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)

Serine-threonine kinase receptor-associated protein (STRAP) interacts with transforming growth factor beta (TGF-beta) receptors and inhibits TGF-beta signaling. Here, we identify STRAP as an interacting partner of ASK1 (apoptosis signal-regulating kinase 1). The association between ASK1 and STRAP is mediated through the C-terminal domain of ASK1 and the fourth and sixth WD40 repeats of STRAP. Using cysteine-to-serine amino acid substitution mutants of ASK1 (C1005S, C1351S, C1360S, and C1351S/C1360S) and STRAP (C152S, C270S, and C152S/C270S), we demonstrated that Cys(1351) and Cys(1360) of ASK1 and Cys(152) and Cys(270) of STRAP are required for ASK1-STRAP binding. ASK1 phosphorylated STRAP at Thr(175) and Ser(179), suggesting a potential role for STRAP phosphorylation in ASK1 activity regulation. Expression of wild-type STRAP, but not STRAP mutants (C152S/C270S and T175A/S179A), inhibited ASK1-mediated signaling to both JNK and p38 kinases by stabilizing complex formation between ASK1 and its negative regulators, thioredoxin and 14-3-3, or decreasing complex formation between ASK1 and its substrate MKK3. In addition, STRAP suppressed H(2)O(2)-mediated apoptosis in a dose-dependent manner by inhibiting ASK1 activity through direct interaction. These results suggest that STRAP can act as a negative regulator of ASK1.
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PMID:Serine-threonine kinase receptor-associated protein inhibits apoptosis signal-regulating kinase 1 function through direct interaction. 1988 May 23

Activation of p38 MAPK by ROS involves dissociation of an inactive, reduced thioredoxin-ASK1 complex [(SH)(2)Trx-ASK1]. Release of ASK1 activates its kinase activity thus stimulating the p38 MAPK pathway. The level of p38 MAPK activity is, therefore, regulated by the balance of free vs. bound ASK1. Longevity of Ames dwarf mice is attributed to their resistance to oxidative stress. The levels of (SH)(2) Trx-ASK1 are more abundant in young and old dwarf mice compared to their age-matched controls suggesting that the levels of this complex may play a role in their resistance to oxidative stress. In these studies we demonstrate that dermal fibroblasts from these long-lived mice exhibit (a) higher levels of (SH)(2)Trx-ASK1 that correlate with their resistance to ROS generated by inhibitors of electron transport chain complexes CI (rotenone), CII (3-nitropropionic acid), CIII, (antimycin A), and H(2)O(2)-mediated activation of p38 MAPK, and (b) maintain their in vivo resistance to ROS generated by 3NPA. We propose that elevated levels of (SH)(2)Trx-ASK1 play a role in conferring resistance to mitochondrial generated oxidative stress and decreased endogenous ROS which are characteristics of longevity determination.
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PMID:Dermal fibroblasts from long-lived Ames dwarf mice maintain their in vivo resistance to mitochondrial generated reactive oxygen species (ROS). 2015 67

Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making it difficult to identify molecular targets of therapeutic relevance. We have addressed this question in human dopaminergic neuroblastoma SH-SY5Y cells exposed to the parkinsonian toxin paraquat (PQ). This toxin elicited a dose-dependent increase in reactive oxygen species and cell death that correlated with activation of ASK1 and the stress kinases p38 and JNK. The relevance of these kinases in channeling PQ neurotoxicity was demonstrated with the use of interference RNA for ASK1 and two well-established pharmaceutical inhibitors for JNK and p38. The toxic effect of PQ was substantially attenuated by preincubation with vitamin E, blocking ASK1 pathways and preventing oxidative stress and cell death. In a search for a physiological pathway that might counterbalance PQ-induced ASK1 activation, we analyzed the role of the transcription factor Nrf2, master regulator of redox homeostasis, and its target thioredoxin (Trx), which binds and inhibits ASK1. Trx levels were undetectable in Nrf2-deficient mouse embryo fibroblasts (MEFs), whereas they were constitutively high in Keap1-deficient MEFs as well as in SH-SY5Y cells treated with sulforaphane (SFN). Consistent with these data, Nrf2-deficient MEFs were more sensitive and Keap1-deficient MEFs and SH-SY5Y cells incubated with SFN were more resistant to PQ-induced cell death. This study identifies ASK1/JNK and ASK1/p38 as two critical pathways involved in the activation of cell death under oxidative stress conditions and identifies the Nrf2/Trx axis as a new target to block these pathways and protect from oxidant exposure such as that found in Parkinson and other neurodegenerative diseases.
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PMID:Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death: modulation by the Nrf2/Trx axis. 2020 76

