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)

It has been reported that a prior exposure of isoflurane, a commonly used volatile anesthetic in clinical practice, reduces brain cell death after ischemia. This isoflurane preconditioning-induced neuroprotection has been shown in rat in vivo and in vitro brain ischemia models. To investigate the mechanisms of this protection, we used the human neuroblastoma SH-SY5Y cells and simulated ischemia in vitro by oxygen-glucose deprivation. We found that isoflurane exposure for 30 min at 24 h before a 5-h oxygen-glucose deprivation dose-dependently reduced cell death. Isoflurane exposure induced phosphorylation/activation of extracellular signal-regulated kinase (ERK). Inhibition of the phospho-ERK expression abolished the isoflurane preconditioning-induced protection. Isoflurane exposure also increased the expression of early growth response gene 1 (Egr-1) and Bcl-2, proteins downstream of ERK. Egr-1 is a transcription factor and plays a role in cell survival. Bcl-2 is an anti-apoptotic protein. The increased expression of Egr-1 and Bcl-2 by isoflurane was inhibited by ERK inhibition. Thus, our results suggest a role of ERK/Egr-1/Bcl-2 pathway in the isoflurane preconditioning-induced protection in the human neuroblastoma SH-SY5Y cells.
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PMID:Isoflurane preconditioning protects human neuroblastoma SH-SY5Y cells against in vitro simulated ischemia-reperfusion through the activation of extracellular signal-regulated kinases pathway. 1680 62

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa). TF is constitutively expressed in a variety of tumor cells and has been shown to play a role in cellular signaling and tumor progression. In this study, we investigated the effect of TF-FVIIa mediated signaling on apoptosis in human breast cancer cells. Apoptosis was induced by prolonged serum starvation and studied using the Adr-MCF-7 cell line, which has high endogenous TF expression. Treatment of the cells with the combination of FVIIa (10 nM) and FX (150 nM), reduced apoptosis by nearly 50% compared with untreated, control cells using an ELISA that detects histone-DNA fragments. In contrast, FVIIa (10 nM) alone did not significantly prevent apoptosis. Pretreatment of the Adr-MCF-7 cells with hirudin, a specific thrombin inhibitor, did not inhibit the anti-apoptotic effect of the combination of FVIIa and FX, whereas this effect could be abrogated by inhibition of phosphorylation of either p44/42 mitogen-activated protein kinase (MAPK) or protein kinase B (PKB/Akt). In addition, treatment of the Adr-MCF-7 cells with the combination of FVIIa and FX led to a 30-50% increase in the level of the anti-apoptotic protein, survivin, compared with untreated cells using Western blot analysis. These results indicate that formation of TF-FVIIa-FXa complex prevents apoptosis in breast cancer cells by a thrombin-independent pathway. Moreover, the anti-apoptotic effect of this signaling pathway involves phosphorylation of both p44/42 MAPK and PKB/Akt and might be mediated in part by an increase in cell survivin levels.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. 1689 64

Increased levels of vascular endothelial growth factor (VEGF) are associated with a poor response of breast cancer to anti-hormone treatment. Although VEGF is regarded as an endothelial-specific growth factor, recent reports have shown that VEGF can promote proliferation of other cell types, including breast tumor cells. We have characterized the proliferative effects of VEGF in breast cancer cell lines that are commonly used for understanding the role of estrogens, progestins, and anti-hormones on tumor growth. Since steroid hormones can increase the level of VEGF in certain breast cancer cells, we evaluated the effects of exogenous VEGF on the growth-suppressive effects of anti-estrogen (ICI 182,780) and RU-486 (anti-progestin mifepristone) in human breast cancer cells. VEGF165 and VEGF121 increased the proliferation of tumor cell lines that expressed VEGFR-2 (VEGF receptor 2) (flk/kdr) via the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway. Furthermore, VEGF induced the expression of the anti-apoptotic protein Bcl-2 and blocked down-regulation of Bcl-2 by ICI 182,780 and induced Bcl-2 in BT-474 and T47-D cells even in the presence of RU-486. Increased Bcl-2 levels in response to VEGF were associated with increased proliferation and survival of tumor cells even in the presence of anti-hormones. These results suggest that VEGF stimulates proliferation of VEGFR2-positive tumor cells, promotes survival via the expression and activity of Bcl-2 and overrides the growth-suppressive effects of anti-hormones. This represents a potential explanation for anti-hormone resistance and tumor progression in clinical samples. Thus, it may be useful to use combined modality treatment involving anti-hormones and anti-angiogenic agents to treat breast cancers that express elevated levels of VEGF.
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PMID:Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. 1695 39

