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ROS and ROS-Mediated Cellular Signaling

ROS and ROS-Mediated Cellular Signaling Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 4350965, 18 pages http://dx.doi.org/10.1155/2016/4350965 Review Article 1 2 1 3 1 Jixiang Zhang, Xiaoli Wang, Vikash Vikash, Qing Ye, Dandan Wu, 1 1 Yulan Liu, and Weiguo Dong Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China Department of PlasticSurgery,RenminHospitalofWuhan University,Wuhan,Hubei 430060,China Department of Hospital Infection Office, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China Correspondence should be addressed to Weiguo Dong; dwg@whu.edu.cn Received 10 August 2015; Revised 1 December 2015; Accepted 20 December 2015 Academic Editor: Javier Egea Copyright © 2016 Jixiang Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS 2+ impacting on cell-signaling proteins (NF-𝜅 B, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System. 1. Introduction ROS act on cell-signaling proteins, how the cell-signaling proteins influence the level of intracellular ROS in turn, Reactive oxygen species (ROS), generated through a vari- and if there are complex interactions between different ROS ety of extracellular and intracellular actions, have drawn associated signaling pathways have been clarified, but the attention as novel signal mediators which are involved in systemic summary is necessary. In this review, we focus on growth, differentiation, progression, and death of the cell the pattern of the generation and homeostasis of intracellular [1, 2]. As a group of chemical species that include at least ROS, the mechanisms and targets of ROS impacting on oneoxygenatomineachmoleculebut displaystronger cell-signaling proteins, ion channels and transporters, and reactivity than molecular oxygen, ROS comprise free radicals modifying kinases and Ubiquitination/Proteasome System. such as superoxide, hydroxyl radical, and singlet oxygen, as well as nonradical species such as hydrogen peroxide 2. The Homeostasis of ROS formed by the partial reduction of oxygen [3–5]. Oxygen free radicals are highly reactive and have the capacity to damage Under a physiological state, the level of cellular ROS is stable cellular components such as proteins, lipids, and nucleic in a dynamic equilibrium, and this balance is modulated acids. Classically, ROS were regarded as host defending by cellular processes that produce ROS and eliminate them molecule released by neutrophil for destructing exogenous (Figure 1). pathogens such as bacteria; however, accumulated evidence The resource of cellular ROS could be broadly divided indicates that ROS play central roles in determination of cell into two main categories: firstly, there are those biological fate as second messengers and modifying of various signaling processes, mainly the mitochondrial oxidative metabolism, molecules [6–9]. that release ROS as a byproduct, or a waste product, of various It has been demonstrated that ROS have impacts on other necessary reactions and, secondly, there are those several signaling pathways and the mechanisms of how processes, in cellular response to xenobiotics, cytokines, and 2 Oxidative Medicine and Cellular Longevity TNF-𝛼 IL-1𝛽 TNFR IL-1R TRADD NOX TRAF2 NOX NOX RIP EGF PL Rac LPS MyD88 EGFR TLR Grb2 MyD88 Rac NOX SOS AA PKC ERK ROS CPLA2 Cu-Zn-SOD CPLA2 Mn-SOD GPx GST-pi MT3 FHC Mitochondria DDH Figure 1: Homeostasis of intracellular reactive oxygen species. NOX, NADPH oxidases; TNF-𝛼 , tumor necrosis factor-𝛼 ; EGF, epidermal growth factor; IL-1𝛽 , Interleukin-1𝛽 ; SOD, superoxide dismutase; GPx, glutathione peroxidase; GST-pi, glutathione S-transferase pi; MT3, metallothionein-3; FHC, ferritin heavy chain; DDH1, dihydrodiol dehydrogenase; TNFR, tumor necrosis factor receptor; TRADD, TNFRSF1A-associated via death domain; MyD88, myeloid differentiation factor 88; TLR, Toll-like receptor; cPLA2, cytosolic phospholipases A2. bacterial invasion, that generate ROS intentionally, either in (SOD1) and Mn-SOD (SOD2) [25]. SOD2, in the matrix, con- molecular synthesis or in breakdown, as part of a signal trans- verts superoxide, which cannot diffuse across membranes, to ductionpathway,oraspartofacell defense mechanism[10– H O which then is reduced to water by catalase. Compared 2 2 12]. The initial product of the mitochondrial respiratory chain to SOD2, SOD1 mainly reduces the superoxide of inter- −∙ is O mainly generated by complexes I and III and could membrane space and cytosol to H O . Besides, glutathione 2 2 2 be quickly transformed into H O by theenzymesuperoxide peroxidase (GPx), glutathione S-transferase pi (GST-pi), 2 2 dismutase (SOD) and then could be reduced to water by metallothionein-3 (MT3), ferritin heavy chain (FHC), and catalase or glutathione peroxidase [13–16]. NADPH oxidases dihydrodiol dehydrogenase (DDH1 or AKR1C1) and so on (Nox) including Nox1 to Nox5 and Duox1 and Duox2, which also play decisive roles in the process of antioxidant [26–29]. are classified into three groups, according to the presence of domains in addition to the gp91phox (NOX2) domain, 3. ROS and NF-𝜅 B Signaling Pathway are another important source of cellular ROS [17, 18]: NOX1, NOX3, and NOX4 are similar in size and domain structure The transcription factor NF- 𝜅 Biscrucial in aseriesofcel- to NOX2, catalyzing the NADPH-dependent reduction of lular processes, including immune, inflammatory response, oxygen to form superoxide, which can react with itself to cellular adhesion, differentiation, proliferation, autophagy, form H O ; NOX5 is slightly different in domain structure senescence, and apoptosis [30]. Likewise, the disorder of NF- 2 2 to NOX2 but with similar process of superoxide formation; 𝜅 Bhas alreadybeenconrfi medtobeassociatedwithcancer, Duox1 and Duox2 contain a peroxidase-homology domain, arthritis, inflammation, asthma, neurodegenerative diseases, utilizing ROS generated by the catalytic core to generate and heart disease [31]. The family of NF- 𝜅 BconsistsofRel more powerful oxidant species that then oxidize extracellular (c-Rel), RelA (p65), RelB, p50/p105 (NF-𝜅 B1), and p52/p100 substrates [19]. Meanwhile, external stimuli including tumor (NF-𝜅 B2). NF-𝜅 B pathway may be activated by at least two necrosis factor-𝛼 (TNF-𝛼 ), epidermal growth factor (EGF), distinct pathways named the canonical and noncanonical Interleukin-1𝛽 (IL-1𝛽 ), and hypoxia and irradiation also pathways. eTh canonical NF- 𝜅 B-activating pathway is trig- stimulate the formation of ROS [20–24]. gered in response to microbial products, stress, and proin- And, as a critical role to withstand the excessive formation flammatory cytokines and it depends on the phosphorylation of intracellular ROS, series of antioxidant proteins have been of I𝜅 B-kinase (IKK)𝛽 and the phosphorylation and ubiqui- found. The main category of these antioxidant proteins is tination of I𝜅 Ba and its degradation by the proteasome, and superoxide dismutases (SOD) which contain Cu-Zn-SOD then NF-𝜅 B translocates into the nucleus where it activates Oxidative Medicine and Cellular Longevity 3 the transcription of target genes [32–34]. In contrast, the Ras. Subsequently activated Ras recruits cytoplasmic Raf noncanonical NF-𝜅 B-activating pathway is activated by B- (MAPKKK) to the cell membrane for activation. Activated cell activating factor (BAFF) [35], lymphotoxin𝛽 (LT𝛽 )[36], Raf phosphorylates MEK1/2 (MAPKK), which then phos- CD40 ligand [37], CD27 ligand [38], human T-cell leukemia phorylates ERK1/2 (MAPK) that translocate to the nucleus virus (HTLV) [39], and Epstein-Barr virus (EBV) [40] and and activates several transcription factors [54, 55]. ROS have it relies on IKK𝛼 and causes activation of NF-𝜅 B2/RelB been showntoactivatethe receptorsofEGF andPDGF, complexes by inducing the proteolytic processing of the NF- though without corresponding ligands, which can stimulate 𝜅 B2/p100 precursor. Ras and the subsequent activation of ERK pathway [56, 57]. Recently, cumulative evidence has indicated that there In addition, it has been demonstrated that ROS generated by is an interrelation between ROS and NF-𝜅 B. Firstly, ROS commensal bacteria inactivated dual-specific phosphatase 3 influence the activation of NF- 𝜅 B pathway mainly by inhibit- (DUSP3) by oxidation on Cys-124 results in ERK activation O leads ing the phosphorylation of I𝜅 B𝛼 .Aseries of studieshas [58]. Meanwhile, in some cells, treatment with H 2 2 testiefi d that I 𝜅 B𝛼 is usually phosphorylated on serines 32 to the phosphorylation and activation of phospholipase C- and 36 by IKK leading to its ubiquitination and degradation (PLC-) gamma which results in the generation of inositol and exogenously added H O affects the phosphorylation of trisphosphate (IP3) and diacylglycerol (DAG) [59]. IP3 could 2 2 I𝜅 B𝛼 on Tyr42 or other tyrosine residues and subsequent increase the intracellular calcium by inducing the release of degradation of I𝜅 B𝛼 and activation of NF-𝜅 B pathway [41, calcium from intracellular stores that can mediate activation 42]. In addition, IKK is also the primary target for ROS in of ERK pathway and generation of DAG and increases in influencing NF- 𝜅 B and the S-glutathionylation of IKK𝛽 on intracellular calcium which results in the activation of several cysteine 179 by ROS results in the inhibition of IKK𝛽 activity forms of protein kinase C (PKC) leading to Ras and Raf [43]. en, Th MEKK1, the kinases upstream of IKK, may be activation [60, 61]. potentially regulated by ROS. MEKK1 is a redox-sensitive The JNK pathway is activated by environmental stress kinase that could be glutathionylated at C1238 leading to (oxidative stress) and cytokines (tumor necrosis factor, TNF, its inactivation [44]. Thirdly, ROS also could disturb the and FAS) and involves a kinase cascade similar to the ubiquitination and degradation of I𝜅 B and then the activation ERK pathway with a MAPKKK activating a MAPKK and of NF-𝜅 B by inactivating Ubc12. Furthermore, NIK, the the MAPKK subsequently phosphorylating JNK on critical upstream kinase in the noncanonical pathway, is believed threonine and tyrosine residues resulting in the activation of to be activated by ROS through inhibition of phosphatases JNK; aer ft wards JNK translocate to the nucleus and regulate and oxidation of cysteine residues [45, 46]. Meanwhile, NF- the activity of multiple transcription factors. eTh MAPKKK 𝜅 B pathway also can influence the ROS levels by increasing in JNK pathway includes MEKK1, MEKK2, MEKK3, and expression of antioxidant proteins such as Cu-Zn-SOD, Mn- MEKK4, MLK, and ASK1 and MAPKK contain MKK4, SOD, GPx, GST-pi, MT3, and FHC (Figure 2). MKK3, MKK6, and MKK7 [62, 63]. ROS could act on TRX and glutaredoxin, a kind of redox-sensitive proteins, to disso- 4. ROS and MAPKs Signaling Pathway ciate from ASK-1 for its activation, resulting in the activation of JNK [64]. Also, ROS could trigger the detachment of JNK The mitogen-activated protein kinase (MAPK) cascades, con- from glutathione S-transferase pi (GSTp), which can interact sisting of the extracellular signal-related kinases (ERK1/2), with JNK to suppress its activation, thereby facilitating JNK the c-Jun N-terminal kinases (JNK), the p38 kinase (p38), activation [65]. ROS could be able to allow ASK1 to be and the big MAP kinase 1 (BMK1/ERK5) pathway [47], are oligomerized and autophosphorylated and become activated major intracellular signal transduction pathways that play by oxidizing thioredoxin, which inhibits the activation of an important role in various cellular processes such as cell ASK1 via binding to the N-terminal of ASK1 [66]. TNF growth, differentiation, development, cell cycle, survival, and receptor-associated JNK activation is thought to be mediated cell death [48]. Similarly, ERK, JNK, p38, and BMK1 are in part by oxygen radicals because superoxide anion and lipid all serine/threonine kinases that are directed by a proline peroxide-scavengers inhibit JNK activation. Furthermore, residue. Along with the pathways in which these four MAP it is possible that low levels of ROS intermediates leave kinases are activated share similarity by extracellular or phosphatase activity intact, leading to a transient activation intracellular stimuli, a MAP kinase kinase kinase (MAPKKK) of JNK. Higher levels of ROS may activate JNK pathway is activated and then phosphorylating and activating a MAP and inactivate the phosphatases resulting in a prolonged kinase kinase (MAPKK) and the MAPKK phosphorylating activation of JNK (Figure 3). and activating a MAP kinase (MAPK) and activated MAPKs The p38 pathway is activated by extracellular stresses, phosphorylate various substrate proteins, resulting in regula- growth factor, and cytokines, such as tumor necrosis factor- tion of various cellular activities [49–51]. a (TNF-a) and IL-1𝛽 .TheTNF receptorsswitchonthe The ERK pathway is activated mainly by growth fac- p38 pathway via the activation of cdc42, whereas growth tors (epidermal growth factor, EGF, and platelet-derived factor receptors switch on the p38 pathway by the sequential growth factor, PDGF) and cytokines (IL-1𝛽 and TNF-𝛼 ), activation of Ras and Rac1 [67]. Small G-proteins Rac1 and its activation is related to the stimulation of tyrosine kinase receptors [52, 53]. When these receptors of growth andcdc42 activate ASK1,MLK3, andMLK3thatdirectly activate MKK3 and MKK6 which phosphorylates p38 on both factors and cytokines are bound with their ligands, the GDP bound Ras is converted to GTP that in turn activates tyrosine and threonine residue resulting in the activation of 4 Oxidative Medicine and Cellular Longevity ROS Noncanonical pathway Canonical pathway NIK MEKK1 IKK𝛼 IKK𝛼 IKK𝛽 IKK𝛼 C179 IKK𝛼 IKK𝛾 Mn-SOD IKK𝛼 IKK𝛽 IKK𝛼 Ox IKK𝛾 RelB p100 NEDD8 Ubc12 Rel B IKB𝛼 p100 RelA p50 IKB𝛼 RelB RelA p52 p50 Ub Ub RelB p100 Ub Ub Ub Ub P IKB𝛼 RelA p50 Degradation RelA p50 Figure 2: Cross talk between ROS and NF- 𝜅 B signaling pathway. MEKK1, mitogen-activated protein kinase kinase kinase 1; PKC, protein kinase C; NIK, NF-𝜅 B inducing kinase; NEDD8, neural precursor cell expressed developmentally downregulated 8. p38 pathway [68, 69]. Some initial proteins, such as ASK- downstream targets including Mef2C, c-Myc, and possibly 1, in the JNK pathway, are also involved in the activation of Nrf2 (Figure 3). the p38 pathway. Oxidative stress directly or indirectly aeff cts ASK1, MEKK1, MEKK2, MEKK3, MEKK4, and MLK3 and 5. ROS and Keap1-Nrf2-ARE subsequently activates p38 pathway (Figure 3). Signaling Pathway The BMK1 (also known as ERK5) pathway, which has been involved in cell survival, antiapoptotic signaling, angio- Another signaling pathway, Keap1-Nrf2-ARE, performs crit- genesis, cell motility, differentiation, and cell proliferation, ical role in maintaining the cellular redox balance and is one of the least studied members of the MAPK family metabolism andinducinganadaptiveresponsefor oxidative [70]. Oxidative stress (H O ) could influence BMK1 pathway stress that can otherwise lead to many inflammatory diseases 2 2 by activating MEKK2 and MEKK3 directly. en Th MEK5 including cancer, Alzheimer’s disease (AD), Parkinson’s dis- and BMK1 are activated sequentially and BMK1 acts on its ease (PD), and diabetes. This pathway consists of three main RelA p50 RelB p52 Oxidative Medicine and Cellular Longevity 5 ROS 2+ Ca RTK SOS Ras PLC𝛾 Grb2 Shc MEKK1/2/3/4 2+ Ca MKK3 PKC MLK3 ASK1 MKP Raf MKK4/7 MKK5 MKK3/6 MEK1/2 JNK BMK1 p38 MAPK ERK Stat1/3 ELK1 c-Jun ELK1 ATF-2 ELK1 MEF-2C ATF-2 MEF-2A/2C/2D Figure 3: Cross talk between ROS and MAPKs signaling pathway. MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinases; JNK, c-Jun N-terminal kinases; p38, p38 kinase; BMK1/ERK5, big MAP kinase 1; MAPKKK, MAP kinase kinase kinase; MAPKK, MAP kinase kinase; MAPK, MAP kinase; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol. cellular components: Kelch-like ECH-associated protein 1 an inhibitor of Nrf2 (INrf2), is associated with Nrf2 (the (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), majority of which resides in the cytoplasm) and recruits and interacts with the cullin-3 E3-ubiquitin ligase (Cul3) [77]. and antioxidant response elements (ARE) [71–76]. Under And the ubiquitination of Nrf2 is stimulated that targeted normal physiological conditions, Keap1, which is also called 6 Oxidative Medicine and Cellular Longevity 2+ Nrf2 for degradation by the 26S proteasome (more related 7. Cross Talk between ROS and Ca information has been provided in “ROS and Ubiquitina- 2+ In eukaryotic cells, Ca is one of the most versatile signals tion/Proteasome System” section) [78]. involved in the control cellular processes and functions, such However, under oxidizing conditions, the increased level as contraction, secretion, metabolism, gene expression, cell of intracellular ROS promotes the dissociation of Nrf2 and 2+ survival,andcelldeath[96,97].CytosolicCa concentration Keap1, either by the oxidization of key reactive cysteine 2+ ([Ca ] ) is determined by a dynamic balance between the residues (Cys273, Cys288, and Cys151) that govern Keap1 2+ activity or via the activation of kinases, such as protein mechanisms that pour Ca into the cytoplasm, including 2+ kinase C (PKC), MAPK, phosphatidylinositide 3-kinases Ca influx from the extracellular medium and intracellular (PI3Ks), and protein kinase-like endoplasmic reticulum stores such as endoplasmic reticulum (ER) or sarcoplas- kinase (PERK) that phosphorylate Nrf2 [79–81]. Aeft r that mic reticulum (SR), and those processes that remove it 2+ the dissociated Nrf2 is transferred to the nucleus where it out, involving Ca efflux across the plasma membrane dimerizes with members of another b-zip family, the small and sequestration into mitochondria [98, 99]. The uptake 2+ Maf proteins (Maf-F, Maf-G, and Maf-K), binds to ARE of mechanisms of Ca into the cytoplasm refer to the inositol phase II genes, and translates detoxification enzymes such 1,4,5-trisphosphate receptor (IP R), the ryanodine receptor as glutathione synthetase (GSS), glutathione reductase (GR), (RyR), and the nicotinic acid-adenine dinucleotide phos- 2+ Gpx, thioredoxin (TRX), thioredoxin reductase (TRR), and phate (NAADP) that are responsible for Ca release from ER 2+ peroxiredoxin (PRX) to prevent the oxidative stress [73, and SR, as well as voltage-dependent Ca channels (VDCC) 2+ 82]. Meanwhile, oxidative stress activates GSK3𝛽 leading to and store-operated Ca channel (SOC), which are in charge nuclearimportofSrc kinasessuchasSrc,Yes,Fyn,and 2+ of Ca influx from extracellular matrix [100–102]. Mean- Fgr, which phosphorylates Nrf2 (Tyr568) followed by the 2+ while, the mechanisms of removing Ca are determined nuclear export with Keap1 and degradation of Nrf2 [83, 84] 2+ by the plasma membrane Ca ATPase (PMCA), which (Figure 4). 