The Tubby mouse is a phenotypic model for sensorineural deafness and retinal dystrophy including Usher syndrome type 1. Thioredoxin is a small 13kDa protein which, when ubiquitously expressed as a transgene in the mouse, provides protection against multiple disease states including light-induced and oxidative stress-induced neurodegeneration and is down-regulated in the Tubby retina. We tested if overexpression of human thioredoxin in the Tubby mouse inhibits retinal degeneration and loss of visual function. Electroretinography, immunocytochemistry, quantitative histology, RT-PCR and Western blots were used to obtain data which showed that thioredoxin overexpression prevented loss of photoreceptors and retinal function. Analysis of signal pathways showed that thioredoxin up-regulated neurotrophic factors BDNF and GDNF and activated survival signaling pathways Akt, Ras/Raf1/ and the ERKs while inhibiting the ASK1/JNK apoptosis pathway. Relationships between the Tubby gene, its pathological phenotype and regulation of the thioredoxin system remain to be established.
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PMID:Neuroprotective effect of overexpression of thioredoxin on photoreceptor degeneration in Tubby mice. 2029 86

Diisocyanate is a leading cause of occupational asthma (OA). Diisocyanate-induced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose- and time-dependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, 15-deoxy-Delta(12,14)-PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK-Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.
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PMID:Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma. 2034 75

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes severe neurological disease with high mortality. Molecular mechanisms of JEV pathogenesis such as upstream apoptotic processes and pathways are not yet completely resolved or understood. In this study, JEV replication in human promonocyte cells induced time-dependent apoptosis and activated virus dose-dependent caspases 3, 8 and 9. Proteomic analysis demonstrated up- and down-regulated (more or less than 1.5-fold) proteins in JEV-infected promonocyte cells. Biological process categorization showed processes of antioxidation, free radical removal, and sulfur redox metabolism entailed many identified up- and down-regulated proteins. Down-regulation of thioredoxin, confirmed by using Western blotting, was involved in the apoptosis process of the oxidative stress response pathway. JEV infection caused increased intracellular ROS production and activation of ASK1-ERK/p38 MAPK signaling. ERK/p38 MAPK inhibitor PD98059 treatment definitely suppressed this apoptosis. Down-regulation of thioredoxin, increased intracellular ROS, and activation of ASK1-ERK/p38 MAPK signaling all were associated with JEV-induced apoptosis. These results are suggestive of an oxidative stress-pathway as a key element of JE pathogenesis.
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PMID:Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human promonocyte cells. 2043 Jan 9

Cytochrome P4502E1 (CYP2E1) potentiates TNFalpha toxicity by a mechanism involving increased oxidative stress and activation of JNK and p38 MAPKs. This study evaluated the upstream mediators of this MAPK activation with a special focus on studying whether apoptosis signal regulating kinase-1 (ASK-1) is activated in the CYP2E1-TNFalpha hepatotoxic model. Wild-type and CYP2E1(-/-) mice were treated with pyrazole (PY) for 3days to induce CYP2E1 and challenged with TNFalpha on day 3. Liver injury occurred between 8 and 12h after TNFalpha administration only to the wild-type PY-treated mice. Oxidative stress was elevated in the PY mice at 4h, a time before the liver injury. ASK-1 was dissociated from the thioredoxin-ASK-1 complex and was activated at 4h after administration of TNFalpha to PY mice. This was followed by activation of MKK3/MKK6 and MKK4/MKK7 at 4-8 or 12h and then JNK/p38 MAPK at 8 to 12h. MAPK phosphatase-1 was decreased 12 to 24h after TNFalpha administration. This may promote a sustained activation of JNK. Bax was elevated, whereas Bcl-2 and cFLIP(S/L) were lowered at 4h after administration of TNFalpha. These changes were followed by increases in caspase 8 and 3 activities and apoptosis. None of the above changes were observed when TNFalpha was administered to PY-treated CYP2E1(-/-) mice. These studies show that TNFalpha increases oxidative stress in mice with elevated CYP2E1, with subsequent activation of ASK-1 via a mechanism involving thioredoxin-ASK-1 dissociation, followed by activation of downstream MKK and MAPK. We speculate that similar interactions between CYP2E1 and TNFalpha may be important for alcohol-induced liver injury.
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PMID:Activation of ASK-1 and downstream MAP kinases in cytochrome P4502E1 potentiated tumor necrosis factor alpha liver injury. 2043 34

