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)

Garlic-derived organosulfides (OSCs) including diallyl trisulfide (DATS) are highly effective in affording protection against chemically induced cancer in animals. Evidence is also mounting to indicate that some naturally occurring OSCs can suppress proliferation of cancer cells by causing apoptosis, but the sequence of events leading to proapoptotic effect of OSCs is poorly defined. Using PC-3 and DU145 human prostate cancer cells as a model, we now demonstrate that DATS is a significantly more potent apoptosis inducer than diallyl sulfide (DAS) or diallyl disulfide (DADS). DATS-induced apoptosis in PC-3 cells was associated with phosphorylation of Bcl-2, reduced Bcl-2 : Bax interaction, and cleavage of procaspase-9 and -3. Bcl-2 overexpressing PC-3 cells were significantly more resistant to apoptosis induction by DATS compared with vector-transfected control cells. DATS treatment resulted in activation of extracellular-signal regulated kinase 1/2 (ERK1/2) and c-jun N-terminal kinase 1 (JNK1) and/or JNK2, but not p38 mitogen-activated protein kinase. Phosphorylation of Bcl-2 in DATS-treated PC-3 cells was fully blocked in the presence of JNK-specific inhibitor SP600125. Moreover, JNK inhibitor afforded significant protection against DATS-induced apoptosis in both cells. DATS-induced Bcl-2 phosphorylation and apoptosis were partially attenuated by pharmacological inhibition of ERK1/2 using PD98059 or U0126. Overexpression of catalase inhibited DATS-mediated activation of JNK1/2, but not ERK1/2, and apoptosis induction in DU145 cells suggesting involvement of hydrogen peroxide as a second messenger in DATS-induced apoptosis. In conclusion, our data point towards important roles for Bcl-2, JNK and ERK in DATS-induced apoptosis in human prostate cancer cells.
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PMID:Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. 1518 82

In this study, we evaluated the possibility that the anti-proliferative effects of paclitaxel on vascular smooth muscle cells (VSMCs) of the rat might be due to the induction of HO-1 gene expression. Treatment of the cells with paclitaxel resulted in marked time- and dose-dependent inductions of HO-1 mRNA, followed by corresponding increases in HO-1 protein expression and HO enzymatic activities. Furthermore, paclitaxel rapidly activated the JNK, ERK, and p38 mitogen-activated protein kinase pathways. A specific inhibitor of JNK, SP600125, abolished paclitaxel-induced HO-1 mRNA expression, whereas PD98059, a specific inhibitor of ERK, and SB203580, a specific inhibitor of p38, had no significant effect. Finally, the suppression of platelet-derived growth factor induced VSMC proliferation was abolished by the HO inhibitor, ZnPP, as well as by the CO scavenger, hemoglobin. These results demonstrated that paclitaxel induces the expression of HO-1 via the JNK pathway in VSMC and that HO-1 expression might be responsible for the anti-proliferative effect of paclitaxel on VSMC.
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PMID:Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells. 1535 25

We now evaluated the anti-inflammatory mechanisms of andrographolide on complement 5a (C5a)-induced macrophage recruitment in vitro. Andrographolide concentration dependently inhibited cell migration toward C5a with an IC50 of 5.6+/-0.7 microM. With relatively specific kinase inhibitors (PD98059, SB203580, SP600125, wortmannin and LY294002, respectively) the results showed that extracellular signal-regulated kinase1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol-3-kinase (PI3K) were necessary for C5a-induced migration, whereas c-Jun N-terminal kinase (JNK) was nonessential. Andrographolide significantly attenuated C5a-stimulated phosphorylation of ERK1/2, and of its upstream activator, MAP kinase-ERK kinase (MEK1/2). C5a-activated ERK1/2 phosphorylation was 86+/-9% inhibited by 30 microM andrographolide. Under the same conditions, however, andrographolide failed to affect C5a-stimulated p38 MAPK and JNK phosphorylation. Andrographolide also strongly abolished C5a-stimulated Akt phosphorylation, a downstream target protein for PI3K. These results indicate that inhibition of cell migration by interfering with ERK1/2 and PI3K/Akt signal pathways may contribute to the anti-inflammatory activity of andrographolide.
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PMID:Andrographolide acts through inhibition of ERK1/2 and Akt phosphorylation to suppress chemotactic migration. 1536 74

