Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of the transcription factor AP-1 to DNA has been shown to be modulated by redox control mechanisms. Selenite and selenodiglutathione (GS-Se-SG), inhibit mammalian cell growth and are efficient oxidants of reduced thioredoxin and reduced thioredoxin reductase. Here, we report that selenite and GS-Se-SG efficiently inhibited AP-1 DNA-binding in nuclear extracts from 3B6 lymphocytes. A GS-Se-SG concentration of 0.75 microM resulted in 50% inhibition of AP-1 DNA-binding, whereas the same effect was achieved with 7.5 microM selenite. Nuclear extracts prepared from human 3B6 lymphocytes exposed for 4 h to 10 microM selenite showed a 50% reduction of AP-1 binding. These data suggest that selenite and selenodiglutathione inactivate the AP-1 factor and provide a mechanism by which selenium compounds inhibit cell growth.
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PMID:AP-1 DNA-binding activity is inhibited by selenite and selenodiglutathione. 761 89

The stress-activated protein kinases (SAPKs, also called c-Jun NH(2)-terminal kinases) and the p38s, two mitogen-activated protein kinase (MAPK) subgroups activated by cytokines of the tumor necrosis factor (TNF) family, are pivotal to the de novo gene expression elicited as part of the inflammatory response. Apoptosis signal-regulating kinase 1 (ASK1) is a MAPK kinase kinase (MAP3K) that activates both the SAPKs and p38s in vivo. Here we show that TNF receptor (TNFR) associated factor 2 (TRAF2), an adapter protein that couples TNFRs to the SAPKs and p38s, can activate ASK1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ASK1 polypeptide. Expression of the amino-terminal noncatalytic domain of ASK1 can inhibit TNF and TRAF2 activation of SAPK. TNF can stimulate the production of reactive oxygen species (ROS), and the redox-sensing enzyme thioredoxin (Trx) is an endogenous inhibitor of ASK1. We also show that expression of TRAF2 fosters the production of ROS in transfected cells. We demonstrate that Trx significantly inhibits TRAF2 activation of SAPK and blocks the ASK1-TRAF2 interaction in a reaction reversed by oxidants. Finally, the mechanism of ASK1 activation involves, in part, homo-oligomerization. We show that expression of ASK1 with TRAF2 enhances in vivo ASK1 homo-oligomerization in a manner dependent, in part, upon the TRAF2 RING effector domain and the generation of ROS. Thus, activation of ASK1 by TNF requires the ROS-mediated dissociation of Trx possibly followed by the binding of TRAF2 and consequent ASK1 homo-oligomerization.
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PMID:Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. 1068 66

Peroxidases of the peroxiredoxin (Prx) family contain a Cys residue that is preceded by a conserved sequence in the NH(2)-terminal region. A new type of mammalian Prx, designated PrxV, has now been identified as the result of a data base search with this conserved Cys-containing sequence. The 162-amino acid PrxV shares only approximately 10% sequence identity with previously identified mammalian Prx enzymes and contains Cys residues at positions 73 and 152 in addition to that (Cys(48)) corresponding to the conserved Cys. Analysis of mutant human PrxV proteins in which each of these three Cys residues was individually replaced with serine suggested that the sulfhydryl group of Cys(48) is the site of oxidation by peroxides and that oxidized Cys(48) reacts with the sulfhydryl group of Cys(152) to form an intramolecular disulfide linkage. The oxidized intermediate of PrxV is thus distinct from those of other Prx enzymes, which form either an intermolecular disulfide or a sulfenic acid intermediate. The disulfide formed by PrxV is reduced by thioredoxin but not by glutaredoxin or glutathione. Thus, PrxV mutants lacking Cys(48) or Cys(152) showed no detectable thioredoxin-dependent peroxidase activity, whereas mutation of Cys(73) had no effect on activity. Immunoblot analysis revealed that PrxV is widely expressed in rat tissues and cultured mammalian cells and is localized intracellularly to cytosol, mitochondria, and peroxisomes. The peroxidase function of PrxV in vivo was demonstrated by the observations that transient expression of the wild-type protein, but not that of the Cys(48) mutant, in NIH 3T3 cells inhibited H(2)O(2) accumulation and activation of c-Jun NH(2)-terminal kinase induced by tumor necrosis factor-alpha.
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PMID:Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate. 1075 10

