Regulation of Nrf2 – An update

Abstract

Nrf2:INrf2 (Keap1) are cellular sensors of oxidative and electrophilic stress. Nrf2 is a nuclear factor that controls the expression and coordinated induction of a battery of genes which encode detoxifying enzymes, drug transporters (MRPs), anti-apoptotic proteins and proteasomes. In the basal state, Nrf2 is constantly degraded in the cytoplasm by its inhibitor, INrf2. INrf2 functions as an adapter for Cul3/Rbx1 E3 ubiquitin ligase mediated degradation of Nrf2. Chemicals including antioxidants, tocopherols including α-tocopherol (vitamin E), phytochemicals and radiations antagonize the Nrf2:INrf2 interaction and leads to the stabilization and activation of Nrf2. The signaling events involve pre-induction, induction and post-induction responses that tightly control Nrf2 activation and repression back to the basal state. Oxidative/electrophilic signals activate unknown tyrosine kinase(s) in a pre-induction response which phosphorylates specific residues on Nrf2 negative-regulators, INrf2, Fyn and Bach1, leading to their nuclear export, ubiquitination and degradation. This prepares nuclei for unhindered import of Nrf2. Oxidative/electrophilic modification of INrf2cysteine151 followed by PKC phosphorylation of Nrf2serine40 in the induction response results in the escape or release of Nrf2 from INrf2. Nrf2 is thus stabilized and translocates to the nucleus resulting in a coordinated activation of gene expression. This is followed by a post-induction response that controls the ‘switching off’ of Nrf2-activated gene expression. GSK3β under the control of AKT and PI3K, phosphorylates Fyn leading to Fyn nuclear localization. Fyn phosphorylates Nrf2Y568 resulting in nuclear export and degradation of Nrf2. The activation and repression of Nrf2 provides protection against oxidative/electrophilic stress and associated diseases, including cancer. However, deregulation of INrf2 and Nrf2 due to mutations may lead to nuclear accumulation of Nrf2 that reduces apoptosis and promotes oncogenesis and drug resistance.

Oxidative Stress

Cells are constantly challenged by environmental (xenobiotics, drugs and UV) and endogenous (reactive oxygen species, hydroperoxides and quinone) stressors [1–2]. If unchecked, these lead to oxidative stress and diseases of many organs (Fig. 1). Oxidative stress related diseases include skin (dermatitis, psoriasis and burn); kidney (renal graft and glomeruloneph); eye (Retinal damage and cataract); cardiovascular (heart and vessels diseases including atherosclerosis); lung [(hyperoxia, ashthma and acute respiratory distress syndrome (ARDS)]; Joints (rheumatoid arthritis); liver (injury and Ischemic bowel); Brain (Trauma, Parkinson’s and Alezheimer’s) and multi-organ diseases including diabetes, aging and cancer [Fig. 1, Ref. 1–2].

Fig. 1.

Oxidative stress related diseases.

Chemical Protection against Oxidative Stress

Phenolic antioxidants, vitamins and naturally occurring phytochemicals are known to reduce oxidative stress leading to protection of cells against its adverse effects [3–6]. Many of these compounds are well known drugs in prevention and cure of cancer. The chemical structures of a few representative phenolic antioxidants, vitamins and phytochemicals are shown (Fig. 2). The phenolic antioxidants BHA (tert-butyl-4-hydroxyanisole) and BHT [3,5-di-tert-butyl-4-hydroxytoluene] inhibit chemical carcinogenesis [7–8]. Vitamins are essential for the normal growth and development of organisms. Vitamin E among the various vitamins demonstrated antioxidant properties. Vitamin E is a group of tocopherols and tocotrienols. However, only α-tocopherol functions as the vitamin E in vivo. Each Tocopherol contains a chromanol ring system and a 16 carbons phytyl chain (Fig. 2). Depending on the position and number of methyl groups they exist as α, β, γ, δ-tocopherols (Fig. 2). All tocopherols are antioxidants. However, γ- and δ-tocopherols are stronger antioxidants than others because of unmethylated carbon 5 [9]. Epidemiological studies have shown cancer preventive activity of vitamin E (α-tocopherol) [4]. However, its role in cancer prevention is controversial. More recent studies suggest that γ- and δ-tocopherols are cancer preventive, whereas α-tocopherol is not [4]. Phytochemicals includes a large number of wide varieties of compounds produced from plants [10]. A few of phytochemicals are sulforaphane, silibinin, honokiol, (−)-epigallocatechin gallate (EGCG), and quercetin. Sulforaphane, a product from broccoli sprouts retarded prostate tumor growth in TRAMP mouse and suppressed the growth of prostate cancer PC-3 cells in nude mice [11–12]. Silymarin and its major constituent, silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases [13]. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas [13]. Honokiol is a product of Mangnolia officinalis that restarted growth of PC-3 xenografts in nude mice [14]. EGCG reduced tumor size and completely abrogated tumors in both androgen repressed prostate cancer LNCaP and androgen-refractory the PC3 tumor xenograft in athymic nude mice [15]. Quercetin from vegetables and fruits suppressed development of preneoplastic lesions and proliferation of azoxymethane induced aberrant crypt foci [16]. Therefore, phenolic antioxidants, vitamins and naturally occurring phytochemicals have one thing in common that they prevent oxidative stress and other diseases.

