Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nrf2 is the regulator of the oxidative/electrophilic stress response. Its turnover is maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge and latch. The E3 ligase adaptor Keap1 recognizes Nrf2 through its conserved ETGE and DLG motifs. In this study, we examined how the ETGE and DLG motifs bind to Keap1 in a very similar fashion but with different binding affinities by comparing the crystal complex of a Keap1-DC domain-DLG peptide with that of a Keap1-DC domain-ETGE peptide. We found that these two motifs interact with the same basic surface of either Keap1-DC domain of the Keap1 homodimer. The DLG motif works to correctly position the lysines within the Nrf2 Neh2 domain for efficient ubiquitination. Together with the results from calorimetric and functional studies, we conclude that different electrostatic potentials primarily define the ETGE and DLG motifs as a hinge and latch that senses the oxidative/electrophilic stress.
Mol Cell Biol 2007 Nov
PMID:Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. 1778 52

Parkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S beta5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S beta5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.
Hum Mol Genet 2007 Dec 01
PMID:Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice. 1782 2

3H-1,2-Dithiole-3-thione (D3T), a potent member of dithiolethiones, induces phase 2 enzymes by activating an Nrf2/Keap1-dependent signaling pathway. It was proposed that interaction between D3T and two adjacent sulfhydryl groups of Keap1 might cause dissociation of Keap1 from Nrf2, leading to Nrf2 activation. This study was undertaken to investigate the reactions between D3T and thiols, including the dithiol compound, dithiothreitol (DTT), and the monothiol, glutathione (GSH). We reported here that under physiologically relevant conditions incubation of D3T with DTT caused remarkable oxygen consumption, indicating a redox reaction between D3T and the dithiol molecule. Incubation of D3T with GSH also led to oxygen consumption, but to a less extent. Electron paramagnetic resonance (EPR) studies showed that the redox reaction between D3T and DTT generated superoxide. Superoxide was also formed from the redox reaction of D3T with GSH. These findings demonstrate that D3T reacts with thiols, particularly a dithiol, generating superoxide, which may provide a mechanistic explanation for induction of Nrf2-dependent phase 2 enzymes by D3T.
Mol Cell Biochem 2008 Jan
PMID:Generation of superoxide from reaction of 3H-1,2-dithiole-3-thione with thiols: implications for dithiolethione chemoprotection. 1789 50

Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. We attempted to clarify the association of these polymorphisms with the development of peptic ulcer diseases. The study was performed with 384 stocked DNAs obtained from subjects with no evidence of gastric malignancy. In all 384 DNAs, 77 and 48 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and the -686/-684 G/G carrier (OR, 2.52; 95% CI, 1.19-5.45; p=0.016) were associated with a significantly increased risk for developing gastric ulcer, whereas the -686/-684 A/G homozygote was linked to a significantly reduced risk for developing gastric ulcer (OR, 0.26; 95% CI, 0.099-0.67; p=0.0055). On the other hand, infection with H. pylori and male gender were significantly associated with the development of duodenal ulcer, whereas Nrf2 promoter polymorphisms were not. By the analysis, after adjustment for age, gender, non-steroidal anti-inflammatory drug/aspirin use and H. pylori infection status, the -686/-684 A/G homozygote was associated with a significantly reduced risk for gastric ulcer (OR, 0.25; 95% CI, 0.088-0.73; p=0.011). Our results suggest that promoter polymorphisms of the Nrf2 gene are associated with the susceptibility to gastric ulcer.
Int J Mol Med 2007 Dec
PMID:Association between promoter polymorphisms of nuclear factor-erythroid 2-related factor 2 gene and peptic ulcer diseases. 1798 93