NF-kappaB is a redox-sensitive transcription factor known to be activated by oxidative stress as well as chemical and biological reductants. Its DNA binding activity requires reduced cysteines present in the p65 subunit of the dimer. Thioredoxin (Trx) is an endogenous disulfide oxidoreductase known to modulate several redox-dependent functions in the cell. NF-kappaB was activated by addition of Escherichia coli thioredoxin in a redox-dependent manner in A549 cells. Such activation was accompanied by degradation of IkappaB in the cytosol. In addition, only the reduced form of thioredoxin activated NF-kappaB, whereas the oxidized form was without any effect. Overexpression of human thioredoxin also caused activation of NF-kappaB and degradation of IkappaB. On the contrary, dominant-negative redox-inactive mutant thioredoxin expression did not activate NF-kappaB, further confirming the redox-dependent activation of NF-kappaB. We also investigated the mechanism of activation of NF-kappaB by thioredoxin. We demonstrate that thioredoxin activates c-Jun NH(2)-terminal kinase (JNK)-signaling cascade, and dominant-negative expression of mitogen-activated protein kinase kinase kinase 1 (MEKK1), JNK kinase, or JNK inhibits NF-kappaB activation by thioredoxin. In contrast, wild-type MEKK1 or JNK kinase induced NF-kappaB activation alone or in combination with thioredoxin expression plasmid. These findings were also confirmed by NF-kappaB-dependent luciferase reporter gene transcription.
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PMID:c-Jun NH2-terminal kinase-mediated redox-dependent degradation of IkappaB: role of thioredoxin in NF-kappaB activation. 1106 42

In retinitis pigmentosa, retinal detachment, age-related macular degeneration, and glaucoma, retinal neuronal cells are damaged by a common mechanism, apoptosis. Because apoptosis is an active process that requires de novo expression of a "death message", this process can be controlled by inhibiting the expression of the "death message". We first studied whether a retinal ischemia-reperfusion model can be used as a model for retinal neuronal apoptosis. In the retinal ischemia-reperfusion injuries, typical features of apoptosis, including TUNEL-positive cells, DNA ladder formation, and ultrastructural features of apoptosis were found. Using the model, systematic research to identify the "death message" was done by DNA microarray analysis. About 200 messages were found to be up- or down-regulated during the process of retinal ischemia-reperfusion. These genes were divided into four groups: (1) transcription factor genes, (2) cell cycle-related genes, (3) reactive oxygen scavenger genes and (4) molecular chaperon genes. The possible roles of such genes in neuronal apoptosis following retinal ischemia-reperfusion injury were studied. In the model, reactive oxygen species produced by reperfusion was found to generate lipid peroxides and induced up-regulation of a transcription factor, c-Jun, that further induced aberrant expression of cell cycle-related genes such as cyclin D1 in amacrine cells. However, because no controlled expression of cell cycle-related genes takes place in retinal neurons, amacrine cells died by a G1 arrest mechanism. On the other hand, horizontal cells never expressed cyclin D1 and the cells were found to die by necrosis. The study revealed a possible mechanism of retinal neuronal apoptosis and it also became apparent that different types of neurons use different "death messages". Furthermore, the possibility that inhibition of a "death message" sometimes induces necrosis rather than apoptosis was shown. This means that we need to try inhibition of the death mechanism upstream rather than downstream. Administration of thioredoxin, an endogenous reactive oxygen species that blocks generation of lipid peroxides and thus inhibits the death process upstream, was found to be neuroprotective against retinal ischemia-reperfusion injury. Aberrant expression of c-Jun and cyclin D1 was down-regulated by the treatment. Possible roles of caspases were also studied by using the ischemia-reperfusion injury, RCS rat, and excessive light exposure damage in wild type and caspase-1 deficient mice. Also, application of adeno-associated virus that carries Bcl-xL was tested to find possible neuroprotective effects on RCS rats. Our studies showed that caspase-1 played a more important role in the retinal photoreceptors and caspase-3 was important in neurons in the inner nuclear layer. Caspase-2 was found to be a major caspase in the retinal ganglion cell layer. In agreement with the findings, caspase-1 deficient mice showed less prominent light damage than wild type mice. Gene therapy by Bcl-xL was effective to protect retinal photoreceptor damage in RCS rats.
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PMID:[Retinal neuronal cell death: molecular mechanism and neuroprotection]. 1180 59