Leflunomide, a disease-modifying anti-rheumatic drug, protects against T-cell-mediated liver injury by poorly understood mechanisms. The active metabolite of leflunomide, A77 1726 (teriflunomide) has been shown to inhibit stress-activated protein kinases (JNK pathway), which are key regulators of mitochondria-mediated cell death. Therefore, we hypothesized that leflunomide may protect from drugs that induce the mitochondrial permeability transition (mPT) by blocking the JNK signaling pathway. To this end, we exposed cultured immortalized human hepatocytes (HC-04) to the standard protoxicant drug acetaminophen (APAP), which induces CsA-sensitive mPT-mediated cell death. We determined the effects of leflunomide on the extent of APAP-induced hepatocyte injury and the upstream JNK-mediated mitochondrial signaling pathways. We found that leflunomide or A77 1726 concentration-dependently protected hepatocytes from APAP (1 mM)-induced mitochondrial permeabilization and lethal cell injury. This was not due to proximal inhibition of CYP-catalyzed APAP bioactivation to its thiol-reactive metabolite. Instead, we demonstrate that leflunomide (20 microM) inhibited the APAP-induced early (3 h) activation (phosphorylation) of JNK1/2, thus inhibiting phosphorylation of the anti-apoptotic protein Bcl-2 and preventing P-Bcl-2-mediated induction of the mPT. This greatly attenuated mitochondrial cytochrome c release, which we used as a marker for mitochondrial permeabilization. The specific JNK2 inhibitor SP600125 similarly protected from APAP-induced cell death. In conclusion, these findings are consistent with our hypothesis that leflunomide protects from protoxicant-induced hepatocyte injury by inhibiting JNK signaling and preventing mPT induction.
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PMID:Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. 1697 4

Tributyltin (TBT) has been shown to disrupt the ability of natural killer (NK) cells to destroy tumor targets in vitro even at exposures of 25 nM for 24 h, but cell viability was not significantly impacted. Thus, evaluation of intracellular molecular events that regulate cell viability in TBT exposed NK cells are of interest. It has been suggested that activation of the mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), may promote apoptosis while activation of the MAPK p44/42 may be crucial in mediating anti-apoptotic stimuli. However, it is well established that increases in pro-apoptotic BCL-2 family members, such as Bax, results in cell death. We have set out to study the effects of a range of TBT concentrations on the MAPKs, JNK and p44/42. Additionally, we examined the effects of TBT on the levels of pro-apoptotic proteins Bax and p53 as well as anti-apoptotic protein Bcl-2. The results show that 300-25 nM TBT activated JNK within 10 min. MAPK p44/42 was also activated by 300-50 nM TBT within 10 min. These data show that while 300-200 nM TBT activates p44/42 significantly more than JNK, the pattern of 100-25 nM TBT activation of these MAPKs may be similar. TBT exposure alters neither pro-apoptotic proteins Bax and p53 nor anti-apoptotic protein Bcl-2 levels at any exposure studied. The results suggest that exposure to TBT activated the anti-apoptotic regulatory p44/42 pathway to a greater extent than the pro-apoptotic JNK pathway, which may explain to some extent how NK cell viability is maintained.
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PMID:Pattern of MAP kinases p44/42 and JNK activation by non-lethal doses of tributyltin in human natural killer cells. 1701 60

Focal adhesion kinase (FAK) is important to cellular functions such as proliferation, migration, and survival of anchorage-dependent cells. We investigated the role of FAK in modulating normal cellular responses, specifically cell survival in response to inflammatory stimuli and serum withdrawal, using FAK-knockout (FAK(-/-)) embryonic fibroblasts. FAK(-/-) fibroblasts were more vulnerable to TNF-alpha-induced apoptosis, as measured by terminal deoxynucleotidyl transferase positivity. FAK(-/-) fibroblasts also demonstrated increased procaspase-3 cleavage to p17 subunit, whereas this was undetectable in FAK(+/+) fibroblasts. Insulin receptor substrate-1 expression was completely abolished and NF-kappaB activity was reduced, with a concomitant decrease in abundance of the anti-apoptotic protein Bcl-x(L) in FAK(-/-) cells. Upon serum withdrawal, FAK(+/+) cells exhibited marked attenuation of basal ERK phosphorylation, while FAK(-/-) cells, in contrast, maintained high basal ERK phosphorylation. Moreover, inhibition of ERK phosphorylation potentiated serum withdrawal-induced caspase-3 activity. This was paralleled by increased insulin receptor substrate (IRS)-2 expression in FAK(-/-) cells, although both insulin- and IGF-1-mediated phosphorylation of Akt/PKB and GSK-3 were impaired. This suggests that IRS-2 protects against apoptosis upon serum withdrawal via the ERK signaling pathway. The specific role of FAK to protect cells from apoptosis is regulated by activation and phosphorylation of NF-kappaB and interaction between activated growth factor anti-apoptotic signaling pathways involving both phosphatidylinositol 3-kinase/Akt and MAPK/ERK1/2. We demonstrate that FAK is necessary for upregulation of the anti-apoptotic NF-kappaB response, as well as for normal expression of growth factor signaling proteins. Thus we propose a novel role for FAK in protection from cytokine-mediated apoptosis.
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PMID:Focal adhesion kinase mediates cell survival via NF-kappaB and ERK signaling pathways. 1713 1