As part of a comprehensive survey of the impact of the environmental pollutant and hepatocarcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the proteome of hepatic cells, we have performed a high resolution two-dimensional gel electrophoresis study on the rat hepatoma cell line 5L. 78 protein species corresponding to 73 different proteins were identified as up- or down-regulated following exposure of the cells to 1 nm TCDD for 8 h. There was an overlap of only nine proteins with those detected as altered by TCDD in our recent study using the non-gel-based isotope-coded protein label method (Sarioglu, H., Brandner, S., Jacobsen, C., Meindl, T., Schmidt, A., Kellermann, J., Lottspeich, F., and Andrae, U. (2006) Quantitative analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome alterations in 5L rat hepatoma cells using isotope-coded protein labels. Proteomics 6, 2407-2421) indicating a strong complementarity of the two approaches. For the majority of the altered proteins, an effect of TCDD on their abundance or posttranslational modifications had not been known before. Several observations suggest that a sizable fraction of the proteins with altered abundance was induced as an adaptive response to TCDD-induced oxidative stress that was demonstrated using the fluorescent probe dihydrorhodamine 123. A prominent group of these proteins comprised various enzymes for which there is evidence that their expression is regulated via the Keap1/Nrf2/antioxidant response element pathway. Other proteins included several involved in the maintenance of mitochondrial energy production and the regulation of the mitochondrial apoptotic pathway. A particularly intriguing finding was the up-regulation of the mitochondrial outer membrane pore protein, voltage-dependent anion channel-selective protein 2 (VDAC2), which was dependent on the presence of a functional aryl hydrocarbon receptor. The regulatability of VDAC2 protein abundance has not been described previously. In view of the recently discovered central role of VDAC2 as an inhibitor of the activation of the proapoptotic protein BAK and the mitochondrial apoptotic pathway, the present data point to a hitherto unrecognized mechanism by which TCDD may affect cellular homeostasis and survival.
Mol Cell Proteomics 2008 Feb
PMID:Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome changes in 5L rat hepatoma cells reveals novel targets of dioxin action including the mitochondrial apoptosis regulator VDAC2. 1799 43

Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated aldehyde present in cigarette smoke and also a product of lipid peroxidation. In this investigation we studied HO-1 induction in response to acrolein and determined the signaling pathways involved in human bronchial epithelial cells (HBE1 cells). We demonstrated that acrolein significantly increased the HO-1 mRNA content and promoter activity. Acrolein-mediated HO-1 induction was significantly attenuated by pan-protein kinase C (PKC) inhibitors RO318220, staurosporine, and PKC-delta selective inhibitor rottlerin and PKC-delta small interfering RNA. The HO-1 induction was also decreased by phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. No significant effects on HO-1 induction were observed with the pretreatment of mitogen-activated protein kinase pathway inhibitors PD98059 (ERK), SB203580 (p38MAPK) and JNKi, and conventional and atypical PKC inhibitors. Furthermore, Nrf2 silencing significantly attenuated the HO-1 induction by acrolein. Inhibition of PKC-delta significantly decreased acrolein-mediated Nrf2 nuclear translocation, though inhibition of PI3K had no effect. Taken together, our results indicate that acrolein up-regulates HO-1 expression through both PKC-delta and PI3K pathways in HBE1 cells; PKC-delta appears to regulate HO-1 induction via modulating Nrf2 nuclear translocation, while PI3K may work through targeting on downstream signaling molecules other than Nrf2.
Am J Respir Cell Mol Biol 2008 Apr
PMID:Acrolein induces heme oxygenase-1 through PKC-delta and PI3K in human bronchial epithelial cells. 1804 4

Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction, but its specific pathomechanism remains unknown. Thus, we performed a systematic expression profiling of genes by microarray analysis in the acute phase and after functional recovery. We studied 3 female patients presenting with TTC. Complementary RNA was isolated from left ventricular biopsies taken in the acute phase (group A) and after functional recovery (group B). It was profiled for gene expression using cDNA microarrays. Functionally related genes were determined with the Gene Set Enrichment Analysis (GSEA) bioinformatic tool. Validation of selected genes was performed by means of real-time PCR and immunohistochemistry. In group A, different functional gene sets, such as Nrf2-induced genes, triggered by oxidative stress, and protein biosynthesis were significantly overrepresented among the upregulated targets. Increased transcription of GPX1, CAT, RPS6, and eIF4E was confirmed by RT-PCR. The targets of the Akt/PKB signaling showed significant upregulation in both groups. Immunohistochemistry showed that the downstream targets NF-kappaB and BcL-X(L) are upregulated and activated. Gene sets involved in energy metabolism (oxidative phosphorylation, mitochondrial genes) showed no differences in group A but were overexpressed in group B. This study demonstrated a significant contribution of oxidative stress to the pathomechanism of TTC; it is possibly triggered by excess catecholamine. Increased protein biosynthesis and an activated cell survival cascade can be interpreted as potential compensatory mechanisms. After functional recovery, processes involved in energy metabolism play a pivotal role, thereby potentially contributing to the normalization of contractile function.
J Mol Cell Cardiol 2008 Feb
PMID:Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy: insight into a new cardiac entity. 1805 41