Fig. 2.

Structures of a few representative antioxidants, tocopherols including α-tocopherol (vitamin E) and phytochemicals.

Cellular Protection against Oxidative Stress: Nrf2:INrf2 or Keap1 system

Cytoprotective proteins

Cells have evolved adaptive mechanisms to endure oxidative stress. These include a battery of cytoprotective/defensive proteins that protect cells against oxidative stress and promote cell survival. Included among the cytoprotective proteins are phase II defenses, such as those involved in biotransformation of xenobiotics and drugs (e.g. NAD(P)H:quinone oxidoreductase 1 (NQO1), NRH:quinone oxidoreductase 2 (NQO2), glutathione S-transferase (GST), and γ-glutamate-cysteine synthetase [GCS], and molecules such as reduced glutathione [GSH], and metallothioneins [17–18]. NQO1 and NQO2 catalyze detoxification of quinones, which prevent the generation of reactive semiquinones, O₂- and H₂O₂ [19–21]. NQO2 is identified as melatonin binding site MT3 with functions in CNS [22–23]. NQO1−/− and NQO2−/− mice demonstrated myelogenous hyperplasia [24–28] and γ-radiation-induced myeloproliferative disease/B-cell lymphoma [27–28] and exhibited significantly increased sensitivity to chemical-induced skin carcinogenesis [29–31]. GST conjugates hydrophobic electrophiles, H₂O₂ and lipid hydroperoxides with glutathione, aiding in their excretion [32–33]. HO-1 catalyzes the rate-limiting step in heme catabolism [34]. γ-GCS play a role in glutathione metabolism [32–33, 35]. Glutathione [GSH], metallothioneins and ferritins scavenge ROS and metal ions. Therefore, GSH and proteins, like metallothioneins and ferritins, act as endogenous factors in protection against oxidative stress and associated diseases including cancer. The battery of cytoprotective proteins also include drug transporters that play important role in drugs intake and efflux [36–40]; anti-apoptotic proteins Bcl-2 and Bcl-xL that prevent apoptotic cell death and promote cell survival [41–43]; and proteasomes that remove oxidized/damaged proteins [44].

NQO1, NQO2 and other cytoprotective genes are ubiquitously expressed and induced in response to xenobiotics, antioxidants, oxidants, heavy metals and UV light [17, 43–48]. Interestingly, the induction of these genes is part of an oxidative/electrophilic stress induced defense mechanism that includes the coordinated induction of two hundred plus genes [17, 43–48]. Both constitutive and inducible expression of defense genes is regulated by antioxidant response element (ARE/Core sequence (TGA****GC) that is present in the upstream regions of such genes [49–51].

NF-E2 Related Factors and INrf2 (Keap1)

