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)

Thioredoxin (Trx) is a small ubiquitous dithiol protein which together with the FAD-containing enzyme thioredoxin reductase (TR) and NADPH (the Trx system) is a hydrogen donor for ribonucleotide reductase essential for DNA synthesis and a general protein disulfide reductase involved in redox regulation. Selenite, selenodiglutathione (GS-Se-SG) and selenocystine are efficiently reduced by thioredoxins and also directly by NADPH and mammalian TR but not by the E. coli enzyme. Incubation of selenite or GS-Se-SG with the Trx system or with mammalian TR results in a rapid formation of selenide, which by redox cycling with oxygen may cause a large non-stoichiometric oxidation of NADPH. Selenocystine is efficiently reduced into two molecules of the selenol amino acid selenocysteine by mammalian TR with a K(m)-value (6 mumol.L-1) and a high turnover number (kappa cat 3200 min-1) almost identical to the natural substrate Trx-S2. TR also directly reduces lipid hydroperoxides and this peroxidase reaction is strongly stimulated by the presence of catalytic amounts of free selenocysteine. Glutaredoxin (Grx) which catalyzes GSH-dependent disulfide reduction also via a redox-active disulfide and Trx are both efficient electron donors to the human plasma glutathione peroxidase providing a mechanism by which human plasma glutathione peroxidase may reduce hydroperoxides in an environment almost free from glutathione. Selenate is reduced by Grx and Trx in the presence of GSH. The DNA-binding of the transcription factor AP-1 is strongly inhibited by GS-Se-SG and selenite. Furthermore, selenide formed by TR-mediated reduction of selenite and GS-Se-SG inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. Mammalian TR with two subunits of 57 kDa has recently been cloned and shown to be homologous to glutathione reductase. The rat enzyme contains a selenocysteine residue in a unique Cterminal position and a conserved SECIS sequence directing insertion of the selenocysteine. The discovery of selenocysteine in mammalian TR may explain the broad substrate specificity of the enzyme and the requirement of selenium for cell proliferation.
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PMID:Selenium and the thioredoxin and glutaredoxin systems. 931 20

Oxidized low-density lipoprotein (oxLDL) is known to activate a number of signal transduction pathways in endothelial cells. Among these are the c-Jun NH(2)-terminal kinase (JNK), also known as stress-activated protein kinase, and extracellular signal-regulated kinase (ERK). These mitogen-activated protein kinases (MAP kinase) determine cell survival in response to environmental stress. Interestingly, JNK signaling involves redox-sensitive mechanisms and is activated by reactive oxygen and nitrogen species derived from both NADPH oxidases, nitric oxide synthases (NOS), peroxides, and oxidized low-density lipoprotein (oxLDL). The role of endothelial NOS (eNOS) in the activation of JNK in response to oxLDL has not been examined. Herein, we show that on exposure of endothelial cells to oxLDL, both ERK and JNK are activated through independent signal transduction pathways. A key role of eNOS activation through a phosphatidylinositol-3-kinase-dependent mechanism leading to phosphorylation of eNOS is demonstrated for oxLDL-dependent activation of JNK. Moreover, we show that activation of ERK by oxLDL is critical in protection against the cytotoxicity of oxLDL.
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PMID:Endothelial NOS-dependent activation of c-Jun NH(2)- terminal kinase by oxidized low-density lipoprotein. 1170 40

Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O2- production in LV homogenates, measured by lucigenin (5 micro mol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by approximately 40% at the stage of LV decompensation; P<0.05). O2- production was fully inhibited by diphenyleneiodonium (100 micromol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22(phox), gp91(phox), p67(phox), and p47(phox) in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O2- production, there was a significant increase in activation of extracellular signal-regulated kinase 1/2, extracellular signal-regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure.
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PMID:Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. 1236 50