Receptor-mediated endocytosis of oxidized LDL (Ox-LDL) has been implicated in lipid accumulation and vascular cell dysfunction. Lectin-like Ox-LDL receptor-1 (LOX-1) is highly inducible by proinflammatory cytokines, as well as angiotensin II and Ox-LDL in vitro. LOX-1 is expressed in macrophages and smooth muscle cells accumulated in the intima of advanced atherosclerotic plaques in vivo. Here we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen for vascular smooth muscle cells, induces LOX-1 expression in cultured bovine aortic smooth muscle cells. HB-EGF (1-100 ng/ml) induced LOX-1 expression, which was peaked between 8 and 16 h after HB-EGF stimulation. HB-EGF-induced expression of LOX-1 was suppressed by ZD1839, an inhibitor of EGF receptor phosphorylation. Both MEK and p38 mitogen-activated protein kinase (MAPK) inhibitors significantly blocked LOX-1 upregulation induced by HB-EGF. Phosphatidylinositol 3-kinase (PI3K) inhibitors also blocked HB-EGF-induced LOX-1 expression. HB-EGF induced phosphorylation of ERK, p38 MAPK and Akt, which were suppressed by ZD1839. Upregulated expression of LOX-1 was associated with enhanced uptake of DiI-labeled Ox-LDL in smooth muscle cells. Taken together, HB-EGF can also act as an inducer of LOX-1 expression and play an integral role in foam cell transformation, cellular dysfunction, and proliferation of smooth muscle cells in atherogenesis.
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PMID:Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized LDL receptor-1 in vascular smooth muscle cells. 1538 Apr 51

To date, glutathione (GSH) depletion is the earliest biochemical alteration shown in brains of Parkinson's disease patients, but the role of GSH in dopamine cell survival is debated. In this study we show that GSH depletion, produced with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), induces selectively neuronal cell death in neuron/glia, but not in neuronal-enriched midbrain cultures and that cell death occurs with characteristics of necrosis and apoptosis. BSO produces a dose- and time-dependent generation of reactive oxygen species (ROS) in neurons. BSO activates extracellular signal-regulated kinases (ERK-1/2), 4 and 6 h after treatment. MEK-1/2 and lipoxygenase (LOX) inhibitors, as well as ascorbic acid, prevent ERK-1/2 activation and neuronal loss, but the inhibition of nitric oxide sintase (NOS), cyclo-oxygenase (COX), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) does not have protective effects. Co-localization studies show that p-ERK-1/2 expression after BSO treatment increased in astrocytes and microglial cells, but not in neurons. Selective metabolic impairment of glial cells with fluoroacetate decreased ERK activation. However, blockade of microglial activation with minocycline did not. Our results indicate that neuronal death induced by GSH depletion is due to ROS-dependent activation of the ERK-1/2 signalling pathway in glial cells. These data may be of relevance in Parkinson's disease, where GSH depletion and glial dysfunction have been documented.
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PMID:Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. 1548 97

Increased vascular endothelial growth factor (VEGF) biosynthesis in vascular endothelial cells has been reported to play an obligatory role in promoting angiogenesis. Nevertheless, the intracellular signaling mechanisms of hypoxia-induced VEGF release remain largely unknown. Human umbilical vein endothelial cell lines (ECV304) were cultured in normoxic or hypoxic conditions for 12 approximately 24 h and harvested for determination of VEGF mRNA expression and phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase (p38 MAPK) by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. Secreted VEGF protein was measured by enzyme-linked immunosorbent assay (ELISA). It has reported that PD98059, an ERK inhibitor, was able to blunt the hypoxia-induced activation of the expression of VEGF gene. In accordance with this report, an increase in ERK1/2 phosphorylation and VEGF biosynthesis was observed in ECV304 cells cultured in hypoxia, and this increase was blocked by PD98059. The novel finding of the present study is that an activation of p38 MAPK is involved in hypoxia-induced increase in VEGF biosynthesis. SB202190, an inhibitor of p38 MAPK was able to blunt the hypoxia-induced increase in VEGF biosynthesis. These dada provide the first direct evidence for a role of p38 MAPK in mediating hypoxia-induced increase in VEGF biosynthesis in human endothelial cells.
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PMID:p38 Mitogen-activated protein kinase mediates hypoxia-induced vascular endothelial growth factor release in human endothelial cells. 1571 30

Mevastatin which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, suppress cell proliferation and induce apoptosis. However, the molecular mechanism of apoptosis induction is not well understood. So, in the present study, we attempted to clarify the mechanism by which mevastatin induces apoptosis in HL60 cells. It was found that mevastatin induced apoptosis. At that time, we observed an increase in caspase-3 activity and morphological fragmentation of the nuclei. The apoptosis induced by mevastatin was not inhibited by the addition of farnesyl pyrophosphate (FPP), squalene, ubiquinone, and isopentenyladenine, but was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of mevastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals, such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38), exhibited no change. In addition, no quantitative change was observed in Bcl-2, which was an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggested that mevastatin induced apoptosis when it inhibited GGPP biosynthesis and consequently decreased the level of phosphorylated ERK, which was a survival signal; moreover, at that time, there was no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggested that mevastatin could be used as an anticancer agent.
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PMID:Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK. 1578 22

