Mechanisms of signal transduction mediated by oxidized lipids: the role of the electrophile-responsive proteome

2004 ◽  
Vol 32 (1) ◽  
pp. 151-155 ◽  
Author(s):  
E.K. Ceaser ◽  
D.R. Moellering ◽  
S. Shiva ◽  
A. Ramachandran ◽  
A. Landar ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cell Signalling ◽  
Antioxidant Response ◽  
Oxidized Lipids ◽  
Reaction Products ◽  
Adaptive Responses ◽  
Post Translational Modification ◽  
Promoter Regions ◽  
Antioxidant Defences ◽  
Electrophilic Lipids

Cellular redox signalling is mediated by the post-translational modification of proteins by reactive oxygen/nitrogen species or the products derived from their reactions. In the case of oxidized lipids, several receptor-dependent and -independent mechanisms are now emerging. At low concentrations, adaptation to oxidative stress in the vasculature appears to be mediated by induction of antioxidant defences, including the synthesis of the intracellular antioxidant glutathione. At high concentrations apoptosis occurs through mechanisms that have yet to be defined in detail. Recent studies have revealed a mechanism through which electrophilic lipids, formed as the reaction products of oxidation, orchestrate these adaptive responses in the vasculature. Using a proteomics approach, we have identified a subset of proteins in cells that we term the electrophile-responsive proteome. Electrophilic modification of thiol groups in these proteins can initiate cell signalling events through the transcriptional activation of genes regulated by consensus sequences for the antioxidant response element found in their promoter regions. The insights gained from our understanding of the biology of these mechanisms will be discussed in the context of cardiovascular disease.

Redox signalling: from nitric oxide to oxidized lipids

2004 ◽  
Vol 71 ◽  
pp. 107-120 ◽  
Author(s):  
Sruti Shiva ◽  
Doug Moellering ◽  
Anup Ramachandran ◽  
Anna-Liisa Levonen ◽  
Aimee Landar ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Conformational Changes ◽  
Soluble Guanylate Cyclase ◽  
Cell Signalling ◽  
Oxidation Reactions ◽  
Reaction Products ◽  
Adaptive Responses ◽  
Post Translational Modification ◽  
Redox Signalling ◽  
Electrophilic Lipids

Cellular redox signalling is mediated by the post-translational modification of proteins in signal-transduction pathways by ROS/RNS (reactive oxygen species/reactive nitrogen species) or the products derived from their reactions. NO is perhaps the best understood in this regard with two important modifications of proteins known to induce conformational changes leading to modulation of function. The first is the addition of NO to haem groups as shown for soluble guanylate cyclase and the newly discovered NO/cytochrome c oxidase signalling pathway in mitochondria. The second mechanism is through the modification of thiols by NO to form an S-nitrosated species. Other ROS/RNS can also modify signalling proteins although the mechanisms are not as clearly defined. For example, electrophilic lipids, formed as the reaction products of oxidation reactions, orchestrate adaptive responses in the vasculature by reacting with nucleophilic cysteine residues. In modifying signalling proteins ROS/RNS appear to change the overall activity of signalling pathways in a process that we have termed 'redox tone'. In this review, we discuss these different mechanisms of redox cell signalling, and give specific examples of ROS/RNS participation in signal transduction.

Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium

2005 ◽  
Vol 33 (6) ◽  
pp. 1385-1389 ◽  
Author(s):  
J.W. Zmijewski ◽  
A. Landar ◽  
N. Watanabe ◽  
D.A. Dickinson ◽  
N. Noguchi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Oxidation ◽  
Protein Function ◽  
Cell Signalling ◽  
Reactive Oxygen ◽  
Oxidation Products ◽  
Oxidized Lipids ◽  
Oxygen Species ◽  
Post Translational Modification ◽  
Lipid Oxidation Products

