Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The catechins, a family of polyphenols found in tea, can evoke various responses, including cell death. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that treatment of human MCF-7 cells with 50 microM (-)-Epigallocatechin-3-gallate (EGCG), a catechin that is highly abundant in green tea, can induce apoptotic changes, including mitochondrial membrane potential changes and activation of c-Jun N-terminal kinase (JNK), caspase-9, and caspase-3. In contrast, higher concentrations of EGCG (100-400 microM) do not induce apoptosis, but rather trigger necrotic cell death in MCF-7 cells. Investigations of the possible mechanisms underlying these differences revealed that treatment with lower concentrations of EGCG (10-50 microM) directly increased intracellular oxidative stress, while higher concentrations (100-400 microM) did not. Immunoblotting revealed that treatment of MCF-7 cells with 10-50 microM EGCG caused increases in Bax protein levels and decreases in Bcl-2 protein levels, shifting the Bax-Bcl-2 ratio to favor apoptosis, while treatment with 100-400 microM EGCG had no such effect. Moreover, we observed a dose-dependent decrease in intracellular ATP levels in cells treated with high-dose EGCG. Blockade of reactive oxygen species (ROS) generation and ATP synthesis using antioxidants and ATP synthesis inhibitors revealed that ROS and ATP play important roles to switch cell death types with apoptosis or necrosis. Collectively, these results indicate for the first time that EGCG treatment has a dose-dependent effect on ROS generation and intracellular ATP levels in MCF-7 cells, leading to either apoptosis or necrosis, and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes, and activation of caspase-9 and caspase-3.
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PMID:Epigallocatechin gallate dose-dependently induces apoptosis or necrosis in human MCF-7 cells. 1740 55

The mechanisms of sodium selenite-induced cell death in cervical carcinoma cells were studied during 24 h of exposure in the HeLa Hep-2 cell line. Selenite at the employed concentrations of 5 and 50 micromol/L produced time- and dose-dependent suppression of DNA synthesis and induced DNA damage which resulted in phosphorylation of histone H2A.X. These effects were influenced by pretreatment of cells with the SOD/catalase mimetic MnTMPyP or glutathione-depleting buthionine sulfoximine, suggesting the significant role of selenite-generated oxidative stress. Following the DNA damage, selenite activated p53-dependent pathway as evidenced by the appearance of phosphorylated p53 and accumulation of p21 in the treated cells. Concomitantly, selenite activated p38 pathway but its effect on JNK was very weak. p53- and p38-dependent signaling led to the accumulation of Bax protein, which was preventable by specific inhibitors of p38 (SB 203580) and p53 (Pifithrin-alpha). Mitochondria in selenite-treated cells changed their dynamics (shape and localization) and released AIF and Smac/Diablo, which initiated caspase-independent apoptosis as confirmed by the caspase-3 activity assay and the low effect of caspase inhibitors z-DEVD-fmk and z-VAD-fmk on cell death. We conclude that selenite induces caspase-independent apoptosis in cervical carcinoma cells mostly by oxidative stress-mediated activation of p53 and p38 pathways, but other selenite-mediated effects, in particular mitochondria-specific ones, are also involved.
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PMID:Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells. 1761 29