2+ mediates Ca extrusion across the plasma membrane into 2+ the cytoplasm, the sarcoplasmic/endoplasmic reticulum Ca 6. ROS and PI3K-Akt Signaling Pathway 2+ ATPase (SERCA), which reintroduces Ca into the ER/SR, + 2+ Na /Ca exchanger (NCX) that involves the clearance of The phosphoinositide-3-kinase- (PI3K-) Akt pathway has 2+ + Ca through its exchange by Na , and the mitochondrial been involved in many critical cellular functions, includ- 2+ 2+ Ca uniporter (MCU) that transports Ca into the mito- ing protein synthesis, cell cycle progression, proliferation, chondria [103, 104]. Recent studies have demonstrated that apoptosis, autophagy, and drug resistance in response to 2+ the ROS and Ca signaling systems influence each other in growth factor (EGF, PDGF, NGF, and VEGF), hormone various ways (Figure 6). (prostaglandin, PGE ), and cytokine (IL-17, IL-6, and IL-2) 2+ Numerous evidences indicate that intracellular Ca stimulation [85–87]. eTh binding of growth factor to its recep- modulates both ROS generation and ROS clearance processes tors directly stimulates class 1A PI3Ks bound via their regula- andthereby shift theredox statetoeithermoreoxidizedor tory subunit or adapter molecules such as the insulin receptor 2+ substrate (IRS) proteins, which subsequently triggers the acti- reducedstate.Theprimary role of Ca is the promotion of vation of PI3K. Afterwards, the activated PI3K catalyzes the ATP synthesis and ROS generation in mitochondria via stim- synthesis of phosphatidylinositol 3,4,5-triphosphate (PIP3), ulating the Krebs cycle enzymes and oxidative phosphoryla- from phosphatidylinositol 4,5-bisphosphate (PIP2) [88]. eTh tion [105]. The mitochondrial respiratory chain provides the −∙ membranal PIP3, a signaling molecule, recruits and acti- main source of physiological ROS production (O ), which vates proteins that contain the pleckstrin homology (PH) is either converted to H O by spontaneous dismutation or 2 2 2+ domain such as the phosphoinositide-dependent protein catalyzed by SOD. Mitochondrial Ca could activate three kinase (PDK) and protein kinase B (Akt) serine/threonine dehydrogenases of the TCA cycle (pyruvate dehydrogenase, kinases and the activation of PDK and Akt successively isocitrate dehydrogenase, and oxoglutarate dehydrogenase), promotes the activation and transcription of their target the ATP synthase (complex V), and the adenine nucleotide genes (GSK3, FOXO, BAD, mTOR1, and p53) [89–92]. translocase and then increase the generation of ROS [106– 2+ ROS not only activate PI3K directly to amplify its down- 108]. Along with that, Ca regulates multiple extramitochon- stream signaling but also concurrently inactivate phosphatase drial ROS generating enzymes, including NOX [109] and and tensin homolog (PTEN), which negatively regulates the nitric oxide synthase (NOS) [110], both in physiological and synthesis of PIP3 and thereby inhibits the activation of Akt, 2+ in pathological processes. Meanwhile, Ca modulates ROS via oxidizing cysteine residues within the active center [93]. clearance processes via regulating the antioxidant defense In addition, ROS is able to promote the phosphorylation by 2+ system: on one hand, Ca can directly activate antioxidant casein kinase II on PTEN which urges PTEN to enter the enzymes (catalase and GSH reductase), increase the level of proteolytic degradation pathway [93]. Furthermore, protein 2+ SOD, andinducemitochondrial GSHrelease earlyinCa - phosphatase 2A (PP2A), which might be deactivated by ROS, induced mitochondrial permeability transition pore (mPTP) could inhibit Akt/PKB. However, it seems that, at lower levels, opening; on the other hand, calmodulin (CaM), ubiquitous ROS oxidize the disulfide bridges in Akt/PKB, leading to 2+ Ca -binding protein, could activate catalases in the presence the association of Akt/PKB with PP2A and thus short-term 2+ activation of Akt/PKB [46, 94, 95] (Figure 5). of Ca and downregulates H O levels [111–113]. 2 2 Oxidative Medicine and Cellular Longevity 7 Cytomembrane Ub Ub Ub Ub Nrf2 Nrf2 Keap1 Keap1 Keap1 Keap1 Keap1 Keap1 Degradation Cul3 Cul3 Cul3 Nrf2 NEDD8 Ubc12 ROS Nrf2 P C273/288/151 Keap1 Keap1 Ub Cul3 GS3K𝛽 Ub PKC Ub Ub GSS GR PRX Nrf2 TRR TRX C273/288/151 Fyn Keap1 Keap1 Nrf2 Cul3 Keap1 Keap1 Cul3 C273/288/151 Nrf2 ARE Nucleus Figure 4: Cross talk between ROS and Keap1-Nrf2-ARE signaling pathway. Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response elements; Cul3, cullin-3 E3-ubiquitin ligase; GSK3𝛽 , glycogen synthase kinase 3; Ubc, E2-ubiquitin conjugating enzyme. 2+ Furthermore, ROS also inu fl ences Ca signaling via oxi- contain numerous free Cys residues which are oxidized by 2+ ROS in the context of oxidation state which inhibits the activ- dizing Cys thiol of Ca channels/pumps/exchangers involv- 2+ ity of SERCA and decreases Ca inufl xfromthecytoplasmto ing RyR, IP R, SERCA, PMCA, and NCX. RyR/IP R, as well 3 3 ER [116]. Additionally, although PMCA is a slower pump than as many of the regulatory proteins that form complex with the SERCA, it can be reversibly inactivated by ROS by altering RyR/IP R, contains multiple reactive Cys thiols that inu fl ence 589 622 831 channel gating or assembly [114]. Thiol oxidation of RyR/IP R the Tyr ,Met ,and Met residues [117]. And ROS both by ROS in general increases channel activity and thereby stimulate and decrease NCX activity: H O generated from 2 2 2+ the xanthine/xanthine oxidase system enhances NCX activity promotes Ca eu ffl x via enhancing intersubunit binding and and oxidants from hypoxanthine/xanthine oxidase depress preventing the binding of the negative regulator calmodulin NCX activity. Moreover, ROS also alter the activity of VDCC, to the receptor [115]. As with RyR/IP R, SERCA pumps also 3 8 Oxidative Medicine and Cellular Longevity Cytomembrane PIP2 PIP3 PIP2 Degradation Akt PTEN Casein kinase II ROS ROS BAD GSK3 mTORC1 FOXO Figure 5: Cross talk between ROS and PI3K-Akt signaling pathway. PI3K, phosphoinositide-3-kinase; Akt, protein kinase B; PTEN, phosphatase and tensin homolog; FOXO, forkhead box protein O; mTOR1, mechanistic target of rapamycin 1. 2+ Na Ca 2+ Ca NCX PMCA VDCC Cytomembrane NOX 2+ 2+ Na Ca 2+ Ca Ca 2+ Ca ROS mPTP ATP IP3R ROS CaM RyR TCA SERCA 2+ 2+ Ca Ca Mitochondria Endoplasmic reticulum 2+ Figure 6: Cross talk between ROS and Ca . IP3R, inositol 1,4,5-trisphosphate receptor; RyR, the ryanodine receptor; VDCC, voltage- 2+ 2+ 2+ dependent Ca channels; SOC, store-operated Ca channel; SERCA, sarcoplasmic/endoplasmic reticulum Ca ATPase; PMCA, plasma 2+ 2+ + 2+ membrane Ca ATPase; MCU, mitochondrial Ca uniporter; TCA cycle, tricarboxylic acid cycle; NCX, Na /Ca exchanger. Oxidative Medicine and Cellular Longevity 9 ROS Bid Cytoplasma JNK jBid 2+ Ca mPTP UP VDCC VDCC C160 ANT ANT C56 Cyp-D Cyp-D C203 2+ Ca ATP ROS Mitochondria TCA Figure 7: Cross talk between ROS and mPTP. VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocator; Cyp-D, cyclophilin-D. 2+ especially the activity of L-type Ca channels, which has that when mPTP opens by the activation of various sig- been associated with the oxidation of -SH groups resulting nals, mitochondrial permeability is changed which dissipates 2+ the proton electrochemical gradient (ΔΨ𝑚) , which drives in altered Ca entry in the cytoplasm [118]. multiple mitochondrial functions, leading to ATP depletion, further reactive oxygen species production, and ultimately swelling and rupture of the organelle. This in turn releases 8. ROS and mPTP proapoptotic proteins: cytochrome c (Cyt C) [124] binds Several studies, lasting for decades, have showed that mPTP, to apoptotic protease activating factor-1 (Apaf1) and then a large, nonspecific channel spanning the inner mitochon- formsapoptosomethatactivates thecaspase-9 andcaspase- drial membrane (IMM) and outer mitochondrial membrane 3 protease system and induces apoptosis, Smac/DIABLO (OMM) [119, 120], mediates the lethal permeability changes [125] activates caspases by sequestering caspase-inhibitory that initiate mitochondrial-driven death. Hitherto, the puta- proteins, and endonuclease-G (endoG) [126] mediates DNA 2+ tive components include the voltage-dependent anion chan- fragmentation. Factors like the changes of intracellular Ca , nel (VDAC) or porin, localized in the OMM; the adenine the level of ATP/ADP, the release of Cyt C, regulation nucleotide translocator (ANT) in the IMM; the peripheral in mitochondrial morphology, and ROS generation often benzodiazepine receptor and the Bcl-2 family proteins; the influence the mPTP opening [127] (Figure 7). The mechanism of ROS mediating the mPTP formation hexokinaseboundtoporin;thecyclophilin-D(Cyp-D),areg- involves several pathways. Firstly, ROS directly modulate ulatory element in the matrix; glycogen synthase kinase-3b (GSK-3b); and cytochrome c [121–123]. It has been described mPTP opening by oxidizing four different sites: Cys of 10 Oxidative Medicine and Cellular Longevity 2+ Ca 2+ Ca channel Na-K ATPase Na channel NCX Cytoplasm Target proteins M281/282 PKC CaMKII C17 PKA C38 ROS Abl Src Complex I Ras/Raf/MAPK PKC RyR S738/742 PKA P Y463 Endoplasmic reticulum Target proteins Figure 8: Cross talk between ROS and protein kinase. CaMKII, calc ium/calmodulin-dependent protein kinase II; RyR, the ryanodine receptor. ANT, regulated by glutathione oxidation and protected by function in various cellular processes via oxidating sulyfh dryl low concentration of N-ethylmaleimide (NEM) or mono- (SH) groups of cysteine residues in protein kinases including bromobimane [128]; Cys56 of ANT, sensitive to the redox protein kinase A (PKA) [136], protein kinase C (PKC) [137], state of the matricial pyridine nucleotides perhaps with the protein kinase D (PKD) [138], receptor tyrosine kinase (RTK) mediation of thioredoxin or lipoamide and also protected [139], and Ca/calmodulin independent protein kinase II by NEM, not by monobromobimane [129]; external thiol (CaMKII) [140] and then activated protein kinases phospho- groups (SH), promoting PTP opening by reaction with NEM rylate their target proteins which are involved in different cellular signaling mechanisms (Figure 8). or copper-orthophenanthroline; and Cys of Cyp-D, S- PKA, also called cAMP-dependent protein kinase A, is glutathionylation of which prevents Cyp-D binding to ANT organized as tetramers comprising two catalytic and two which blocks MPT [130]. Besides, ROS indirectly modulate 2+ regulatory subunits. eTh activation of PKA can occur by the opening of mPTP via increasing the mitochondrial Ca 2+ 2+ binding of two molecules of cAMP to each regulatory subunit concentration ([Ca ] ): ROS promotes Ca efflux from and then this activated PKA phosphorylates its targeting ER/SR to cytoplasm and from cytoplasm to mitochondria. 2+ 2+ proteins, including RyR and L-type Ca channel and phos- The increase of Ca concentration in turn favors ATP pholamban (PLN) [141, 142]. Recently, it has been shown that production and ROS generation during oxidative phospho- type Iregulatorysubunit IofPKA is subjectedtooxidation rylation and promotes the opening of mPTP [131, 132]. In by ROSonCys 17 and38, whichleads to theintersubunit addition, ROS also may translocate Bid to jBid via activating disulfide bond formation (between two regulatory subunits) the JNK pathway, which leads to the opening of mPTP [133– anddissociationofthe PKAholoenzymecomplex. Andthe 135]. translocation (from cytosol to membrane and myofilaments) andactivationoftypeIPKAresultinincreased cellular 9. ROS and Protein Kinase contractility without elevations in cAMP [143]. Meanwhile, not only do ROS influence the phosphorylation of PKA, but Recently, it is becoming increasingly apparent that, like phosphorylation of PKA also has an impact on the ROS physiological second messengers in signal transduction, ROS Oxidative Medicine and Cellular Longevity 11 homeostasis. In mammalian cells, the cAMP/PKA pathway 10. ROS and Ubiquitination/Proteasome regulates the expression, assembly, and catalytic activity System of complex I of the mitochondrial respiratory chain and Ubiquitination/Proteasome System (UPS) includes four subsequently determines the synthesis and accumulation of components: proteasome, ubiquitin, the ubiquitination ROS [144, 145]. Protein kinase C (PKC), containing four homologous machinery, and the deubiquitinases (DUBs) [160]. UPS play indispensable roles in variety of biological processes domains termed C1, C2, C3, and C4, is a superfamily of such as regulation of the cell cycle, inflammatory responses, structurally correlated serine-threonine kinases that cat- alyze numerous critical biochemical reactions, like cellular immune response, protein misfolding, and endoplasmic reticulum-associated degradation of proteins. Initially, responses, gene expression, cell proliferation, survival, and ubiquitin gets activated by an ATP-dependent E1 ubiquitin- migration[146].Inaninactivestate,PKC is looselyassociated activating enzyme which results in the transient adenylation with membrane lipids and chiefly isolated in the cytosolic of ubiquitin and the transference of ubiquitin from E1 to a fraction, whereas activation of PKC increases the an ffi ity of cysteine residue of E2-ubiquitin conjugating enzyme (Ubc); the enzyme for membrane lipids and consequently stabilizes then E3 transfers ubiquitin from E2-ubiquitin to the lysine its membrane association, which causes a conformational residue of a substrate protein by catalyzing the peptidyl change to a catalytically competent form of PKC [147–149]. Both the regulatory and catalytic domains of PKC contain bond formation between ubiquitin and the target protein and subsequently the elongation of the polyubiquitin chain cysteine-rich regions, thus making it a highly susceptible which transfers the client protein to the proteasome for direct target for redox regulation. Oxidants play a dual role in both stimulation and inactivation of PKC with relation degradation through specific proteolytic activities [161–163]. Concurrently, DUBs can remove ubiquitin from substrates to the concentration: higher doses of oxidants react with and disassemble polyubiquitin chains which may lead to catalytically important cysteine residues inactivating PKC; protein stabilization [164]. however, low doses induce stimulation of PKC activity. It Recently, an increasing number of studies have docu- has been found that H O stimulated the activation of 2 2 tyrosine kinases and was able to indirectly regulate the mented the interactions between ROS and UPS [165–168]. tyrosine phosphorylation of PKC-𝛿 at residues 512 and 523 The susceptibility of the UPP to oxidative stress may have [150]. been anticipated, because E1, E2, some E3 enzymes, and PKD isoforms (PKD1, PKD2, and PKD3), the eeff ctors of DUBs have a cysteine residue, which are sensitive to ROS, in diacylglycerol (DAG), and protein kinase c (PKC) effectors their active sites (Figure 9). The rapid depletion of reduced have been described as vital regulators of diverse cellular glutathione (GSH) and improvement of the levels of oxidized pathways and mediate the actions of growth factors, neu- glutathione (GSSG) upon exposure to oxidative stress result rotransmitters, hormones, and other stimuli that activate in the oxidation of cysteine residues in the active sites of E1 PLC𝛽 and PLC𝛾 [151–153]. The binding of the corresponding and E2 and the generation of mixed disulfide bonds which ligand to G-protein coupled receptors (GPCRs) or tyrosine blocks their binding to ubiquitin [169, 170]. It has also been kinase receptors activates PLC𝛽 and PLC𝛾 .Then PLC 𝛽 cleave reported that bacteria elicit ROS generation in epithelial cells PI (4, 5) P2 that generates DAG and IP3. Subsequently, that inactivate the Ubc12 enzyme, preventing the neddylation membranal DAG binds to and activates PKC and recruits 𝛽 -TrCP of cullin-1. Unneddylated cullin in E3-SCF complex PKD, which then is phosphorylated and activated by PKC rendersitunabletocarry outubiquitinationand is thus 744 748 on Ser and Ser residues [154, 155]. ROS inu fl ence the making it inactive [171]. Additionally, numerous reports have activation of PKD in a various manner: ROS trigger PLD1 suggested that Kelch-like ECH-associated protein-1 (Keap1), and phosphatidic acid phosphatase- (PAP-) catalyzed DAG a substrate adaptor protein for a cullin-3 E3-ubiquitin ligase synthesis and concomitant recruitment of PKD1 and PKC𝛿 (Cul3)/Ring-Box1 (Rbx1) dependent complex, plays a critical at the outer mitochondrial membrane [156]; ROS promotes role in the ubiquitination and degradation of Nrf2, IKK𝛽 , phosphorylation of PKD on its Tyr residue by Src that cre- and Bcl-2/Bcl-xL, also being disturbed by ROS via mod- ates a binding site for the PKC𝛿 C2 domain which facilitates ifying the reactive cysteines (Cys273, Cys288, and Cys151) the binding between PKC𝛿 with PKD and the activation of and then inducing a conformational change that leads to PKD[157];ROS also couldleadtothe activation of PKD therelease of Nrf2,IKK𝛽 , and Bcl-2/Bcl-xL from Keap1 via the phosphorylation at Tyr residue by the tyrosine and the suspending of their ubiquitination and degradation kinase Abl. Additionally, expression of mitochondrial Mn- [172–174]. Meanwhile, the proteasome is also a target of SOD induced by PKD1-NF-𝜅 B signaling removes toxic ROS oxidative stress and the 26S proteasome was more sus- [158]. ceptible than the 20S proteasome to oxidative inactivation Moreover, the activation of RTK and CaMKII could be [175]. affected by the level of intracellular ROS. eTh oxidation In turn, UPS regulates cellular redox status via the degra- 281 282 on Met and Met residues in the regulatory domain dation of Nrf2 and the activation of NF-𝜅 Band both could results in the activation of CaMKII [159]. And RTKs such mediate the level of ROS by their downstream antioxidative as the insulin receptor, EGFR, platelet-derived growth factor proteins [176]. In addition, accumulating evidences made it receptor (PGFR), and c-Ret have all been reported to undergo evident that the UPS plays essential roles in regulating mito- direct oxidation on their cysteine residue. chondrial processes: oxidative phosphorylation, TCA cycle, 12 Oxidative Medicine and Cellular Longevity Cytomembrane IkB𝛼 NEDD8 Nrf2 Ubc12 𝛽 -Trcp1 Keap1 Keap1 Skp1 Ub Ub Rbx1 Rbx1 Ub Ub Ub Ub Ub E2 E2 Cul3 Cul3 ROS IkB𝛼 Nrf2 𝛽 -Trcp1 Keap1 Keap1 Skp1 Rbx1 Ubc12 NEDD8 Ub Rbx1 Ub E2 Ub Ub Ub Cul3 Ub E2 Ub Ub Cul3 NEDD8 𝛽 -Trcp1 Ub Ub Skp1 Ub Ub Rbx1 IkB𝛼 Nrf2 E2 Cul3 NEDD8 Keap1 Keap1 Rbx1 NEDD8 E2 Cul3 Degradation Figure 9: Regulation of Ubiquitination/Proteasome System by ROS. Ubc, E2-ubiquitin conjugating enzyme. and mitochondrial dynamics which subsequently regulate signaling pathways which are sensitive to ROS and the high ROS generation [177–179]. degree of complexity in simultaneous actions of ROS, even though we have learnt much about the mechanisms by which ROS influences signaling, in particular, the interactions 11. Conclusions between different ROS associated signaling pathways are yet It has been clearly demonstrated that redox equilibrium to be elucidated. plays pivotal roles in cells’ physiological and pathological events due to ROS’s ability to activate or deactivate a variety Conflict of Interests of receptors, proteins, ions, and other signaling molecules. When the redox equilibrium is disturbed due to the excessive eTh authors declare that there is no conflict of interests accumulation or depletion of ROS, many cellular signal- regarding the publication of this paper. ing pathways are influenced which confers to the cellular dysfunction and subsequently the development of various pathologies. eTh refore, unveiling the mechanisms of ROS Authors’ Contribution regulating redox-associated signaling pathways is essential in providing relevant targets in order to develop innovative and Jixiang Zhang and Xiaoli Wang contributed equally to this effective therapeutic strategies. However, due to numerous work. Ub Oxidative Medicine and Cellular Longevity 13 References [20] M. D. Brand, “eTh sites and topology of mitochondrial superox- ide production,” Experimental Gerontology,vol.45, no.7-8,pp. [1] H. Zhang, A. M. Gomez, X. Wang, Y. Yan, M. Zheng, and H. 466–472, 2010. 