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)

Previous studies indicated that antigen receptor (TcR) stimulation of mature T cells induced rapid generation of reactive oxygen species (ROS). The goal of the current study was to examine the role(s) of ROS in TcR signal transduction, with a focus upon the redox-sensitive MAPK family. TcR cross-linking of primary human T blasts and Jurkat human T cells rapidly activated the ERK, JNK, p38 and Akt kinases within minutes, and was temporally associated with TcR-stimulated production of hydrogen peroxide (H(2)O(2)). TcR-induced activation of ERK was selectively augmented and sustained in the presence of pharmacologic antioxidants that can quench or inhibit H(2)O(2) production (NAC, MnTBAP and Ebselen, but not DPI), while activation of JNK and Akt were largely unaffected. This was paralleled by concurrent changes in MEK1/2 phosphorylation, suggesting that ROS acted upstream of MEK-ERK activation. Molecular targeting of H(2)O(2) by overexpression of peroxiredoxin II, a thioredoxin dependent peroxidase, also increased and sustained ERK and MEK activation upon TcR cross-linking. Enhancement of ERK phosphorylation by antioxidants correlated with increased and sustained serine phosphorylation of the src-family kinase lck, a known ERK substrate. Thus, the data suggest that TcR-stimulated production of hydrogen peroxide negatively feeds back to dampen antigen-stimulated ERK activation and this redox-dependent regulation may serve to modulate key steps in TcR signaling.
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PMID:T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. 1289 42

Overexpression of catalase, but not manganese superoxide dismutase (MnSOD), inhibited glucose deprivation-induced cytotoxicity and c-Jun N-terminal kinase 1 (JNK1) activation in human prostate adenocarcinoma DU-145 cells. Suppression of JNK1 activation by catalase overexpression resulted from inhibition of apoptosis signal-regulating kinase 1 (ASK1) activation by preventing dissociation of thioredoxin (TRX) from ASK1. Overexpression of catalase also inhibited relocalization of Daxx from the nucleus to the cytoplasm as well as association of Daxx with ASK1 during glucose deprivation. Taken together, hydrogen peroxide (H(2)O(2)) rather than superoxide anion (O(2) (*-)) acts as a second messenger of metabolic oxidative stress to activate the ASK1-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-mitogen-activated protein kinase (MAPK) signal transduction pathway.
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PMID:Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: hydrogen peroxide as a major second messenger of metabolic oxidative stress. 1450 47

The possible roles of a 14-kDa human thioredoxin (Trx)-related protein (TRP14) in TNF-alpha signaling were studied in comparison with those of Trx1 by RNA interference in HeLa cells. Depletion of TRP14 augmented the TNF-alpha-induced phosphorylation and degradation of I kappa B alpha as well as the consequent activation of NF-kappa B to a greater extent than did Trx1 depletion. Deficiency of TRP14 or Trx1 enhanced TNF-alpha-induced activation of caspases and subsequent apoptosis by a similar extent. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs), however, was promoted by depletion of TRP14 but not by that of Trx1. Unlike Trx1, TRP14 neither associated with nor inhibited the kinase activity of apoptosis signal-regulating kinase-1 (ASK1), an upstream activator of JNK and p38. In combination with the results in the accompanying paper that TRP14 did not reduce the known substrates of Trx1, these results suggest that TRP14 modulates TNF-alpha signaling pathways, provably by interacting with proteins distinct from the targets of Trx1. In an effort to identify target proteins of TRP14, a mutant of TRP14, in which the active site cysteine (Cys(46)) was substituted with serine, was shown to form a disulfide-linked complex with LC8 cytoplasmic dynein light chain. The complex was detected in HeLa cells treated with H(2)O(2) or TNF-alpha but not in untreated cells, suggesting that LC8 cytoplasmic dynein light chain is a possible substrate of TRP14.
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PMID:Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-alpha signaling pathways. 1460 43

The gp91phox homologue Nox1 produces H2O2, which induces cell growth, transformation, and tumorigenicity. However, it has not been clear whether H2O2 effects are mediated indirectly via a generally oxidizing cellular environment or whether H2O2 more directly targets specific signaling pathways. Here, we investigated signaling by H2O2 induced by Nox1 overexpression using a luciferase reporter regulated by the antioxidant response element ARE4. Surprisingly, Nox1-derived H2O2 activated the reporter gene 15-fold with no effect on the redox state of the major thiol antioxidant substances, glutathione and thioredoxin. H2O2 signaling to ARE4 was mediated by activation of both the c-Jun N-terminal kinase and ERK1/2 pathways modulated by Ras. Thus, "redox signaling" resulting in kinase signaling pathways is distinct from "oxidative stress," and is mediated by discrete, localized redox circuitry.
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PMID:H2O2-dependent activation of GCLC-ARE4 reporter occurs by mitogen-activated protein kinase pathways without oxidation of cellular glutathione or thioredoxin-1. 1463 94