Hydrogen sulfide (H2S), produced by commensal sulfate-reducing bacteria, is an environmental insult that potentially contributes to chronic intestinal epithelial disorders. We tested the hypothesis that exposure of nontransformed intestinal epithelial cells (IEC-18) to the reducing agent sodium hydrogen sulfide (NaHS) activates molecular pathways that underlie epithelial hyperplasia, a phenotype common to both ulcerative colitis (UC) and colorectal cancer. Exposure of IEC-18 cells to NaHS rapidly increased the NADPH/NADP ratio, reduced the intracellular redox environment, and inhibited mitochondrial respiratory activity. The addition of 0.2-5 mM NaHS for 4 h increased the IEC-18 proliferative cell fraction (P<0.05), as evidenced by analysis of the cell cycle and proliferating cell nuclear antigen expression, while apoptosis occurred only at the highest concentration of NaHS. Thirty minutes of NaHS exposure increased (P<0.05) c-Jun mRNA concentrations, consistent with the observed activation of mitogen activated protein kinases (MAPK). Microarray analysis confirmed an increase (P<0.05) in MAPK-mediated proliferative activity, likely reflecting the reduced redox environment of NaHS-treated cells. These data identify functional pathways by which H2S may initiate epithelial dysregulation and thereby contribute to UC or colorectal cancer. Thus, it becomes crucial to understand how genetic background may affect epithelial responsiveness to this bacterial-derived environmental insult.
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PMID:Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells. 1273 7

The molecular mechanisms driving angiogenesis in tissues derived from embryonic stem (ES) cells are currently unknown. Herein we investigated the effects of direct current (DC) electrical field treatment on endothelial cell differentiation and angiogenesis of mouse ES cells. Treatment of ES cell-derived embryoid bodies with field strengths ranging from 250 V/m to 750 V/m, applied for 60 s, dose-dependently increased the capillary area staining positive for the endothelial-specific marker platelet endothelial cell adhesion molecule-1 (PECAM-1), indicating stimulation of endothelial cell differentiation and angiogenesis. Consequently, increased expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) within 24 h was observed. Electric field treatment raised reactive oxygen species (ROS) generation for at least 48 h, which was blunted by NADPH-oxidase inhibitors diphenylen iodonium chloride (DPI) as well as 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), and increased the expression of NADPH-oxidase subunits p22-phox, p47-phox, p67-phox, and gp91-phox within 24 h. Electrical field treatment resulted in activation of extracellular regulated kinase 1,2 (ERK1,2), p38, as well as c-Jun NH2-terminal kinase (JNK). Pretreatment with the JNK inhibitor SP600125 resulted in a significant decrease in capillary areas under control conditions as well as under conditions of electrical field treatment, whereas the p38 inhibitor SB203580 was without effects. By contrast, the ERK1,2 antagonist UO126 inhibited electrical field-induced angiogenesis, whereas angiogenesis under control conditions was unimpaired. The increase in capillary areas and VEGF expression as well as activation of JNK and ERK1,2 was significantly inhibited in the presence of the free radical scavenger vitamin E underscoring the role of ROS in electrical field-induced angiogenesis of ES cells.
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PMID:Redox control of angiogenic factors and CD31-positive vessel-like structures in mouse embryonic stem cells after direct current electrical field stimulation. 1574 85

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91phox (Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47phox. gp91phox (Nox 2) and p47phox were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta). These inhibitors and p47phox protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCzeta are upstream events of the CD95L-induced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to N-acetylcysteine, inhibitors of NADPH oxidase, PKCzeta, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCzeta, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47phox, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCzeta-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation.
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PMID:Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. 1591 50

