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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In RAW 264.7 cells, a mouse leukaemic monocyte cell line, apicularen A decreased cell growth and survival as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in a concentration-dependent manner at 10-1000 nM. Apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was 10-100-fold less effective than apicularen A. Apicularen A induced a DNA ladder, an increase in the percentage of sub-G(1) cells and annexin V-binding cells, and promoted the activation of caspase as revealed by the cleavage of poly(ADP-ribose) polymerase, indicating that apicularen A induced apoptosis in RAW 264.7 cells. In addition, apicularen A phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The p44/42 MAPK inhibitor PD98059 rescued the cells from apicularen-induced decrease in cell growth and survival as determined by the MTT assay, while the p38 MAPK inhibitor SB203580 augmented the effect of apicularen A. This suggested the activation of p44/42 MAPK to be pro-apoptotic and the activation of p38 MAPK antiapoptotic in apicularen A-treated RAW 264.7 cells.
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PMID:Induction of apoptosis of RAW 264.7 cells by the cytostatic macrolide apicularen A. 1460 74

Oxidative stress induced by a glucose/glucose oxidase (G/GO) generator system dose-dependently decreased the viability of cultured vascular smooth muscle cells (VSMC) as estimated by MTT assay. Cell death was induced in 40% of cells exposed to 0.2 IU/ml of the free radical generating mixture. Annexin-V labeling, Hoechst staining together with DNA laddering demonstrated that apoptosis was responsible for this cell loss. Pretreatment of the cells with 10(-8) M calcitonin gene-related peptide (CGRP) significantly attenuated the damaging effect of the oxidative stress. Indeed, cell viability was estimated to be 80% in CGRP-treated group, instead of 60% in absence of CGRP treatment. This protective effect of CGRP was antagonized by 8-37 CGRP, an antagonist of CGRP-1 receptors, whereas it was not reproduced by amylin, a CGRP analogue. As indicated by the reduction in Hoechst staining and in DNA laddering, CGRP prevented the onset of apoptosis. We also demonstrated that the peptide significantly up-regulated the activation of ERK1/2 and P38 kinases. Inhibitors of the kinases prevented the protective effect of CGRP. We conclude that CGRP antagonizes oxidative stress-induced apoptosis by up-regulating MAP kinase activation and that activation of these kinases was necessary to protection.
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PMID:Calcitonin gene-related peptide partly protects cultured smooth muscle cells from apoptosis induced by an oxidative stress via activation of ERK1/2 MAPK. 1465 29

Blood flow that is steady and laminar is known to be atheroprotective. One likely mechanism is enhanced endothelial cell (EC) survival. Because the mitogen-activated protein kinases (MAPKs) are known regulators of cell survival, we investigated the role of Big MAPK-1 (BMK1 or ERK5), which is potently stimulated by fluid shear stress. To activate BMK1, we overexpressed constitutively active (CA)-MEK5 in bovine lung microvascular ECs (BLMECs). Cell apoptosis was induced by growth factor deprivation (0% serum for 24 hours). Analysis of cell viability with MTT assay showed that activation of BMK1 by CA-MEK5 significantly improved cell viability from 48% to 87% and decreased apoptotic cells from 49% to 10%. Growth factor deprivation induced caspase-3 activity 5.2-fold, which was inhibited (approximately 60%) by CA-MEK5 overexpression. In contrast, inhibiting BMK1 activity by overexpressing dominant-negative BMK1 (DN-BMK1) stimulated apoptosis in BLMECs. Steady laminar fluid shear stress inhibited BLMEC apoptosis, and this protective effect was also reduced significantly by overexpressing DN-BMK1. Analysis of antiapoptotic mechanisms showed that both shear stress and CA-MEK5 stimulated phosphorylation of Bad on Ser112 and Ser136, whereas DN-BMK1 inhibited phosphorylation. Phosphorylation of Bad induced by BMK1 activation was independent of Akt, PKA, or p90RSK kinase activity. These results suggest that BMK1 activation by steady laminar flow is atheroprotective by inhibiting EC apoptosis via phosphorylation of Bad.
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PMID:Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. 1467 Aug 36

