorylation of IkappaBalpha at residue 42. Furthermore, EGF receptor kinase inhibitor blocked IkappaBalpha phosphorylation and consequent NF-kappaB activation. Overall, our results indicate that tyrosine phosphorylation of IkappaBalpha at residue 42 is critical for EGF-induced NF-kappaB activation pathway.
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PMID:Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. 2647 48

IL-12, the critical factor for the generation of the Th1 type immune response, is produced by dendritic cells (DC) upon stimulation with LPS. Different signal pathways mediate LPS-induced expression of IL-12 and involve PI3K, MAPK and the transcription factor NF-kappaB. Here, we show that the kinase Raf is involved in the expression of IL-12 in human DC stimulated by LPS. We demonstrate that Raf regulates the expression of the IL-12 subunit p40 not via the kinase MEK, the major effector of Raf in growth factor-dependent signaling, but via the receptor-interacting protein 2 (RIP2) using specific inhibitors for MAPK pathways. RIP2 is a kinase participating in LPS/Toll-like receptor 4 signaling. Knockdown of RIP2 by siRNA inhibited LPS-dependent expression of IL-12 p40. In addition, knockdown of RIP2 reduced phosphorylation of p38 MAPK, ERK and IkappaBalpha, which are known upstream regulators of IL-12 production. Thus, in human DC LPS stimulates a signal cascade that involves the Raf-dependent activation of RIP2 leading to expression of IL-12 p40.
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PMID:RIP2 mediates LPS-induced p38 and IkappaBalpha signaling including IL-12 p40 expression in human monocyte-derived dendritic cells. 1757 44

BCR signaling in naive B cells depends on the function of signalosome mediators; however, prior engagement of CD40 or of IL-4R produces an alternate signaling pathway in which Bruton's tyrosine kinase, PI3K, phospholipase Cgamma2, and protein kinase Cbeta are no longer required for BCR-induced downstream events. To explore the range of mediators capable of producing such an alternate pathway for BCR signaling, we examined the TLR4 agonist, LPS. B cell treatment with LPS at relatively low doses altered subsequent BCR signaling such that ERK phosphorylation and NF-kappaB activation occurred in a PI3K-independent manner. This effect of LPS extended to MEK phosphorylation and IkappaBalpha degradation, and it developed slowly over a period of 16-24 h. The involvement of TLRs is suggested by similar effects observed with a structurally distinct TLR agonist, PAM3CSK4 and by the need for MyD88 for induction of alternate BCR signaling by LPS. Thus, LPS-mediated TLR engagement produces an alternate pathway for BCR-triggered signal propagation that differs from the classical, signalosome-dependent pathway.
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PMID:B cell receptor cross-talk: exposure to lipopolysaccharide induces an alternate pathway for B cell receptor-induced ERK phosphorylation and NF-kappa B activation. 1757 42

Dedifferentiated hepatoma cells, in contrast to most other cell types including hepatoma cells, undergo apoptosis when treated with lipopolysaccharide (LPS) plus the protein synthesis inhibitor cycloheximide (CHx). We recently reported that the dedifferentiated hepatoma cells also exhibit a strong and prolonged NF-kappaB induction phenotype upon exposure to LPS, suggesting that NF-kappaB signaling may play a pro-survival role, as reported in several other cell systems. To test the role of NF-kappaB in preventing LPS-mediated apoptosis, we examined the dedifferentiated cell line M38. Results show that antioxidants strongly inhibited LPS + CHx-mediated cell death in the M38 cells, yet only modestly inhibited NF-kappaB induction. In addition, inhibition of NF-kappaB translocation by infection of the M38 cells with an adenoviral vector expressing an IkappaBalpha super-repressor did not result in LPS-mediated cell death. These results suggest that unlike TNFalpha induction, the cell survival pathway activated in response to LPS is independent of NF-kappaB translocation in the dedifferentiated cells. Addition of inhibitors of JNK, p38 and ERK pathways also failed to elicit LPS-mediated apoptosis similar to that observed when protein synthesis is prevented. Thus, cell survival pathways other than those involving NF-kappaB inducible gene expression or other well-known pathways appear to be involved in protecting the dedifferentiated hepatoma variant cells from LPS-mediated apoptosis. Importantly, this pro-apoptotic function of LPS appears to be a function of loss of hepatic gene expression, as the parental hepatoma cells resist LPS-mediated apoptosis in the presence of protein synthesis inhibitors.
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PMID:Apoptosis of dedifferentiated hepatoma cells is independent of NF-kappaB activation in response to LPS. 1765 37

Progastrin (PG) exerts proliferative and antiapoptotic effects on intestinal epithelial and colon cancer cells via Annexin II (ANX-II). In here, we show that ANX-II similarly mediates proliferative and antiapoptotic effects of PG on a pancreatic cancer cell line, AR42J. The role of several signaling molecules was examined in delineating the biological activity of PG. PG (0.1-1.0 nmol/L) caused a significant increase (2- to 5-fold) in the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt (Thr(308)), p38 mitogen-activated protein kinase (MAPK; Thr(180)/Tyr(182)), extracellular signal-regulated kinases (ERK; Thr(202)/Tyr(204)), IkappaB kinase alpha/beta (IKKalpha/beta; Ser(176)/(180)), IkappaBalpha (Ser(32)), and p65 nuclear factor-kappaB (NF-kappaB; Ser(536)). Inhibition of p44/42 ERKs (PD98059), p38 MAPK (SB203580), Akt, and PI3K (LY294002), individually or combined, partially reversed antiapoptotic effects of PG. The kinetics of phosphorylation of IKKalpha/beta in response to PG matched the kinetics of phosphorylation and degradation of IkappaBalpha and correlated with phosphorylation, nuclear translocation, and activation of p65 NF-kappaB. NF-kappaB essential modulator-binding domain peptide (an inhibitor of IKKalpha/beta) effectively blocked the activity of p65 NF-kappaB in response to PG. Activation of p65 NF-kappaB, in response to PG, was 70% to 80% dependent on phosphorylation of MAPK/ERK and PI3K/Akt molecules. Down-regulation of p65 NF-kappaB by specific small interfering RNA resulted in the loss of antiapoptotic effects of PG on AR42J cells. These studies show for the first time that the canonical pathway of activation of p65 NF-kappaB mediates antiapoptotic effects of PG. Therefore, targeting PG and/or p65 NF-kappaB may be useful for treating cancers, which are dependent on autocrine or circulating PGs for their growth.
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PMID:Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor-{kappa}B. 1767 Nov 95


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