Increased intracellular reactive oxygen species (ROS) contribute to vascular disease and pro-atherosclerotic effects of diabetes mellitus may be mediated by oxidative stress. Several ROS-scavenging systems tightly control cellular redox balance; however, their role in hyperglycemia-induced oxidative stress is unclear. A ubiquitous antioxidative mechanism for regulating cellular redox balance is thioredoxin, a highly conserved thiol reductase that interacts with an endogenous inhibitor, thioredoxin-interacting protein (Txnip). Here we show that hyperglycemia inhibits thioredoxin ROS-scavenging function through p38 MAPK-mediated induction of Txnip. Overexpression of Txnip increased oxidative stress, while Txnip gene silencing restored thioredoxin activity in hyperglycemia. Diabetic animals exhibited increased vascular expression of Txnip and reduced thioredoxin activity, which normalized with insulin treatment. These results provide evidence for the impairment of a major ROS-scavenging system in hyperglycemia. These studies implicate reduced thioredoxin activity through interaction with Txnip as an important mechanism for vascular oxidative stress in diabetes mellitus.
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PMID:Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. 1512 45

Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro. Recent evidence suggests that this particular action of Trx requires S-nitrosation at Cys-69. The present study sought to investigate whether or not exogenously applied Trx reduces MI/R injury in vivo and to which extent this effect depends on S-nitrosation. Adult mice were subjected to 30 min of MI and treated with either vehicle or human Trx (hTrx, 2 mg/kg, i.p.) 10 min before reperfusion. Native hTrx was incorporated into myocardial tissue as shown by immunostaining, and reduced MI/R injury as evidenced by decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, DNA fragmentation, caspase-3 activity, and infarct size. When hTrx was partially S-nitrosated by preincubation with S-nitrosoglutathione, its cardioprotective effect was markedly enhanced. Treatment with hTrx significantly reduced p38 mitogen-activated protein kinase (MAPK) activity, and this effect was also potentiated by S-nitrosation. To further address the role of S-nitrosation for the overall antiapoptotic effect to Trx, the action of Escherichia coli Trx (eTrx) was investigated in the same model. Whereas eTrx inhibited MI/R-induced apoptosis to a degree similar to hTrx, S-nitrosation of this protein, which lacks Cys-69, failed to further enhance its antiapoptotic action. Collectively, our results demonstrate that systemically applied Trx is taken up by the myocardium to exert potent cardioprotective effects in vivo, offering interesting therapeutic avenues. In the case of hTrx, these effects are further potentiated by S-nitrosation, but this posttranslational modification is not essential for protection.
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PMID:Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected]. 1527 64

Repression of activation of c-Jun N-terminal kinase (JNK) participates in the anti-apoptotic effect of nuclear factor-kappaB (NF-kappaB) in TNFalpha-treated Ewing sarcoma cells. As oxidative stress is one of the most prominent activators of JNK, we investigated the relationship between TNFalpha-induced NF-kappaB activation and the control of oxidative stress. Inhibition of NF-kappaB activation resulted in an increase in TNFalpha-induced ROS production, lipid peroxidation and protein oxidation. Those ROS and lipid peroxides were both involved in TNFalpha-induced apoptosis, whereas only ROS elevation triggered sustained JNK activation. TNFalpha increased the level of two antioxidant enzymes, thioredoxin and manganese superoxide dismutase by an NF-kappaB-dependent mechanism. Inhibition of expression or activity of these enzymes sensitized cells to TNFalpha-induced apoptosis, indicating their functional role in protection from cell death. Thus, agents that inhibit activities of these enzymes may prove helpful in the treatment of Ewing tumors.
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PMID:NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells. 1558 26

