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

---

Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingosylphosphorylcholine (SPC) produces reactive oxygen species (ROS) in MS1 pancreatic islet endothelial cells. In the present study, we explored the physiological significance of the SPC-induced ROS generation in endothelial cells. SPC induced cell death of MS1 cells at higher than 10 microM concentration through a caspase-3-dependent pathway. SPC treatment induced sustained activation of an extracellular signal-regulated kinase (ERK), in contrast to transient activation of ERK in response to platelet-derived growth factor (PDGF)-BB, which stimulated proliferation of MS1 cells. Both the SPC-induced cell death and ERK activation were abolished by pretreatment of the cells with the MEK inhibitor U0126 or by overexpression of a dominant negative mutant of MEK1 (DN-MEK1). Pretreatment of the cells with N-acetylcysteine, an antioxidant, completely prevented the SPC-induced ROS generation, apoptosis, and ERK activation, whereas the ROS generation was not abrogated by treatment with U0126. Consistent with these results, SPC induced cell death of human umbilical vein endothelial cells (HUVECs) through ROS-mediated activation of ERK. These results suggest that the SPC-induced generation of ROS plays a crucial role in the cell death of endothelial cells through ERK-dependent pathway.
...
PMID:Sphingosylphosphorylcholine induces apoptosis of endothelial cells through reactive oxygen species-mediated activation of ERK. 1713 61

Intercellular adhesion molecule 1 (ICAM-1) has been implicated in playing a key role in the mechanism of inflammatory process initiated in response to environmental agents, and during normal hematopoietic cell differentiation. Though induction of ICAM-1 by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in myeloid cells has been reported, the molecular mechanism by which TPA upregulates ICAM-1 expression remains unclear. In the present study, we investigated the signaling mechanism associated with TPA-induced ICAM-1 expression in ML-1 cells. Herein, our microarray, flow cytometry, and Western blot analysis indicated that ICAM-1 was constitutively expressed at a low level in ML-1 cells, but its expression was further upregulated at both the mRNA and protein levels in response to TPA. ICAM-1 expression in response to TPA was inhibited by pretreatment with GF109203X [a specific inhibitor of protein kinase C (PKC)], or with PD98059 and U0126 (specific inhibitors of MEK), suggesting the importance of PKC, and Erk1/2 signaling cascades in this response. Interestingly, ICAM-1 expression in response to TPA-induced PKC activation was linked to the generation of reactive oxygen species (ROS), as pretreatment with NAC (an ROS scavenger) blocked both ErK1/2 activation and ICAM-1 expression induced by TPA. In addition, TPA-induced ICAM-1 expression was blocked by inhibition of nuclear factor-kappaB (NF-kappaB) activation following pretreatment with BAY11-7085 (a specific inhibitor of NF-kappaB activation). TPA-induced NF-kappaB activation was shown by increased degradation of IkB (NF-kappaB specific inhibitory protein). Together, these observations demonstrated that TPA, a potent activator of PKC, induces ICAM-1 expression via a ROS- and ERK1/2-dependent signaling mechanism in ML-1 cells.
...
PMID:Role of ROS and MAPK in TPA-induced ICAM-1 expression in the myeloid ML-1 cell line. 1713 77

Troglitazone, a PPARgamma agonist, has been reported to induce cell death on different cell types. However, its mechanism of action remains unclear. The present study was undertaken to investigate the effect of troglitazone on cell death and to determine its underlying mechanism in MC3T3-E1 cells, an established osteoblast cell line. Troglitazone induced loss of cell viability in a dose- and time-dependent manner, which was accompanied by apoptosis. Troglitazone increased reactive oxygen species (ROS), but troglitazone-induced cell death was not affected by the antioxidant N-acetylcysteine, suggesting that the ROS generation is not involved in the cytotoxicity of troglitazone. Troglitazone-induced cell death was prevented by the PPARgamma antagonist GW9662. Troglitazone treatment inhibited activation of extracellular signal-regulated protein kinase (ERK) and stimulated p38 activation. Troglitazone-induced cell death was increased by the ERK inhibitor U0126 and prevented by transfection with constitutively active MEK1 and the p38 inhibitor SB203580. Troglitazone induced depolarization of mitochondrial membrane potential and its effect was blocked by SB203580 and GW9662. Caspase-3 was activated by troglitazone treatment and pharmacological inhibition of caspase blocked troglitazone-induced cell death. Taken together, these data suggest that troglitazone induces apoptosis via a caspase-dependent mechanism associated with down-regulation of ERK and up-regulation of p38.
...
PMID:Role of mitogen-activated protein kinase (MAPK) in troglitazone-induced osteoblastic cell death. 1736 28

Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, mimics metabolic actions of insulin to inhibit gluconeogenesis in hepatocytes. Because signaling pathways regulating metabolic and vasodilator actions of insulin are shared in common, we hypothesized that EGCG may also have vasodilator actions to stimulate production of nitric oxide (NO) from endothelial cells. Acute intra-arterial administration of EGCG to mesenteric vascular beds isolated ex vivo from WKY rats caused dose-dependent vasorelaxation. This was inhibitable by L-NAME (NO synthase inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), or PP2 (Src family kinase inhibitor). Treatment of bovine aortic endothelial cells (BAEC) with EGCG (50 microm) acutely stimulated production of NO (assessed with NO-specific fluorescent dye DAF-2) that was inhibitable by l-NAME, wortmannin, or PP2. Stimulation of BAEC with EGCG also resulted in dose- and time-dependent phosphorylation of eNOS that was inhibitable by wortmannin or PP2 (but not by MEK inhibitor PD98059). Specific knockdown of Fyn (but not Src) with small interfering RNA inhibited both EGCG-stimulated phosphorylation of Akt and eNOS as well as production of NO in BAEC. Treatment of BAEC with EGCG generated intracellular H(2)O(2) (assessed with H(2)O(2)-specific fluorescent dye CM-H(2)DCF-DA), whereas treatment with N-acetylcysteine inhibited EGCG-stimulated phosphorylation of Fyn, Akt, and eNOS. We conclude that EGCG has endothelial-dependent vasodilator actions mediated by intracellular signaling pathways requiring reactive oxygen species and Fyn that lead to activation of phosphatidylinositol 3-kinase, Akt, and eNOS. This mechanism may explain, in part, beneficial vascular and metabolic health effects of green tea consumption.
...
PMID:Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn. 1736 66

Arsenic is a widespread environmental toxic agent that has been shown to cause diverse tissue and cell damage and at the same time to be an effective anti-cancer therapeutic agent. The objective of this study is to explore the signaling mechanisms involved in arsenic toxicity. We show that the IkappaB kinase beta (IKKbeta) plays a crucial role in protecting cells from arsenic toxicity. Ikkbeta(-)(/)(-) mouse 3T3 fibroblasts have decreased expression of antioxidant genes, such as metallothionein 1 (Mt1). In contrast to wild type and IKKbeta-reconstituted Ikkbeta(-)(/)(-) cells, IKKbeta-null cells display a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH(2)-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis. Pretreatment with the antioxidant N-acetylcysteine (NAC) and expression of MT1 in the Ikkbeta(-)(/)(-) cells prevented JNK activation; moreover, NAC pretreatment, MT1 expression, MKK4 ablation, and JNK inhibition all protected cells from death induced by arsenic. Our data show that two signaling pathways appear to be important for modulating arsenic toxicity. First, the IKK-NF-kappaB pathway is crucial for maintaining cellular metallothionein-1 levels to counteract ROS accumulation, and second, when this pathway fails, excessive ROS leads to activation of the MKK4-JNK pathway, resulting in apoptosis.
...
PMID:A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity. 1752 90

