Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of cell signaling cascades by oxidants may be important in the pathogenesis of pulmonary and pleural diseases. Here, we demonstrate in rat pleural mesothelial cells that apoptotic concentrations of crocidolite asbestos and H2O2 induce phosphorylation and activation of extracellular signal-regulated protein kinases (ERK). Activation of c-jun-NH2-terminal protein kinases (JNK)/stress-activated protein kinases was also observed in response to H2O2. In contrast, asbestos caused more protracted activation of ERK without JNK activation. Both H2O2- and asbestos-induced activation of ERK was abolished by catalase. Moreover, chelation of surface iron from crocidolite fibers or addition of N-acetyl-L-cysteine prevented ERK activation and apoptosis by crocidolite, indicating an oxidative mechanism of cell signaling. The MEK1 inhibitor PD-98059 abrogated asbestos-induced apoptosis, confirming a causal relationship between ERK activation and apoptosis. These results suggest that distinct cell-signaling cascades may be important in phenotypic responses elicited by oxidant stresses.
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PMID:Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2. 937 31

In response to hypoxia, mammalian cells express multiple gene products [including erythropoietin (EPO) and vascular endothelial growth factor (VEGF)] that serve to increase O2 delivery, as well as glucose transporters and glycolytic enzymes (such as enolase 1) that allow metabolic adaptation to decreased O2 availability. Increased transcription of the genes encoding these proteins in hypoxic cells is mediated by hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. Expression of HIF-1 and downstream genes can also be induced by exposure of cells to divalent metals (such as CoCl2) or iron chelators [such as desferrioxamine (DFO)]. We report here that the organomercurial compound mersalyl induced expression of VEGF and enolase 1 mRNA, as well as HIF-1 activity, in cultured cells. Expression of reporter genes containing hypoxia response elements from the EPO and VEGF genes was also induced by mersalyl treatment. However, mersalyl inhibited endogenous EPO mRNA expression induced by hypoxia, CoCl2, or DFO. In cells lacking expression of the insulin-like growth factor-1 receptor, mersalyl did not induce HIF-1 activity or VEGF mRNA expression, whereas induction by hypoxia, CoCl2, or DFO was unaffected. The mitogen-activated protein kinase kinase inhibitor PD098059 markedly reduced induction of HIF-1 by mersalyl but not by hypoxia. These results indicate that mersalyl induces expression of HIF-1 and a subset of hypoxia-inducible genes by a mechanism, involving the insulin-like growth factor-1 receptor and mitogen-activated protein kinase activity, that is distinct from mechanisms of induction by hypoxia, CoCl2, or DFO.
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PMID:Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. 980 9

Protein adsorption patterns of superparamagnetic iron oxides (SPIO) were evaluated by two-dimensional electrophoresis (2-DE) after in vitro incubation of the particles in plasma or serum. SPIO particles having positive (MKK 1211), negative (MKA 1211), or neutral (MKG 1411) charge were used. Protein adsorption patterns of different charged SPIO particles acquired in vitro and recollected 5 min after intravenous injection into rats (ex vivo) were compared. For the uncharged MKG 1411 particles, the differences of protein adsorption patterns were negligible and only minor differences were found for the negatively charged MKA 1211 and positively charged MKK 1211 particles. A good correlation between in vitro and ex vivo data could be shown. For the evaluation of protein adsorption patterns of SPIO particles determining organ distribution and allowing estimation of site-specific delivery (drug targeting), the currently used protocol for 2-DE analysis could be confirmed.
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PMID:Comparison of protein adsorption patterns onto differently charged hydrophilic superparamagnetic iron oxide particles obtained in vitro and ex vivo. 1166 35