2+ Cheng, “ROS regulation of microdomain Ca signalling at the [21] S. Roberge, J. Roussel, D. C. Andersson et al., “TNF-𝛼 -mediated dyads,” Cardiovascular Research, vol. 98, no. 2, pp. 248–258, caspase-8 activation induces ROS production and TRPM2 acti- vation in adult ventricular myocytes,” Cardiovascular Research, [2] L. A. Sena and N. S. Chandel, “Physiological roles of mitochon- vol. 103, no.1,pp. 90–99, 2014. drial reactive oxygen species,” Molecular Cell,vol.48, no.2,pp. [22] D. V. Ilatovskaya, T. S. Pavlov, V. Levchenko, and A. Star- 158–166, 2012. uschenko, “ROS production as a common mechanism of ENaC [3] M. Giorgio, M. Trinei, E. Migliaccio, and P. G. Pelicci, “Hydro- regulation by EGF, insulin, and IGF-1,” The American Journal of gen peroxide: a metabolic by-product or a common mediator Physiology—Cell Physiology, vol. 304, no. 1, pp. C102–C111, 2013. of ageing signals?” Nature Reviews Molecular Cell Biology,vol. [23] M. Clauzure, A. G. Valdivieso, M. M. Massip Copiz, G. Schul- 8, no. 9, pp. 722–728, 2007. man, M. L. Teiber, and T. A. Santa-Coloma, “Disruption of [4] S. I. Liochev, “Reactive oxygen species and the free radical interleukin-1𝛽 autocrine signaling rescues complex I activity theory of aging,” Free Radical Biology and Medicine,vol.60, pp. and improves ROS levels in immortalized epithelial cells with 1–4, 2013. impaired cystic fibrosis transmembrane conductance regulator (CFTR) function,” PLoS ONE,vol.9,no. 6, ArticleIDe99257, [5] S.G.Rhee, “Cellsignaling.H O , a necessary evil for cell 2 2 signaling,” Science, vol. 312, no. 5782, pp. 1882–1883, 2006. [24] M. Large, S. Reichert, S. Hehlgans, C. Fournier, C. Rodel ¨ , and [6] Y.S.Bae,H.Oh, S. G. Rhee,and Y. D. Yoo, “Regulationof F. Ro¨del, “A non-linear detection of phospho-histone H2AX in reactive oxygen species generation in cell signaling,” Molecules EA.hy926 endothelial cells following low-dose X-irradiation is and Cells,vol.32, no.6,pp. 491–509, 2011. modulated by reactive oxygen species,” Radiation Oncology,vol. [7] A.A.Alfadda andR.M.Sallam, “Reactiveoxygenspecies in 9, article 80, 2014. health and disease,” Journal of Biomedicine and Biotechnology, [25] A.-F. Miller, “Superoxide dismutases: ancient enzymes and new vol. 2012,Article ID 936486,14pages,2012. insights,” FEBS Letters,vol.586,no. 5, pp.585–595,2012. [8] A. Matsuzawa and H. Ichijo, “Stress-responsive protein kinases [26] M. Mar´ı, A. Morales, A. Colell, C. Garc´ıa-Ruiz, and J. C. in redox-regulated apoptosis signaling,” Antioxidants and Redox Fernandez-C ´ heca, “Mitochondrial glutathione, a key survival Signaling,vol.7,no. 3-4, pp.472–481,2005. antioxidant,” Antioxidants and Redox Signaling, vol. 11, no. 11, [9] W. Drog ¨ e, “Free radicals in the physiological control of cell pp. 2685–2700, 2009. function,” Physiological Reviews,vol.82, no.1,pp. 47–95, 2002. [27] R. Kanwal, M. Pandey, N. Bhaskaran et al., “Protection against [10] T. Finkel, “Signal transduction by reactive oxygen species,” oxidative DNA damage and stress in human prostate by glu- Journal of Cell Biology, vol. 194, no. 1, pp. 7–15, 2011. tathione S-transferase P1,” Molecular Carcinogenesis,vol.53, no. [11] V. G. Grivennikova and A. D. Vinogradov, “Mitochondrial 1, pp. 8–18, 2014. production of reactive oxygen species,” Biochemistry,vol.78,no. [28] G. Meloni and M. Vaˇsak, ´ “Redox activity of𝛼 -synuclein-Cu is 13, pp. 1490–1511, 2013. silenced by Zn -metallothionein-3,” Free Radical Biology and [12] A. A. Starkov, “eTh role of mitochondria in reactive oxygen Medicine,vol.50, no.11, pp.1471–1479,2011. species metabolism and signaling,” Annals of the New York [29] J. Chen,M.Adikari,R.Pallai, H. K. Parekh,and H. Simpkins, Academy of Sciences,vol.1147, pp.37–52,2008. “Dihydrodiol dehydrogenases regulate the generation of reac- [13] L. Galluzzi, E. Morselli, O. Kepp et al., “Mitochondrial gateways tive oxygen species and the development of cisplatin resistance to cancer,” Molecular Aspects of Medicine,vol.31, no.1,pp. 1–20, in human ovarian carcinoma cells,” Cancer Chemotherapy and Pharmacology, vol. 61, no. 6, pp. 979–987, 2008. [14] Q. Chen, E. J. Vazquez, S. Moghaddas, C. L. Hoppel, and [30] G. Bonizzi and M. Karin, “eTh two NF- 𝜅 B activation pathways E. J. Lesnefsky, “Production of reactive oxygen species by and their role in innate and adaptive immunity,” Trends in mitochondria: central role of complex III,” The Journal of Immunology, vol. 25, no. 6, pp. 280–288, 2004. Biological Chemistry,vol.278,no. 38,pp. 36027–36031, 2003. [31] A. S. Baldwin, “Regulation of cell death and autophagy by [15] D. G. Nicholls and S. L. Budd, “Mitochondria and neuronal IKK and NF-𝜅 B: critical mechanisms in immune function and survival,” Physiological Reviews,vol.80, no.1,pp. 315–360, 2000. cancer,” Immunological Reviews,vol.246,no. 1, pp.327–345, [16] J. F. Turrens, “Mitochondrial formation of reactive oxygen species,” The Journal of Physiology ,vol.552,part2,pp. 335–344, [32] A. Devin, A. Cook, Y. Lin, Y. Rodriguez, M. Kelliher, and Z.- G. Liu, “eTh distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates [17] D. I. Brown and K. K. Griendling, “Nox proteins in signal IKK activation,” Immunity,vol.12, no.4,pp. 419–429, 2000. transduction,” Free Radical Biology and Medicine,vol.47, no.9, pp.1239–1253,2009. [33] G. Gloire and J. Piette, “Redox regulation of nuclear post- translational modifications during NF- 𝜅 B activation,” Antioxi- [18] I. P. Harrison and S. Selemidis, “Understanding the biology dants and Redox Signaling, vol. 11, no. 9, pp. 2209–2222, 2009. of reactive oxygen species and their link to cancer: NADPH oxidases as novel pharmacological targets,” Clinical and Experi- [34] S. Basak and A. Hoffmann, “Crosstalk via the NF- 𝜅 Bsignaling mental Pharmacology and Physiology,vol.41, no.8,pp. 533–542, system,” Cytokine and Growth Factor Reviews,vol.19, no.3-4, 2014. pp.187–197,2008. [19] J. D. Lambeth, “NOX enzymes and the biology of reactive [35] S. Gardam and R. Brink, “Non-canonical NF-𝜅 B signaling ini- oxygen,” Nature Reviews Immunology,vol.4,no. 3, pp.181–189, tiated by BAFF influences B cell biology at multiple junctures,” 2004. Frontiers in Immunology, vol. 4, article 509, 2014. 14 Oxidative Medicine and Cellular Longevity [36] J. Bauer, S. Namineni, F. Reisinger, J. Zol ¨ ler, D. Yuan, and M. and inflammation,” Physiological Reviews,vol.81, no.2,pp. 807– Heikenwalder ¨ , “Lymphotoxin, NF-𝜅 B, and cancer: the dark side 869, 2001. of cytokines,” Digestive Diseases,vol.30, no.5,pp. 453–468, [51] Z. Chen,T.B.Gibson, F. Robinson et al., “MAP kinases,” Chemical Reviews,vol.101,no. 8, pp.2449–2476,2001. [37] T. Elmetwali, L. S. Young, and D. H. Palmer, “Fas-associated [52] W. M. Stadler, “Targeted agents for the treatment of advanced factor (Faf1) is a novel CD40 interactor that regulates CD40- renalcellcarcinoma,” Cancer,vol.104,no. 11, pp.2323–2333, induced NF-𝜅 B activation via a negative feedback loop,” Cell Death and Disease,vol.5,no. 5, ArticleIDe1213,2014. [53] E.P.SproulandW.S.Argraves,“Acytokineaxisregulateselastin [38] P. Ramakrishnan, W. Wang, and D. Wallach, “Receptor-specific formation and degradation,” Matrix Biology,vol.32, no.2,pp. signaling for both the alternative and the canonical NF-𝜅 B 86–94, 2013. activation pathways by NF-𝜅 B-inducing kinase,” Immunity,vol. [54] B. B. Friday and A. A. Adjei, “Advances in targeting the 21, no. 4, pp. 477–489, 2004. Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade [39] C. Journo, A. Bonnet, A. Favre-bonvin et al., “Human T cell with MEK inhibitors for cancer therapy,” Clinical Cancer leukemia virus type 2 tax-mediated NF-𝜅 B activation involves Research,vol.14, no.2,pp. 342–346, 2008. a mechanism independent of tax conjugation to ubiquitin and [55] A. Plotnikov, E. Zehorai, S. Procaccia, and R. Seger, “The SUMO,” Journal of Virology, vol. 87, no. 2, pp. 1123–1136, 2013. MAPK cascades: signaling components, nuclear roles and [40] Y.-J. Song and M.-S. Kang, “Roles of TRAF2 and TRAF3 in mechanisms of nuclear translocation,” Biochimica et Biophysica Epstein-Barr virus latent membrane protein 1-induced alterna- Acta—Molecular Cell Research,vol.1813, no.9,pp. 1619–1633, tive NF-𝜅 B activation,” Virus Genes,vol.41, no.2,pp. 174–180, [56] A. Leon-B ´ uitimea, L. Rodr´ıguez-Fragoso, F. T. Lauer, H. Bowles, [41] S. Schoonbroodt, V. Ferreira, M. Best-Belpomme et al., “Crucial T. A. Thompson, and S. W. Burchiel, “Ethanol-induced oxidative role of the amino-terminal tyrosine residue 42 and the carboxyl- stress is associated with EGF receptor phosphorylation in MCF- terminal PEST domain of I𝜅 B𝛼 in NF-𝜅 B activation by an 10A cells overexpressing CYP2E1,” Toxicology Letters,vol.209, oxidative stress,” Journal of Immunology,vol.164,no. 8, pp. no. 2, pp. 161–165, 2012. 4292–4300, 2000. [57] H. Lei and A. Kazlauskas, “Growth factors outside of the [42] Y. Takada, A. Mukhopadhyay, G. C. Kundu, G. H. Maha- platelet-derived growth factor (PDGF) family employ reactive beleshwar, S. Singh, and B. B. Aggarwal, “Hydrogen peroxide oxygen species/Src family kinases to activate PDGF receptor activates NF-𝜅 B through tyrosine phosphorylation of I𝜅 B𝛼 and 𝛼 and thereby promote proliferation and survival of cells,” The serine phosphorylation of p65. Evidence for the involvement JournalofBiologicalChemistry,vol.284,no. 10,pp. 6329–6336, of I𝜅 B𝛼 kinase and Syk protein-tyrosine kinase,” The Journal of Biological Chemistry, vol. 278, no. 26, pp. 24233–24241, 2003. [58] C. C. Wentworth, A. Alam,R.M.Jones,A.Nusrat, andA.S. [43] N. L. Reynaert, A. van der Vliet, A. S. Guala et al., “Dynamic Neish, “Enteric commensal bacteria induce extracellular signal- redox control of NF-𝜅 B through glutaredoxin-regulated S- regulated kinase pathway signaling via formyl peptide receptor- glutathionylation of inhibitory𝜅 B kinase𝛽 ,” Proceedings of the dependent redox modulation of dual specific phosphatase 3,” National Academy of Sciences of the United States of America, eTh JournalofBiologicalChemistry ,vol.286,no. 44,pp. 38448– vol. 103, no. 35, pp. 13086–13091, 2006. 38455, 2011. [44] J. V. Cross and D. J. Templeton, “Thiol oxidation of cell signal- [59] A. Banan, J. Z. Fields, Y. Zhang, and A. Keshavarzian, “Phos- ing proteins: controlling an apoptotic equilibrium,” Journal of pholipase C-𝛾 inhibition prevents EGF protection of intestinal Cellular Biochemistry, vol. 93, no. 1, pp. 104–111, 2004. cytoskeleton and barrier against oxidants,” The American Jour- nal of Physiology—Gastrointestinal and Liver Physiology,vol. [45] Q. Li and J. F. Engelhardt, “Interleukin-1𝛽 induction of NF𝜅 B 281, no. 2, pp. G412–G423, 2001. is partially regulated by H O -mediated activation of NF𝜅 B- 2 2 inducing kinase,” eTh JournalofBiologicalChemistry ,vol.281, [60] R. A. Franklin, P. A. Atherfold, and J. A. McCubrey, “Calcium- no. 3, pp. 1495–1505, 2006. induced ERK activation in human T lymphocytes occurs via Lck p56 and CaM-kinase,” Molecular Immunology,vol.37, no.11, [46] J.-H. Kim, H.-J. Na, C.-K. Kim et al., “The non-provitamin A pp. 675–683, 2000. carotenoid, lutein, inhibits NF-𝜅 B-dependent gene expression through redox-based regulation of the phosphatidylinositol [61] S. G. Dann, J. Golas, M. Miranda et al., “P120 catenin is a key 3-kinase/PTEN/Akt and NF-𝜅 B-inducing kinase pathways: effector of a Ras-PKC 𝜀 oncogenic signaling axis,” Oncogene,vol. role of H O in NF-𝜅 B activation,” Free Radical Biology and 33, no. 11, pp. 1385–1394, 2014. 2 2 Medicine,vol.45, no.6,pp. 885–896, 2008. [62] C. Davies and C. Tournier, “Exploring the function of the JNK [47] M. R. Junttila, S.-P. Li, and J. Westermarck, “Phosphatase- (c-Jun N-terminal kinase) signalling pathway in physiological mediated crosstalk between MAPK signaling pathways in the and pathological processes to design novel therapeutic strate- regulation of cell survival,” The FASEB Journal ,vol.22, no.4, gies,” Biochemical Society Transactions,vol.40, no.1,pp. 85–89, pp.954–965,2008. [48] T. Ravingerova, ´ M. Barancˇ´ık, and M. Strniskova, ´ “Mitogen- [63] S. S. Leonard, G. K. Harris, and X. Shi, “Metal-induced oxida- activated protein kinase: a new therapeutic target in cardiac tive stress and signal transduction,” Free Radical Biology and pathology,” Molecular and Cellular Biochemistry,vol.247,no. 1- Medicine,vol.37, no.12, pp.1921–1942,2004. 2, pp. 127–138, 2003. [64] K. Katagiri, A. Matsuzawa, and H. Ichijo, “Regulation of apop- [49] G. Pimienta and J. Pascual, “Canonical and alternative MAPK tosis signal-regulating kinase 1 in redox signaling,” Methods in signaling,” Cell Cycle,vol.6,no. 21,pp. 2628–2632, 2007. Enzymology,vol.474,pp. 277–288, 2010. [50] J. M. Kyriakis and J. Avruch, “Mammalian mitogen-activated [65] M. Castro-Caldas, A. N. Carvalho, E. Rodrigues, C. Henderson, protein kinase signal transduction pathways activated by stress C. R. Wolf, and M. J. Gama, “Glutathione S-transferase pi Oxidative Medicine and Cellular Longevity 15 mediates MPTP-induced c-Jun N-terminal kinase activation in [81] T. Nguyen,P.J.Sherratt, andC.B.Pickett,“Regulatory mecha- the nigrostriatal pathway,” Molecular Neurobiology,vol.45, no. nisms controlling gene expression mediated by the antioxidant 3, pp. 466–477, 2012. response element,” Annual Review of Pharmacology and Toxi- cology,vol.43, pp.233–260,2003. [66] J. Matsukawa, A. Matsuzawa, K. Takeda, and H. Ichijo, “The ASK1-MAP kinase cascades in mammalian stress response,” The [82] A. K. Jain and A. K. Jaiswal, “GSK-3𝛽 acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF- Journal of Biochemistry,vol.136,no. 3, pp.261–265,2004. E2 related factor 2,”eTh JournalofBiologicalChemistry ,vol.282, [67] B. Grill and J. W. Schrader, “Activation of Rac-1, Rac-2, and no. 22, pp. 16502–16510, 2007. Cdc42 by hemopoietic growth factors or cross-linking of the [83] W. K. Yip and H. F. Seow, “Activation of phosphatidylinositol B-lymphocyte receptor for antigen,” Blood,vol.100,no. 9, pp. 3-kinase/Akt signaling by EGF downregulates membranous E- 3183–3192, 2002. cadherin and𝛽 -catenin and enhances invasion in nasopharyn- [68] I. Shin, S. Kim, H. Song, H.-R. C. Kim, and A. Moon, “H-Ras- geal carcinoma cells,” Cancer Letters,vol.318,no. 2, pp.162–172, specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells,” The Journal [84] J. Hong, T. Qian, Q. Le et al., “NGF promotes cell cycle progres- of Biological Chemistry,vol.280,no. 15,pp. 14675–14683, 2005. sion by regulating D-type cyclins via PI3K/Akt and MAPK/Erk [69] A. Cuadrado and A. R. Nebreda, “Mechanisms and functions of activation in human corneal epithelial cells,” Molecular Vision, p38 MAPK signalling,” Biochemical Journal,vol.429,no. 3, pp. vol. 18, pp. 758–764, 2012. 403–417, 2010. [85] X. Qiu, J.-C. Cheng, H.-M. Chang, and P. C. K. Leung, “COX2 [70] M. Hayashi, C. Fearns,B.Eliceiri,Y.Yang, andJ.-D. Lee, and PGE2 mediate EGF-induced E-cadherin-independent “Big mitogen-activated protein kinase 1/extracellular signal- human ovarian cancer cell invasion,” Endocrine-Related Cancer, regulated kinase 5 signaling pathway is essential for tumor- vol. 21,no. 4, pp.533–543,2014. associated angiogenesis,” Cancer Research,vol.65, no.17, pp. [86] I. E. Ahn, J. H. Ju,S.Y.Lee et al., “Upregulationofstromal cell- 7699–7706, 2005. derived factor by IL-17 and IL-18 via a phosphatidylinositol 3- [71] J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: kinase-dependent pathway,” Scandinavian Journal of Immunol- permanent activation of an adaptive response in cancer,” Trends ogy,vol.76, no.4,pp. 433–439, 2012. in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. [87] D. A. Cantrell, “Phosphoinositide 3-kinase signalling pathways,” [72] K. Taguchi, H. Motohashi, and M. Yamamoto, “Molecular Journal of Cell Science,vol.114,part8,pp. 1439–1445, 2001. mechanisms of the Keap1-Nrf2 pathway in stress response and [88] D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, cancer evolution,” Genes to Cells,vol.16, no.2,pp. 123–140, 2011. “Phosphorylation and regulation of Akt/PKB by the rictor- [73] T. W. Kensler, N. Wakabayashi, and S. Biswal, “Cell survival mTOR complex,” Science,vol.307,no. 5712,pp. 1098–1101,2005. responses to environmental stresses via the Keap1-Nrf2-ARE [89] P. Cohen and S. Frame, “eTh renaissance of GSK3,” Nature pathway,” Annual Review of Pharmacology and Toxicology,vol. Reviews Molecular Cell Biology,vol.2,no. 10,pp. 769–776, 2001. 47, pp. 89–116, 2007. [90] Y. Zhang, B. Gan, D. Liu, and J.-H. Paik, “FoxO family members [74] J.-M. Lee and J. A. Johnson, “An important role of Nrf2- in cancer,” Cancer Biology and eTh rapy ,vol.12, no.4,pp. 253– ARE pathway in the cellular defense mechanism,” Journal of 259, 2011. Biochemistry and Molecular Biology,vol.37, no.2,pp. 139–143, [91] X.-S. Zhang, X. Zhang, Q. Wu et al., “Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: [75] K.-A. Jung and M.-K. Kwak, “eTh Nrf2 system as a potential possible involvement of Akt/bad signaling,” Marine Drugs,vol. target for the development of indirect antioxidants,” Molecules, 12, no. 8, pp. 4291–4310, 2014. vol. 15,no. 10,pp. 7266–7291, 2010. [92] A. G. Abraham and E. O’Neill, “PI3K/Akt-mediated regulation [76] M. Furukawa and Y. Xiong, “BTB protein keap1 targets antiox- of p53 in cancer,” Biochemical Society Transactions,vol.42, no. idant transcription factor Nrf2 for ubiquitination by the cullin 4, pp. 798–803, 2014. 