Cerebral ischemia increases neural progenitor cell proliferation and neurogenesis. However, the precise molecular mechanism is poorly understood. The present study was undertaken to determine roles of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt and their signaling pathways in neural progenitor cells exposed to hypoxia/reoxygenation (H/R), an in vitro model of ischemia/reperfusion. Neural progenitor cells were isolated from postnatal mouse brain. ERK and Akt were transiently activated during the early phase of reoxygenation following 4-h of hypoxia. The ERK activation was inhibited by U0126, a specific inhibitor of MEK, but not by LY294002, a specific inhibitor of PI3K, whereas the Akt activation was blocked by LY294002, but not by U0126. Reoxygenation following 4-h hypoxia stimulated cell proliferation, which was dependent on ERK and Akt activation. Inhibitors of growth factor receptor (AG1478) and Src (PP2) and the antioxidant N-acetylcysteine did not affect activation of ERK and Akt, while the Ras and Raf inhibitors inhibited activation of ERK, but not Akt. PKC inhibitors inhibited both ERK and Akt activation. Taken together, these results suggest that H/R induces activation of MEK/ERK and PI3K/Akt survival signaling pathways through a PKC-dependent mechanism. These pathways may be responsible for the repair process during ischemia/reperfusion.
...
PMID:Hypoxia/reoxygenation stimulates proliferation through PKC-dependent activation of ERK and Akt in mouse neural progenitor cells. 1756 63

Reactive oxygen species (ROS) have been shown to play a critical role in propagating the signals of several growth factors, peptide hormones, and cytokines, such as epidermal growth factor, insulin, and interleukin-1. We investigated a possible role for ROS generation in mediating the action of ET-1 on activation of ERK1/2 in cultured feline esophageal smooth muscle cells (ESMC). Confluent layers of ESMC were stimulated by 10nM ET-1; activation of ERK was examined by western blot analysis with phospho-specific antibodies of ERKs. ET-1 induced ERK1/2 phosphorylation in a dose- and time- dependent manner. ERK1/2 activation by ET-1 reached the maximal levels at 5min showing slight activation up to 20min, and then slowly declined. It was confirmed that the activation of ERK1/2 was reduced by MEK inhibitor PD98059. We observed the dose-dependent inhibitory effect of diphenyleneiodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase on the ET-1-enhanced ERK1/2 phosphorylation in ESMC. Pretreatment of ESMC with N-acetylcysteine, a ROS scavenger, also attenuated the ET-1-induced ERK1/2 activation. In addition, DPI significantly inhibited the ET-1- induced ROS production when ROS was measured as a function of DCF fluorescence. The results suggest that ROS might be critical mediators of the ET-1-induced ERK1/2 signaling events in ESMC.
...
PMID:Reactive oxygen species mediate ET-1-induced activation of ERK1/2 signaling in cultured feline esophageal smooth muscle cells. 1795 24

One of the major characteristics of human skin photoaging induced by ultraviolet (UV) radiation is the dehydration of the skin. Water movement across plasma membrane occurs via diffusion through lipid bilayer and via aquaporins (AQPs). We find that UV induces aquaporin-3 (AQP3) down-regulation in human skin keratinocytes. MEK/ERK inhibitors PD98059 and U0126 inhibit UV-induced down-regulation of AQP3. Antioxidant N-acetyl-L-cysteine or NAC blocks UV-induced MEK/ERK activation and down-regulation of AQP3. All-trans retinoic acid or atRA, while alone inducing AQP3 expression, attenuates UV-induced down-regulation of AQP3 and water permeability. Using special inhibitors, we find that activation of EGFR and inhibition on ERK activation are involved in atRA's protective effects against UV-induced AQP3 down-regulation. Using specific AQP3's water transport inhibitors and siRNA knockdown, we observe that AQP3 is involved in cell migration and in vitro wound healing. UV-induced AQP3 down-regulation results in reduced water permeability, decreased cell migration, and delayed wound healing, which are attenuated by atRA pretreatment. We conclude that atRA protects against UV-induced down-regulation AQP3 and decrease in water permeability, reduction in cell migration and delayed in vitro wound healing via trans-activation of EGFR and inhibition on ROS-mediated MEK/ERK pathway. This novel finding provides evidence to support possible involvement of AQP3 in UV induced skin dehydration.
...
PMID:All-trans retinoic acid attenuates ultraviolet radiation-induced down-regulation of aquaporin-3 and water permeability in human keratinocytes. 1806 29