Coordinated induction of cytoprotective gene transcription through the ARE is essential for cellular protection against oxidative stress and related disorders [17, 45–48]. Induction is controlled by cap ‘n’ collar (CNC) family of factors that comprises four members namely Nrf1, Nrf2, Nrf3 and, p45 NF-E2 [17, 43–48, 52–54]. Nrf1 and Nrf2 are ubiquitously expressed, whereas the expression of Nrf3 is restricted to placenta and liver and NF-E2 restricted to erythrocytes [55, 54]. Knockout studies reveal that Nrf1 and Nrf2 have distinct phenotypes and different roles [56–57]. The Nrf1 gene is essential for embryonic development and liver-specific Nrf1 knockout mice develop non-alcoholic steatohepatitis [58–59]. In contrast, Nrf2 knockout mice are viable and exhibit no obvious phenotypic defects, but are nevertheless sensitive to oxidative stress [60–63]. Nrf2 reportedly is the main mediator of cellular adaptation to redox stress [17, 45–48]. Nrf2 is a leucine zipper/CNC protein which when present in the nucleus functions as transcription factor that regulates coordinated activation of a battery of cytoprotective genes that include biotransformation enzymes, antioxidant proteins, drug transporters, anti-apoptotic proteins and proteasomes [17, 45–48]. The various domains of Nrf2 are depicted in Fig. 3. It contains an N-terminal hydrophobic domain, followed by INrf2 (Keap1) binding domain, transcriptional activation domain, CNC domain, basic and leucine zipper domain. Nrf2 through its leucine zipper domain heterodimerizes with small Maf or Jun proteins and bind to ARE [17, 45–48]. INrf2 (Inhibitor of Nrf2) or KEAP1 (Kelch-like ECH-associated protein1), a homodimeric protein, retains Nrf2 in the cytoplasm [64–66]. INrf2 functions as an adapter for Cul3/Rbx1 mediated degradation of Nrf2 [67–71]. INrf2 with its N-terminal BTB domain binds to Rbx1 bound Cul3 and with C-terminal DGR domain binds to Nrf2. This leads to ubiquitination and degradation of Nrf2.

Fig. 3.

Protein domain structures of Nrf2 and INrf2 (Keap1).

Antioxidant induction of Nrf2/ARE-mediated cytoprotective gene expression as mechanism of antioxidant protection

Nrf2:INrf2 complex serves as a sensor of chemical and radiation-induced oxidative stress in the cells. Antioxidants are strong activators of Nrf2 since these after metabolism produce small amount of oxidative stress that signals Nrf2 activation. Antioxidants have been frequently used to study the mechanism of signal transduction from antioxidant to the coordinated induction of cytoprotective gene expression that is essential for cytoprotection and cell survival. The mechanism of signal transduction from antioxidant to Nrf2 is complex and involves basal, pre-induction, induction and post-induction phases (Fig. 4).

Fig. 4.

Mechanism of signal transduction from antioxidants, tocopherols including α-topherol (vitamin E) and phytochemicals to Nrf2.

Under physiological/basal conditions, INrf2/Cul3-RBX1 complex is present in the cytosol constantly degrading Nrf2 [67–70; Fig. 4]. While the INrf2-mediated ubiquitination and degradation occurs primarily in the cytosol, INrf2/Cul3-RBX1 complex is also present in the nucleus and degrades Nrf2 under basal conditions [72]. Along with INrf2/Cul3-RBX1 complex additional negative regulators of Nrf2 are present in the nucleus. These include Src subfamily A members Fyn, Src, Yes and Fgr that phosphorylate Nrf2Tyr568 leading to nuclear export and degradation of Nrf2 [73] and Bach1 that competes with Nrf2 for binding to ARE resulting in suppression of ARE-mediated gene expression [74]. It is noteworthy that active GSK3β phosphorylates Src A sub-family members including Fyn that enter in the nucleus leading to phosphorylation of Nrf2Tyr568, nuclear export and degradation of Nrf2 [75–76, 73]. More recently, β-TrCP present in the cytosol is also shown to degrade GSK3β phosphorylated Nrf2 [77]. Therefore, two independent mechanisms degrade Nrf2 under basal conditions.

Cellular exposure to antioxidant leads to pre-induction response in which negative regulators of Nrf2 are exported out of nucleus (Fig. 4). It is reported that unknown tyrosine kinase(s) phosphorylate INrf2Tyr85, FynTyr213 and Bach1 Tyr486 within 0.5–1 hour of antioxidant exposure leading to nuclear export, ubiquitination and degradation of INrf2, Fyn and Bach1 [78–80]. The Nrf2 ubiquitin factors Cul3-Rbx1 are also exported out of nucleus through its interaction with INrf2 [78]. It is suggested that nuclear export and degradation of Nrf2 negative regulators allows for unhindered nuclear import of Nrf2 and efficient induction of cytoprotective gene expression [78–80].

