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 role of regulation of nitric oxide synthase (NOS) activity in mitigating oxidative stress in neonatal lungs and contributing to pulmonary vasodilation at birth is still unclear. Furthermore, it is known that, depending on interactions between the individual components of the mitogen-activated protein kinase (MAPK) signaling cascades, many biological consequences, including apoptosis, are initiated. Although the importance of nitric oxide (NO) in apoptosis is controversial and likely depends on NO concentrations and cell types, this highly reactive free radical can activate the p38 MAPK signal cascade. Recent studies have suggested that thioredoxin may play an important role as an effector for some of these functions. Thioredoxin is a major redox protein for many enzymes/transcription factors and is involved in cellular functions, such as viability, activation, and proliferation. In addition to its redox regulation, thioredoxin binds directly to the apoptosis signal-regulating kinase 1 (ASK1), thus inhibiting the activation of stress-induced MAPK signaling cascades that lead to apoptosis. Furthermore, NO produced from newly induced neuronal NOS was reported to induce expression of thioredoxin and several other genes for preconditioning-induced neuroprotection. Moreover, although exposure of endothelial cells to NO decreases NOS activity, this inhibition was shown to be reversed by thioredoxin. Finally, the correlation of expression of thioredoxin with endothelial NOS activity seems to suggest an important role played by this protein in perinatal changes of pulmonary artery functions. Therefore, thioredoxin may participate in the regulation of NOS activity and be involved in NO functions via multiple mechanisms.
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PMID:Thioredoxin-related regulation of NO/NOS activities. 1207 71

Despite the importance of the stress-activated protein kinase pathways in cell death and survival, it is unclear how stressful stimuli lead to their activation. In the case of heat shock, the existence of a specific mechanism of activation has been evidenced, but the molecular nature of this pathway is undefined. Here, we found that Ask1 (apoptosis signal-regulating kinase 1), an upstream activator of the stress-activated protein kinase p38 during exposure to oxidative stress and other stressful stimuli, was also activated by heat shock. Ask1 activity was required for p38 activation since overexpression of a kinase dead mutant of Ask1, Ask1(K709M), inhibited heat shock-induced p38 activation. The activation of Ask1 by oxidative stress involves the oxidation of thioredoxin, an endogenous inhibitor of Ask1. A different activation mechanism takes place during heat shock. In contrast to p38 induction by H(2)O(2), induction by heat shock was not antagonized by pretreatment with the antioxidant N-acetyl-l-cysteine or by overexpressing thioredoxin and was not accompanied by the dissociation of thioredoxin from Ask1. Instead, heat shock caused the dissociation of glutathione S-transferase Mu1-1 (GSTM1-1) from Ask1 and overexpression of GSTM1-1-inhibited induction of p38 by heat shock. We concluded that because of an alternative regulation by the two distinct repressors thioredoxin and GSTM1-1, Ask1 constitutes the converging point of the heat shock and oxidative stress-sensing pathways that lead to p38 activation.
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PMID:Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. 1207 34

It has been shown that thioredoxin (Trx) in a reduced form binds to and inhibits apoptosis signal-regulating kinase 1 (ASK1). Apoptotic stimuli such as tumor necrosis factor (TNF) and reactive oxygen species (ROS) activate ASK1 in part by oxidizing Trx (forming intramolecular disulfide between C32 and C35) to release Trx from ASK1. In the present study, we examined if Trx affects ASK1 protein stability and whether the redox activity of Trx is critical in regulating ASK1 activity. First, we showed that overexpression of the wild-type Trx (Trx-WT) in endothelial cells induced ASK1 ubiquitination and degradation. Trx-induced ASK1 ubiquitination/degradation could be blocked by ASK1 activators TNF and TRAF2. We then tested the single-mutation of Trx at the catalytic site C32 or C35 (Trx-C32S or Trx-C35S) and the double-mutation (Trx-CS). The results showed that the single mutants (but not Trx-CS) retained the binding activity for ASK1 and the ability to induce ASK1 ubiquitination/degradation. Unlike Trx-WT, Trx-C32S and Trx-C35S mutants constitutively bind to ASK1 even in the presence of hydrogen peroxide in vitro and TNF in vivo. Finally, we showed that the single mutants (not Trx-WT) significantly (n=4 and P<0.05) inhibited ASK1-induced JNK activation, caspase 3 activity, and apoptosis in TNF/ROS-resistant manner. Our data suggest that association of Trx with ASK1 through a single Cysteine (C32 or C35) is necessary and sufficient for Trx activity in inducing ASK1 ubiquitination/degradation leading to inhibition of ASK1-induced apoptosis.
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PMID:Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. 1208 59