3-Roc1 ligase,” Molecular and Cellular Biology,vol.25, no.1,pp. [93] N. R. Leslie and C. P. Downes, “PTEN: the down side of PI 3- 162–171, 2005. kinase signalling,” Cellular Signalling,vol.14, no.4,pp. 285–295, [77] N. F. Villeneuve, A. Lau, and D. D. Zhang, “Regulation of the 2002. Nrf2-Keap1 antioxidant response by the ubiquitin proteasome [94] S.-R. Lee, K.-S. Yang, J. Kwon, C. Lee, W. Jeong, and S. G. system: an insight into cullin-ring ubiquitin ligases,” Antioxi- Rhee, “Reversible inactivation of the tumor suppressor PTEN dants & Redox Signaling,vol.13, no.11, pp.1699–1712,2010. O ,” The Journal of Biological Chemistry ,vol.277,no. 23, by H 2 2 pp. 20336–20342, 2002. [78] A. T. Dinkova-Kostova, W. D. Holtzclaw, R. N. Cole et al., “Direct evidence that sulfhydryl groups of Keap1 are the sensors [95] H. Murata, Y. Ihara, H. Nakamura, J. Yodoi, K. Sumikawa, regulating induction of phase 2 enzymes that protect against and T. Kondo, “Glutaredoxin exerts an antiapoptotic eeff ct by carcinogens and oxidants,” Proceedings of the National Academy regulating theredox stateofAkt,” The Journal of Biological of Sciences of the United States of America,vol.99, no.18, pp. Chemistry, vol. 278, no. 50, pp. 50226–50233, 2003. 11908–11913, 2002. [96] A. I. Tarasov, E. J. Griffiths, and G. A. Rutter, “Regulation of ATP 2+ production by mitochondrial Ca ,” Cell Calcium,vol.52, no.1, [79] K. C. Kim, K. A. Kang, R. Zhang et al., “Up-regulation of Nrf2- mediated heme oxygenase-1 expression by eckol, a phlorotan- pp.28–35,2012. 2+ nin compound, through activation of Erk and PI3K/Akt,” [97] J. R. Naranjo and B. Mellstrom, ¨ “Ca -dependent transcrip- 2+ International Journal of Biochemistry and Cell Biology,vol.42, tional control of Ca homeostasis,” The Journal of Biological no. 2, pp. 297–305, 2010. Chemistry, vol. 287, no. 38, pp. 31674–31680, 2012. [80] J. W. Kaspar,S.K.Niture, andA.K.Jaiswal,“Nrf2:INrf2 (Keap1) [98] M. J. Berridge, M. D. Bootman, and H. L. Roderick, “Calcium signaling in oxidative stress,” Free Radical Biology and Medicine, signalling: dynamics, homeostasis and remodelling,” Nature vol. 47,no. 9, pp.1304–1309,2009. Reviews Molecular Cell Biology,vol.4,no. 7, pp.517–529,2003. 16 Oxidative Medicine and Cellular Longevity [99] A. Felsenfeld,M.Rodriguez,and B. Levine,“Newinsights [114] R. Chaube,D.T.Hess, Y.-J.Wangetal.,“Regulation of the 2+ in regulation of calcium homeostasis,” Current Opinion in skeletal muscle ryanodine receptor/Ca -release channel RyR1 Nephrology and Hypertension,vol.22, no.4,pp. 371–376, 2013. by S-palmitoylation,” The Journal of Biological Chemistry ,vol. 289, no. 12, pp. 8612–8619, 2014. [100] P.B.StathopulosandM.Ikura,“Partialunfoldingandoligomer- ization of stromal interaction molecules as an initiation mech- [115] I. Bogeski and B. A. Niemeyer, “Redox regulation of ion anism of store operated calcium entry,” Biochemistry and Cell channels,” Antioxidants and Redox Signaling,vol.21, no.6,pp. Biology, vol. 88, no. 2, pp. 175–183, 2010. 859–862, 2014. 2+ [101] T.Kurosakiand Y.Baba,“Ca signaling and STIM1,” Progress in [116] P. Kaplan, E. Babusikova, J. Lehotsky, and D. Dobrota, “Free 2+ Biophysics and Molecular Biology,vol.103,no. 1, pp.51–58,2010. radical-induced protein modification and inhibition of Ca - ATPase of cardiac sarcoplasmic reticulum,” Molecular and [102] M. Mandi ´ and J. Bak, “Nicotinic acid adenine dinucleotide 2+ Cellular Biochemistry,vol.248,no. 1-2, pp.41–47,2003. phosphate (NAADP) and Ca mobilization,” Journal of Recep- tors and Signal Transduction,vol.28, no.3,pp. 163–184, 2008. [117] G. H. Lushington, A. Zaidi, and M. L. Michaelis, “eo Th retically 2+ predicted structures of plasma membrane Ca -ATPase and [103] M. Brini, T. Cal`ı, D. Ottolini, and E. Carafoli, “The plasma their susceptibilities to oxidation,” Journal of Molecular Graphics membrane calcium pump in health and disease,” The FEBS and Modelling,vol.24, no.3,pp. 175–185, 2005. Journal,vol.280,no. 21,pp. 5385–5397, 2013. [104] K.Samanta,S.Douglas,and A. B. Parekh,“Mitochondrialcal- [118] M. Nishida, T. Ishikawa, S. Saiki et al., “Voltage-dependent N- 2+ 2+ cium uniporter MCU supports cytoplasmic Ca oscillations, type Ca channels in endothelial cells contribute to oxidative 2+ 2+ store-operated Ca entry and Ca -dependent gene expression stress-related endothelial dysfunction induced by angiotensin in response to receptor stimulation,” PLoS ONE,vol.9,no. 7, II in mice,” Biochemical and Biophysical Research Communica- Article ID e101188, 2014. tions,vol.434,no. 2, pp.210–216,2013. [105] A.Lewis,T.Hayashi,T.-P. Su,and M. J. Betenbaugh,“Bcl-2 [119] G. Morciano, C. Giorgi, M. Bonora et al., “Molecular identity of family in inter-organelle modulation of calcium signaling; roles the mitochondrial permeability transition pore and its role in in bioenergetics and cell survival,” Journal of Bioenergetics and ischemia-reperfusion injury,” Journal of Molecular and Cellular Biomembranes,vol.46, no.1,pp. 1–15,2014. Cardiology,vol.78, pp.142–153,2015. [106] A. Hatano, J.-I. Okada, T. Washio, T. Hisada, and S. Sugiura, [120] V.K.Rao,E.A.Carlson,and S. S. Yan, “Mitochondrial 2+ “Mitochondrial colocalization with Ca release sites is crucial permeability transition pore is a potential drug target for to cardiac metabolism,” Biophysical Journal,vol.104,no. 2, pp. neurodegeneration,” Biochimica et Biophysica Acta (BBA)— 496–504, 2013. Molecular Basis of Disease,vol.1842, no.8,pp. 1267–1272, 2014. [107] C. Konrad ` , G. Kiss, B. Tor ¨ ocsi ¨ k et al., “A distinct sequence in [121] G. Basanez, ˜ L. Soane, and J. M. Hardwick, “A new view of the the adenine nucleotide translocase from Artemia franciscana lethal apoptotic pore,” PLoS Biology,vol.10, no.9,Article ID embryosisassociatedwithinsensitivity to bongkrekateand e1001399, 2012. 2+ atypical effects of adenine nucleotides on Ca uptake and [122] Y. Liu and X. J. Chen, “Adenine nucleotide translocase, sequestration,” eTh FEBS Journal ,vol.278,no. 5, pp.822–836, mitochondrial stress, and degenerative cell death,” Oxidative Medicine and Cellular Longevity,vol.2013, ArticleID146860, [108] K.J.Menzies,B.H.Robinson,andD.A.Hood,“Eeff ctofthyroid 10 pages, 2013. hormone on mitochondrial properties and oxidative stress in [123] K. S. McCommis and C. P. Baines, “The role of VDAC in cell cells from patients with mtDNA defects,” American Journal of death: friend or foe?” Biochimica et Biophysica Acta,vol.1818, Physiology—Cell Physiology,vol.296,no. 2, pp.C355–C362, no. 6, pp. 1444–1450, 2012. [124] A.P.Halestrap,E.Doran,J.P.Gillespie, andA.O’Toole,“Mito- [109] A.C.Montezano,D.Burger, G. S. Ceravolo,H.Yusuf,M. chondria and cell death,” Biochemical Society Transactions,vol. Montero, and R. M. Touyz, “Novel nox homologues in the 28,no. 2, pp.170–177,2000. vasculature: focusing on Nox4 and Nox5,” Clinical Science,vol. [125] L. Ghibelli and M. Diederich, “Multistep and multitask Bax 120, no. 4, pp. 131–141, 2011. activation,” Mitochondrion,vol.10, no.6,pp. 604–613,2010. [110] N. D. Roe, E. Y. He, Z. Wu, and J. Ren, “Folic acid reverses nitric [126] G. Gouspillou, N. Sgarioto, S. Kapchinsky et al., “Increased sen- oxide synthase uncoupling and prevents cardiac dysfunction 2+ sitivity to mitochondrial permeability transition and myonu- in insulin resistance: role of Ca /calmodulin-activated protein clear translocation of endonuclease G in atrophied muscle of kinase II,” Free Radical Biology and Medicine,vol.65, pp.234– physically active older humans,” The FASEB Journal ,vol.28, no. 243, 2013. 4, pp. 1621–1633, 2014. [111] A. V. Gordeeva, R. A. Zvyagilskaya, and Y. A. Labas, “Cross- [127] A.P.Halestrap,S.J.Clarke, andS.A.Javadov,“Mitochon- talk between reactive oxygen species and calcium in living cells,” drial permeability transition pore opening during myocar- Biochemistry,vol.68, no.10, pp.1077–1080,2003. dial reperfusion—a target for cardioprotection,” Cardiovascular [112] M. D. Thompson, Y. Mei, R. M. Weisbrod et al., “Glutathione 2+ Research,vol.61, no.3,pp. 372–385, 2004. adducts on sarcoplasmic/endoplasmic reticulum Ca ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic [128] A. P. Halestrap, “What is the mitochondrial permeability tran- sition pore?” Journal of Molecular and Cellular Cardiology,vol. function as well as promote ischemic blood flow recovery,” The Journal of Biological Chemistry,vol.289,no. 29,pp. 19907–19916, 46, no. 6, pp. 821–831, 2009. [129] G.P.McStay, S. J. Clarke,and A. P. Halestrap, “Roleof 2+ [113] B. An, Y. Chen, B. Li, G. Qin, and S. Tian, “Ca -CaM regulating critical thiol groups on the matrix surface of the adenine viability of Candida guilliermondii under oxidative stress by nucleotide translocase in the mechanism of the mitochondrial acting on detergent resistant membrane proteins,” Journal of permeability transition pore,” Biochemical Journal,vol.367,no. Proteomics,vol.109,pp. 38–49, 2014. 2, pp.541–548,2002. Oxidative Medicine and Cellular Longevity 17 [130] G. Sanc ´ hez, C. Fernandez, ´ L. Montecinos, R. J. Domenech, and [146] I.-T. Lee and C.-M. Yang, “Inflammatory signalings involved P. Donoso, “Preconditioning tachycardia decreases the activity in airway and pulmonary diseases,” Mediators of Inflammation , of the mitochondrial permeability transition pore in the dog vol. 2013,Article ID 791231,12pages,2013. heart,” Biochemical and Biophysical Research Communications, [147] M.Nitti,M.A.Pronzato, U. M. Marinari,and C. Domenicotti, vol. 410, no. 4, pp. 916–921, 2011. “PKC signaling in oxidative hepatic damage,” Molecular Aspects of Medicine,vol.29, no.1-2,pp. 36–42, 2008. [131] P.-T.Brinkkoetter,H.Song,R.Los ¨ el et al., “Hypothermic injury: the mitochondrial calcium, ATP and ROS love-hate triangle out [148] D. Mochly-Rosen, K. Das, and K. V. Grimes, “Protein kinase C, of balance,” Cellular Physiology and Biochemistry,vol.22, no.1– an elusive therapeutic target?” Nature Reviews Drug Discovery, 4, pp. 195–204, 2008. vol. 11, no. 12, pp. 937–957, 2012. [132] S. Voronina, E. Okeke, T. Parker, and A. Tepikin, “How to win [149] A. Welman, J. R. Griffiths, A. D. Whetton, and C. Dive, “Protein 2+ ATP and influence Ca signaling,” Cell Calcium,vol.55, no.3, kinase C delta is phosphorylated on five novel Ser/Thr sites pp. 131–138, 2014. following inducible overexpression in human colorectal cancer cells,” Protein Science,vol.16, no.12, pp.2711–2715,2007. [133] Y. Deng,X.Ren,L.Yang, Y. Lin, andX.Wu, “A JNK-dependent [150] C. Aicart-Ramos, L. Sanc ´ hez-Ruiloba, M. Go´mez-Parrizas, C. pathway is required for TNF𝛼 -induced apoptosis,” Cell, vol. 115, no. 1, pp. 61–70, 2003. Zaragoza, T. Iglesias, and I. Rodr´ıguez-Crespo, “Protein kinase D activity controls endothelial nitric oxide synthesis,” Journal of [134] M. Maryanovich and A. Gross, “A ROS rheostat for cell fate Cell Science,vol.127,part15, pp.3360–3372,2014. regulation,” Trends in Cell Biology,vol.23, no.3,pp. 129–134, [151] L. O. Olala, B. A. Shapiro, T. C. Merchen, J. J. Wynn, and W. B. Bollag, “Protein kinase C and Src family kinases mediate [135] S. Wagner,A.G.Rokita, M. E. Anderson,and L. S. Maier, angiotensin II-induced protein kinase D activation and acute “Redox regulation of sodium and calcium handling,” Antioxi- aldosterone production,” Molecular and Cellular Endocrinology, dants and Redox Signaling,vol.18, no.9,pp. 1063–1077, 2013. vol. 392, no. 1-2, pp. 173–181, 2014. [136] J. W. Thompson, S. V. Narayanan, and M. A. Perez-Pinzon, [152] G. Li and Y. Wang, “Protein kinase D: a new player among “Redox signaling pathways involved in neuronal ischemic the signaling proteins that regulate functions in the nervous preconditioning,” Current Neuropharmacology,vol.10,no.4,pp. system,” Neuroscience Bulletin,vol.30, no.3,pp. 497–504, 2014. 354–369, 2012. [153] M. A. Olayioye, S. Barisic, and A. Hausser, “Multi-level control [137] A. Eisenberg-Lerner and A. Kimchi, “PKD is a kinase of Vps34 of actin dynamics by protein kinase D,” Cellular Signalling,vol. that mediates ROS-induced autophagy downstream of DAPk,” 25,no. 9, pp.1739–1747,2013. Cell Death and Dieff rentiation ,vol.19, no.5,pp. 788–797, 2012. [154] Q. J. Wang, “PKD at the crossroads of DAG and PKC signaling,” [138] J. S. Kruk,M.S.Vase,J fi .J.Heikkila, andM.A.Beazely, Trends in Pharmacological Sciences,vol.27, no.6,pp. 317–323, “Reactive oxygen species are required for 5-HT-induced trans- activation of neuronal platelet-derived growth factor and TrkB [155] C. F. Cowell,H.Do¨ppler,I.K.Yan,A.Hausser,Y.Umazawa,and receptors, but not for ERK1/2 activation,” PLoS ONE,vol.8,no. P. Storz, “Mitochondrial diacylglycerol initiates protein-kinase- 9, Article ID e77027, 2013. D1-mediated ROS signaling,” JournalofCellScience,vol.122,no. [139] C. M. Sag, H. A. Wolff, K. Neumann et al., “Ionizing radiation 7, pp.919–928,2009. regulates cardiac Ca handling via increased ROS and activated [156] P. Storz and A. Toker, “Protein kinase D mediates a stress- CaMKII,” Basic Research in Cardiology,vol.108,no. 6, article induced NF-𝜅 B activation and survival pathway,” The EMBO 385, 2013. Journal,vol.22, no.1,pp. 109–120, 2003. [140] G.A.Ramirez-Correa, S. Cortassa,B.Stanley,W.D.Gao,and A. [157] P. Storz, H. Dop ¨ pler, and A. Toker, “Activation loop phos- M. Murphy, “Calcium sensitivity, force frequency relationship phorylation controls protein kinase D-dependent activation of and cardiac troponin I: critical role of PKA and PKC phospho- nuclear factor𝜅 B,” Molecular Pharmacology,vol.66, no.4,pp. rylation sites,” Journal of Molecular and Cellular Cardiology,vol. 870–879, 2004. 48, no. 5, pp. 943–953, 2010. [158] C. M. Sag, S. Wagner, and L. S. Maier, “Role of oxidants on [141] S.S.Taylor, P. Zhang, J. M. Steichen,M.M.Keshwani, andA.P. calcium and sodium movement in healthy and diseased cardiac Kornev, “PKA: Lessons learned aer ft twenty years,” Biochimica myocytes,” Free Radical Biology and Medicine,vol.63, pp.338– et Biophysica Acta—Proteins and Proteomics,vol.1834, no.7,pp. 349, 2013. 1271–1278, 2013. [159] S. Dietrich, R. Uppalapati, T. Y. Seiwert, and P. C. Ma, “Role of [142] J.P.Brennan,S.C.Bardswell,J.R.Burgoyneetal.,“Oxidant- c-MET in upper aerodigestive malignancies—from biology to induced activation of type I protein kinase A is mediated by RI novel therapies,” Journal of Environmental Pathology, Toxicology subunit interprotein disulfide bond formation,” The Journal of and Oncology, vol. 24, no. 3, pp. 149–162, 2005. Biological Chemistry,vol.281,no. 31,pp. 21827–21836, 2006. [160] J. Calise and S. R. Powell, “The ubiquitin proteasome system and [143] S. Papa, D. D. Rasmo, Z. Technikova-Dobrova et al., “Res- myocardial ischemia,” The American Journal of Physiology— piratory chain complex I, a main regulatory target of the Heart and Circulatory Physiology,vol.304,no. 3, pp.H337– cAMP/PKA pathway is defective in different human diseases,” H349, 2013. FEBS Letters,vol.586,no. 5, pp.568–577,2012. [161] I. A. Voutsadakis, “The ubiquitin-proteasome system and sig- [144] S. Papa and D. De Rasmo, “Complex I deficiencies in neurolog- nal transduction pathways regulating Epithelial Mesenchymal ical disorders,” Trends in Molecular Medicine,vol.19, no.1,pp. transition of cancer,” Journal of Biomedical Science,vol.19, no.1, 61–69, 2013. article 67, 2012. [145] A.doCarmo,J.Balc¸a-Silva,D.Matias, andM.C.Lopes,“PKC [162] M. Isasa, A. Zuin, and B. Crosas, “Integration of multiple ubiq- signaling in glioblastoma,” Cancer Biology and Therapy ,vol.14, uitin signals in proteasome regulation,” Methods in Molecular no. 4, pp. 287–294, 2013. Biology,vol.910,pp. 337–370, 2012. 18 Oxidative Medicine and Cellular Longevity [163] M.Kim, R. Otsubo,H.Morikawaetal.,“Bacterialeeff ctors and Biophysical Research Communications,vol.357,no. 3, pp. and their functions in the ubiquitin-proteasome system: insight 731–736, 2007. from the modes of substrate recognition,” Cells,vol.3,no. 3, pp. [179] J.Peng, D. Schwartz,J.E.Elias et al., “A proteomicsapproach 848–864, 2014. to understanding protein ubiquitination,” Nature Biotechnology, [164] S.R.Powell, J. Herrmann, A. Lerman,C.Patterson,and X. vol. 21, no. 8, pp. 921–926, 2003. Wang, “The ubiquitin-proteasome system and cardiovascular disease,” Progress in Molecular Biology and Translational Science, vol. 109, pp. 295–346, 2012. [165] K. M. S. E. Reyskens and M. F. Essop, “HIV protease inhibitors and onset of cardiovascular diseases: a central role for oxidative stress and dysregulation of the ubiquitin-proteasome system,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Dis- ease,vol.1842, no.2,pp. 256–268, 2014. [166] A. Segref, E. Kevei, W. Pokrzywa et al., “Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system,” Cell Metabolism,vol.19, no.4, pp.642–652,2014. [167] A. Warnatsch, T. Bergann, and E. Krug ¨ er, “Oxidation matters: the ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation,” Molecular Immunology,vol.55, no.2,pp. 106–109, 2013. [168] Y.-D. Kwak, B. Wang, J. J. Li et al., “Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration,” The Journal of Neuroscience , vol. 32, no. 32, pp. 10971–10981, 2012. [169] M. Obin, F. Shang, X. Gong, G. Handelman, J. Blumberg, and A. Taylor, “Redox regulation of ubiquitin-conjugating enzymes: mechanistic insights using the thiol-specific oxidant diamide,” The FASEB Journal ,vol.12, no.7,pp. 561–569, 1998. [170] J.Jahngen-Hodge,M.S.Obin, X. Gong et al., “Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress,” The Journal of Biological Chemistry ,vol.272, no.45, pp.28218–28226,1997. [171] A. Kumar, H. Wu, L. S. Collier-Hyams et al., “Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species,” The EMBO Journal ,vol.26, no.21, pp. 4457–4466, 2007. [172] H. Tian, B. Zhang, J. Di et al., “Keap1: one stone kills three birds Nrf2, IKK𝛽 and Bcl-2/Bcl-xL,” Cancer Letters,vol.325,no. 1, pp. 26–34, 2012. [173] K. K. S. Nordgren and K. B. Wallace, “Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts,” Toxicology and Applied Pharmacology,vol. 274, no. 1, pp. 107–116, 2014. [174] H. Kanzaki, F. Shinohara, M. Kajiya, and T. Kodama, “The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling,” eTh JournalofBiologicalChemistry ,vol.288, no.32, pp.23009– 23020, 2013. [175] T. Reinheckel, O. Ullrich, N. Sitte, and T. Grune, “Differential impairment of 20S and 26S proteasome activities in human hematopoietic K562 cells during oxidative stress,” Archives of Biochemistry and Biophysics,vol.377,no. 1, pp.65–68,2000. [176] F.Shang andA.Taylor, “Ubiquitin-proteasome pathwayand cellular responses to oxidative stress,” Free Radical Biology and Medicine,vol.51, no.1,pp. 5–16,2011. [177] A. Sickmann, J. Reinders, Y. Wagner et al., “The proteome of Saccharomyces cerevisiae mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 23, pp. 13207–13212, 2003. [178] H.B.Jeon,E.S.Choi,J.H.Yoonetal.,“Aproteomicsapproachto identify the ubiquitinated proteins in mouse heart,” Biochemical http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxidative Medicine and Cellular Longevity Pubmed Central