Epidermal growth factor (EGF) is a survival signal for transforming growth factor-beta (TGF-beta)-induced apoptosis in hepatocytes, phosphatidylinositol 3-kinase (PI 3-K) being involved in this effect. Here, we analyze the possible cross talks between EGF and TGF-beta signals to understand how EGF impairs the early pro-apoptotic events induced by TGF-beta. Data have indicated that neither SMAD nor c-Jun NH2 Terminal Kinase (JNK) activations are altered by EGF, which clearly interferes with events directly related to the radical oxygen species (ROS) production, impairing oxidative stress, p38 MAP kinase activation, and cell death. Activation of a NADPH-oxidase-like system, which is responsible for the early ROS production by TGF-beta, is completely inhibited by EGF, through a PI 3-K-dependent mechanism. Activity of RAC1 increases by TGF-beta, but also by EGF, and both act synergistically to get maximum effects. Fetal rat hepatocytes express nox4, in addition to nox1 and nox2, and TGF-beta clearly upregulates nox4. EGF blocks up-regulation of nox4 by TGF-beta. Interestingly, in the presence of PI 3-K inhibitors, EGF is not able to counteract the nox4 upregulation by TGF-beta. Taking together these results indicate that impairment of TGF-beta-induced NADPH oxidase activation by EGF is a RAC1-independent process and correlates with an inhibition of the mechanisms that address the increase of nox4 mRNA levels by TGF-beta.
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PMID:EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. 1633 83

The AP-1 transcription factor modulates a wide range of cellular processes, including cellular proliferation, programmed cell death, and survival. JunD is a major component of the AP-1 complex following liver ischemia/reperfusion (I/R) injury; however, its precise function in this setting remains unclear. We investigated the functional significance of JunD in regulating AP-1 transcription following partial lobar I/R injury to the liver, as well as the downstream consequences for hepatocellular remodeling. Our findings demonstrate that JunD plays a protective role, reducing I/R injury to the liver by suppressing acute transcriptional activation of AP-1. In the absence of JunD, c-Jun phosphorylation and AP-1 activation in response to I/R injury were elevated, and this correlated with increased caspase activation, injury, and alterations in hepatocyte proliferation. The expression of dominant negative JNK1 inhibited c-Jun phosphorylation, AP-1 activation, and hepatic injury following I/R in JunD-/- mice but, paradoxically, led to an enhancement of AP-1 activation and liver injury in JunD+/- littermates. Enhanced JunD/JNK1-dependent liver injury correlated with the acute induction of diphenylene iodonium-sensitive NADPH-dependent superoxide production by the liver following I/R. In this context, dominant negative JNK1 expression elevated both Nox2 and Nox4 mRNA levels in the liver in a JunD-dependent manner. These findings suggest that JunD counterbalances JNK1 activation and the downstream redox-dependent hepatic injury that results from I/R, and may do so by regulating NADPH oxidases.
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PMID:JunD protects the liver from ischemia/reperfusion injury by dampening AP-1 transcriptional activation. 1818 93

Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating "binge" cocaine administration (milligrams per kilogram): days 1 to 4 at 3 x 15 mg, days 5 to 8 at 3 x 20 mg, days 9 to 12 at 3 x 25 mg, and days 13 to 14 at 3 x 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent O(2)(.) production (1.96- +/- 0.4-fold) as detected by tiron (an O(2)(.) scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases ( approximately 2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22(phox), p67(phox), p47(phox), p40(phox), and Rac1, and in p47(phox) phosphorylation as detected by immunoblotting (all p < 0.03). Increased Nox2 activity was accompanied by the activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH(2)-terminal kinase, notably in the cardiomyocytes. Cell culture experiments revealed that cocaine-induced ROS production was primarily a direct action of cocaine on cardiac myocytes, which caused severe oxidative damage to myocytes and cell death as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. These could be inhibited by inhibitors to protein kinase C (bisindolymaleimide) or by depletion of Nox2 using small interfering RNA. In conclusion, chronic cocaine administration directly causes severe myocardial oxidative stress through the activation of Nox2 oxidase. Increased ROS production contributes to MAPK activation and the subsequent myocyte damage. Inhibitors to NADPH oxidase or antioxidants may have therapeutic potential in the treatment of cocaine cardiotoxicity.
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PMID:Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase. 1895 86

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
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PMID:Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. 1971 31


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