Cellular redox is controlled by the thioredoxin (Trx) and glutathione (GSH) systems that scavenge harmful intracellular reactive oxygen species (ROS). Oxidative stress also evokes many intracellular events including apoptosis. There are two major pathways through which apoptosis is induced; one involves death receptors and is exemplified by Fas-mediated caspase-8 activation, and another is the stress- or mitochondria-mediated caspase-9 activation pathway. Both pathways converge on caspase-3 activation, resulting in nuclear degradation and cellular morphological change. Oxidative stress induces cytochrome c release from mitochondria and activation of caspases, p53, and kinases, including apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Trx inhibits apoptosis signaling not only by scavenging intracellular ROS in cooperation with the GSH system, but also by inhibiting the activity of ASK1 and p38. Mitochondria-specific thioredoxin (Trx-2) and Trx peroxidases (peroxiredoxins) are suggested to regulate cytochrome c release from mitochondria, which is a critical early step in the apoptotis-signaling pathway. dATP/ATP and reducing factors including Trx determine the manifestation of cell death, apoptosis or necrosis, by regulating the activation process and the activity of redox-sensitive caspases. As mitochondria are the most redox-active organelle and indispensable for cells to initiate or inhibit the apoptosis process, the regulation of mitochondrial function is the central focus in the research field of apoptosis and redox.
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PMID:Redox control of cell death. 1221 8

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

Changes in the intracellular reduced/oxidized glutathione ratio (GSH/GSSG) are crucial reduction-oxidation (redox) events that trigger downstream proliferation or death responses. We investigated the molecular mechanisms underlying redox-mediated cell signaling upon an oxidative insult by treating U937 cells with exogenous nonpermeable GSSG. This treatment results in a significant decrease of exofacial cell membrane thiol groups and intracellular decrement of GSH content, owing to its engagement in the formation of mixed disulfides. Changes in thioredoxin redox state were also observed, and they may be related to the activation of upstream ASK1 and selective induction of downstream p38 mitogen-activated protein kinase (MAPK) pathway, detectable by phosphorylation of MKK3/6 and p38 MAPK. Moreover, an increase in reactive oxygen species production was detected, and cells were committed to apoptosis along the mitochondrial pathway, evidenced by Bcl-2 down-regulation, cytochome c release from mitochondria, caspase-9 cleavage, and caspase-3 activation. GSH ethyl ester, a precursor of GSH, by counteracting intracellular mixed disulfide formation, canceled both p38 MAPK activation and GSSG-mediated apoptosis via inhibition of thioredoxin oxidation and stabilization of thioredoxin/ASK1 complex, whereas, blockage of p38 MAPK by specific inhibitor SB 203580 allowed apoptosis at a very reduced extent. Results suggest that kinase cascade may serve as a primary transducer of cytoplasmic oxidative signals to the nucleus before apoptosis-inducing signals are activated.
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PMID:Glutathione disulfide induces apoptosis in U937 cells by a redox-mediated p38 MAP kinase pathway. 1242 21

We observed previously that glucose deprivation induces cytotoxicity, increases the intracellular levels of hydroperoxide, and activates the stress-activated protein kinase (SEK) pathway. In this study, we hypothesized that 1-methylpropyl 2-imidazolyl disulfide (IV-2), a thioredoxin (TRX) inhibitor, augments glucose deprivation-induced cytotoxicity by promoting c-Jun N-terminal kinase (JNK) activation. Human prostatic carcinoma DU-145 cells were exposed to glucose-free medium containing various concentrations of IV-2 (10-50 microM). Glucose deprivation alone or IV-2 alone induced minimal cytotoxicity within 7 h. However, the combination of glucose deprivation and IV-2 increased cell death in a dose-dependent manner. The cytotoxicity was suppressed by treatment with an antioxidant, N-acetyl-L-cysteine or overexpressing TRX. The combined glucose deprivation and IV-2 treatment also promoted glucose deprivation-induced JNK1 activation by disrupting the interaction between TRX and apoptosis signal-regulating kinase 1 (ASK1). Overexpression of the JNK1 dominant-negative mutant inhibited the activation of the SEK pathway and protected cells from glucose deprivation and IV-2-induced cytotoxicity. Therefore, IV-2 enhances glucose deprivation-induced cytotoxicity by promoting glucose deprivation-induced activation of the ASK1-SEK1-JNK1 pathway.
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PMID:Enhancement of metabolic oxidative stress-induced cytotoxicity by the thioredoxin inhibitor 1-methylpropyl 2-imidazolyl disulfide is mediated through the ASK1-SEK1-JNK1 pathway. 1243 9