Mitochondrial alterations have been associated with the cytotoxic effect of 6-hydroxydopamine (6-OHDA), a widely used toxin to study Parkinson's disease. In previous work, we have demonstrated that 6-OHDA increases mitochondrial membrane permeability leading to cytochrome c release, but the precise mechanisms involved in this process remain unknown. Herein we studied the mechanism of increased mitochondrial permeability of SH-SY5Y neuroblastoma cells in response to 6-OHDA. Cytochrome c release induced by 6-OHDA occurred, in both SH-SY5Y cells and primary cultures, in the absence of mitochondrial swelling or a decrease in mitochondrial calcein fluorescence, suggesting little involvement of the mitochondrial permeability transition pore in this process. In contrast, 6-OHDA-induced cell death was associated with a significant translocation of the pro-apoptotic Bax protein from the cytosol to mitochondria and with a significant induction of the BH3-only protein PUMA. Experiments in mouse embryonic fibroblasts deficient in Bax or PUMA demonstrated a role for both proteins in 6-OHDA-induced apoptosis. Although 6-OHDA elevated both total and nuclear p53 protein levels, activation of p53 was not essential for subsequent cell death. In contrast, we found that p38 mitogen-activated protein kinase (MAPK) was activated early during 6-OHDA-induced apoptosis, and that treatment with the p38 MAPK inhibitor SKF86002 potently inhibited PUMA induction, green fluorescent protein-Bax redistribution and apoptosis in response to 6-OHDA. These data demonstrate a critical involvement of p38 MAPK, PUMA, and Bax in 6-OHDA-induced apoptosis.
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PMID:6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. 1799 28

TNNI3K is a new cardiac-specific MAP kinase whose gene is localized to 1p31.1 and that belongs to a tyrosine kinase-like branch in the kinase tree of the human genome. In the present study we investigated the role of TNNI3K in the cardiac myogenesis process and in the repair of ischemic injury. Pluripotent P19CL6 cells with or without transfection by pcDNA6-TNNI3K plasmid were used to induce differentiation into beating cardiomyocytes. TNNI3K promoted the differentiation process, judging from the increasing beating mass and increased number of alpha-actinin-positive cells. TNNI3K improved cardiac function by enhancing beating frequency and increasing the contractile force and epinephrine response of spontaneous action potentials without an increase of the single-cell size. TNNI3K suppressed phosphorylation of cardiac troponin I, annexin-V(+) cells, Bax protein, and p38/JNK-mediated apoptosis. Intramyocardial administration of TNNI3K-overexpressing P19CL6 cells in mice with myocardial infarction improved cardiac performance and attenuated ventricular remodeling compared with injection of wild-type P19CL6 cells. In conclusion, our study clearly indicates that TNNI3K promotes cardiomyogenesis, enhances cardiac performance, and protects the myocardium from ischemic injury by suppressing p38/JNK-mediated apoptosis. Therefore, modulation of TNNI3K activity would be a useful therapeutic approach for ischemic cardiac disease.
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PMID:Overexpression of TNNI3K, a cardiac-specific MAP kinase, promotes P19CL6-derived cardiac myogenesis and prevents myocardial infarction-induced injury. 1855 63

Parathyroid hormone-related protein (PTHrP) (107-139), in contrast to the N-terminal fragment PTHrP (1-36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre-incubation with PTHrP (107-139) for 1-24 h dose-dependently (0.1-100 nM) inhibited dexamethasone- or etoposide-induced cell death in human osteoblastic MG-63 cells and human osteoblast-like cells from trabecular bone. This effect, but not that elicited by PTHrP (1-36), was abolished by the VEGF receptor (VEGFR)-2 inhibitors SU5614 and SU1498 or VEGFR-2 siRNA transfection in these cells. PTHrP (107-139), but not PTHrP (1-36), at 100 nM, rapidly (within 2 min) increased VEGFR-2 tyrosine-phosphorylation in MG-63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF(165) or VEGFR-2 antibodies, or the VEGF binding inhibitor CBO-PP1. The latter two antagonists also failed to affect (125)I-[Tyr(116)] PTHrP (107-115) binding to these cells. Consistent with its effect on VEGFR-2 activation, PTHrP (107-139) rapidly induced extracellular signal-regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol-3 kinase (PI3K) inhibitors abolished its pro-survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG-63 cells. Transfection with a dominant-negative Runx2 construct abolished the pro-survival effect of PTHrP (107-139), associated with a decrease in Bcl-2/Bax protein ratio. Our findings demonstrate that PTHrP (107-139) interacts with VEGFR-2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation.
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PMID:Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2. 1865 20