Cervical cancer is the second most common malignancy among women worldwide and is highly radioresistant, often resulting in local treatment failure. For locally advanced disease, radiation is combined with low-dose chemotherapy; however, this modality often leads to severe toxicity. Curcumin, a polyphenol extracted from rhizomes of the plant Curcuma longa, is a widely studied chemopreventive agent that was shown to have a low toxicity profile in three human clinical trials. Here, we show that pretreatment of two cervical carcinoma cell lines, HeLa and SiHa, with curcumin before ionizing radiation (IR) resulted in significant dose-dependent radiosensitization of these cells. It is noteworthy that curcumin failed to radiosensitize normal human diploid fibroblasts. Although in tumor cells, curcumin did not significantly affect IR-induced activation of AKT and nuclear factor-kappaB, we found that it caused a significant increase in the production of reactive oxygen species, which further led to sustained extracellular signal-regulated kinase (ERK) 1/2 activation. The antioxidant compound N-acetylcysteine blocked the curcumin-induced increased reactive oxygen species (ROS), sustained activation of ERK1/2, and decreased survival after IR in HeLa cells, implicating a ROS-dependent mechanism for curcumin radiosensitivity. Moreover, PD98059 (2'-amino-3'-methoxyflavone)-, PD184352- [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynylthio)butadiene]-specific inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) blocked curcumin-mediated radiosensitization, demonstrating that the sustained ERK1/2 activation resulting from ROS generation leads to curcumin-mediated radiosensitization. Together, these results suggest a novel mechanism for curcumin-mediated radiosensitization involving increased ROS and ERK1/2 activation and suggest that curcumin application (either systemically or topically) may be an effective radiation modifying modality in the treatment of cervical cancer.
...
PMID:The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway. 1825 5

Although previous studies have indicated that the neuroprotective effect of N-acetylcysteine (NAC) required activation of the Ras-extracellular-signal-regulated kinase (ERK) pathway, the detailed mechanisms and signal cascades leading to activation ERK are not clear. In the present study, we investigated the effect of NAC on A beta(25-35)-induced neuronal death. Pretreatment of neurons with NAC 1 hr before application of A beta prevented A beta-mediated cell death. NAC increased cyclin-dependent kinase 5 (Cdk5) phosphorylation, an effect that was blocked by Cdk5 inhibitor. The neuroprotective effect of NAC was significantly attenuated by Cdk5 inhibitors or in neurons transfected with Cdk5 or p35 small interfering RNA (siRNA). Conversely, pretreatment of neurons with the calpain inhibitors calpeptin or MDL28170 enhanced the neuroprotective effect of NAC. A beta(25-35) caused a significant decrease in the level of p35, with a concomitant increase in p25, which was completely prevented by NAC. This effect of NAC was blocked by the Cdk5 inhibitors roscovitine and butyrolactone. In addition, NAC increased Cdk5/p35 kinase activity but reduced Cdk5 kinase activity. A beta(25-35) treatment decreased phosphorylated levels of ERK, which could be reversed by NAC. The effect of NAC was completely blocked by Cdk5 inhibitors. NAC reversed the A beta(25-35)-induced decrease in the expression of Bcl-2, which could be blocked by the MAPK kinase (MEK) inhibitor or Cdk5 inhibitors. These results suggest that NAC-mediated neuroprotection against A beta toxicity is likely mediated by the p35/Cdk5-ERKs-Bcl-2 signal pathway.
...
PMID:N-acetylcysteine prevents beta-amyloid toxicity by a stimulatory effect on p35/cyclin-dependent kinase 5 activity in cultured cortical neurons. 1851 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---