Reactive oxygen species (ROS) during normal metabolism signal cells to stimulate proliferation or to cause cellular damages, depending on a specific concentration. Energy restriction (ER) increases life span in animals, which can explain an effective modulator for reducing oxidative stress. Oxidative stress can result from a decrease in the protection against ROS. The deleterious effects of oxidative stress generally occur after exposure to a relatively high concentration of ROS. Alternatively, it has been suggested that a low concentration of ROS can exert important physiological roles in cellular signaling and proliferation. Signal pathways are crucial for cell survival or death. It is generally acceptable that aged cells have less response to stresses such as ROS than young cells. Oxidative stresses induce JNK and p38 kinase pathways regulated by redox regulatory proteins: thioredoxin and glutathione s-transferase, respectively. Antioxidants such as selenium block apoptosis induced by ROS through blocking apoptotic signal ASK1 and stimulating survival signal Akt activity. Old hepatocytes are more susceptible to ROS-induced apoptosis than young hepatocytes, which is associated with low expression of ERK and Akt kinases. Pharmacological inhibition of ERK and Akt activation in the young cells markedly increase their sensitivity to H(2)O(2), and ER, by preventing loss of ERK and Akt activities, enhances survival of old hepatocytes to a level similar to those of young cells. Expressions of signal pathways such as survival and apoptotic signals can regulate cells' fate and aging process. Further studies on the interaction of signal pathways may change the scientific direction of the study of aging.
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PMID:Dose effect of oxidative stress on signal transduction in aging. 1247 Aug 97

Redox-sensing molecules such as thioredoxin (TRX) and glutaredoxin (GRX) bind to apoptosis signal-regulating kinase 1 (ASK1) and suppress its activation. Glucose deprivation disrupted the interaction between TRX/GRX and ASK1 and subsequently activated the ASK1-stress-activated protein kinase/extracellular-signal-regulated kinase kinase-c-Jun N-terminal kinase 1 (JNK1) signal-transduction pathway. L-Buthionine-( S, R )-sulphoximine, which decreases intracellular glutathione content, enhanced glucose deprivation-induced activation of JNK1 by promoting the dissociation of TRX, but not GRX, from ASK1. Treatment of cells with exogenous glutathione disulphide ester resulted in the dissociation of GRX, but not TRX, from ASK1 and the subsequent activation of JNK1. Nonetheless, overexpression of calatase, an H(2)O(2) scavenger, inhibited JNK1 activation and cytotoxicity as well as the dissociation of TRX and GRX from ASK1 during combined glucose deprivation and L-buthionine-( S, R )-sulphoximine treatment. Taken together, glucose deprivation-induced metabolic oxidative stress may activate ASK1 through two different pathways: glutathione-dependent GRX-ASK1 and glutathione-independent TRX-ASK1 pathways.
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PMID:Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1. 1272 71

Recently, acute total glucose deprivation has been shown to cause activation of ASK1-MEK-MAPK signal transduction and dissociation of glutaredoxin (GRX) from apoptosis signal-regulating kinase 1 (ASK1). In this study, we investigated whether clinically relevant concentrations (0.01-0.1 mM) of glucose promote ASK1 activation. We observed that a prominent activation of JNK1 occurred at a glucose concentration less than or equal to 0.01 mM. Similar to JNK1 activation, we also observed that low glucose-induced ASK1 activation, dissociation of GRX and thioredoxin (TRX) from ASK1, dimerization of ASK1, and association of Daxx and TRAF2 with ASK1 significantly occurred at a glucose concentration less than or equal to 0.01 mM.
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PMID:Effect of glucose concentration on activation of the ASK1-SEK1-JNK1 signal transduction pathway. 1285 32


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