ROS and ROS-Mediated Cellular Signaling

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Abstract

Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 4350965, 18 pages http://dx.doi.org/10.1155/2016/4350965 Review Article 1 2 1 3 1 Jixiang Zhang, Xiaoli Wang, Vikash Vikash, Qing Ye, Dandan Wu, 1 1 Yulan Liu, and Weiguo Dong Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China Department of PlasticSurgery,RenminHospitalofWuhan University,Wuhan,Hubei 430060,China Department of Hospital Infection Office, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China Correspondence should be addressed to Weiguo Dong; dwg@whu.edu.cn Received 10 August 2015; Revised 1 December 2015; Accepted 20 December 2015 Academic Editor: Javier Egea Copyright © 2016 Jixiang Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS 2+ impacting on cell-signaling proteins (NF-𝜅 B, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System. 1. Introduction ROS act on cell-signaling proteins, how the cell-signaling proteins influence the level of intracellular ROS in turn, Reactive oxygen species (ROS), generated through a vari- and if there are complex interactions between different ROS ety of extracellular and intracellular actions, have drawn associated signaling pathways have been clarified, but the attention as novel signal mediators which are involved in systemic summary is necessary. In this review, we focus on growth, differentiation, progression, and death of the cell the pattern of the generation and homeostasis of intracellular [1, 2]. As a group of chemical species that include at least ROS, the mechanisms and targets of ROS impacting on oneoxygenatomineachmoleculebut displaystronger cell-signaling proteins, ion channels and transporters, and reactivity than molecular oxygen, ROS comprise free radicals modifying kinases and Ubiquitination/Proteasome System. such as superoxide, hydroxyl radical, and singlet oxygen, as well as nonradical species such as hydrogen peroxide 2. The Homeostasis of ROS formed by the partial reduction of oxygen [3–5]. Oxygen free radicals are highly reactive and have the capacity to damage Under a physiological state, the level of cellular ROS is stable cellular components such as proteins, lipids, and nucleic in a dynamic equilibrium, and this balance is modulated acids. Classically, ROS were regarded as host defending by cellular processes that produce ROS and eliminate them molecule released by neutrophil for destructing exogenous (Figure 1). pathogens such as bacteria; however, accumulated evidence The resource of cellular ROS could be broadly divided indicates that ROS play central roles in determination of cell into two main categories: firstly, there are those biological fate as second messengers and modifying of various signaling processes, mainly the mitochondrial oxidative metabolism, molecules [6–9]. that release ROS as a byproduct, or a waste product, of various It has been demonstrated that ROS have impacts on other necessary reactions and, secondly, there are those several signaling pathways and the mechanisms of how processes, in cellular response to xenobiotics, cytokines, and 2 Oxidative Medicine and Cellular Longevity TNF-𝛼 IL-1𝛽 TNFR IL-1R TRADD NOX TRAF2 NOX NOX RIP EGF PL Rac LPS MyD88 EGFR TLR Grb2 MyD88 Rac NOX SOS AA PKC ERK ROS CPLA2 Cu-Zn-SOD CPLA2 Mn-SOD GPx GST-pi MT3 FHC Mitochondria DDH Figure 1: Homeostasis of intracellular reactive oxygen species. NOX, NADPH oxidases; TNF-𝛼 , tumor necrosis factor-𝛼 ; EGF, epidermal growth factor; IL-1𝛽 , Interleukin-1𝛽 ; SOD, superoxide dismutase; GPx, glutathione peroxidase; GST-pi, glutathione S-transferase pi; MT3, metallothionein-3; FHC, ferritin heavy chain; DDH1, dihydrodiol dehydrogenase; TNFR, tumor necrosis factor receptor; TRADD, TNFRSF1A-associated via death domain; MyD88, myeloid differentiation factor 88; TLR, Toll-like receptor; cPLA2, cytosolic phospholipases A2. bacterial invasion, that generate ROS intentionally, either in (SOD1) and Mn-SOD (SOD2) [25]. SOD2, in the matrix, con- molecular synthesis or in breakdown, as part of a signal trans- verts superoxide, which cannot diffuse across membranes, to ductionpathway,oraspartofacell defense mechanism[10– H O which then is reduced to water by catalase. Compared 2 2 12]. The initial product of the mitochondrial respiratory chain to SOD2, SOD1 mainly reduces the superoxide of inter- −∙ is O mainly generated by complexes I and III and could membrane space and cytosol to H O . Besides, glutathione 2 2 2 be quickly transformed into H O by theenzymesuperoxide peroxidase (GPx), glutathione S-transferase pi (GST-pi), 2 2 dismutase (SOD) and then could be reduced to water by metallothionein-3 (MT3), ferritin heavy chain (FHC), and catalase or glutathione peroxidase [13–16]. NADPH oxidases dihydrodiol dehydrogenase (DDH1 or AKR1C1) and so on (Nox) including Nox1 to Nox5 and Duox1 and Duox2, which also play decisive roles in the process of antioxidant [26–29]. are classified into three groups, according to the presence of domains in addition to the gp91phox (NOX2) domain, 3. ROS and NF-𝜅 B Signaling Pathway are another important source of cellular ROS [17, 18]: NOX1, NOX3, and NOX4 are similar in size and domain structure The transcription factor NF- 𝜅 Biscrucial in aseriesofcel- to NOX2, catalyzing the NADPH-dependent reduction of lular processes, including immune, inflammatory response, oxygen to form superoxide, which can react with itself to cellular adhesion, differentiation, proliferation, autophagy, form H O ; NOX5 is slightly different in domain structure senescence, and apoptosis [30]. Likewise, the disorder of NF- 2 2 to NOX2 but with similar process of superoxide formation; 𝜅 Bhas alreadybeenconrfi medtobeassociatedwithcancer, Duox1 and Duox2 contain a peroxidase-homology domain, arthritis, inflammation, asthma, neurodegenerative diseases, utilizing ROS generated by the catalytic core to generate and heart disease [31]. The family of NF- 𝜅 BconsistsofRel more powerful oxidant species that then oxidize extracellular (c-Rel), RelA (p65), RelB, p50/p105 (NF-𝜅 B1), and p52/p100 substrates [19]. Meanwhile, external stimuli including tumor (NF-𝜅 B2). NF-𝜅 B pathway may be activated by at least two necrosis factor-𝛼 (TNF-𝛼 ), epidermal growth factor (EGF), distinct pathways named the canonical and noncanonical Interleukin-1𝛽 (IL-1𝛽 ), and hypoxia and irradiation also pathways. eTh canonical NF- 𝜅 B-activating pathway is trig- stimulate the formation of ROS [20–24]. gered in response to microbial products, stress, and proin- And, as a critical role to withstand the excessive formation flammatory cytokines and it depends on the phosphorylation of intracellular ROS, series of antioxidant proteins have been of I𝜅 B-kinase (IKK)𝛽 and the phosphorylation and ubiqui- found. The main category of these antioxidant proteins is tination of I𝜅 Ba and its degradation by the proteasome, and superoxide dismutases (SOD) which contain Cu-Zn-SOD then NF-𝜅 B translocates into the nucleus where it activates Oxidative Medicine and Cellular Longevity 3 the transcription of target genes [32–34]. In contrast, the Ras. Subsequently activated Ras recruits cytoplasmic Raf noncanonical NF-𝜅 B-activating pathway is activated by B- (MAPKKK) to the cell membrane for activation. Activated cell activating factor (BAFF) [35], lymphotoxin𝛽 (LT𝛽 )[36], Raf phosphorylates MEK1/2 (MAPKK), which then phos- CD40 ligand [37], CD27 ligand [38], human T-cell leukemia phorylates ERK1/2 (MAPK) that translocate to the nucleus virus (HTLV) [39], and Epstein-Barr virus (EBV) [40] and and activates several transcription factors [54, 55]. ROS have it relies on IKK𝛼 and causes activation of NF-𝜅 B2/RelB been showntoactivatethe receptorsofEGF andPDGF, complexes by inducing the proteolytic processing of the NF- though without corresponding ligands, which can stimulate 𝜅 B2/p100 precursor. Ras and the subsequent activation of ERK pathway [56, 57]. Recently, cumulative evidence has indicated that there In addition, it has been demonstrated that ROS generated by is an interrelation between ROS and NF-𝜅 B. Firstly, ROS commensal bacteria inactivated dual-specific phosphatase 3 influence the activation of NF- 𝜅 B pathway mainly by inhibit- (DUSP3) by oxidation on Cys-124 results in ERK activation O leads ing the phosphorylation of I𝜅 B𝛼 .Aseries of studieshas [58]. Meanwhile, in some cells, treatment with H 2 2 testiefi d that I 𝜅 B𝛼 is usually phosphorylated on serines 32 to the phosphorylation and activation of phospholipase C- and 36 by IKK leading to its ubiquitination and degradation (PLC-) gamma which results in the generation of inositol and exogenously added H O affects the phosphorylation of trisphosphate (IP3) and diacylglycerol (DAG) [59]. IP3 could 2 2 I𝜅 B𝛼 on Tyr42 or other tyrosine residues and subsequent increase the intracellular calcium by inducing the release of degradation of I𝜅 B𝛼 and activation of NF-𝜅 B pathway [41, calcium from intracellular stores that can mediate activation 42]. In addition, IKK is also the primary target for ROS in of ERK pathway and generation of DAG and increases in influencing NF- 𝜅 B and the S-glutathionylation of IKK𝛽 on intracellular calcium which results in the activation of several cysteine 179 by ROS results in the inhibition of IKK𝛽 activity forms of protein kinase C (PKC) leading to Ras and Raf [43]. en, Th MEKK1, the kinases upstream of IKK, may be activation [60, 61]. potentially regulated by ROS. MEKK1 is a redox-sensitive The JNK pathway is activated by environmental stress kinase that could be glutathionylated at C1238 leading to (oxidative stress) and cytokines (tumor necrosis factor, TNF, its inactivation [44]. Thirdly, ROS also could disturb the and FAS) and involves a kinase cascade similar to the ubiquitination and degradation of I𝜅 B and then the activation ERK pathway with a MAPKKK activating a MAPKK and of NF-𝜅 B by inactivating Ubc12. Furthermore, NIK, the the MAPKK subsequently phosphorylating JNK on critical upstream kinase in the noncanonical pathway, is believed threonine and tyrosine residues resulting in the activation of to be activated by ROS through inhibition of phosphatases JNK; aer ft wards JNK translocate to the nucleus and regulate and oxidation of cysteine residues [45, 46]. Meanwhile, NF- the activity of multiple transcription factors. eTh MAPKKK 𝜅 B pathway also can influence the ROS levels by increasing in JNK pathway includes MEKK1, MEKK2, MEKK3, and expression of antioxidant proteins such as Cu-Zn-SOD, Mn- MEKK4, MLK, and ASK1 and MAPKK contain MKK4, SOD, GPx, GST-pi, MT3, and FHC (Figure 2). MKK3, MKK6, and MKK7 [62, 63]. ROS could act on TRX and glutaredoxin, a kind of redox-sensitive proteins, to disso- 4. ROS and MAPKs Signaling Pathway ciate from ASK-1 for its activation, resulting in the activation of JNK [64]. Also, ROS could trigger the detachment of JNK The mitogen-activated protein kinase (MAPK) cascades, con- from glutathione S-transferase pi (GSTp), which can interact sisting of the extracellular signal-related kinases (ERK1/2), with JNK to suppress its activation, thereby facilitating JNK the c-Jun N-terminal kinases (JNK), the p38 kinase (p38), activation [65]. ROS could be able to allow ASK1 to be and the big MAP kinase 1 (BMK1/ERK5) pathway [47], are oligomerized and autophosphorylated and become activated major intracellular signal transduction pathways that play by oxidizing thioredoxin, which inhibits the activation of an important role in various cellular processes such as cell ASK1 via binding to the N-terminal of ASK1 [66]. TNF growth, differentiation, development, cell cycle, survival, and receptor-associated JNK activation is thought to be mediated cell death [48]. Similarly, ERK, JNK, p38, and BMK1 are in part by oxygen radicals because superoxide anion and lipid all serine/threonine kinases that are directed by a proline peroxide-scavengers inhibit JNK activation. Furthermore, residue. Along with the pathways in which these four MAP it is possible that low levels of ROS intermediates leave kinases are activated share similarity by extracellular or phosphatase activity intact, leading to a transient activation intracellular stimuli, a MAP kinase kinase kinase (MAPKKK) of JNK. Higher levels of ROS may activate JNK pathway is activated and then phosphorylating and activating a MAP and inactivate the phosphatases resulting in a prolonged kinase kinase (MAPKK) and the MAPKK phosphorylating activation of JNK (Figure 3). and activating a MAP kinase (MAPK) and activated MAPKs The p38 pathway is activated by extracellular stresses, phosphorylate various substrate proteins, resulting in regula- growth factor, and cytokines, such as tumor necrosis factor- tion of various cellular activities [49–51]. a (TNF-a) and IL-1𝛽 .TheTNF receptorsswitchonthe The ERK pathway is activated mainly by growth fac- p38 pathway via the activation of cdc42, whereas growth tors (epidermal growth factor, EGF, and platelet-derived factor receptors switch on the p38 pathway by the sequential growth factor, PDGF) and cytokines (IL-1𝛽 and TNF-𝛼 ), activation of Ras and Rac1 [67]. Small G-proteins Rac1 and its activation is related to the stimulation of tyrosine kinase receptors [52, 53]. When these receptors of growth andcdc42 activate ASK1,MLK3, andMLK3thatdirectly activate MKK3 and MKK6 which phosphorylates p38 on both factors and cytokines are bound with their ligands, the GDP bound Ras is converted to GTP that in turn activates tyrosine and threonine residue resulting in the activation of 4 Oxidative Medicine and Cellular Longevity ROS Noncanonical pathway Canonical pathway NIK MEKK1 IKK𝛼 IKK𝛼 IKK𝛽 IKK𝛼 C179 IKK𝛼 IKK𝛾 Mn-SOD IKK𝛼 IKK𝛽 IKK𝛼 Ox IKK𝛾 RelB p100 NEDD8 Ubc12 Rel B IKB𝛼 p100 RelA p50 IKB𝛼 RelB RelA p52 p50 Ub Ub RelB p100 Ub Ub Ub Ub P IKB𝛼 RelA p50 Degradation RelA p50 Figure 2: Cross talk between ROS and NF- 𝜅 B signaling pathway. MEKK1, mitogen-activated protein kinase kinase kinase 1; PKC, protein kinase C; NIK, NF-𝜅 B inducing kinase; NEDD8, neural precursor cell expressed developmentally downregulated 8. p38 pathway [68, 69]. Some initial proteins, such as ASK- downstream targets including Mef2C, c-Myc, and possibly 1, in the JNK pathway, are also involved in the activation of Nrf2 (Figure 3). the p38 pathway. Oxidative stress directly or indirectly aeff cts ASK1, MEKK1, MEKK2, MEKK3, MEKK4, and MLK3 and 5. ROS and Keap1-Nrf2-ARE subsequently activates p38 pathway (Figure 3). Signaling Pathway The BMK1 (also known as ERK5) pathway, which has been involved in cell survival, antiapoptotic signaling, angio- Another signaling pathway, Keap1-Nrf2-ARE, performs crit- genesis, cell motility, differentiation, and cell proliferation, ical role in maintaining the cellular redox balance and is one of the least studied members of the MAPK family metabolism andinducinganadaptiveresponsefor oxidative [70]. Oxidative stress (H O ) could influence BMK1 pathway stress that can otherwise lead to many inflammatory diseases 2 2 by activating MEKK2 and MEKK3 directly. en Th MEK5 including cancer, Alzheimer’s disease (AD), Parkinson’s dis- and BMK1 are activated sequentially and BMK1 acts on its ease (PD), and diabetes. This pathway consists of three main RelA p50 RelB p52 Oxidative Medicine and Cellular Longevity 5 ROS 2+ Ca RTK SOS Ras PLC𝛾 Grb2 Shc MEKK1/2/3/4 2+ Ca MKK3 PKC MLK3 ASK1 MKP Raf MKK4/7 MKK5 MKK3/6 MEK1/2 JNK BMK1 p38 MAPK ERK Stat1/3 ELK1 c-Jun ELK1 ATF-2 ELK1 MEF-2C ATF-2 MEF-2A/2C/2D Figure 3: Cross talk between ROS and MAPKs signaling pathway. MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinases; JNK, c-Jun N-terminal kinases; p38, p38 kinase; BMK1/ERK5, big MAP kinase 1; MAPKKK, MAP kinase kinase kinase; MAPKK, MAP kinase kinase; MAPK, MAP kinase; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol. cellular components: Kelch-like ECH-associated protein 1 an inhibitor of Nrf2 (INrf2), is associated with Nrf2 (the (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), majority of which resides in the cytoplasm) and recruits and interacts with the cullin-3 E3-ubiquitin ligase (Cul3) [77]. and antioxidant response elements (ARE) [71–76]. Under And the ubiquitination of Nrf2 is stimulated that targeted normal physiological conditions, Keap1, which is also called 6 Oxidative Medicine and Cellular Longevity 2+ Nrf2 for degradation by the 26S proteasome (more related 7. Cross Talk between ROS and Ca information has been provided in “ROS and Ubiquitina- 2+ In eukaryotic cells, Ca is one of the most versatile signals tion/Proteasome System” section) [78]. involved in the control cellular processes and functions, such However, under oxidizing conditions, the increased level as contraction, secretion, metabolism, gene expression, cell of intracellular ROS promotes the dissociation of Nrf2 and 2+ survival,andcelldeath[96,97].CytosolicCa concentration Keap1, either by the oxidization of key reactive cysteine 2+ ([Ca ] ) is determined by a dynamic balance between the residues (Cys273, Cys288, and Cys151) that govern Keap1 2+ activity or via the activation of kinases, such as protein mechanisms that pour Ca into the cytoplasm, including 2+ kinase C (PKC), MAPK, phosphatidylinositide 3-kinases Ca influx from the extracellular medium and intracellular (PI3Ks), and protein kinase-like endoplasmic reticulum stores such as endoplasmic reticulum (ER) or sarcoplas- kinase (PERK) that phosphorylate Nrf2 [79–81]. Aeft r that mic reticulum (SR), and those processes that remove it 2+ the dissociated Nrf2 is transferred to the nucleus where it out, involving Ca efflux across the plasma membrane dimerizes with members of another b-zip family, the small and sequestration into mitochondria [98, 99]. The uptake 2+ Maf proteins (Maf-F, Maf-G, and Maf-K), binds to ARE of mechanisms of Ca into the cytoplasm refer to the inositol phase II genes, and translates detoxification enzymes such 1,4,5-trisphosphate receptor (IP R), the ryanodine receptor as glutathione synthetase (GSS), glutathione reductase (GR), (RyR), and the nicotinic acid-adenine dinucleotide phos- 2+ Gpx, thioredoxin (TRX), thioredoxin reductase (TRR), and phate (NAADP) that are responsible for Ca release from ER 2+ peroxiredoxin (PRX) to prevent the oxidative stress [73, and SR, as well as voltage-dependent Ca channels (VDCC) 2+ 82]. Meanwhile, oxidative stress activates GSK3𝛽 leading to and store-operated Ca channel (SOC), which are in charge nuclearimportofSrc kinasessuchasSrc,Yes,Fyn,and 2+ of Ca influx from extracellular matrix [100–102]. Mean- Fgr, which phosphorylates Nrf2 (Tyr568) followed by the 2+ while, the mechanisms of removing Ca are determined nuclear export with Keap1 and degradation of Nrf2 [83, 84] 2+ by the plasma membrane Ca ATPase (PMCA), which (Figure 4). 