The controlled formation of ROS (reactive oxygen species) and RNS (reactive nitrogen species) is now known to be critical in cellular redox signalling. As with the more familiar phosphorylation-dependent signal transduction pathways, control of protein function is mediated by the post-translational modification at specific amino acid residues, notably thiols. Two important classes of oxidant-derived signalling molecules are the lipid oxidation products, including those with electrophilic reactive centres, and decomposition products such as lysoPC (lysophosphatidylcholine). The mechanisms can be direct in the case of electrophiles, as they can modify signalling proteins by post-translational modification of thiols. In the case of lysoPC, it appears that secondary generation of ROS/RNS, dependent on intracellular calcium fluxes, can cause the secondary induction of H2O2 in the cell. In either case, the intracellular source of ROS/RNS has not been defined. In this respect, the mitochondrion is particularly interesting since it is now becoming apparent that the formation of superoxide from the respiratory chain can play an important role in cell signalling, and oxidized lipids can stimulate ROS formation from an undefined source. In this short overview, we describe recent experiments that suggest that the cell signalling mediated by lipid oxidation products involves their interaction with mitochondria. The implications of these results for our understanding of adaptation and the response to stress in cardiovascular disease are discussed.

scholarly journals Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products

2004 ◽  
Vol 378 (2) ◽  
pp. 373-382 ◽  
Author(s):  
Anna-Liisa LEVONEN ◽  
Aimee LANDAR ◽  
Anup RAMACHANDRAN ◽  
Erin K. CEASER ◽  
Dale A. DICKINSON ◽  
...  
Keyword(s):  
Lipid Oxidation ◽  
Molecular Mechanisms ◽  
Intact Cell ◽  
Cell Signalling ◽  
Oxidation Products ◽  
Oxidized Lipids ◽  
Related Factor ◽  
Lipid Oxidation Products ◽  
Electrophilic Lipids ◽  
Prostaglandin J2

The molecular mechanisms through which oxidized lipids and their electrophilic decomposition products mediate redox cell signalling is not well understood and may involve direct modification of signal-transduction proteins or the secondary production of reactive oxygen or nitrogen species in the cell. Critical in the adaptation of cells to oxidative stress, including exposure to subtoxic concentrations of oxidized lipids, is the transcriptional regulation of antioxidant enzymes, many of which are controlled by antioxidant-responsive elements (AREs), also known as electrophile-responsive elements. The central regulator of the ARE response is the transcription factor Nrf2 (NF-E2-related factor 2), which on stimulation dissociates from its cytoplasmic inhibitor Keap1, translocates to the nucleus and transactivates ARE-dependent genes. We hypothesized that electrophilic lipids are capable of activating ARE through thiol modification of Keap1 and we have tested this concept in an intact cell system using induction of glutathione synthesis by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2. On exposure to 15-deoxy-Δ12,14-prostaglandin J2, the dissociation of Nrf2 from Keap1 occurred and this was dependent on the modification of thiols in Keap1. This mechanism appears to encompass other electrophilic lipids, since 15-A2t-isoprostane and the lipid aldehyde 4-hydroxynonenal were also shown to modify Keap1 and activate ARE. We propose that activation of ARE through this mechanism will have a major impact on inflammatory situations such as atherosclerosis, in which both enzymic as well as non-enzymic formation of electrophilic lipid oxidation products are increased.

ZFARED: A Database of the Antioxidant Response Elements in Zebrafish

2020 ◽  
Vol 15 (5) ◽  
pp. 415-419
Author(s):  
Azhwar Raghunath ◽  
Raju Nagarajan ◽  
Ekambaram Perumal
Keyword(s):  
Target Genes ◽  
Antioxidant Response ◽  
Zebrafish Genome ◽  
Promoter Regions ◽  
Protein Coding ◽  
Response Elements ◽  
Toxic Agents ◽  
Upstream Promoter ◽  
Its Gene ◽  
Antioxidant Response Elements