All organisms have defense systems against oxidative stress that include multiple genes of antioxidant defense. These genes are induced by reactive oxygen species under condition of oxidative stress. In this study, we found that a 28-bp motif is conserved on the promoter regions of three antioxidant defense genes in rice (Oryza sativa): cytosolic superoxide dismutase (sodCc1), cytosolic thioredoxin (trxh), and glutaredoxin (grx). We demonstrated that the 28-bp sequence acts as a cis-element responsive to oxidative stress by transient expression assay and designated it as CORE (coordinate regulatory element for antioxidant defense). The CORE was activated by methyl viologen treatment and induced a 3.1-fold increase in expression of the reporter gene, but it did not respond to hydrogen peroxide. The expressions of the sodCc1, trxh, and grx genes were coordinately induced by methyl viologen, suggesting that multiple genes involved in antioxidant defense are controlled by a common regulatory mechanism via CORE. Application of the mitogen-activated protein kinase kinase inhibitor caused the constitutive induction of the sodCc1, trxh, and grx genes and the activation of CORE without methyl viologen treatment. These results indicate that a mitogen-activated protein kinase cascade is involved in the gene regulation mediated by CORE.
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PMID:A novel cis-element that is responsive to oxidative stress regulates three antioxidant defense genes in rice. 1561 34

Regions in the vasculature that are exposed to steady laminar blood flow are protected from atherosclerosis as compared with regions where flow is disturbed. We found that flow decreased TNF-mediated VCAM1 expression by inhibiting JNK and p38. JNK inhibition correlated with inhibition of apoptosis signal-regulating kinase 1 (ASK1), a JNK and p38 activator. Thioredoxin-interacting protein (TXNIP) is a stress-responsive protein that inhibits thioredoxin (TRX) activity. Since thioredoxin inhibits ASK1, we hypothesized that changes in TXNIP-TRX-ASK1 interactions mediate the antiinflammatory effects of flow. To explore this, we used perfused vessels and cultured ECs. Exposure of rabbit aortae or ECs to normal flow (12 dyn/cm2, 24 hours) was associated with decreased TXNIP expression and increased TRX activity compared with exposure to low flow (0.4 dyn/cm2). Normal flow inhibited TNF activation of JNK/p38 and VCAM1 expression. In cultured ECs, reduction of TXNIP expression by small interfering RNA increased TRX binding to ASK1 and inhibited TNF activation of JNK/p38 and VCAM1 expression. Conversely, overexpression of TXNIP stimulated JNK and p38. In aortae from TXNIP-deficient mice, TNF-induced VCAM1 expression was inhibited. The data suggest that TXNIP and TRX are key components of biomechanical signal transduction and establish them as potentially novel regulators of TNF signaling and inflammation in ECs.
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PMID:Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. 1569 99

The apoptosis signal-regulating kinase 1 (ASK1)-JNK/p38 signaling pathway is pivotal component in cell apoptosis and can be activated by a variety of death stimuli including tumor necrosis factor (TNF) alpha and oxidative stress (reactive oxygen species). However, the mechanism for ASK1 activation is not fully understood. We have recently identified ASK1-interacting protein (AIP1) as novel signal transducer in TNFalpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. In the present study, we employed yeast two-hybrid system using the N-terminal domain of AIP1 as bait and identified homeodomain-interacting protein kinase 1 (HIPK1) as an AIP1-associated protein. Interestingly, we showed that TNFalpha induced HIPK1 desumoylation concomitant with a translocation from nucleus to cytoplasm at 15 min followed by a return to nucleus by 60 min. The kinetics of HIPK1 translocation correlates with those of stress-induced ASK1-JNK/P38 activation. A specific JNK inhibitor blocked the reverse but not the initial translocation of HIPK1, suggesting that the initial translocation is an upstream event of ASK1-JNK/p38 signaling and JNK activation regulates the reverse translocation as a feedback mechanism. Consistently, expression of HIPK1 increased, whereas expression of a kinase-inactive form (HIPK1-D315N) or small interference RNA of HIPK1 decreased stress-induced ASK1-JNK/P38 activation without effects on IKK-NF-kappaB signaling. Moreover, a sumoylation-defective mutant of HIPK1 (KR5) localizes to the cytoplasm and is constitutively active in ASK1-JNK/P38 activation. Furthermore, HIPK1-KR5 induces dissociation of ASK1 from its inhibitors 14-3-3 and thioredoxin and synergizes with AIP1 to induce ASK1 activation. Our study suggests that TNFalpha-induced desumoylation and cytoplasmic translocation of HIPK1 are critical in TNFalpha-induced ASK1-JNK/p38 activation.
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PMID:Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation. 1570 37


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