Mineral nutrient deficiencies constitute major limitations for plant growth on agricultural soils around the world. To identify genes that possibly play roles in plant mineral nutrition, we recently generated a high-density array consisting of 1,280 genes from tomato (Lycopersicon esculentum) roots for expression profiling in nitrogen (N) nutrition. In the current study, we used the same array to search for genes induced by phosphorus (P), potassium (K(+)), and iron (Fe) deficiencies. RNA gel-blot analysis was conducted to study the time-dependent kinetics for expression of these genes in response to withholding P, K, or Fe. Genes previously not associated with P, K, and Fe nutrition were identified, such as transcription factor, mitogen-activated protein (MAP) kinase, MAP kinase kinase, and 14-3-3 proteins. Many of these genes were induced within 1 h after withholding the specific nutrient from roots of intact plants; thus, RNA gel-blot analysis was repeated for specific genes (transcription factor and MAP kinase) in roots of decapitated plants to investigate the tissue-specific location of the signal triggering gene induction. Both genes were induced just as rapidly in decapitated plants, suggesting that the rapid response to the absence of P, K, or Fe in the root-bathing medium is triggered either by a root-localized signal or because of root sensing of the mineral environment surrounding the roots. We also show that expression of Pi, K, and Fe transporter genes were up-regulated by all three treatments, suggesting coordination and coregulation of the uptake of these three essential mineral nutrients.
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PMID:Rapid induction of regulatory and transporter genes in response to phosphorus, potassium, and iron deficiencies in tomato roots. Evidence for cross talk and root/rhizosphere-mediated signals. 1242 1

Increased iron store in the body may increase the risk of many diseases such as cancer and inflammation. However, the precise pathogenic mechanism of iron has not yet been elucidated. In the present study, the early biological responses of cells to iron treatment were investigated in AP-1 luciferase reporter stably transfected mouse epidermal JB6 cells and primary rat hepatocytes. It was shown that water-soluble iron compounds, such as FeSO4 and Fe2(SO4)3, were more active in inducing AP-1 in JB6 cells than water-insoluble iron compounds, such as Fe2O3 and FeS. Iron stimulated mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-jun NH2 terminal kinases (JNKs), both in JB6 cells and in primary rat hepatocytes, as determined by the phosphorylation assay. Interestingly, the increase in AP-1 luciferase activity by iron was inhibited by the pretreatment of the cells with PD98059, a specific MEK1 inhibitor, and SB202190, a p38 kinase inhibitor. Levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, were increased in JB6 cells by iron in a dose-dependent manner. The increase in IL-6 and its mRNA by iron was also eliminated by the pretreatment of the cells with PD98059 and SB202190. Since the IL-6 promoter contains an AP-1 binding site, our studies indicate that the iron-induced IL-6 gene expression may be mediated through ERKs and p38 MAPK pathways, possibly one of the important mechanisms for the pathogenesis of iron overload.
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PMID:Iron-induced interleukin-6 gene expression: possible mediation through the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. 1536 95

The mitogen-activated protein kinase p38 is activated by mechanical force, but the cellular elements that mediate force-induced p38 phosphorylation are not defined. As alpha-smooth muscle actin (SMA) is an actin isoform associated with force generation in fibroblasts, we asked if SMA participates in the activation of p38 by force. Tensile forces (0.65 pn/mum(2)) generated by magnetic fields were applied to collagen-coated magnetite beads bound to Rat-2 cells. Immunoblotting showed that p38alpha was the predominant p38 isoform. Analysis of bead-associated proteins demonstrated that SMA enrichment of collagen receptor complexes required the alpha2beta1 integrin. SMA was present almost entirely as filaments. Swinholide depolymerized SMA filaments and blocked force-induced p38 phosphorylation and force-induced increases of SMA. Knockdown of SMA (70% reduction) using RNA interference did not affect beta-actin but inhibited force-induced p38 phosphorylation by 50%. Inhibition of Rho kinase blocked SMA filament assembly, force-induced increases of SMA, and force-induced p38 activation. Force application increased SMA content and enhanced the association of phosphorylated p38 with SMA filaments. Blockade of p38 phosphorylation by SB203586 abrogated force-induced increases of SMA. In cells transfected with SMA promoter-beta-galactosidase fusion constructs, co-transfection with constitutively active p38 or MKK6 increased SMA promoter activity by 2.5-3-fold. Dominant negative p38 blocked force-induced activation of the SMA promoter. In SMA negative cells, there was no force-induced p38 phosphorylation. We conclude that force-induced p38 phosphorylation is dependent on an SMA filament-dependent pathway that uses a feed-forward amplification loop to synergize force-induced SMA expression with p38 activation.
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PMID:Smooth muscle actin determines mechanical force-induced p38 activation. 1559 Oct 55