The induction phase presumably runs in parallel to pre-induction phase upon exposure to antioxidant. As the Nrf2 negative regulators are going out of nucleus, Nrf2 is imported in the nucleus to activate ARE-mediated cytoprotective gene expression. Antioxidant modification of INrf2Cys151 followed by PKCδ phosphorylation of Nrf2Ser40 results in the escape or release of Nrf2 from INrf2 [70–71]. Nrf2 is stabilized, translocate to the nucleus, heterodimerize with small Maf or c-Jun protein, and binds with ARE that leads to coordinated activation of cytoprotective gene expression [17, 81].

Induction phase is followed by post-induction phase that switches ‘OFF’ Nrf2 activation. Activation of GSK3β phosphorylates Fyn leading to nuclear localization of Fyn [76]. Fyn phosphorylates Nrf2Tyr568 resulting in nuclear export of Nrf2, binding with INrf2, and degradation of Nrf2 [75]. By this time the negative regulators of Nrf2 including INrf2/Cul3-RBX1, Fyn and Bach1 are de novo synthesized and imported in the nucleus. INrf2 through ubiquitination and degradation of Nrf2; Fyn through phosphorylation of Nrf2Tyr568 followed by ubiquitination and degradation of Nrf2 and Bach1 through competition with Nrf2 for binding to ARE leads to switching ‘OFF’ of Nrf2 and suppression of cytoprotective gene expression to basal level. Bach1 is known to form heterodimers with small Maf proteins and Bach1:Maf dimers compete with Nrf2 for binding to ARE [74].

Autoregulatory loop that controls cellular abundance of Nrf2 and INrf2/Cul3-Rbx1

Recently, we have shown that a feedback auto-regulatory loop between Nrf2 and INrf2 exist that controls cellular abundance of Nrf2 and INrf2 [Ref. 82; Fig. 5]. Nrf2 regulated transcription of INrf2 and INrf2 degraded Nrf2. More recently, we found that another autoregulatory loop exists between Nrf2 and Cul3-Rbx1 [83]. Nrf2 controls transcription of Cul3 and Rbx1 and Cul3-Rbx1 complex ubiquitinate and degrade Nrf2. In other words, there exist cellular homeostasis between Nrf2 and INrf2/Cul3-RBX1 complex. The autoregulatory loop between Nrf2 and INrf2/Cul3-Rbx1 is deregulated in cells carrying mutations in one of the component of the autoregulatory loop. Many cancer cells have loss of function mutations in INrf2 resulting in nuclear accumulation of Nrf2 and persistent activation of cytoprotective proteins [84–85]. Similarly, mutations are also known in Nrf2 that leads to abrogation of the interaction between Nrf2 and INrf2 and nuclear accumulation of Nrf2 [86].

Fig. 5.

Autoregulatory loop between Nrf2 and INrf2/Cul3-Rbx1.

Proteins that regulate Nrf2 and INrf2

Protein-protein and protein-DNA interactions are known that affect Nrf2 and/or INrf2 stabilization and/or expression with implications in cytoprotective gene expression/induction. Nrf2 interaction with INrf2 and PKCδ are described above. The role of Cul3-Rbx1, Bach1, Src subfamily members, GSK3β and β-TrCP all are also described above. In addition, p21 through its KRR motif is known to directly interact with the DLG and ETGE motifs in Nrf2 resulting in Nrf2 stabilization and accumulation [87]. Autophagy related p62 protein sequesters INrf2 into aggregates resulting in stabilization and activation of Nrf2 [88–90]. PALB2 through its ETGE motif interacts directly with Kelch domain of INrf2 that leads to stabilization of Nrf2 [91]. K-Ras, B-Raf and Myc all increase Nrf2 transcription and increase basal Nrf2 expression [92]. Casein kinase II phosphorylates INrf2Thre55 leading to INrf2 interaction with HSP90 and stabilization of INrf2 [93]. Prothymosin-α interaction with INrf2 is required for nuclear import of INrf2 [72].