Oncostatin M (OSM), a member of interleukin-6 family cytokines, contributes to the development of nociceptive sensory neurons. However, little is known about the role of OSM in dorsal root ganglia (DRGs) of adult mice after peripheral inflammation. In the present study, we showed that OSM mRNA was highly expressed in the inflamed skin during acute inflammation induced by complete Freund's adjuvant (CFA), while the expression of oncostatin M receptor (OSMR) did not change in the ipsilateral DRG. Although peripheral inflammation induced significant increases in the number of neurons with phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 mitogen-activated protein kinase (p-p38) in ipsilateral DRGs, OSMR-positive neurons exhibited neither p-ERK nor p-p38. In addition, we found significant increases in the number of neurons with phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated cAMP-responsive element binding protein (p-CREB) in the ipsilateral DRGs. Interestingly, OSMR-positive neurons with p-STAT3 and p-CREB were significantly increased after peripheral inflammation. Thus, our results suggest that acute inflammation induce the phosphorylations of several signal molecules, including ERK, p38, cAMP-responsive element binding protein, and STAT3. Among them, the up-regulation of p-STAT3 and p-CREB may be induced possibly through OSMR.
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PMID:Up-regulated phosphorylation of signal transducer and activator of transcription 3 and cyclic AMP-responsive element binding protein by peripheral inflammation in primary afferent neurons possibly through oncostatin M receptor. 1589 81

The heterophil is the major polymorphonuclear cell in birds with a functional capacity akin to that of the mammalian neutrophil. Herein, we demonstrate that heterophils constitutively express TLR1/6/10, TLR2 type 1, TLR2 type 2, TLR3, TLR4, TLR5, and TLR7 mRNA. Furthermore, TLR agonists, including flagellin (from Salmonella typhimurium, FGN), peptidoglycan (from Staphylococcus aureus, PGN), ultra-pure lipopolysaccharide (from Salmonella minnesota, LPS), the synthetic double stranded RNA analog [poly(I:C)], and the guanosine analog, loxoribine (LOX) directly induced both an oxidative burst and a degranulation response. Interestingly, the synthetic bacterial lipoprotein Pam3CSK4 (palmitoyl-3-cysteine-serine-lysine-4, PAM) induced degranulation, but no oxidative burst. The bacterial TLR agonists (PAM, PGN, LPS, and FGN) all induced an up-regulation of expression of mRNA of the pro-inflammatory cytokines IL-1beta, IL-6, and IL-8; whereas both poly(I:C) and LOX induced a down-regulation of these cytokine mRNAs. Stimulation of heterophils with each specific TLR agonist led to a differential increase in the phosphorylation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation, but not the phosphorylation of c-Jun NH2-terminal kinase (JNK). The broad TLR expression profile in heterophils reflects their principal role as first line effector cells in avian host defense against bacterial, viral, fungal, and parasitic infections. The results demonstrate the differential involvement of TLR-induced signals in the stimulation of transduction pathways that regulate the oxygen-dependent and -independent antimicrobial defense mechanisms of avian heterophils.
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PMID:Expression and function of Toll-like receptors in chicken heterophils. 1593 35

As experimental evidence suggests that leptin may have direct effects on peripheral tissues, we investigated some of the transductional molecules induced by leptin in C2C12 cells. In immunoprecipitation experiments using anti-p85 antibodies (a regulatory subunit of phosphatidylinositol-3-kinase; PI3K), we observed a significant increase in PI3K activity. Immunoblot analyses showed that Akt, GSK3, ERK1, ERK2, and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation significantly increased after leptin treatment. Protein kinase C (PKC)-zeta was also activated by leptin, as documented by an immunocomplex kinase assay and immunoblotting experiments. The treatment of C2C12 cells with Wortmannin before leptin administration inhibited induction of the phosphorylation of ERKs (extracellular signal-regulated kinases) but not that of p38 MAPK, whereas pre-treatment with a PKC-zeta inhibitor partially decreased ERK phosphorylation. Taken together, our in vitro results further support the hypothesis that leptin acts acutely on skeletal muscle tissue through some of the components of insulin signalling, including PKC-zeta.
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PMID:Intracellular signal transduction pathways induced by leptin in C2C12 cells. 1597 10


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