Background: Antioxidant Response Elements (ARE) play a key role in the expression of Nrf2 target genes by regulating the Keap1-Nrf2-ARE pathway, which offers protection against toxic agents and oxidative stress-induced diseases. Objective: To develop a database of putative AREs for all the genes in the zebrafish genome. This database will be helpful for researchers to investigate Nrf2 regulatory mechanisms in detail. Methods: To facilitate researchers functionally characterize zebrafish AREs, we have developed a database of AREs, Zebrafish Antioxidant Response Element Database (ZFARED), for all the protein-coding genes including antioxidant and mitochondrial genes in the zebrafish genome. The front end of the database was developed using HTML, JavaScript, and CSS and tested in different browsers. The back end of the database was developed using Perl scripts and Perl-CGI and Perl- DBI modules. Results: ZFARED is the first database on the AREs in zebrafish, which facilitates fast and efficient searching of AREs. AREs were identified using the in-house developed Perl algorithms and the database was developed using HTML, JavaScript, and Perl-CGI scripts. From this database, researchers can access the AREs based on chromosome number (1 to 25 and M for mitochondria), strand (positive or negative), ARE pattern and keywords. Users can also specify the size of the upstream/promoter regions (5 to 30 kb) from transcription start site to access the AREs located in those specific regions. Conclusion: ZFARED will be useful in the investigation of the Keap1-Nrf2-ARE pathway and its gene regulation. ZFARED is freely available at http://zfared.buc.edu.in/.

scholarly journals Epigenetic Regulation of Skeletal Tissue Integrity and Osteoporosis Development

2020 ◽  
Vol 21 (14) ◽  
pp. 4923
Author(s):  
Yu-Shan Chen ◽  
Wei-Shiung Lian ◽  
Chung-Wen Kuo ◽  
Huei-Jing Ke ◽  
Shao-Yu Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Formation ◽  
Histone Modification ◽  
Skeletal Development ◽  
Premature Death ◽  
Protein Translation ◽  
Bone Homeostasis ◽  
Post Translational Modification ◽  
Promoter Regions ◽  
Processing Enzymes

Bone turnover is sophisticatedly balanced by a dynamic coupling of bone formation and resorption at various rates. The orchestration of this continuous remodeling of the skeleton further affects other skeletal tissues through organ crosstalk. Chronic excessive bone resorption compromises bone mass and its porous microstructure as well as proper biomechanics. This accelerates the development of osteoporotic disorders, a leading cause of skeletal degeneration-associated disability and premature death. Bone-forming cells play important roles in maintaining bone deposit and osteoclastic resorption. A poor organelle machinery, such as mitochondrial dysfunction, endoplasmic reticulum stress, and defective autophagy, etc., dysregulates growth factor secretion, mineralization matrix production, or osteoclast-regulatory capacity in osteoblastic cells. A plethora of epigenetic pathways regulate bone formation, skeletal integrity, and the development of osteoporosis. MicroRNAs inhibit protein translation by binding the 3′-untranslated region of mRNAs or promote translation through post-transcriptional pathways. DNA methylation and post-translational modification of histones alter the chromatin structure, hindering histone enrichment in promoter regions. MicroRNA-processing enzymes and DNA as well as histone modification enzymes catalyze these modifying reactions. Gain and loss of these epigenetic modifiers in bone-forming cells affect their epigenetic landscapes, influencing bone homeostasis, microarchitectural integrity, and osteoporotic changes. This article conveys productive insights into biological roles of DNA methylation, microRNA, and histone modification and highlights their interactions during skeletal development and bone loss under physiological and pathological conditions.

scholarly journals Heat shock and titanium dioxide nanoparticles decrease superoxide dismutase and glutathione enzymes activities in Saccharomyces cerevisiae

2015 ◽  
Vol 4 (3) ◽  
Author(s):  
Joana Capela-Pires ◽  
Rui Ferreira ◽  
Isabel Alves-Pereira
Keyword(s):  
Oxidative Stress ◽  
Titanium Dioxide Nanoparticles ◽  
Antioxidant Response ◽  
Engineered Nanoparticles ◽  
Eukaryotic Cells ◽  
Oxygen Species ◽  
Antioxidant Defences ◽  
Intensive Use ◽  
Living Organisms ◽  
Glutathione Enzymes