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ-) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ- rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ-/+) or partially depleted by feeding the PQQ- diet to PQQ+ rats for 48 h (PQQ+/-). RNA extracted from liver and a Codelink(R) UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ- diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P<0.01). PQQ repletion reversed the changes in transcript expression caused by PQQ deficiency and resulted in an alteration of 847 of the total transcripts examined (P<0.01). Genes important for cellular stress (e.g. thioredoxin), mitochondriogenesis, cell signalling [JAK (Janus kinase)/STAT (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) pathways] and transport were most affected. qRT-PCR (quantitative real-time PCR) and functional assays aided in validating such processes as principal targets. Collectively, the results provide a mechanistic basis for previous functional observations associated with PQQ deficiency or PQQ administered in pharmacological amounts.
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PMID:Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways. 2049 55

c-Jun NH(2)-terminal kinase (JNK) and p38 kinase are key regulators of cardiac hypertrophy and apoptosis during pathological stress, but their role in regulating ion channels in the diseased heart is unclear. Thus, we compared the kinase profile and electrophysiological phenotype of the rat ventricle 6-8 weeks after myocardial infarction (MI). Molecular analyses showed that JNK and p38 activities were markedly increased in post-MI hearts, while parallel voltage-clamp studies in ventricular myocytes revealed a characteristic downregulation of transient outward K(+) current (I(to)) density. When post-MI myocytes were treated with JNK or p38 inhibitors, I(to) density increased to control levels. Upregulation of I(to) was also elicited by insulin-like growth factor-1, which decreased JNK/p38 activity in post-MI hearts, and these changes were blocked by the thioredoxin (Trx) reductase inhibitor auranofin. Consistent with activation of JNK-p38 signaling, binding of apoptosis signal-regulating kinase-1 with Trx1 was also markedly decreased post-MI, and was reversed by insulin-like growth factor-1 in an auranofin-sensitive manner. We conclude that expression of ventricular K(+) channels is redox regulated and that chronic impairment of the Trx system in the post-MI heart contributes to I(to) remodeling through sustained activation of apoptosis signal-regulating kinase-1-JNK-p38 signaling. The cardiac Trx system may thus be a novel therapeutic target to reverse or prevent ventricular arrhythmias in the failing heart.
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PMID:Role of apoptosis signal-regulating kinase-1-c-Jun NH2-terminal kinase-p38 signaling in voltage-gated K+ channel remodeling of the failing heart: regulation by thioredoxin. 2051 94

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family and elicits a wide variety of cellular responses to various types of stress through activation of the JNK and p38 MAPK pathways. ASK1 is preferentially activated in response to oxidative stress, but this regulatory mechanism is still not completely understood. In our previous report, thioredoxin (Trx), which is an antioxidant protein and plays pivotal roles in maintaining intracellular redox balance, inhibited ASK1 kinase activity by direct binding to ASK1 under normal conditions. Under oxidative conditions, ASK1 is dissociated from Trx and therefore fully activated. The active site of Trx contains two cysteine residues that undergo reversible oxidation to form a disulfide bond with each other, so that the conformation of Trx is changed by intracellular redox conditions. Thus, the oxidative stress-induced conformational change of Trx is particularly important for interaction with and regulation of ASK1, and elucidation of the regulatory mechanisms of ASK1 by Trx is critical to understanding the intracellular redox signaling. In this chapter, we review the regulatory mechanisms of ASK1 activity by Trx, and describe a method for monitoring in vitro binding between Trx and ASK1 under various redox conditions. In addition, we present methods to detect the oxidative stress-induced activation of ASK1 in the cells by Western blot analysis and in vitro kinase assay. The techniques presented in this chapter will be useful for a range of investigations into intracellular redox signaling.
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PMID:Regulation of apoptosis signal-regulating kinase 1 in redox signaling. 2060 16


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