1. Cardiac ryanodine RyR2 receptors regulate Ca(2+) release from the sarcoplasmic reticulum (SR). FK506 binding protein (FKBP) 12.6 prevents aberrant SR Ca(2+) leakage during diastole, thereby maintaining the integrity of RyR2 function. Previous studies have focused mainly on FKBP12.6 deficiency and so the pathophysiological consequences of FKBP12.6 overexpression remain unclear. Herein, we investigate the effect of FKBP12.6 overexpression on cardiac hypertrophic and apoptotic signalling. 2. Human FKBP12.6 cDNA was cloned into pAdTrack-CMV and the resulting plasmid, along with a control empty plasmid, were transfected into bacteria. The resulting virus, namely Ad-FKBP12.6 containing green fluorescent protein, was propagated and purified. Neonatal rat cardiomyocytes were infected with this virus. Protein and DNA synthesis were measured by [(3)H]-leucine and [(3)H]-thymidine incorporation, respectively. Expression of p38 mitogen-activated protein kinase (MAPK), phosphorylated extracellular signal-regulated kinase 1 or 2 (p-ERK1/2) and Bax were examined by western blotting. 3. Compared with control cells, cardiomyocytes that overexpressed FKBP12.6 became hypertrophic and hyperplastic, with increased levels of both p38 MAPK and p-ERK1/2. At the same time, overexpression of FKBP12.6 induced apoptosis of cardiomyocytes, as determined by both Bax protein expression and DNA fragmentation. Rapamycin treatment downregulated the expression of p-ERK1/2, p38 MAPK and Bax in stimulated cardiomyocytes, with or without FKBP12.6 overexpression, and enhanced protein synthesis, but had no effect on DNA synthesis in cardiomyocytes. 4. In conclusion, FKBP12.6 overexpression may participate in pathophysiological processes through both hypertrophic and apoptotic signalling pathways, leading to cardiomyocyte damage and death.
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PMID:Adenovirus-mediated FKBP12.6 overexpression induces hypertrophy and apoptosis in cultured neonatal cardiomyocytes. 1875 59

Cytochrome P450 (CYP) omega-hydroxylases and their arachidonic acid metabolites play important roles in myocardial ischemia-reperfusion injury. In this study we investigated the effects of several selective CYP omega-hydroxylase inhibitors on myocardial ischemia/reperfusion-induced myocardial apoptosis. Rats were subjected 30 min of ischemia and 2 h of reperfusion. Groups received either 17-octadecynoic acid (17-ODYA, 0.3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, 0.4 or 0.8 mg/kg), N-hydroxy-N'-(4-butyl-2-methylphenyl) formamidine (HET0016, 0.1 or 1 mg/kg) or vehicle 10 min prior to ischemia. To further assess the role of mitogen-activated protein kinases (MAPKs) in the CYP omega-hydroxylase inhibitor-induced anti-apoptotic effect, rats also received PD98059 (1 mg/kg), SB203580 (1 mg/kg) or SP600125 (6 mg/kg) 15 min prior to ischemia, with subsets of rats also receiving HET0016 10 min prior to ischemia. Compared with vehicle group, 17-ODYA, DDMS and HET0016 significantly inhibited myocardial apoptosis as evidenced by decreased DNA ladder formation, terminal dUTP deoxynucleotidyltransferase nick end-labeling (TUNEL) positive nuclear staining. They also decreased caspase-3 activity and Bax protein expression but up-regulated the expression of Bcl-2. Conversely, exogenous 20-HETE administration exerted opposite effects. Moreover, HET0016 increased the activity of extracellular signal-related protein kinases 1 and 2 (ERK1/2) but had no significant effect on p38 MAPK or c-Jun N-terminal kinase (JNK) during ischemia/reperfusion. Pretreatment with PD98059, the inhibitor of ERK1/2, but not SB203580 or SP600125, almost completely blocked the effect exerted by HET0016. Taken together, these data suggest that CYP omega-hydroxylase inhibition exerts significant anti-apoptosis effects, at least in part, by activation of ERK1/2 in ischemia/reperfusion heart.
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PMID:Cytochrome P450 omega-hydroxylase inhibition reduces cardiomyocyte apoptosis via activation of ERK1/2 signaling in rat myocardial ischemia-reperfusion. 1877 65