Role of Nrf2:INrf2 system in tocopherols including α-tocopherol (vitamin E) and Phytochemicals protection of cells against adverse effects of oxidative stress

Epidemiological studies suggested a role of tocopherols in cancer prevention [94]. However, the chemoprevention studies with α-tocopherols were disappointing [95–96]. Recently, several reports have suggested a role of γ and not α-tocopherol in cancer prevention [4]. Dietary tocopherols especially γ-tocopherol inhibits cell proliferation and decrease serum inflammatory markers during development of mammary hyperplasia [97]. In addition, γ-tocopherol enriched diet was reported to inhibit prostate carcinogenesis in TRAMP mice [98]. The role of Nrf2 in tocopherols-mediated protection is also controversial. Nrf2 is shown to mediate tocopherol including α-tocopherol (vitamin E) protection against acrolein-induced oxidative stress and mitochondrial dysfunction [99]; allergens-induced alveolar macrophages in vivo [100]; development of mammary hyperplasia [97; and prostate tumors in TRAMP mice [101]. On contrary, it is also reported that the antioxidant and anti-inflammatory activities of tocopherols are independent of Nrf2 in mice [102]. Further studies are required to determine the relative role of Nrf2 in different tocopherols-mediated protection against oxidative stress and associated diseases.

Phytochemicals are promising chemopreventive agents that can prevent macromolecular damages including mutations and block carcinogenesis [6]. Several different mechanisms involving direct reaction with carcinogens and/or modulation of phase I enzymes and/or alterations in phase II enzymes contribute to the mode of action of phytochemicals. Phytochemicals are also known to protect against neurodegenerative, cardiovascular and renal diseases [6]. We will discuss here phytochemicals activation of phase II enzymes as mechanism of its activity as cytoprotective agent. Sulforaphane is a potent Nrf2 dependent inducer of phase II gene expression that leads to protection against oxidative stress and associated adverse effects [103]. Sulforaphane stabilizes Nrf2 through the modification of INrf2 (Keap1) and release of Nrf2 as described above [104]. Curcumin and (−)-epigallo-catechin-3-gallate are also known to activate Nrf2 for its antioxidant function [105–106]. Similarly, the flavanol (−)-epicatechin prevents stroke damage through activation of Nrf2/HO-1 pathway [107]. In addition, food polyphenols activated Nrf2 protect against neurodegenerative disorders [108]. In summary, many phytochemicals activate Nrf2 to coordinately increase phase II detoxifying enzymes and other cytoprotective proteins that play significant role not only in chemoprotection but also prevention of neurodegenerative, cardiovascular and renal diseases.

Nrf2 in cancer prevention, oncogenesis and drug resistance

The precise role of Nrf2 in cancer prevention and cancer remains unknown. It is considered to be both tumor suppressor, as well as tumor promoter [81]. The property of Nrf2 to coordinately activate cytoprotective proteins including detoxifying enzymes, drug transporters, antioxidants and anti-inflammatory proteins as described above plays significant role in reducing electrophiles and ROS, decrease genomic instability and mutations that leads to chemoprotection and tumor suppression. Tumor suppressor function of Nrf2 is also supported by in vivo studies using Nrf2-null mice. Nrf2−/− mice are prone to acute damages induced by acetaminophen, ovalbumin, pentachlorophenol and 4-vinylcyclohexene diepoxide [109–113]. Nrf2−/− mice showed increased pulmonary DNA adducts and bladder tumors when exposed to diesel exhaust and N-nitrosobutyl (4-hydroxybutyl) amine, respectively [114–116]. Moreover, loss of Nrf2 in lung cancer cells has been associated with providing a microenvironment that favors metastasis [117]. Nrf2 and downstream protein level declines with age that could also contribute to tumorigenesis [118]. Another line of evidence supporting Nrf2 as tumor suppressor is that one of the important property of chemopreventive compounds, such as curcumin, sulforaphane, isothiocynates, green and black tea, and others, is their ability to activate Nrf2 [45, 116]. Tumor suppressor function of Nrf2 is further supported by observations that tumor suppressors target Nrf2 stabilization and oncoproteins degrade Nrf2. Tumor suppressors p21 and BRCA2 (PALB2) are known to stabilize Nrf2 by preventing INrf2 interaction with Nrf2 [87, 91]. In addition, oncoproteins Src subfamily A members Fyn and Src and SCFβ-TrCP degrade Nrf2 [73, 77]. It is noteworthy that SCFβ-TrCP degradation of Nrf2 is independent of INrf2 (Keap1). Collectively, the above observations suggest that Nrf2 is chemoprotector and a tumor suppressor.