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the anti-proliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells.
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PMID:Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. 1468 75

Epidermal growth factor (EGF) has been shown to induce proliferation in cells, however, the role of prostaglandin E(2) (PGE(2)) plays in EGF-induced proliferation in still unclear. EGF and PGE(2) showed proliferation responses in epidermoid carcinoma cell A431 by MTT and [(3)H] thymidine incorporation assay. Activation of the EGF receptor and extracellular signal-regulated protein kinases (ERK1/2), but not p38 and JNK, appeared 10 min after EGF treatment, whereas total amounts of ERK1/2, p38 and JNK remained unchanged in A431 cells, accompanied by induction of COX-2 and PGE(2) production. PD98059, a specific ERK1/2 inhibitor, inhibited EGF-induced proliferation with concomitant decreases in ERK1/2 phosphorylation and COX-2/PGE(2) induction. Non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and diclofenac, a COX activity inhibitor, inhibited EGF-induced proliferation by blocking PGE(2) production. The addition of PGE(2) reversed the inhibitory effects of PD98059, aspirin, and diclofenac on EGF-induced proliferation. This suggests that COX-2/PGE(2) activation involves in EGF-induced proliferation and locates at the downstream of ERK1/2 activation. Furthermore, the natural product, 3-OH flavone, showed the most-potent inhibitory activity on EGF-induced proliferation among 9 structurally-related compounds, and suppression of EGF receptor phosphorylation, ERK1/2 phosphorylation, and COX-2/PGE(2) production by 3-OH flavone was identified. PGE(2) addition attenuates the inhibitory activity of 3-OH flavone on EGF-induced proliferation by MTT assay and colony formation by soft agar assay. Additionally, 3-OH flavone also showed more-specific inhibition on EGF- than on fetal bovine serum (FBS)-induced proliferation in A431 cells. Results of our present study provide evidence to demonstrate that PGE(2) is an important downstream molecule in EGF-induced proliferation, and 3-OH flavone, which inhibits PGE(2) production by blocking MAPK cascade, might reserve potential for development as an anti-cancer drug.
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PMID:3-OH flavone inhibition of epidermal growth factor-induced proliferaton through blocking prostaglandin E2 production. 1469 13

Lead (Pb(2+)) is widely recognized as a neurotoxicant whose mechanisms of action are not completely established. We have previously demonstrated that Pb(2+) can activate the p38(MAPK) pathway and increase the phosphorylation of Hsp27 in bovine adrenal chromaffin cells and human SH SY5Y cells over a short incubation period (1 h). In the present work we analyzed the effects of Pb(2+) administered in vivo on the level and the phosphorylation state of ERK1/2 and p38(MAPK) in the hippocampus of immature rats. Rats were treated with lead acetate (2, 8 or 12 mg/kg, i.p.) or saline (control) over the 8th to 12th postnatal days, and hippocampal slices were prepared on the 14th day. The Pb(2+) level in the lead-treated animals increased 2.5-6-fold in the blood (3.0-6.0 microg/dl) and 2.0-3.0-fold in the forebrain (78-103 ng/g wet weight), compared to control (saline). The phosphorylation of both ERK1/2 and p38(MAPK) was significantly increased by prior exposure to Pb(2+) in vivo. In in vitro experiments, hippocampal slices from 14-day-old rats were exposed to Pb(2+) (1-10 microM) for 1 and 3 h. There were no changes in the phosphorylation state of ERK and p38(MAPK) for 1-h incubation, whereas a significant increase of ERK1/2 and p38(MAPK) phosphorylation by Pb(2+) (5 microM) was observed for the 3-h incubation. Cell viability measured using MTT was not modified in any of the conditions tested. These results indicate that the phosphorylation of hippocampal ERK1/2 and p38(MAPK) is stimulated by lead in a period of rapid brain development, an effect that may underlie, at least in part, the neurotoxicty elicited by this metal.
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PMID:Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats. 1472 69