We investigated pharmacological effects of rutin isolated form Lonicera japonica on H2O2-induced cell death in H9c2 cells in vitro and rat myocardial ischemia-reperfusion injury model in vivo. Western blot analysis showed that H2O2 increased expression of cleaved form of caspase-3 and proapoptotic Bax protein, but decreased antiapoptotic Bcl-2 protein in H9c2 cell. However, treatment with rutin decreased expression of both cleaved from of caspase-3 and increased Bcl-2/Bax ratio in H9c2 cells. The protective effect of rutin was inhibited not by JNK inhibitor or p38 MAPK inhibitor but by PI3K inhibitor or ERK inhibitor. Rutin increased phosphorylation of ERK and Akt in H9c2 cells. These anti-apoptotic effects of rutin were confirmed both by annexin-V and TUNEL assay. Furthermore, rutin improved I/R-induced myocardial contractile function and reduced infarct size. Rutin administration also inhibited apoptosis in myocardial tissues in I/R rats by increasing Bcl-2/bax ratio and decreasing active caspase-3 expression. These results suggest that rutin reduced oxidative stress-mediated myocardial damage in vitro model and in vivo model, which might be useful in treatment of myocardial infarction.
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PMID:Rutin from Lonicera japonica inhibits myocardial ischemia/reperfusion-induced apoptosis in vivo and protects H9c2 cells against hydrogen peroxide-mediated injury via ERK1/2 and PI3K/Akt signals in vitro. 1936 15

Lipopolysaccharide (LPS) can cause damage to the epithelia of the respiratory tract. However, taurine can protect the lung tissue from such oxidant-induced inflammation. This study examined the effects of a LPS treatment on the intracellular calcium levels ([Ca(2+)]i) as well as the specific mechanisms of LPS-induced cell death in pneumocytes. In addition, the effects of taurine on the LPS-induced increase in the accumulation of reactive oxygen species (ROS) in pneumocytes were investigated. The [Ca(2+)]i in cultured pneumocytes was determined using microfluorescence techniques. The level of activation of the mitogen-activated protein kinases (MAPKs) and Bax protein were measured by Western blotting. LPS at 10 and 100 ng/ml induced cell death and decreased the viability of MRC-5 cells. Moreover, the intracellular Ca(2+) and ROS levels were increased by LPS. The LPS treatment led to the phosphorylation of ERK1/2, JNK and the activation of Bax. A pretreatment with 20 mM taurine reduced the LPS-induced production of ROS and MARK activity. These results show that a LPS treatment induces cell death in MRC-5 cells by increasing the intracellular ROS and Ca(2+) levels. The increase in the intracellular level of ROS promotes MAPKs activation and Bax translocation. Overall, LPS induces lung cell death by activating MAPKs. Furthermore, taurine decreased the LPS-induced generation of ROS and activation of MAPK and Bax.
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PMID:The antioxidant, taurine reduced lipopolysaccharide (LPS)-induced generation of ROS, and activation of MAPKs and Bax in cultured pneumocytes. 1966 57

The antitumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly inhibited the growth of HCT-15 cells (human colon carcinoma cells). After HCT-15 cells were treated with fucoidan, several apoptotic events such as DNA fragmentation, chromatin condensation and increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Bax protein expression levels and activation of caspases. Fucoidan decreased Bcl-2 expression, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and caspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP), a vital substrate of effector caspase, was observed. Furthermore, the induction of apoptosis was also accompanied by a strong activation of extracellular signal-regulated kinase (ERK) and p38 kinase and an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
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PMID:Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. 1980 40


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