Both acute (24 h) and chronic (10-20 week) exposure of human fibroblast cells to low dose sodium arsenite (As(III)) significantly affects activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) DNA binding activity. Short-term treatment with 0.1-5 microM As(III) up-regulates expression of c-Fos and c-Jun and the redox regulators, thioredoxin (Trx) and Redox factor-1 (Ref-1) and activates both AP-1 and NF-kappa B binding. Chronic exposure to 0.1 or 0.5 microM As(III) decreased c-Jun, c-Fos and Ref-1 protein levels and AP-1 and NF-kappa B binding activity, but increased Trx expression. Short term exposure to phorbol 12-myristate 13-acetate (TPA), a phorbol ester tumour promoter, or hydrogen peroxide (H(2)O(2)) also activates AP-1 and NF-kappa B binding. However, pre-treatment with As(III) prevents this increase. These results suggest that As(III) may alter AP-1 and NF-kappa B activity, in part, by up-regulating Trx and Ref-1. The different effects of short- versus long-term As(III) treatment on acute-phase response to oxidative stress reflect changes in the expression of Ref-1, c-Fos and c-Jun, but not Trx.
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PMID:Effect of arsenic on transcription factor AP-1 and NF-kappaB DNA binding activity and related gene expression. 1207 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

In response to stresses, mammalian cells induce heat shock proteins (HSP). Overproduction of a stress-inducible 70-kDa protein (Hsp70) results in the acquisition of tolerance against various types of stresses. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp 70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa. GGA also primed other types of cells for enhanced induction of Hsp70, when exposed to stress. Pretreatment of rats with GGA markedly suppressed ischemia-reperfusion injury of the liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. GGA can block insult-induced apoptosis at multiple levels; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apaf-1. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit protective actions independently of Hsp70 induction. HSP are members of molecular chaperones that are essential for the quality control of intracellular proteins. New compounds specifically targeting molecular chaperones that function to prevent the accumulation of misfolded proteins may be useful for the treatment of neurodegenerative disorders in the near future.
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PMID:[Molecular chaperone inducers in medicine and diseases]. 1261 33

Apoptosis signal-regulating kinase 1 (ASK1) was recently discovered as a typical member of the mitogen-activated protein (MAP) kinase kinase kinase family, which induces apoptosis by activation of c-Jun-N-terminal kinase/p38 MAP kinase pathways. In normal cells ASK1 is directly inhibited by thioredoxin (Trx), a 12-kDa protein ubiquitously expressed in all living cells, which has a variety of biological functions related to cell proliferation and apoptosis. Here we found that purified Trx is sensitive to S-nitrosylation. Stimulation of HEK-293 cells with S-nitrosoglutathione (GSNO) for 2, 4, 8, and 16h also caused Trx S-nitrosylation, which showed straight correlation with ASK1 activation based on Western blot detection of the enzyme, immunoprecipitation assay, and measurement of its catalytic activity. These results suggest that S-nitrosylation of Trx induces ASK1 activation. Treatment of cells with N-acetyl-cysteine for 2h after 8h of pretreatment with GSNO caused an increase in glutathione and nullified ASK1 activation.
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PMID:S-nitrosylation of thioredoxin mediates activation of apoptosis signal-regulating kinase 1. 1280 22

Reperfusion of ischemic myocardium produces reactive oxygen species (ROS) and results in apoptotic cell death and DNA fragmentation. Several redox-sensitive anti- and pro- apoptotic transcription factors including nuclear factor kappaB (NF-kappaB) and heterodimeric transcription factor AP-1 progressively and steadily increase in the heart as a function of the duration of ischemia and reperfusion. When the heart is adapted to ischemic stress by repeated short-term ischemia and reperfusion, NF-kappaB remains high, while AP-1 is lowered to almost baseline value. The anti-apoptotic gene Bcl-2 is downregulated in the ischemic/reperfused heart, while it is upregulated in the adapted myocardium. Cardioprotective abilities of the adapted myocardium are abolished when heart is pre-perfused with N-acetyl cysteine to scavenge ROS, suggesting a role of redox signaling. Mammalian heart is protected by several defense systems, which include, among others, the redox-regulated protein thioredoxin. Reperfusion of ischemic myocardium results in the downregulation of thioredoxin 1 (Trx 1) expression, which was upregulated in the adapted myocardium. The increased expression of Trx 1 is completely blocked with an inhibitor of Trx 1, cis-diammine-dichloroplatinum, which also abolished cardioprotection afforded by ischemic adaptation. The cardioprotective role of Trx 1 is further confirmed with transgenic mouse hearts overexpressing Trx 1. The Trx 1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size and apoptosis compared to the corresponding wild-type mouse hearts. The results of this study implicate a crucial role of redox signaling in transmitting anti-death signal.
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PMID:Conversion of death signal into survival signal by redox signaling. 1497 12


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