The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to L-methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests. However, while aminoindan (1 microM), the major metabolite of rasagiline does not interfere with the neuroprotective activities of rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, L-methamphetamine (1 microM), inhibits them. In contrast to L-methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of rasagiline is blocked by ERK inhibitor, PD98059 (20 microM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of rasagiline in treatment of Parkinson's disease.
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PMID:Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. 1473 58

In this study, we investigated whether carbofuran, a commonly used carbamate pesticide, and N-nitrosocarbofuran (NOCF), the N-nitroso metabolite of carbofuran, have cytotoxicity in mouse brain microvascular endothelial cells (bEnd.3). Results from the MTT assay in bEnd.3 cells showed that NOCF but not carbofuran caused a remarkable decrease in cell viability. The cell death induced by NOCF appeared to involve apoptosis, based on our results from annexin V staining and electron microscopy. To investigate the mechanism of the NOCF-induced cell death, we examined the effects of selective inhibitors for MAP kinase pathways, PD98059 (for MEK/ERK), SB202190 (for p38 MAP kinase), and SP600125 (for JNK), on the NOCF-induced cell death. The NOCF-induced cell death was significantly reduced by PD98059, but not by SB202190 or SP600125. NOCF increased ERK phosphorylation as early as 15 min after the treatment and this increase was maintained for 2 h. In summary, our results suggest that NOCF can induce apoptotic cell death, at least in part, through the ERK pathway in brain microvascular endothelial cells.
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PMID:N-nitrosocarbofuran induces apoptosis in mouse brain microvascular endothelial cells (bEnd.3). 1473 22

Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (colAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT.
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PMID:Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. 1476 3

Cell proliferation and migration are important repair mechanisms in cell defect type mucosal injuries, such as peptic ulcers. To evaluate the level of cell restitution in vitro, we established a normalized assay system for analyzing the area of a tissue defect created in the center of a cultured cell layer. Although proton pump inhibitors are known to be potently effective in the treatment of peptic ulcers by inducing acid suppression, they are also effective in low-acid conditions, such as in gastric ulcers associated with severe atrophic gastritis of the corpus. The present study was designed to examine the pH-independent effect of lansoprazole (LPZ) on cell restitution in vitro. The mouse gastric mucosal cell line, GSM06, was cultured to confluence. A 4-fluoric ethylene-tipped aluminum stick was then used to produce a cell-free area in the center of the culture well. After measuring the area of the cell defect using a digital analyzer equipped with an inverted microscope, LPZ was added to each well; the area of the residual cell defect was then measured 6 and 24 hours after LPZ administration. To investigate the involvement of the p44/p42 mitogen-activated protein kinase (MAPK) and p38 MAPK in this process, PD98059 (a MEK inhibitor) or FR167653 (a p38 MAPK inhibitor) was added to the cell cultures. In a separate experiment, GSM06 cells were cultured to the subconfluent level, each test agent was added, and the cell number in each well was measured using an MTT assay 16 hours after the administration of the agents. Six hours after the addition of LPZ, a slight but significant increase in the cell restitution rate was observed in the LPZ-treated groups compared with that in the control group. After 24 hours, a further significant increase in the cell restitution rate was observed in the LPZ groups compared with that in the control group. While the addition of PD98059 significantly attenuated the cell restitution rate in the LPZ groups, the addition of FR167653 had no such effect. The total cell number in the subconfluent cell cultures was significantly increased in the LPZ-treated groups compared with that in the control group. In conclusion, LPZ promotes the healing of injured gastric mucosal cells following injury by enhancing cell proliferation and migration. Furthermore, the mechanism by which cell proliferation and migration is promoted by LPZ may involve the activation of p44/p42 MAPK.
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PMID:Lansoprazole promotes gastric mucosal cell proliferation and migration by activating p44/p42 mitogen-activated protein kinase. 1497 70


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