Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea.
Planta Medica (Impact Factor: 2.34). 11/2008; 74(13):1526-39. DOI: 10.1055/s-0028-1088302
Source: PubMed

ABSTRACT A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

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    • "Neuroscience 304 (2015) 14–28 it then binds to promoter sequences known as antioxidant response elements (AREs) (Keum, 2012). Nuclear accumulation of Nrf2 results in the upregulation of phase II detoxifying anti-oxidant enzymes such as NAD(P)H, quinone oxidoreductase, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit, and glutamate-cysteine ligase modifier subunit (Surh et al., 2008). Among the various known cytoprotective enzymes, HO-1 has received considerable attention (Nakaso et al., 2006). "
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    • "Under conditions of oxidative stress, electrophilic substances modify Keap1, inactivate the E3 ligase complex, and allow Nrf2 to accumulate by preventing its degradation by the proteasome (Fig. 2). Nrf2 not bound to the Keap1-E3 ligase complex is phosphorylated (Surh et al., 2008; Zhang et al., 2013) Fig. 1. 'Three birds with one stone' model of Tian et al., 2012. The ubiquitin ligase complex, Keap1-Cul3-Rbx1, ubiquitinates Nrf2, IkB kinase, and Bcl-2 prior to degradation in the proteasome. "
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    • "nase ) , and PKC ( protein kinase C ) . NRF - 2 is activated by these kinases , and thus it is transported from the cytoplasm to the nucleus . In the nucleus Nrf - 2 is connected to anti - oxidant response elements ( ARE ) and elements that promote antioxidant and detoxification genes such as SOD , GPX , and GTS ( glutathione - S - transferase ) ( Surh et al . , 2008 ) . According to study results , the absence of NRF - 2 in the body leads to a defect in the detoxification process of chemical compounds and increases tumor formation induced by chemical agents ( Ramos - Gomez et al . , 2003 ; Kwak et al . , 2004 ) . However , NRF - 2 plays an important role in the induction of defense factors , such a"
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