2+ mediates Ca extrusion across the plasma membrane into 2+ the cytoplasm, the sarcoplasmic/endoplasmic reticulum Ca 6. ROS and PI3K-Akt Signaling Pathway 2+ ATPase (SERCA), which reintroduces Ca into the ER/SR, + 2+ Na /Ca exchanger (NCX) that involves the clearance of The phosphoinositide-3-kinase- (PI3K-) Akt pathway has 2+ + Ca through its exchange by Na , and the mitochondrial been involved in many critical cellular functions, includ- 2+ 2+ Ca uniporter (MCU) that transports Ca into the mito- ing protein synthesis, cell cycle progression, proliferation, chondria [103, 104]. Recent studies have demonstrated that apoptosis, autophagy, and drug resistance in response to 2+ the ROS and Ca signaling systems influence each other in growth factor (EGF, PDGF, NGF, and VEGF), hormone various ways (Figure 6). (prostaglandin, PGE ), and cytokine (IL-17, IL-6, and IL-2) 2+ Numerous evidences indicate that intracellular Ca stimulation [85–87]. eTh binding of growth factor to its recep- modulates both ROS generation and ROS clearance processes tors directly stimulates class 1A PI3Ks bound via their regula- andthereby shift theredox statetoeithermoreoxidizedor tory subunit or adapter molecules such as the insulin receptor 2+ substrate (IRS) proteins, which subsequently triggers the acti- reducedstate.Theprimary role of Ca is the promotion of vation of PI3K. Afterwards, the activated PI3K catalyzes the ATP synthesis and ROS generation in mitochondria via stim- synthesis of phosphatidylinositol 3,4,5-triphosphate (PIP3), ulating the Krebs cycle enzymes and oxidative phosphoryla- from phosphatidylinositol 4,5-bisphosphate (PIP2) [88]. eTh tion [105]. The mitochondrial respiratory chain provides the −∙ membranal PIP3, a signaling molecule, recruits and acti- main source of physiological ROS production (O ), which vates proteins that contain the pleckstrin homology (PH) is either converted to H O by spontaneous dismutation or 2 2 2+ domain such as the phosphoinositide-dependent protein catalyzed by SOD. Mitochondrial Ca could activate three kinase (PDK) and protein kinase B (Akt) serine/threonine dehydrogenases of the TCA cycle (pyruvate dehydrogenase, kinases and the activation of PDK and Akt successively isocitrate dehydrogenase, and oxoglutarate dehydrogenase), promotes the activation and transcription of their target the ATP synthase (complex V), and the adenine nucleotide genes (GSK3, FOXO, BAD, mTOR1, and p53) [89–92]. translocase and then increase the generation of ROS [106– 2+ ROS not only activate PI3K directly to amplify its down- 108]. Along with that, Ca regulates multiple extramitochon- stream signaling but also concurrently inactivate phosphatase drial ROS generating enzymes, including NOX [109] and and tensin homolog (PTEN), which negatively regulates the nitric oxide synthase (NOS) [110], both in physiological and synthesis of PIP3 and thereby inhibits the activation of Akt, 2+ in pathological processes. Meanwhile, Ca modulates ROS via oxidizing cysteine residues within the active center [93]. clearance processes via regulating the antioxidant defense In addition, ROS is able to promote the phosphorylation by 2+ system: on one hand, Ca can directly activate antioxidant casein kinase II on PTEN which urges PTEN to enter the enzymes (catalase and GSH reductase), increase the level of proteolytic degradation pathway [93]. Furthermore, protein 2+ SOD, andinducemitochondrial GSHrelease earlyinCa - phosphatase 2A (PP2A), which might be deactivated by ROS, induced mitochondrial permeability transition pore (mPTP) could inhibit Akt/PKB. However, it seems that, at lower levels, opening; on the other hand, calmodulin (CaM), ubiquitous ROS oxidize the disulfide bridges in Akt/PKB, leading to 2+ Ca -binding protein, could activate catalases in the presence the association of Akt/PKB with PP2A and thus short-term 2+ activation of Akt/PKB [46, 94, 95] (Figure 5). of Ca and downregulates H O levels [111–113]. 2 2 Oxidative Medicine and Cellular Longevity 7 Cytomembrane Ub Ub Ub Ub Nrf2 Nrf2 Keap1 Keap1 Keap1 Keap1 Keap1 Keap1 Degradation Cul3 Cul3 Cul3 Nrf2 NEDD8 Ubc12 ROS Nrf2 P C273/288/151 Keap1 Keap1 Ub Cul3 GS3K𝛽 Ub PKC Ub Ub GSS GR PRX Nrf2 TRR TRX C273/288/151 Fyn Keap1 Keap1 Nrf2 Cul3 Keap1 Keap1 Cul3 C273/288/151 Nrf2 ARE Nucleus Figure 4: Cross talk between ROS and Keap1-Nrf2-ARE signaling pathway. Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response elements; Cul3, cullin-3 E3-ubiquitin ligase; GSK3𝛽 , glycogen synthase kinase 3; Ubc, E2-ubiquitin conjugating enzyme. 2+ Furthermore, ROS also inu fl ences Ca signaling via oxi- contain numerous free Cys residues which are oxidized by 2+ ROS in the context of oxidation state which inhibits the activ- dizing Cys thiol of Ca channels/pumps/exchangers involv- 2+ ity of SERCA and decreases Ca inufl xfromthecytoplasmto ing RyR, IP R, SERCA, PMCA, and NCX. RyR/IP R, as well 3 3 ER [116]. Additionally, although PMCA is a slower pump than as many of the regulatory proteins that form complex with the SERCA, it can be reversibly inactivated by ROS by altering RyR/IP R, contains multiple reactive Cys thiols that inu fl ence 589 622 831 channel gating or assembly [114]. Thiol oxidation of RyR/IP R the Tyr ,Met ,and Met residues [117]. And ROS both by ROS in general increases channel activity and thereby stimulate and decrease NCX activity: H O generated from 2 2 2+ the xanthine/xanthine oxidase system enhances NCX activity promotes Ca eu ffl x via enhancing intersubunit binding and and oxidants from hypoxanthine/xanthine oxidase depress preventing the binding of the negative regulator calmodulin NCX activity. Moreover, ROS also alter the activity of VDCC, to the receptor [115]. As with RyR/IP R, SERCA pumps also 3 8 Oxidative Medicine and Cellular Longevity Cytomembrane PIP2 PIP3 PIP2 Degradation Akt PTEN Casein kinase II ROS ROS BAD GSK3 mTORC1 FOXO Figure 5: Cross talk between ROS and PI3K-Akt signaling pathway. PI3K, phosphoinositide-3-kinase; Akt, protein kinase B; PTEN, phosphatase and tensin homolog; FOXO, forkhead box protein O; mTOR1, mechanistic target of rapamycin 1. 2+ Na Ca 2+ Ca NCX PMCA VDCC Cytomembrane NOX 2+ 2+ Na Ca 2+ Ca Ca 2+ Ca ROS mPTP ATP IP3R ROS CaM RyR TCA SERCA 2+ 2+ Ca Ca Mitochondria Endoplasmic reticulum 2+ Figure 6: Cross talk between ROS and Ca . IP3R, inositol 1,4,5-trisphosphate receptor; RyR, the ryanodine receptor; VDCC, voltage- 2+ 2+ 2+ dependent Ca channels; SOC, store-operated Ca channel; SERCA, sarcoplasmic/endoplasmic reticulum Ca ATPase; PMCA, plasma 2+ 2+ + 2+ membrane Ca ATPase; MCU, mitochondrial Ca uniporter; TCA cycle, tricarboxylic acid cycle; NCX, Na /Ca exchanger. Oxidative Medicine and Cellular Longevity 9 ROS Bid Cytoplasma JNK jBid 2+ Ca mPTP UP VDCC VDCC C160 ANT ANT C56 Cyp-D Cyp-D C203 2+ Ca ATP ROS Mitochondria TCA Figure 7: Cross talk between ROS and mPTP. VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocator; Cyp-D, cyclophilin-D. 2+ especially the activity of L-type Ca channels, which has that when mPTP opens by the activation of various sig- been associated with the oxidation of -SH groups resulting nals, mitochondrial permeability is changed which dissipates 2+ the proton electrochemical gradient (ΔΨ𝑚) , which drives in altered Ca entry in the cytoplasm [118]. multiple mitochondrial functions, leading to ATP depletion, further reactive oxygen species production, and ultimately swelling and rupture of the organelle. This in turn releases 8. ROS and mPTP proapoptotic proteins: cytochrome c (Cyt C) [124] binds Several studies, lasting for decades, have showed that mPTP, to apoptotic protease activating factor-1 (Apaf1) and then a large, nonspecific channel spanning the inner mitochon- formsapoptosomethatactivates thecaspase-9 andcaspase- drial membrane (IMM) and outer mitochondrial membrane 3 protease system and induces apoptosis, Smac/DIABLO (OMM) [119, 120], mediates the lethal permeability changes [125] activates caspases by sequestering caspase-inhibitory that initiate mitochondrial-driven death. Hitherto, the puta- proteins, and endonuclease-G (endoG) [126] mediates DNA 2+ tive components include the voltage-dependent anion chan- fragmentation. Factors like the changes of intracellular Ca , nel (VDAC) or porin, localized in the OMM; the adenine the level of ATP/ADP, the release of Cyt C, regulation nucleotide translocator (ANT) in the IMM; the peripheral in mitochondrial morphology, and ROS generation often benzodiazepine receptor and the Bcl-2 family proteins; the influence the mPTP opening [127] (Figure 7). The mechanism of ROS mediating the mPTP formation hexokinaseboundtoporin;thecyclophilin-D(Cyp-D),areg- involves several pathways. Firstly, ROS directly modulate ulatory element in the matrix; glycogen synthase kinase-3b (GSK-3b); and cytochrome c [121–123]. It has been described mPTP opening by oxidizing four different sites: Cys of 10 Oxidative Medicine and Cellular Longevity 2+ Ca 2+ Ca channel Na-K ATPase Na channel NCX Cytoplasm Target proteins M281/282 PKC CaMKII C17 PKA C38 ROS Abl Src Complex I Ras/Raf/MAPK PKC RyR S738/742 PKA P Y463 Endoplasmic reticulum Target proteins Figure 8: Cross talk between ROS and protein kinase. CaMKII, calc ium/calmodulin-dependent protein kinase II; RyR, the ryanodine receptor. ANT, regulated by glutathione oxidation and protected by function in various cellular processes via oxidating sulyfh dryl low concentration of N-ethylmaleimide (NEM) or mono- (SH) groups of cysteine residues in protein kinases including bromobimane [128]; Cys56 of ANT, sensitive to the redox protein kinase A (PKA) [136], protein kinase C (PKC) [137], state of the matricial pyridine nucleotides perhaps with the protein kinase D (PKD) [138], receptor tyrosine kinase (RTK) mediation of thioredoxin or lipoamide and also protected [139], and Ca/calmodulin independent protein kinase II by NEM, not by monobromobimane [129]; external thiol (CaMKII) [140] and then activated protein kinases phospho- groups (SH), promoting PTP opening by reaction with NEM rylate their target proteins which are involved in different cellular signaling mechanisms (Figure 8). or copper-orthophenanthroline; and Cys of Cyp-D, S- PKA, also called cAMP-dependent protein kinase A, is glutathionylation of which prevents Cyp-D binding to ANT organized as tetramers comprising two catalytic and two which blocks MPT [130]. Besides, ROS indirectly modulate 2+ regulatory subunits. eTh activation of PKA can occur by the opening of mPTP via increasing the mitochondrial Ca 2+ 2+ binding of two molecules of cAMP to each regulatory subunit concentration ([Ca ] ): ROS promotes Ca efflux from and then this activated PKA phosphorylates its targeting ER/SR to cytoplasm and from cytoplasm to mitochondria. 2+ 2+ proteins, including RyR and L-type Ca channel and phos- The increase of Ca concentration in turn favors ATP pholamban (PLN) [141, 142]. Recently, it has been shown that production and ROS generation during oxidative phospho- type Iregulatorysubunit IofPKA is subjectedtooxidation rylation and promotes the opening of mPTP [131, 132]. In by ROSonCys 17 and38, whichleads to theintersubunit addition, ROS also may translocate Bid to jBid via activating disulfide bond formation (between two regulatory subunits) the JNK pathway, which leads to the opening of mPTP [133– anddissociationofthe PKAholoenzymecomplex. Andthe 135]. translocation (from cytosol to membrane and myofilaments) andactivationoftypeIPKAresultinincreased cellular 9. ROS and Protein Kinase contractility without elevations in cAMP [143]. Meanwhile, not only do ROS influence the phosphorylation of PKA, but Recently, it is becoming increasingly apparent that, like phosphorylation of PKA also has an impact on the ROS physiological second messengers in signal transduction, ROS Oxidative Medicine and Cellular Longevity 11 homeostasis. In mammalian cells, the cAMP/PKA pathway 10. ROS and Ubiquitination/Proteasome regulates the expression, assembly, and catalytic activity System of complex I of the mitochondrial respiratory chain and Ubiquitination/Proteasome System (UPS) includes four subsequently determines the synthesis and accumulation of components: proteasome, ubiquitin, the ubiquitination ROS [144, 145]. Protein kinase C (PKC), containing four homologous machinery, and the deubiquitinases (DUBs) [160]. UPS play indispensable roles in variety of biological processes domains termed C1, C2, C3, and C4, is a superfamily of such as regulation of the cell cycle, inflammatory responses, structurally correlated serine-threonine kinases that cat- alyze numerous critical biochemical reactions, like cellular immune response, protein misfolding, and endoplasmic reticulum-associated degradation of proteins. Initially, responses, gene expression, cell proliferation, survival, and ubiquitin gets activated by an ATP-dependent E1 ubiquitin- migration[146].Inaninactivestate,PKC is looselyassociated activating enzyme which results in the transient adenylation with membrane lipids and chiefly isolated in the cytosolic of ubiquitin and the transference of ubiquitin from E1 to a fraction, whereas activation of PKC increases the an ffi ity of cysteine residue of E2-ubiquitin conjugating enzyme (Ubc); the enzyme for membrane lipids and consequently stabilizes then E3 transfers ubiquitin from E2-ubiquitin to the lysine its membrane association, which causes a conformational residue of a substrate protein by catalyzing the peptidyl change to a catalytically competent form of PKC [147–149]. Both the regulatory and catalytic domains of PKC contain bond formation between ubiquitin and the target protein and subsequently the elongation of the polyubiquitin chain cysteine-rich regions, thus making it a highly susceptible which transfers the client protein to the proteasome for direct target for redox regulation. Oxidants play a dual role in both stimulation and inactivation of PKC with relation degradation through specific proteolytic activities [161–163]. Concurrently, DUBs can remove ubiquitin from substrates to the concentration: higher doses of oxidants react with and disassemble polyubiquitin chains which may lead to catalytically important cysteine residues inactivating PKC; protein stabilization [164]. however, low doses induce stimulation of PKC activity. It Recently, an increasing number of studies have docu- has been found that H O stimulated the activation of 2 2 tyrosine kinases and was able to indirectly regulate the mented the interactions between ROS and UPS [165–168]. tyrosine phosphorylation of PKC-𝛿 at residues 512 and 523 The susceptibility of the UPP to oxidative stress may have [150]. been anticipated, because E1, E2, some E3 enzymes, and PKD isoforms (PKD1, PKD2, and PKD3), the eeff ctors of DUBs have a cysteine residue, which are sensitive to ROS, in diacylglycerol (DAG), and protein kinase c (PKC) effectors their active sites (Figure 9). The rapid depletion of reduced have been described as vital regulators of diverse cellular glutathione (GSH) and improvement of the levels of oxidized pathways and mediate the actions of growth factors, neu- glutathione (GSSG) upon exposure to oxidative stress result rotransmitters, hormones, and other stimuli that activate in the oxidation of cysteine residues in the active sites of E1 PLC𝛽 and PLC𝛾 [151–153]. The binding of the corresponding and E2 and the generation of mixed disulfide bonds which ligand to G-protein coupled receptors (GPCRs) or tyrosine blocks their binding to ubiquitin [169, 170]. It has also been kinase receptors activates PLC𝛽 and PLC𝛾 .Then PLC 𝛽 cleave reported that bacteria elicit ROS generation in epithelial cells PI (4, 5) P2 that generates DAG and IP3. Subsequently, that inactivate the Ubc12 enzyme, preventing the neddylation membranal DAG binds to and activates PKC and recruits 𝛽 -TrCP of cullin-1. Unneddylated cullin in E3-SCF complex PKD, which then is phosphorylated and activated by PKC rendersitunabletocarry outubiquitinationand is thus 744 748 on Ser and Ser residues [154, 155]. ROS inu fl ence the making it inactive [171]. Additionally, numerous reports have activation of PKD in a various manner: ROS trigger PLD1 suggested that Kelch-like ECH-associated protein-1 (Keap1), and phosphatidic acid phosphatase- (PAP-) catalyzed DAG a substrate adaptor protein for a cullin-3 E3-ubiquitin ligase synthesis and concomitant recruitment of PKD1 and PKC𝛿 (Cul3)/Ring-Box1 (Rbx1) dependent complex, plays a critical at the outer mitochondrial membrane [156]; ROS promotes role in the ubiquitination and degradation of Nrf2, IKK𝛽 , phosphorylation of PKD on its Tyr residue by Src that cre- and Bcl-2/Bcl-xL, also being disturbed by ROS via mod- ates a binding site for the PKC𝛿 C2 domain which facilitates ifying the reactive cysteines (Cys273, Cys288, and Cys151) the binding between PKC𝛿 with PKD and the activation of and then inducing a conformational change that leads to PKD[157];ROS also couldleadtothe activation of PKD therelease of Nrf2,IKK𝛽 , and Bcl-2/Bcl-xL from Keap1 via the phosphorylation at Tyr residue by the tyrosine and the suspending of their ubiquitination and degradation kinase Abl. Additionally, expression of mitochondrial Mn- [172–174]. Meanwhile, the proteasome is also a target of SOD induced by PKD1-NF-𝜅 B signaling removes toxic ROS oxidative stress and the 26S proteasome was more sus- [158]. ceptible than the 20S proteasome to oxidative inactivation Moreover, the activation of RTK and CaMKII could be [175]. affected by the level of intracellular ROS. eTh oxidation In turn, UPS regulates cellular redox status via the degra- 281 282 on Met and Met residues in the regulatory domain dation of Nrf2 and the activation of NF-𝜅 Band both could results in the activation of CaMKII [159]. And RTKs such mediate the level of ROS by their downstream antioxidative as the insulin receptor, EGFR, platelet-derived growth factor proteins [176]. In addition, accumulating evidences made it receptor (PGFR), and c-Ret have all been reported to undergo evident that the UPS plays essential roles in regulating mito- direct oxidation on their cysteine residue. chondrial processes: oxidative phosphorylation, TCA cycle, 12 Oxidative Medicine and Cellular Longevity Cytomembrane IkB𝛼 NEDD8 Nrf2 Ubc12 𝛽 -Trcp1 Keap1 Keap1 Skp1 Ub Ub Rbx1 Rbx1 Ub Ub Ub Ub Ub E2 E2 Cul3 Cul3 ROS IkB𝛼 Nrf2 𝛽 -Trcp1 Keap1 Keap1 Skp1 Rbx1 Ubc12 NEDD8 Ub Rbx1 Ub E2 Ub Ub Ub Cul3 Ub E2 Ub Ub Cul3 NEDD8 𝛽 -Trcp1 Ub Ub Skp1 Ub Ub Rbx1 IkB𝛼 Nrf2 E2 Cul3 NEDD8 Keap1 Keap1 Rbx1 NEDD8 E2 Cul3 Degradation Figure 9: Regulation of Ubiquitination/Proteasome System by ROS. Ubc, E2-ubiquitin conjugating enzyme. and mitochondrial dynamics which subsequently regulate signaling pathways which are sensitive to ROS and the high ROS generation [177–179]. degree of complexity in simultaneous actions of ROS, even though we have learnt much about the mechanisms by which ROS influences signaling, in particular, the interactions 11. Conclusions between different ROS associated signaling pathways are yet It has been clearly demonstrated that redox equilibrium to be elucidated. plays pivotal roles in cells’ physiological and pathological events due to ROS’s ability to activate or deactivate a variety Conflict of Interests of receptors, proteins, ions, and other signaling molecules. When the redox equilibrium is disturbed due to the excessive eTh authors declare that there is no conflict of interests accumulation or depletion of ROS, many cellular signal- regarding the publication of this paper. ing pathways are influenced which confers to the cellular dysfunction and subsequently the development of various pathologies. eTh refore, unveiling the mechanisms of ROS Authors’ Contribution regulating redox-associated signaling pathways is essential in providing relevant targets in order to develop innovative and Jixiang Zhang and Xiaoli Wang contributed equally to this effective therapeutic strategies. However, due to numerous work. Ub Oxidative Medicine and Cellular Longevity 13 References [20] M. D. Brand, “eTh sites and topology of mitochondrial superox- ide production,” Experimental Gerontology,vol.45, no.7-8,pp. [1] H. Zhang, A. M. Gomez, X. Wang, Y. Yan, M. Zheng, and H. 466–472, 2010. 