We show that the synthetic oleanane triterpenoid, CDDO-methyl ester (CDDO-Me; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate) is an effective agent for suppressing angiogenesis, both in cell culture and in vivo. The potency of CDDO-Me is particularly striking when dosed in vivo to inhibit the angiogenic effects of vascular endothelial growth factor and tumor necrosis factor-alpha in Matrigel sponge assays; activity is seen at i.p. doses of CDDO-Me as low as 0.003 mg/kg of body weight. If the Matrigel sponges are impregnated with CDDO-Me just before implantation in the mice, picomolar doses of CDDO-Me will suppress angiogenesis. CDDO-Me also inhibits growth of endothelial cells in monolayer cultures and suppresses neovascular morphogenesis in three-dimensional cultures, but significantly higher doses (50-200 nmol/L) are required. We also show antiangiogenic effects of CDDO-Me on xenografts of Kaposi's sarcoma cells in immunocompromised mice, using CD31 as a marker. Several known individual molecular targets of CDDO-Me and related triterpenoids that are relevant to all of these findings include nuclear factor-kappaB signaling, signal transducers and activators of transcription signaling, and transforming growth factor-beta signaling, as well as Keap1, the endogenous inhibitor of the transcription factor Nrf2. However, the particularly potent antiangiogenic activity seen in vivo in the present experiments suggest that CDDO-Me, as an angioprevention agent, may be interacting with an entire network of molecular and cellular targets, rather than at a single molecular locus or in a single-cell type.
Mol Cancer Ther 2007 Dec
PMID:The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. 1806 92

Oxidative injury has been found to be associated with proteasomal inactivity. In this study, the extent of oxidative damage and its effects on proteasomal function has been critically assessed. Left anterior descending coronary artery was occluded (ischemia) and reperfused with or without preconditioning in male Sprague-Dawley rats. For further validation, H9c2 cardiac myoblasts cultures were used. We demonstrate that ischemia-reperfusion causes extensive endoplasmic reticulum stress as evident from the degradation of GRP78 transcript followed by its rapid induction. Western blot analysis and immunohistochemistry showed that increasing duration of ischemia and reperfusion causes accumulation of phosphorylated IkappaB (p-IkappaB), thereby suggesting proteasomal inactivity. However, similar analysis for Nrf2, a key mediator of antioxidant defense, showed sustained activation, suggesting intact proteasomal function. Preconditioning of the myocardium preserves the degradation of p-IkappaB, suggesting effective functioning of proteasome after preconditioning. Further analysis with specific proteosomal inhibitors like epoxomicin (100 nM, inhibits chymotrypsin-like activities of proteasomes) and lactacystin (2 microM, inhibits chymotrypsin as well as some trypsin-like activities of proteasomes) suggests that degradation of p-IkappaB and Keap-1 in the proteasome occurs by independent mechanisms. This study gives further insight into interrelationship between oxidative injury and catalytic function of the proteasome in heart, where oxidative injury causes selective rather than global inhibition of proteasome.
J Mol Cell Cardiol 2008 Feb
PMID:Oxidative injury induces selective rather than global inhibition of proteasomal activity. 1807 53

Cigarette smoking, which exposes the lung to high concentrations of reactive oxidant species (ROS) is the major risk factor for chronic obstructive pulmonary disease (COPD). Recent studies indicate that ROS interfere with protein folding in the endoplasmic reticulum and elicit a compensatory response termed the "unfolded protein response" (UPR). The importance of the UPR lies in its ability to alter expression of a variety of genes involved in antioxidant defense, inflammation, energy metabolism, protein synthesis, apoptosis, and cell cycle regulation. The present study used comparative proteomic technology to test the hypothesis that chronic cigarette smoking induces a UPR in the human lung. Studies were performed on lung tissue samples obtained from three groups of human subjects: nonsmokers, chronic cigarette smokers, and ex-smokers. Proteomes of lung samples from chronic cigarette smokers demonstrated 26 differentially expressed proteins (20 were up-regulated, 5 were down-regulated, and 1 was detected only in the smoking group) compared with nonsmokers. Several UPR proteins were up-regulated in smokers compared with nonsmokers and ex-smokers, including the chaperones, glucose-regulated protein 78 (GRP78) and calreticulin; a foldase, protein disulfide isomerase (PDI); and enzymes involved in antioxidant defense. In cultured human airway epithelial cells, GRP78 and the UPR-regulated basic leucine zipper, transcription factors, ATF4 and Nrf2, which enhance expression of important anti-oxidant genes, increased rapidly (< 24 h) with cigarette smoke extract. These data indicate that cigarette smoke induces a UPR response in the human lung that is rapid in onset, concentration dependent, and at least partially reversible with smoking cessation. We speculate that activation of a UPR by cigarette smoke may protect the lung from oxidant injury and the development of COPD.
Am J Respir Cell Mol Biol 2008 May
PMID:Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. 1807 89


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