On contrary to above, Nrf2 is also considered as tumor promoter that promotes oncogenesis. Several reports support a role of Nrf2 in oncogenesis. First, a report showed that oncogenes K-Ras, B-Raf and Myc targeted the transcription and amplification of Nrf2 in cancer cells [92]. Overexpression of these oncogenes in mice led to increased Nrf2 transcription, increased basal expression of Nrf2, and decreased ROS leading to oncogenesis. In addition, genetic knock down of Nrf2 led to decreased ability of K-Ras to induce oncogenesis. These results supported a role of Nrf2 in oncogenesis due to escaping of cancer cell death because of lower ROS. Second, recently a paper showed that higher Nrf2 in tumor cells up-regulates many of the enzymes of glucose metabolism towards glycolysis that redirects cells in anabolic mode, which promotes nucleotide synthesis and cell proliferation [119]. This also supported a role of Nrf2 in oncogenesis. Third, more recently, we have shown that Nrf2 up-regulates transcription of anti-apoptotic genes encoding Bcl-2 and Bcl-xL [42, 120]. This leads to increased anti-apoptotic proteins Bcl-2 and Bcl-xL that reduces apoptosis. Therefore, Nrf2-mediated decreased apoptosis contributes to increased cancer cell survival and oncogenesis. Fourth, many cancers show up-regulation of Nrf2 because of mutations in INrf2 and Nrf2 that abolishes INrf2 and Nrf2 interaction and degradation of Nrf2 [84–86]. Mutations in INrf2 resulting in loss of expression and function and hypermethylation of INrf2 leading to decreased INrf2 expression are known in many cancers including that of lung, breast and prostate cancer [84–85]. The loss of INrf2 because of mutations leads to stabilization and nuclear accumulation of Nrf2 and increased expression of cytoprotective proteins and cell survival. Mutations are also known in the region of Nrf2 that interacts with INrf2 leading to stabilization of Nrf2, nuclear accumulation of Nrf2, activation of cytoprotective proteins, reduced apoptosis and increased cell survival [86]. The above evidences suggest that Nrf2 is an oncoprotein that reduces apoptosis and promotes cell survival and oncogenesis.

The persistent activation of Nrf2 due to mutations or deregulation of factors controlling Nrf2 also leads to drug resistance [121–123]. Nuclear accumulation of Nrf2 leads to higher levels of cytoprotective proteins including detoxifying/biotransformation enzymes, drug transporters, antioxidants and anti-apoptotic proteins. This leads to decreased apoptosis, increased cell survival and drug resistance.

The dual function of Nrf2 under different circumstances suggests that Nrf2 is a protooncogene [81]. Nrf2 when expressed at normal level and is properly regulated by positive and negative factors is essential for cellular protection against chemical and radiation stressors, normal growth and survival of cells. However, deregulation of Nrf2 either due to gain of function mutations or altered because of regulatory factors becomes oncogenic.

Future Perspectives

Future investigations are required to understand a complete mechanism of signal transduction from antioxidant, tocopherols including α-tocopherol (vitamin E) and phytochemicals to Nrf2 leading to coordinated activation of Nrf2 downstream gene expression. In addition, in vivo role of Nrf2 and INrf2 in apoptosis and protection against chemical and radiation induced neurodegeneration, cardiovascular diseases and cancer also requires further investigation. INrf2 is mutated in many cancers including that of lung, breast and prostate. However, the precise role of Nrf2 and/or INrf2 in oncogenesis remains obscure and warrants further studies. Similarly, the role of Nrf2 in cancer metastasis is another area that requires investigation. Development of natural activators of Nrf2 as effective agents of chemoprotection is also warranted. Similarly, development of inhibitors of Nrf2 is expected to help reduce drug resistance and improve therapy.

Highlights.

• Nrf2:INrf2 system protects cells against chemical and radiation stress.

• Antioxidants, tocopherols and phytochemicals are activators of Nrf2.

• Positive and negative factors regulate activation and suppression of Nrf2.

• Nrf2 if properly regulated protects against inflammation and cancer.

• Nuclear accumulation of Nrf2 promotes oncogenesis and drug resistance.

• Nrf2 may be a proto-oncogene?

Abbreviations

Nrf2

NF-E2 Related Factor 2

INrf2

Inhibitor of Nrf2 also known as Keap1

ARE

Antioxidant Response Element

ROS

Reactive Oxygen Species