2+ Cheng, “ROS regulation of microdomain Ca signalling at the [21] S. Roberge, J. Roussel, D. C. Andersson et al., “TNF-𝛼 -mediated dyads,” Cardiovascular Research, vol. 98, no. 2, pp. 248–258, caspase-8 activation induces ROS production and TRPM2 acti- vation in adult ventricular myocytes,” Cardiovascular Research, [2] L. A. Sena and N. S. Chandel, “Physiological roles of mitochon- vol. 103, no.1,pp. 90–99, 2014. drial reactive oxygen species,” Molecular Cell,vol.48, no.2,pp. [22] D. V. Ilatovskaya, T. S. Pavlov, V. Levchenko, and A. Star- 158–166, 2012. uschenko, “ROS production as a common mechanism of ENaC [3] M. Giorgio, M. Trinei, E. Migliaccio, and P. G. Pelicci, “Hydro- regulation by EGF, insulin, and IGF-1,” The American Journal of gen peroxide: a metabolic by-product or a common mediator Physiology—Cell Physiology, vol. 304, no. 1, pp. C102–C111, 2013. of ageing signals?” Nature Reviews Molecular Cell Biology,vol. [23] M. Clauzure, A. G. Valdivieso, M. M. Massip Copiz, G. Schul- 8, no. 9, pp. 722–728, 2007. man, M. L. Teiber, and T. A. Santa-Coloma, “Disruption of [4] S. I. Liochev, “Reactive oxygen species and the free radical interleukin-1𝛽 autocrine signaling rescues complex I activity theory of aging,” Free Radical Biology and Medicine,vol.60, pp. and improves ROS levels in immortalized epithelial cells with 1–4, 2013. impaired cystic fibrosis transmembrane conductance regulator (CFTR) function,” PLoS ONE,vol.9,no. 6, ArticleIDe99257, [5] S.G.Rhee, “Cellsignaling.H O , a necessary evil for cell 2 2 signaling,” Science, vol. 312, no. 5782, pp. 1882–1883, 2006. [24] M. Large, S. Reichert, S. Hehlgans, C. Fournier, C. Rodel ¨ , and [6] Y.S.Bae,H.Oh, S. G. Rhee,and Y. D. Yoo, “Regulationof F. Ro¨del, “A non-linear detection of phospho-histone H2AX in reactive oxygen species generation in cell signaling,” Molecules EA.hy926 endothelial cells following low-dose X-irradiation is and Cells,vol.32, no.6,pp. 491–509, 2011. modulated by reactive oxygen species,” Radiation Oncology,vol. [7] A.A.Alfadda andR.M.Sallam, “Reactiveoxygenspecies in 9, article 80, 2014. health and disease,” Journal of Biomedicine and Biotechnology, [25] A.-F. Miller, “Superoxide dismutases: ancient enzymes and new vol. 2012,Article ID 936486,14pages,2012. insights,” FEBS Letters,vol.586,no. 5, pp.585–595,2012. [8] A. Matsuzawa and H. Ichijo, “Stress-responsive protein kinases [26] M. Mar´ı, A. Morales, A. Colell, C. Garc´ıa-Ruiz, and J. C. in redox-regulated apoptosis signaling,” Antioxidants and Redox Fernandez-C ´ heca, “Mitochondrial glutathione, a key survival Signaling,vol.7,no. 3-4, pp.472–481,2005. antioxidant,” Antioxidants and Redox Signaling, vol. 11, no. 11, [9] W. Drog ¨ e, “Free radicals in the physiological control of cell pp. 2685–2700, 2009. function,” Physiological Reviews,vol.82, no.1,pp. 47–95, 2002. [27] R. Kanwal, M. Pandey, N. Bhaskaran et al., “Protection against [10] T. Finkel, “Signal transduction by reactive oxygen species,” oxidative DNA damage and stress in human prostate by glu- Journal of Cell Biology, vol. 194, no. 1, pp. 7–15, 2011. tathione S-transferase P1,” Molecular Carcinogenesis,vol.53, no. [11] V. G. Grivennikova and A. D. Vinogradov, “Mitochondrial 1, pp. 8–18, 2014. production of reactive oxygen species,” Biochemistry,vol.78,no. [28] G. Meloni and M. Vaˇsak, ´ “Redox activity of𝛼 -synuclein-Cu is 13, pp. 1490–1511, 2013. silenced by Zn -metallothionein-3,” Free Radical Biology and [12] A. A. Starkov, “eTh role of mitochondria in reactive oxygen Medicine,vol.50, no.11, pp.1471–1479,2011. species metabolism and signaling,” Annals of the New York [29] J. Chen,M.Adikari,R.Pallai, H. K. Parekh,and H. Simpkins, Academy of Sciences,vol.1147, pp.37–52,2008. “Dihydrodiol dehydrogenases regulate the generation of reac- [13] L. Galluzzi, E. Morselli, O. Kepp et al., “Mitochondrial gateways tive oxygen species and the development of cisplatin resistance to cancer,” Molecular Aspects of Medicine,vol.31, no.1,pp. 1–20, in human ovarian carcinoma cells,” Cancer Chemotherapy and Pharmacology, vol. 61, no. 6, pp. 979–987, 2008. [14] Q. Chen, E. J. Vazquez, S. Moghaddas, C. L. Hoppel, and [30] G. Bonizzi and M. Karin, “eTh two NF- 𝜅 B activation pathways E. J. Lesnefsky, “Production of reactive oxygen species by and their role in innate and adaptive immunity,” Trends in mitochondria: central role of complex III,” The Journal of Immunology, vol. 25, no. 6, pp. 280–288, 2004. Biological Chemistry,vol.278,no. 38,pp. 36027–36031, 2003. [31] A. S. Baldwin, “Regulation of cell death and autophagy by [15] D. G. Nicholls and S. L. Budd, “Mitochondria and neuronal IKK and NF-𝜅 B: critical mechanisms in immune function and survival,” Physiological Reviews,vol.80, no.1,pp. 315–360, 2000. cancer,” Immunological Reviews,vol.246,no. 1, pp.327–345, [16] J. F. Turrens, “Mitochondrial formation of reactive oxygen species,” The Journal of Physiology ,vol.552,part2,pp. 335–344, [32] A. Devin, A. Cook, Y. Lin, Y. Rodriguez, M. Kelliher, and Z.- G. Liu, “eTh distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates [17] D. I. Brown and K. K. Griendling, “Nox proteins in signal IKK activation,” Immunity,vol.12, no.4,pp. 419–429, 2000. transduction,” Free Radical Biology and Medicine,vol.47, no.9, pp.1239–1253,2009. [33] G. Gloire and J. Piette, “Redox regulation of nuclear post- translational modifications during NF- 𝜅 B activation,” Antioxi- [18] I. P. Harrison and S. Selemidis, “Understanding the biology dants and Redox Signaling, vol. 11, no. 9, pp. 2209–2222, 2009. of reactive oxygen species and their link to cancer: NADPH oxidases as novel pharmacological targets,” Clinical and Experi- [34] S. Basak and A. Hoffmann, “Crosstalk via the NF- 𝜅 Bsignaling mental Pharmacology and Physiology,vol.41, no.8,pp. 533–542, system,” Cytokine and Growth Factor Reviews,vol.19, no.3-4, 2014. pp.187–197,2008. [19] J. D. Lambeth, “NOX enzymes and the biology of reactive [35] S. Gardam and R. Brink, “Non-canonical NF-𝜅 B signaling ini- oxygen,” Nature Reviews Immunology,vol.4,no. 3, pp.181–189, tiated by BAFF influences B cell biology at multiple junctures,” 2004. Frontiers in Immunology, vol. 4, article 509, 2014. 14 Oxidative Medicine and Cellular Longevity [36] J. Bauer, S. Namineni, F. Reisinger, J. Zol ¨ ler, D. Yuan, and M. and inflammation,” Physiological Reviews,vol.81, no.2,pp. 807– Heikenwalder ¨ , “Lymphotoxin, NF-𝜅 B, and cancer: the dark side 869, 2001. of cytokines,” Digestive Diseases,vol.30, no.5,pp. 453–468, [51] Z. Chen,T.B.Gibson, F. Robinson et al., “MAP kinases,” Chemical Reviews,vol.101,no. 8, pp.2449–2476,2001. [37] T. Elmetwali, L. S. Young, and D. H. Palmer, “Fas-associated [52] W. M. Stadler, “Targeted agents for the treatment of advanced factor (Faf1) is a novel CD40 interactor that regulates CD40- renalcellcarcinoma,” Cancer,vol.104,no. 11, pp.2323–2333, induced NF-𝜅 B activation via a negative feedback loop,” Cell Death and Disease,vol.5,no. 5, ArticleIDe1213,2014. [53] E.P.SproulandW.S.Argraves,“Acytokineaxisregulateselastin [38] P. Ramakrishnan, W. Wang, and D. Wallach, “Receptor-specific formation and degradation,” Matrix Biology,vol.32, no.2,pp. signaling for both the alternative and the canonical NF-𝜅 B 86–94, 2013. activation pathways by NF-𝜅 B-inducing kinase,” Immunity,vol. [54] B. B. Friday and A. A. Adjei, “Advances in targeting the 21, no. 4, pp. 477–489, 2004. Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade [39] C. Journo, A. Bonnet, A. Favre-bonvin et al., “Human T cell with MEK inhibitors for cancer therapy,” Clinical Cancer leukemia virus type 2 tax-mediated NF-𝜅 B activation involves Research,vol.14, no.2,pp. 342–346, 2008. a mechanism independent of tax conjugation to ubiquitin and [55] A. Plotnikov, E. Zehorai, S. Procaccia, and R. Seger, “The SUMO,” Journal of Virology, vol. 87, no. 2, pp. 1123–1136, 2013. MAPK cascades: signaling components, nuclear roles and [40] Y.-J. Song and M.-S. Kang, “Roles of TRAF2 and TRAF3 in mechanisms of nuclear translocation,” Biochimica et Biophysica Epstein-Barr virus latent membrane protein 1-induced alterna- Acta—Molecular Cell Research,vol.1813, no.9,pp. 1619–1633, tive NF-𝜅 B activation,” Virus Genes,vol.41, no.2,pp. 174–180, [56] A. Leon-B ´ uitimea, L. Rodr´ıguez-Fragoso, F. T. Lauer, H. Bowles, [41] S. Schoonbroodt, V. Ferreira, M. Best-Belpomme et al., “Crucial T. A. Thompson, and S. W. Burchiel, “Ethanol-induced oxidative role of the amino-terminal tyrosine residue 42 and the carboxyl- stress is associated with EGF receptor phosphorylation in MCF- terminal PEST domain of I𝜅 B𝛼 in NF-𝜅 B activation by an 10A cells overexpressing CYP2E1,” Toxicology Letters,vol.209, oxidative stress,” Journal of Immunology,vol.164,no. 8, pp. no. 2, pp. 161–165, 2012. 4292–4300, 2000. [57] H. Lei and A. Kazlauskas, “Growth factors outside of the [42] Y. Takada, A. Mukhopadhyay, G. C. Kundu, G. H. Maha- platelet-derived growth factor (PDGF) family employ reactive beleshwar, S. Singh, and B. B. Aggarwal, “Hydrogen peroxide oxygen species/Src family kinases to activate PDGF receptor activates NF-𝜅 B through tyrosine phosphorylation of I𝜅 B𝛼 and 𝛼 and thereby promote proliferation and survival of cells,” The serine phosphorylation of p65. Evidence for the involvement JournalofBiologicalChemistry,vol.284,no. 10,pp. 6329–6336, of I𝜅 B𝛼 kinase and Syk protein-tyrosine kinase,” The Journal of Biological Chemistry, vol. 278, no. 26, pp. 24233–24241, 2003. [58] C. C. Wentworth, A. Alam,R.M.Jones,A.Nusrat, andA.S. [43] N. L. Reynaert, A. van der Vliet, A. S. Guala et al., “Dynamic Neish, “Enteric commensal bacteria induce extracellular signal- redox control of NF-𝜅 B through glutaredoxin-regulated S- regulated kinase pathway signaling via formyl peptide receptor- glutathionylation of inhibitory𝜅 B kinase𝛽 ,” Proceedings of the dependent redox modulation of dual specific phosphatase 3,” National Academy of Sciences of the United States of America, eTh JournalofBiologicalChemistry ,vol.286,no. 44,pp. 38448– vol. 103, no. 35, pp. 13086–13091, 2006. 38455, 2011. [44] J. V. Cross and D. J. Templeton, “Thiol oxidation of cell signal- [59] A. Banan, J. Z. Fields, Y. Zhang, and A. Keshavarzian, “Phos- ing proteins: controlling an apoptotic equilibrium,” Journal of pholipase C-𝛾 inhibition prevents EGF protection of intestinal Cellular Biochemistry, vol. 93, no. 1, pp. 104–111, 2004. cytoskeleton and barrier against oxidants,” The American Jour- nal of Physiology—Gastrointestinal and Liver Physiology,vol. [45] Q. Li and J. F. Engelhardt, “Interleukin-1𝛽 induction of NF𝜅 B 281, no. 2, pp. G412–G423, 2001. is partially regulated by H O -mediated activation of NF𝜅 B- 2 2 inducing kinase,” eTh JournalofBiologicalChemistry ,vol.281, [60] R. A. Franklin, P. A. Atherfold, and J. A. McCubrey, “Calcium- no. 3, pp. 1495–1505, 2006. induced ERK activation in human T lymphocytes occurs via Lck p56 and CaM-kinase,” Molecular Immunology,vol.37, no.11, [46] J.-H. Kim, H.-J. Na, C.-K. Kim et al., “The non-provitamin A pp. 675–683, 2000. carotenoid, lutein, inhibits NF-𝜅 B-dependent gene expression through redox-based regulation of the phosphatidylinositol [61] S. G. Dann, J. Golas, M. Miranda et al., “P120 catenin is a key 3-kinase/PTEN/Akt and NF-𝜅 B-inducing kinase pathways: effector of a Ras-PKC 𝜀 oncogenic signaling axis,” Oncogene,vol. role of H O in NF-𝜅 B activation,” Free Radical Biology and 33, no. 11, pp. 1385–1394, 2014. 2 2 Medicine,vol.45, no.6,pp. 885–896, 2008. [62] C. Davies and C. Tournier, “Exploring the function of the JNK [47] M. R. Junttila, S.-P. Li, and J. Westermarck, “Phosphatase- (c-Jun N-terminal kinase) signalling pathway in physiological mediated crosstalk between MAPK signaling pathways in the and pathological processes to design novel therapeutic strate- regulation of cell survival,” The FASEB Journal ,vol.22, no.4, gies,” Biochemical Society Transactions,vol.40, no.1,pp. 85–89, pp.954–965,2008. [48] T. Ravingerova, ´ M. Barancˇ´ık, and M. Strniskova, ´ “Mitogen- [63] S. S. Leonard, G. K. Harris, and X. Shi, “Metal-induced oxida- activated protein kinase: a new therapeutic target in cardiac tive stress and signal transduction,” Free Radical Biology and pathology,” Molecular and Cellular Biochemistry,vol.247,no. 1- Medicine,vol.37, no.12, pp.1921–1942,2004. 2, pp. 127–138, 2003. [64] K. Katagiri, A. Matsuzawa, and H. Ichijo, “Regulation of apop- [49] G. Pimienta and J. Pascual, “Canonical and alternative MAPK tosis signal-regulating kinase 1 in redox signaling,” Methods in signaling,” Cell Cycle,vol.6,no. 21,pp. 2628–2632, 2007. Enzymology,vol.474,pp. 277–288, 2010. [50] J. M. Kyriakis and J. Avruch, “Mammalian mitogen-activated [65] M. Castro-Caldas, A. N. Carvalho, E. Rodrigues, C. Henderson, protein kinase signal transduction pathways activated by stress C. R. Wolf, and M. J. Gama, “Glutathione S-transferase pi Oxidative Medicine and Cellular Longevity 15 mediates MPTP-induced c-Jun N-terminal kinase activation in [81] T. Nguyen,P.J.Sherratt, andC.B.Pickett,“Regulatory mecha- the nigrostriatal pathway,” Molecular Neurobiology,vol.45, no. nisms controlling gene expression mediated by the antioxidant 3, pp. 466–477, 2012. response element,” Annual Review of Pharmacology and Toxi- cology,vol.43, pp.233–260,2003. [66] J. Matsukawa, A. Matsuzawa, K. Takeda, and H. Ichijo, “The ASK1-MAP kinase cascades in mammalian stress response,” The [82] A. K. Jain and A. K. Jaiswal, “GSK-3𝛽 acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF- Journal of Biochemistry,vol.136,no. 3, pp.261–265,2004. E2 related factor 2,”eTh JournalofBiologicalChemistry ,vol.282, [67] B. Grill and J. W. Schrader, “Activation of Rac-1, Rac-2, and no. 22, pp. 16502–16510, 2007. Cdc42 by hemopoietic growth factors or cross-linking of the [83] W. K. Yip and H. F. Seow, “Activation of phosphatidylinositol B-lymphocyte receptor for antigen,” Blood,vol.100,no. 9, pp. 3-kinase/Akt signaling by EGF downregulates membranous E- 3183–3192, 2002. cadherin and𝛽 -catenin and enhances invasion in nasopharyn- [68] I. Shin, S. Kim, H. Song, H.-R. C. Kim, and A. Moon, “H-Ras- geal carcinoma cells,” Cancer Letters,vol.318,no. 2, pp.162–172, specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells,” The Journal [84] J. Hong, T. Qian, Q. Le et al., “NGF promotes cell cycle progres- of Biological Chemistry,vol.280,no. 15,pp. 14675–14683, 2005. sion by regulating D-type cyclins via PI3K/Akt and MAPK/Erk [69] A. Cuadrado and A. R. Nebreda, “Mechanisms and functions of activation in human corneal epithelial cells,” Molecular Vision, p38 MAPK signalling,” Biochemical Journal,vol.429,no. 3, pp. vol. 18, pp. 758–764, 2012. 403–417, 2010. [85] X. Qiu, J.-C. Cheng, H.-M. Chang, and P. C. K. Leung, “COX2 [70] M. Hayashi, C. Fearns,B.Eliceiri,Y.Yang, andJ.-D. Lee, and PGE2 mediate EGF-induced E-cadherin-independent “Big mitogen-activated protein kinase 1/extracellular signal- human ovarian cancer cell invasion,” Endocrine-Related Cancer, regulated kinase 5 signaling pathway is essential for tumor- vol. 21,no. 4, pp.533–543,2014. associated angiogenesis,” Cancer Research,vol.65, no.17, pp. [86] I. E. Ahn, J. H. Ju,S.Y.Lee et al., “Upregulationofstromal cell- 7699–7706, 2005. derived factor by IL-17 and IL-18 via a phosphatidylinositol 3- [71] J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: kinase-dependent pathway,” Scandinavian Journal of Immunol- permanent activation of an adaptive response in cancer,” Trends ogy,vol.76, no.4,pp. 433–439, 2012. in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. [87] D. A. Cantrell, “Phosphoinositide 3-kinase signalling pathways,” [72] K. Taguchi, H. Motohashi, and M. Yamamoto, “Molecular Journal of Cell Science,vol.114,part8,pp. 1439–1445, 2001. mechanisms of the Keap1-Nrf2 pathway in stress response and [88] D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, cancer evolution,” Genes to Cells,vol.16, no.2,pp. 123–140, 2011. “Phosphorylation and regulation of Akt/PKB by the rictor- [73] T. W. Kensler, N. Wakabayashi, and S. Biswal, “Cell survival mTOR complex,” Science,vol.307,no. 5712,pp. 1098–1101,2005. responses to environmental stresses via the Keap1-Nrf2-ARE [89] P. Cohen and S. Frame, “eTh renaissance of GSK3,” Nature pathway,” Annual Review of Pharmacology and Toxicology,vol. Reviews Molecular Cell Biology,vol.2,no. 10,pp. 769–776, 2001. 47, pp. 89–116, 2007. [90] Y. Zhang, B. Gan, D. Liu, and J.-H. Paik, “FoxO family members [74] J.-M. Lee and J. A. Johnson, “An important role of Nrf2- in cancer,” Cancer Biology and eTh rapy ,vol.12, no.4,pp. 253– ARE pathway in the cellular defense mechanism,” Journal of 259, 2011. Biochemistry and Molecular Biology,vol.37, no.2,pp. 139–143, [91] X.-S. Zhang, X. Zhang, Q. Wu et al., “Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: [75] K.-A. Jung and M.-K. Kwak, “eTh Nrf2 system as a potential possible involvement of Akt/bad signaling,” Marine Drugs,vol. target for the development of indirect antioxidants,” Molecules, 12, no. 8, pp. 4291–4310, 2014. vol. 15,no. 10,pp. 7266–7291, 2010. [92] A. G. Abraham and E. O’Neill, “PI3K/Akt-mediated regulation [76] M. Furukawa and Y. Xiong, “BTB protein keap1 targets antiox- of p53 in cancer,” Biochemical Society Transactions,vol.42, no. idant transcription factor Nrf2 for ubiquitination by the cullin 4, pp. 798–803, 2014. 