NF-kappaB/Rel transcription factors block apoptosis or programmed cell death (PCD) induced by tumor necrosis factor (TNF) alpha. The antiapoptotic activity of NF-kappaB is also crucial for immunity, lymphocyte development, tumorigenesis, and cancer chemoresistance. With respect to TNFalpha, the NF-kappaB-mediated suppression of apoptosis involves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activity of NF-kappaB depends upon transcriptional upregulation of blockers of the JNK cascade such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase Gadd45beta/Myd118. Moreover, NF-kappaB blunts accumulation of reactive oxygen species (ROS) induced by TNFalpha, and this antioxidant effect of NF-kappaB is also critical for inhibition of TNFalpha-induced JNK activation. Suppression of ROS by NF-kappaB is mediated by Ferritin heavy chain (FHC)--the primary iron-storage mechanism in cells--and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means by which NF-kappaB controls proapoptotic JNK signaling. These findings identify potential new targets for anti-inflammatory and anti-cancer therapy.
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PMID:NF-kappaB and JNK: an intricate affair. 1561 22

Reactive oxygen species (ROS) play a critical role in cardiac hypertrophy. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO A) is an important source of hydrogen peroxide in rat heart. In the present study, we investigated the potential role of hydrogen peroxide generated by MAO A in cardiomyocyte hypertrophy by serotonin. Serotonin (5 microM, 48 h) induced hypertrophy in cultured adult rat ventricular myocytes, as reflected by increased 3H-leucine incorporation (+43%, P<0.001) and total protein content (+22%, P<0.001). Serotonin also increased intracellular hydrogen peroxide and oxidative stress production, measured respectively by DCF fluorescence intensity and GSH/GSSG ratio, and promoted ERK1/2 phosphorylation (P<0.001). Serotonin effects were only partially inhibited by the 5-HT2B receptor antagonist SB 206553. In contrast, they were extensively (>80%) prevented by the amine uptake inhibitor imipramine, the MAO inhibitor pargyline and the MEK inhibitor PD 98059. Cardiomyocyte hypertrophy and ERK activation were also inhibited by decreasing intracellular ROS by adenoviral overexpression of catalase or cardiomyocytes treatment with the iron chelator deferoxamine. These data suggest that part of cardiac hypertrophic effect of serotonin requires hydrogen peroxide production by MAO A and ERK1/2 activation. This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure.
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PMID:A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. 1570 74

Mechanical forces can induce differentiation of fibroblasts into myofibroblasts, a process which requires activation of the MAP kinase p38. Currently, the identification of other phospho-kinases involved in myofibroblast differentiation has not been explored. We applied static tensile forces to rat cardiac fibroblasts via collagen-coated magnetite beads and examined activation of protein phospho-kinases by the Kinexus phospho-antibody screening system. Of 75 candidate protein kinases screened, 39 were detected and, of these, 31 phospho-kinases were analyzed. Following force application, 12 out of 31 phospho-kinases exhibited increases of phosphorylation including PKR (>4-fold), MKK3 (3-fold), MKK6 ( approximately 2-fold), and p38 ( approximately 2-fold). In several types of mechanically sensitive, contractile fibroblasts including rat cardiac, human gingival, and Rat-2 fibroblasts, tensile forces increased eIF-2alpha phosphorylation, a downstream effector of PKR. We conclude that phospho-antibody screening is an efficient method for discovery of novel mechanical force-induced phospho-kinases and force can activate eIF-2alpha phospho-kinases in fibroblasts.
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PMID:Mechanical force activates eIF-2alpha phospho-kinases in fibroblast. 1578 Dec 41

Lactoferrin, a member of the transferrin family, is iron-binding and a strongly cationic 76 kDa glycoprotein. In breast milk it is secreted in high concentrations from glandular epithelia and is also present in other exocrine fluids including saliva. In the present study, we examined the biological mechanisms of apoptosis induced by pepsin-digested-lactoferrin peptide (Lfn-p) in the human oral squamous cell carcinoma cell line SAS. We found that treatment with Lfn-p induced cell death with apoptotic nuclear changes, preceded by the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in the apoptotic cells. Treatment with Lfn-p induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), a member of the MAP kinase family, at early stages of apoptosis. Another MAP kinase, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), was also phosphorylated by treatment with Lfn-p. Pretreatment of SAS cells with SP600125, a JNK/SAPK inhibitor, diminished Lfn-induced apoptosis, as assessed by determining released lactate dehydrogenase activity. On the other hand, the MEK1 inhibitors PD98059 or U0126 showed no effect on repression of cell death, but rather an increase. These results suggest that JNK/SAPK activation may play an important role in Lfn-p-induced apoptotic cell death of human oral squamous cell carcinoma cells.
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PMID:Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. 1587 78


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