The molecular mechanisms underlying ultrasound-induced apoptosis remain poorly understood. We have demonstrated that in Jurkat cells, the over-expression of the anti-apoptotic protein Bcl-2 inhibited ultrasound-induced apoptosis, but not necrosis. Inhibition of caspase activity also protected the cells from apoptosis, but not from necrosis, showing the involvement of different mechanisms in ultrasound-induced apoptosis and necrosis. Bak, a pro-apoptotic member of the Bcl-2 family proteins, was activated by ultrasound and its activation was completely inhibited by Bcl-2 over-expression, but not by caspase inhibition. Antioxidant N-acetyl cysteine did not protect the cells from ultrasound-induced apoptosis or necrosis, nor did the inhibition of either c-Jun N-terminal kinase or p38, key factors in the radical oxygen species (ROS)-mediated cell stress response, suggesting that ROS do not play a crucial role in ultrasound-induced apoptosis. Our results confirm that ultrasound induces apoptosis via a pathway that involves Bak, Bcl-2, and caspases, but not ROS.
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PMID:Activation of Bak in ultrasound-induced, JNK- and p38-independent apoptosis and its inhibition by Bcl-2. 1718 40

Salsolinol, an endogenous neurotoxin, is known to be involved in the pathogenesis of Parkinson's disease (PD). In the present study, we have investigated the effects of salsolinol on the activation of two different signaling pathways that involve c-Jun N-terminal kinase (JNK), and nuclear factor-kappaB, (NF-kappaB) in human dopaminergic neuroblastoma SH-SY5Y cells. Salsolinol treatment caused upregulation in the levels of c-Jun and phosphorylated c-Jun. It also caused degradation of IkappaBalpha and translocated the active NF-kappaB into the nucleus. The binding activity of NF-kappaB to DNA was enhanced by salsolinol in a concentration dependent manner. Furthermore, salsolinol decreased the levels of the anti-apoptotic protein Bcl-2, and increased pro-apoptotic protein Bax, while enhancing the release of cytochrome-c from mitochondria. Mitochondrial complex-I activity was significantly decreased and reactive oxygen species (ROS) were increased in salsolinol treated cells. These results partly suggest that salsolinol-induced JNK and NF-kappaB signaling pathways may be involved in induction of apoptosis in human dopaminergic neurons, as seen in Parkinson's disease.
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PMID:Salsolinol, an endogenous neurotoxin, activates JNK and NF-kappaB signaling pathways in human neuroblastoma cells. 1726 50

Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.
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PMID:Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1). 1748 38

The Bax inhibitor-1 (BI-1) is an anti-apoptotic protein that is located in endoplasmic reticulum (ER) membranes and protects cells from ER stress-induced apoptosis. The ER is associated with generation of reactive oxygen species (ROS) through oxidative protein folding. This study examined the role of BI-1 in the regulation of ER stress-induced accumulation of ROS and expression of unfolded protein response-associated proteins. BI-1 reduced the expression levels of glucose response protein 78, C/EBP homologous protein, phospho-eukaryotic initiation factor 2alpha, IRE1alpha, XBP-1, and phospho-JNK and inhibited the cleavage of ATF-6alpha p-90, leading to the inhibition of ROS. Although ROS scavengers offer some protection against ER stress-induced apoptosis, the expression of pro-apoptotic ER stress proteins was not affected. This study shows that the response of unfolded proteins is followed by ROS accumulation under ER stress, which is regulated in BI-1 cells. The mechanism for these BI-1-associated functions involves the expression of heme oxygenase-1 (HO-1) through nuclear factor erythroid 2-related factor 2. In BI-1 cells, the transfection of HO-1 small interfering RNA completely abolished the BI-1-induced protection. The endogenous expression of HO-1 through ER stress-initiated ROS is believed to be as a protection signal. In conclusion, these observations suggest that BI-1 can inhibit the ER stress proteins as well as the accumulation of ROS, thereby protecting the cells. Moreover, HO-1 plays an important role in the BI-1-associated protection against ER stress.
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PMID:Bax inhibitor-1 regulates endoplasmic reticulum stress-associated reactive oxygen species and heme oxygenase-1 expression. 1752


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