AbstractThe exposure of living organisms to metals can generate reactive oxygen species and failure in their antioxidant defences, triggering oxidative stress and oxidative damage. Despite the intensive use of engineered nanoparticles in numerous consumer and industrial products, data on their potential hazards in eukaryotic cells and their dependence on environmental factors such as temperature are still scarce. The aim of this study was to evaluate the antioxidant response of

Measurement and meaning of markers of reactive species of oxygen, nitrogen and sulfur in healthy human subjects and patients with inflammatory joint disease

2011 ◽  
Vol 39 (5) ◽  
pp. 1226-1232 ◽  
Author(s):  
Paul G. Winyard ◽  
Brent Ryan ◽  
Paul Eggleton ◽  
Ahuva Nissim ◽  
Emma Taylor ◽  
...  
Keyword(s):  
Human Subjects ◽  
Cell Signalling ◽  
Type Ii Collagen ◽  
Reactive Species ◽  
Joint Disease ◽  
Protein Damage ◽  
Antioxidant Defences ◽  
Healthy Human ◽  
Resting Blood Pressure ◽  
Plasma Nitrite

Reactive species of oxygen, nitrogen and sulfur play cell signalling roles in human health, e.g. recent studies have shown that increased dietary nitrate, which is a source of RNS (reactive nitrogen species), lowers resting blood pressure and the oxygen cost of exercise. In such studies, plasma nitrite and nitrate are readily determined by chemiluminescence. At sites of inflammation, such as the joints of RA (rheumatoid arthritis) patients, the generation of ROS (reactive oxygen species) and RNS overwhelms antioxidant defences and one consequence is oxidative/nitrative damage to proteins. For example, in the inflamed joint, increased RNS-mediated protein damage has been detected in the form of a biomarker, 3-nitrotyrosine, by immunohistochemistry, Western blotting, ELISAs and MS. In addition to NO•, another cell-signalling gas produced in the inflamed joint is H2S (hydrogen sulfide), an RSS (reactive sulfur species). This gas is generated by inflammatory induction of H2S-synthesizing enzymes. Using zinc-trap spectrophotometry, we detected high (micromolar) concentrations of H2S in RA synovial fluid and levels correlated with clinical scores of inflammation and disease activity. What might be the consequences of the inflammatory generation of reactive species? Effects on inflammatory cell-signalling pathways certainly appear to be crucial, but in the current review we highlight the concept that ROS/RNS-mediated protein damage creates neoepitopes, resulting in autoantibody formation against proteins, e.g. type-II collagen and the complement component, C1q. These autoantibodies have been detected in inflammatory autoimmune diseases.

scholarly journals Aryl Hydrocarbon Receptor-Mediated Transcription: Ligand-Dependent Recruitment of Estrogen Receptor α to 2,3,7,8-Tetrachlorodibenzo- p-Dioxin-Responsive Promoters

2005 ◽  
Vol 25 (13) ◽  
pp. 5317-5328 ◽  
Author(s):  
Jason Matthews ◽  
Björn Wihlén ◽  
Jane Thomsen ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Aryl Hydrocarbon Receptor ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Time Course ◽  
Estrogen Receptor Α ◽  
Time Dependent ◽  
Promoter Regions ◽  
Aryl Hydrocarbon ◽  
H3 Acetylation

ABSTRACT Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several coregulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor α (ERα) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by cotreatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ERα enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ERα to the estrogen-responsive pS2 promoter, and after 120 min of cotreatment with estradiol, ERα is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ERα in TCDD-dependent CYP1A1 expression. Our data suggest that ERα acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ERα by AhR represents a novel mechanism AhR-ERα cross talk.