3-Roc1 ligase,” Molecular and Cellular Biology,vol.25, no.1,pp. [93] N. R. Leslie and C. P. Downes, “PTEN: the down side of PI 3- 162–171, 2005. kinase signalling,” Cellular Signalling,vol.14, no.4,pp. 285–295, [77] N. F. Villeneuve, A. Lau, and D. D. Zhang, “Regulation of the 2002. Nrf2-Keap1 antioxidant response by the ubiquitin proteasome [94] S.-R. Lee, K.-S. Yang, J. Kwon, C. Lee, W. Jeong, and S. G. system: an insight into cullin-ring ubiquitin ligases,” Antioxi- Rhee, “Reversible inactivation of the tumor suppressor PTEN dants & Redox Signaling,vol.13, no.11, pp.1699–1712,2010. O ,” The Journal of Biological Chemistry ,vol.277,no. 23, by H 2 2 pp. 20336–20342, 2002. [78] A. T. Dinkova-Kostova, W. D. Holtzclaw, R. N. Cole et al., “Direct evidence that sulfhydryl groups of Keap1 are the sensors [95] H. Murata, Y. Ihara, H. Nakamura, J. Yodoi, K. Sumikawa, regulating induction of phase 2 enzymes that protect against and T. Kondo, “Glutaredoxin exerts an antiapoptotic eeff ct by carcinogens and oxidants,” Proceedings of the National Academy regulating theredox stateofAkt,” The Journal of Biological of Sciences of the United States of America,vol.99, no.18, pp. Chemistry, vol. 278, no. 50, pp. 50226–50233, 2003. 11908–11913, 2002. [96] A. I. Tarasov, E. J. Griffiths, and G. A. Rutter, “Regulation of ATP 2+ production by mitochondrial Ca ,” Cell Calcium,vol.52, no.1, [79] K. C. Kim, K. A. Kang, R. Zhang et al., “Up-regulation of Nrf2- mediated heme oxygenase-1 expression by eckol, a phlorotan- pp.28–35,2012. 2+ nin compound, through activation of Erk and PI3K/Akt,” [97] J. R. Naranjo and B. Mellstrom, ¨ “Ca -dependent transcrip- 2+ International Journal of Biochemistry and Cell Biology,vol.42, tional control of Ca homeostasis,” The Journal of Biological no. 2, pp. 297–305, 2010. Chemistry, vol. 287, no. 38, pp. 31674–31680, 2012. [80] J. W. Kaspar,S.K.Niture, andA.K.Jaiswal,“Nrf2:INrf2 (Keap1) [98] M. J. Berridge, M. D. Bootman, and H. L. Roderick, “Calcium signaling in oxidative stress,” Free Radical Biology and Medicine, signalling: dynamics, homeostasis and remodelling,” Nature vol. 47,no. 9, pp.1304–1309,2009. Reviews Molecular Cell Biology,vol.4,no. 7, pp.517–529,2003. 16 Oxidative Medicine and Cellular Longevity [99] A. Felsenfeld,M.Rodriguez,and B. Levine,“Newinsights [114] R. Chaube,D.T.Hess, Y.-J.Wangetal.,“Regulation of the 2+ in regulation of calcium homeostasis,” Current Opinion in skeletal muscle ryanodine receptor/Ca -release channel RyR1 Nephrology and Hypertension,vol.22, no.4,pp. 371–376, 2013. by S-palmitoylation,” The Journal of Biological Chemistry ,vol. 289, no. 12, pp. 8612–8619, 2014. [100] P.B.StathopulosandM.Ikura,“Partialunfoldingandoligomer- ization of stromal interaction molecules as an initiation mech- [115] I. Bogeski and B. A. Niemeyer, “Redox regulation of ion anism of store operated calcium entry,” Biochemistry and Cell channels,” Antioxidants and Redox Signaling,vol.21, no.6,pp. Biology, vol. 88, no. 2, pp. 175–183, 2010. 859–862, 2014. 2+ [101] T.Kurosakiand Y.Baba,“Ca signaling and STIM1,” Progress in [116] P. Kaplan, E. Babusikova, J. Lehotsky, and D. Dobrota, “Free 2+ Biophysics and Molecular Biology,vol.103,no. 1, pp.51–58,2010. radical-induced protein modification and inhibition of Ca - ATPase of cardiac sarcoplasmic reticulum,” Molecular and [102] M. Mandi ´ and J. Bak, “Nicotinic acid adenine dinucleotide 2+ Cellular Biochemistry,vol.248,no. 1-2, pp.41–47,2003. phosphate (NAADP) and Ca mobilization,” Journal of Recep- tors and Signal Transduction,vol.28, no.3,pp. 163–184, 2008. [117] G. H. Lushington, A. Zaidi, and M. L. Michaelis, “eo Th retically 2+ predicted structures of plasma membrane Ca -ATPase and [103] M. Brini, T. Cal`ı, D. Ottolini, and E. Carafoli, “The plasma their susceptibilities to oxidation,” Journal of Molecular Graphics membrane calcium pump in health and disease,” The FEBS and Modelling,vol.24, no.3,pp. 175–185, 2005. Journal,vol.280,no. 21,pp. 5385–5397, 2013. [104] K.Samanta,S.Douglas,and A. B. Parekh,“Mitochondrialcal- [118] M. Nishida, T. Ishikawa, S. Saiki et al., “Voltage-dependent N- 2+ 2+ cium uniporter MCU supports cytoplasmic Ca oscillations, type Ca channels in endothelial cells contribute to oxidative 2+ 2+ store-operated Ca entry and Ca -dependent gene expression stress-related endothelial dysfunction induced by angiotensin in response to receptor stimulation,” PLoS ONE,vol.9,no. 7, II in mice,” Biochemical and Biophysical Research Communica- Article ID e101188, 2014. tions,vol.434,no. 2, pp.210–216,2013. [105] A.Lewis,T.Hayashi,T.-P. Su,and M. J. Betenbaugh,“Bcl-2 [119] G. Morciano, C. Giorgi, M. Bonora et al., “Molecular identity of family in inter-organelle modulation of calcium signaling; roles the mitochondrial permeability transition pore and its role in in bioenergetics and cell survival,” Journal of Bioenergetics and ischemia-reperfusion injury,” Journal of Molecular and Cellular Biomembranes,vol.46, no.1,pp. 1–15,2014. Cardiology,vol.78, pp.142–153,2015. [106] A. Hatano, J.-I. Okada, T. Washio, T. Hisada, and S. Sugiura, [120] V.K.Rao,E.A.Carlson,and S. S. Yan, “Mitochondrial 2+ “Mitochondrial colocalization with Ca release sites is crucial permeability transition pore is a potential drug target for to cardiac metabolism,” Biophysical Journal,vol.104,no. 2, pp. neurodegeneration,” Biochimica et Biophysica Acta (BBA)— 496–504, 2013. Molecular Basis of Disease,vol.1842, no.8,pp. 1267–1272, 2014. [107] C. Konrad ` , G. Kiss, B. Tor ¨ ocsi ¨ k et al., “A distinct sequence in [121] G. Basanez, ˜ L. Soane, and J. M. Hardwick, “A new view of the the adenine nucleotide translocase from Artemia franciscana lethal apoptotic pore,” PLoS Biology,vol.10, no.9,Article ID embryosisassociatedwithinsensitivity to bongkrekateand e1001399, 2012. 2+ atypical effects of adenine nucleotides on Ca uptake and [122] Y. Liu and X. J. Chen, “Adenine nucleotide translocase, sequestration,” eTh FEBS Journal ,vol.278,no. 5, pp.822–836, mitochondrial stress, and degenerative cell death,” Oxidative Medicine and Cellular Longevity,vol.2013, ArticleID146860, [108] K.J.Menzies,B.H.Robinson,andD.A.Hood,“Eeff ctofthyroid 10 pages, 2013. hormone on mitochondrial properties and oxidative stress in [123] K. S. McCommis and C. P. Baines, “The role of VDAC in cell cells from patients with mtDNA defects,” American Journal of death: friend or foe?” Biochimica et Biophysica Acta,vol.1818, Physiology—Cell Physiology,vol.296,no. 2, pp.C355–C362, no. 6, pp. 1444–1450, 2012. [124] A.P.Halestrap,E.Doran,J.P.Gillespie, andA.O’Toole,“Mito- [109] A.C.Montezano,D.Burger, G. S. Ceravolo,H.Yusuf,M. chondria and cell death,” Biochemical Society Transactions,vol. Montero, and R. M. Touyz, “Novel nox homologues in the 28,no. 2, pp.170–177,2000. vasculature: focusing on Nox4 and Nox5,” Clinical Science,vol. [125] L. Ghibelli and M. Diederich, “Multistep and multitask Bax 120, no. 4, pp. 131–141, 2011. activation,” Mitochondrion,vol.10, no.6,pp. 604–613,2010. [110] N. D. Roe, E. Y. He, Z. Wu, and J. Ren, “Folic acid reverses nitric [126] G. Gouspillou, N. Sgarioto, S. Kapchinsky et al., “Increased sen- oxide synthase uncoupling and prevents cardiac dysfunction 2+ sitivity to mitochondrial permeability transition and myonu- in insulin resistance: role of Ca /calmodulin-activated protein clear translocation of endonuclease G in atrophied muscle of kinase II,” Free Radical Biology and Medicine,vol.65, pp.234– physically active older humans,” The FASEB Journal ,vol.28, no. 243, 2013. 4, pp. 1621–1633, 2014. [111] A. V. Gordeeva, R. A. Zvyagilskaya, and Y. A. Labas, “Cross- [127] A.P.Halestrap,S.J.Clarke, andS.A.Javadov,“Mitochon- talk between reactive oxygen species and calcium in living cells,” drial permeability transition pore opening during myocar- Biochemistry,vol.68, no.10, pp.1077–1080,2003. dial reperfusion—a target for cardioprotection,” Cardiovascular [112] M. D. Thompson, Y. Mei, R. M. Weisbrod et al., “Glutathione 2+ Research,vol.61, no.3,pp. 372–385, 2004. adducts on sarcoplasmic/endoplasmic reticulum Ca ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic [128] A. P. Halestrap, “What is the mitochondrial permeability tran- sition pore?” Journal of Molecular and Cellular Cardiology,vol. function as well as promote ischemic blood flow recovery,” The Journal of Biological Chemistry,vol.289,no. 29,pp. 19907–19916, 46, no. 6, pp. 821–831, 2009. [129] G.P.McStay, S. J. Clarke,and A. P. Halestrap, “Roleof 2+ [113] B. An, Y. Chen, B. Li, G. Qin, and S. Tian, “Ca -CaM regulating critical thiol groups on the matrix surface of the adenine viability of Candida guilliermondii under oxidative stress by nucleotide translocase in the mechanism of the mitochondrial acting on detergent resistant membrane proteins,” Journal of permeability transition pore,” Biochemical Journal,vol.367,no. Proteomics,vol.109,pp. 38–49, 2014. 2, pp.541–548,2002. Oxidative Medicine and Cellular Longevity 17 [130] G. Sanc ´ hez, C. Fernandez, ´ L. Montecinos, R. J. Domenech, and [146] I.-T. Lee and C.-M. Yang, “Inflammatory signalings involved P. Donoso, “Preconditioning tachycardia decreases the activity in airway and pulmonary diseases,” Mediators of Inflammation , of the mitochondrial permeability transition pore in the dog vol. 2013,Article ID 791231,12pages,2013. heart,” Biochemical and Biophysical Research Communications, [147] M.Nitti,M.A.Pronzato, U. M. Marinari,and C. Domenicotti, vol. 410, no. 4, pp. 916–921, 2011. “PKC signaling in oxidative hepatic damage,” Molecular Aspects of Medicine,vol.29, no.1-2,pp. 36–42, 2008. [131] P.-T.Brinkkoetter,H.Song,R.Los ¨ el et al., “Hypothermic injury: the mitochondrial calcium, ATP and ROS love-hate triangle out [148] D. Mochly-Rosen, K. Das, and K. V. Grimes, “Protein kinase C, of balance,” Cellular Physiology and Biochemistry,vol.22, no.1– an elusive therapeutic target?” Nature Reviews Drug Discovery, 4, pp. 195–204, 2008. vol. 11, no. 12, pp. 937–957, 2012. [132] S. Voronina, E. Okeke, T. Parker, and A. Tepikin, “How to win [149] A. Welman, J. R. Griffiths, A. D. Whetton, and C. Dive, “Protein 2+ ATP and influence Ca signaling,” Cell Calcium,vol.55, no.3, kinase C delta is phosphorylated on five novel Ser/Thr sites pp. 131–138, 2014. following inducible overexpression in human colorectal cancer cells,” Protein Science,vol.16, no.12, pp.2711–2715,2007. [133] Y. Deng,X.Ren,L.Yang, Y. Lin, andX.Wu, “A JNK-dependent [150] C. Aicart-Ramos, L. Sanc ´ hez-Ruiloba, M. Go´mez-Parrizas, C. pathway is required for TNF𝛼 -induced apoptosis,” Cell, vol. 115, no. 1, pp. 61–70, 2003. Zaragoza, T. Iglesias, and I. Rodr´ıguez-Crespo, “Protein kinase D activity controls endothelial nitric oxide synthesis,” Journal of [134] M. Maryanovich and A. Gross, “A ROS rheostat for cell fate Cell Science,vol.127,part15, pp.3360–3372,2014. regulation,” Trends in Cell Biology,vol.23, no.3,pp. 129–134, [151] L. O. Olala, B. A. Shapiro, T. C. Merchen, J. J. Wynn, and W. B. Bollag, “Protein kinase C and Src family kinases mediate [135] S. Wagner,A.G.Rokita, M. E. Anderson,and L. S. Maier, angiotensin II-induced protein kinase D activation and acute “Redox regulation of sodium and calcium handling,” Antioxi- aldosterone production,” Molecular and Cellular Endocrinology, dants and Redox Signaling,vol.18, no.9,pp. 1063–1077, 2013. vol. 392, no. 1-2, pp. 173–181, 2014. [136] J. W. Thompson, S. V. Narayanan, and M. A. Perez-Pinzon, [152] G. Li and Y. Wang, “Protein kinase D: a new player among “Redox signaling pathways involved in neuronal ischemic the signaling proteins that regulate functions in the nervous preconditioning,” Current Neuropharmacology,vol.10,no.4,pp. system,” Neuroscience Bulletin,vol.30, no.3,pp. 497–504, 2014. 354–369, 2012. [153] M. A. Olayioye, S. Barisic, and A. Hausser, “Multi-level control [137] A. Eisenberg-Lerner and A. Kimchi, “PKD is a kinase of Vps34 of actin dynamics by protein kinase D,” Cellular Signalling,vol. that mediates ROS-induced autophagy downstream of DAPk,” 25,no. 9, pp.1739–1747,2013. Cell Death and Dieff rentiation ,vol.19, no.5,pp. 788–797, 2012. [154] Q. J. Wang, “PKD at the crossroads of DAG and PKC signaling,” [138] J. S. Kruk,M.S.Vase,J fi .J.Heikkila, andM.A.Beazely, Trends in Pharmacological Sciences,vol.27, no.6,pp. 317–323, “Reactive oxygen species are required for 5-HT-induced trans- activation of neuronal platelet-derived growth factor and TrkB [155] C. F. Cowell,H.Do¨ppler,I.K.Yan,A.Hausser,Y.Umazawa,and receptors, but not for ERK1/2 activation,” PLoS ONE,vol.8,no. P. Storz, “Mitochondrial diacylglycerol initiates protein-kinase- 9, Article ID e77027, 2013. D1-mediated ROS signaling,” JournalofCellScience,vol.122,no. [139] C. M. Sag, H. A. Wolff, K. Neumann et al., “Ionizing radiation 7, pp.919–928,2009. regulates cardiac Ca handling via increased ROS and activated [156] P. Storz and A. Toker, “Protein kinase D mediates a stress- CaMKII,” Basic Research in Cardiology,vol.108,no. 6, article induced NF-𝜅 B activation and survival pathway,” The EMBO 385, 2013. Journal,vol.22, no.1,pp. 109–120, 2003. [140] G.A.Ramirez-Correa, S. Cortassa,B.Stanley,W.D.Gao,and A. [157] P. Storz, H. Dop ¨ pler, and A. Toker, “Activation loop phos- M. Murphy, “Calcium sensitivity, force frequency relationship phorylation controls protein kinase D-dependent activation of and cardiac troponin I: critical role of PKA and PKC phospho- nuclear factor𝜅 B,” Molecular Pharmacology,vol.66, no.4,pp. rylation sites,” Journal of Molecular and Cellular Cardiology,vol. 870–879, 2004. 48, no. 5, pp. 943–953, 2010. [158] C. M. Sag, S. Wagner, and L. S. Maier, “Role of oxidants on [141] S.S.Taylor, P. Zhang, J. M. Steichen,M.M.Keshwani, andA.P. calcium and sodium movement in healthy and diseased cardiac Kornev, “PKA: Lessons learned aer ft twenty years,” Biochimica myocytes,” Free Radical Biology and Medicine,vol.63, pp.338– et Biophysica Acta—Proteins and Proteomics,vol.1834, no.7,pp. 349, 2013. 1271–1278, 2013. [159] S. Dietrich, R. Uppalapati, T. Y. Seiwert, and P. C. Ma, “Role of [142] J.P.Brennan,S.C.Bardswell,J.R.Burgoyneetal.,“Oxidant- c-MET in upper aerodigestive malignancies—from biology to induced activation of type I protein kinase A is mediated by RI novel therapies,” Journal of Environmental Pathology, Toxicology subunit interprotein disulfide bond formation,” The Journal of and Oncology, vol. 24, no. 3, pp. 149–162, 2005. Biological Chemistry,vol.281,no. 31,pp. 21827–21836, 2006. [160] J. Calise and S. R. Powell, “The ubiquitin proteasome system and [143] S. Papa, D. D. Rasmo, Z. Technikova-Dobrova et al., “Res- myocardial ischemia,” The American Journal of Physiology— piratory chain complex I, a main regulatory target of the Heart and Circulatory Physiology,vol.304,no. 3, pp.H337– cAMP/PKA pathway is defective in different human diseases,” H349, 2013. FEBS Letters,vol.586,no. 5, pp.568–577,2012. [161] I. A. Voutsadakis, “The ubiquitin-proteasome system and sig- [144] S. Papa and D. De Rasmo, “Complex I deficiencies in neurolog- nal transduction pathways regulating Epithelial Mesenchymal ical disorders,” Trends in Molecular Medicine,vol.19, no.1,pp. transition of cancer,” Journal of Biomedical Science,vol.19, no.1, 61–69, 2013. article 67, 2012. [145] A.doCarmo,J.Balc¸a-Silva,D.Matias, andM.C.Lopes,“PKC [162] M. Isasa, A. Zuin, and B. Crosas, “Integration of multiple ubiq- signaling in glioblastoma,” Cancer Biology and Therapy ,vol.14, uitin signals in proteasome regulation,” Methods in Molecular no. 4, pp. 287–294, 2013. Biology,vol.910,pp. 337–370, 2012. 18 Oxidative Medicine and Cellular Longevity [163] M.Kim, R. Otsubo,H.Morikawaetal.,“Bacterialeeff ctors and Biophysical Research Communications,vol.357,no. 3, pp. and their functions in the ubiquitin-proteasome system: insight 731–736, 2007. from the modes of substrate recognition,” Cells,vol.3,no. 3, pp. [179] J.Peng, D. Schwartz,J.E.Elias et al., “A proteomicsapproach 848–864, 2014. to understanding protein ubiquitination,” Nature Biotechnology, [164] S.R.Powell, J. Herrmann, A. Lerman,C.Patterson,and X. vol. 21, no. 8, pp. 921–926, 2003. Wang, “The ubiquitin-proteasome system and cardiovascular disease,” Progress in Molecular Biology and Translational Science, vol. 109, pp. 295–346, 2012. [165] K. M. S. E. Reyskens and M. F. Essop, “HIV protease inhibitors and onset of cardiovascular diseases: a central role for oxidative stress and dysregulation of the ubiquitin-proteasome system,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Dis- ease,vol.1842, no.2,pp. 256–268, 2014. [166] A. Segref, E. Kevei, W. Pokrzywa et al., “Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system,” Cell Metabolism,vol.19, no.4, pp.642–652,2014. [167] A. Warnatsch, T. Bergann, and E. Krug ¨ er, “Oxidation matters: the ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation,” Molecular Immunology,vol.55, no.2,pp. 106–109, 2013. [168] Y.-D. Kwak, B. Wang, J. J. Li et al., “Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration,” The Journal of Neuroscience , vol. 32, no. 32, pp. 10971–10981, 2012. [169] M. Obin, F. Shang, X. Gong, G. Handelman, J. Blumberg, and A. Taylor, “Redox regulation of ubiquitin-conjugating enzymes: mechanistic insights using the thiol-specific oxidant diamide,” The FASEB Journal ,vol.12, no.7,pp. 561–569, 1998. [170] J.Jahngen-Hodge,M.S.Obin, X. Gong et al., “Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress,” The Journal of Biological Chemistry ,vol.272, no.45, pp.28218–28226,1997. [171] A. Kumar, H. Wu, L. S. Collier-Hyams et al., “Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species,” The EMBO Journal ,vol.26, no.21, pp. 4457–4466, 2007. [172] H. Tian, B. Zhang, J. Di et al., “Keap1: one stone kills three birds Nrf2, IKK𝛽 and Bcl-2/Bcl-xL,” Cancer Letters,vol.325,no. 1, pp. 26–34, 2012. [173] K. K. S. Nordgren and K. B. Wallace, “Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts,” Toxicology and Applied Pharmacology,vol. 274, no. 1, pp. 107–116, 2014. [174] H. Kanzaki, F. Shinohara, M. Kajiya, and T. Kodama, “The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling,” eTh JournalofBiologicalChemistry ,vol.288, no.32, pp.23009– 23020, 2013. [175] T. Reinheckel, O. Ullrich, N. Sitte, and T. Grune, “Differential impairment of 20S and 26S proteasome activities in human hematopoietic K562 cells during oxidative stress,” Archives of Biochemistry and Biophysics,vol.377,no. 1, pp.65–68,2000. [176] F.Shang andA.Taylor, “Ubiquitin-proteasome pathwayand cellular responses to oxidative stress,” Free Radical Biology and Medicine,vol.51, no.1,pp. 5–16,2011. [177] A. Sickmann, J. Reinders, Y. Wagner et al., “The proteome of Saccharomyces cerevisiae mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 23, pp. 13207–13212, 2003. [178] H.B.Jeon,E.S.Choi,J.H.Yoonetal.,“Aproteomicsapproachto identify the ubiquitinated proteins in mouse heart,” Biochemical

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