Nitric oxide stimulates myoglobin gene and protein expression in vascular smooth muscle

2009 ◽  
Vol 423 (2) ◽  
pp. 169-177 ◽  
Author(s):  
Benjamin S. Rayner ◽  
Susan Hua ◽  
Tharani Sabaretnam ◽  
Paul K. Witting
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Viability ◽  
Transcriptional Activation ◽  
Cell Signalling ◽  
No Production ◽  
Parallel Increase ◽  
Signalling Molecule ◽  
Gene And Protein Expression

Mb (myoglobin) is a haemoprotein present in cardiac, skeletal and smooth muscle and is primarily responsible for the storage and ‘facilitated transfer’ of molecular oxygen from the cell membrane to mitochondria. Also, Mb plays a role in regulating •NO (nitric oxide) homoeostasis through (i) binding •NO (Mb–NO complex); (ii) oxidation of •NO to nitrate; and (iii) formation of vasoactive S-nitroso-Mb [Rayner, B.S., Wu, B.-J., Raftery, M., Stocker, R. and Witting, P.K. (2005) J. Biol. Chem. 280, 9985–9993]. Pathological •NO concentrations affect mitochondrial function and decrease cell viability through inducing apoptosis. Treatment of cultured rat VSMCs (vascular smooth muscle cells) with cumulative doses (0.1, 1 or 10 μM) of •NO from the donors diethylamineNONOate or spermineNONOate (N-[2-aminoethyl]-N-[2-hydroxy-3-nitrosohydrazine]-1,2-ethelenediamine) yielded a time-dependent increase in Mb gene expression. Concomitant transcriptional activation increased the concentration of Mb within cultured rat or primary human VSMCs as judged by Western blot analysis and indirect immunofluorescence microscopy. Cell viability did not decrease in these cells at the •NO doses tested. Importantly, sub-culturing isolated rat aortic segments for 7 days in the presence of L-arginine at 37 °C stimulated •NO production with a parallel increase in Mb in the underlying VSMCs. Overall, exposure of VSMCs (either in cell culture or intact vessels) to pathological •NO promotes an up-regulation of the Mb gene and protein, suggesting a feedback relationship between •NO and Mb that regulates the concentration of the potent cell signalling molecule in the vessel wall, similar to the role haemoglobin plays in the vessel lumen.

scholarly journals RR06 Activates Transcription of spr1996 and cbpA in Streptococcus pneumoniae

2007 ◽  
Vol 189 (6) ◽  
pp. 2497-2509 ◽  
Author(s):  
Zhuo Ma ◽  
Jing-Ren Zhang
Keyword(s):  
Streptococcus Pneumoniae ◽  
Transcriptional Activation ◽  
Protective Antigen ◽  
Response Regulator ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Conserved Sequence ◽  
Antibody Staining ◽  
Regulator Protein ◽  
Bacterial Replication

ABSTRACT Streptococcus pneumoniae colonizes at the nasopharynx of humans and is able to disseminate and cause various infections. The hallmark of pneumococcal disease is rapid bacterial replication in different tissue sites leading to intense inflammation. The genetic basis of pneumococcal adaptation to different host niches remains sketchy. In this study, we investigated the regulatory effect of RR06, a response regulator protein, on gene expression of S. pneumoniae. Microarray and Northern blot analyses showed that RR06 is specifically required for transcription of spr1996 and cbpA. While the function of Spr1996 is unknown, CbpA has been well characterized as a surface-exposed protective antigen and a virulence factor of S. pneumoniae. A recombinant form of RR06 was able to bind to a 19-bp conserved sequence shared by the spr1996 and cbpA promoter regions. Furthermore, inactivation of rr06 resulted in loss of CbpA expression as detected by antibody staining and bacterial adhesion. CbpA expression was restored in trans by the intact rr06 gene. However, a mutant, RR06(D51A), with a point mutation in the aspartate residue at position 51 (a predicted major phosphorylation site) of RR06, completely abolished the CbpA expression, suggesting that RR06 phosphorylation is required for transcriptional activation of spr1996 and cbpA. Finally, inactivation of rr06 in additional pneumococcal strains also led to the loss of CbpA expression. These data implicate that RR06 activates the expression of spr1996 and cbpA in many other pneumococcal strains.

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