br Regulation of Nrf activation The core of

Regulation of Nrf2 activation The core of the Nrf2 regulation is Keap1. Keap1 functions as a negative regulator of Nrf2 by promoting ubiquitination and proteasomal degradation of Nrf2 [15]. Since Keap1 has highly reactive sulfhydryl groups in its cysteine residues, it is considered as a sensor for electrophilic compounds including heavy metals and chemopreventive agents. Many xenobiotics undergoing oxidative metabolism can interact with thiol residues present in the functionally critical motifs of different proteins. Nuclear accumulation and activation of Nrf2 involves the alteration of Keap1 structure by oxidation or covalent modification of critical cysteine residues in Keap1 [16]. At present, two general mechanisms have been proposed to explain nuclear accumulation of Nrf2 in response to inducers. The first is the down-regulation of Nrf2 ubiquitination. The second mechanism involves the alteration of the nuclear import/export of Nrf2 [17]. At least one previous study has reported that a casein kinase 2 inhibitor with high electron withdrawing potency could also function as an Nrf2 activator through the modification of cysteine residues in Keap1 [18]. For example, sulforaphane can form the thionoacyl adduct of sulforaphane–Keap1 and modify the tertiary structure of Keap1 most readily at the cysteine residues localized at the Kelch domain, thereby to stabilize Nrf2 [19]. This suggests that the selection of compounds that do not induce cellular toxicity and are capable of modifying the structure and function of Keap1 may provide important clues for the development of therapeutically applicable drugs targeting Nrf2. In addition to covalent modification of thiol groups in Keap1, the activation of protein kinase signaling pathways including protein kinase C, mitogen activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI-3K), ER-localized pancreatic endoplasmic reticulum kinase (PERK) or casein kinase 2 (CK2), can also phosphorylate Nrf2, thus they can affect the release process of Nrf2 from the Nrf2–Keap1 complex as well as the stability and nuclear translocation of Nrf2. Research to date has suggested that the phosphorylation of Nrf2 serine and threonine residues by the above-listed kinases may be potentially involved in Nrf2-mediated signal transduction at AREs [20–23]. Previous studies have reported that PKC directly phosphorylates Nrf2 at serine 40, thereby promoting the dissociation of Nrf2 from Keap1 [24,25]. Nrf2 may also be activated by MAPKs. In MAPKs, ERK and JNK appear to enhance Nrf2 signaling pathways through the recruitment and phosphorylation of transcriptional co-activators such as p300 and PBP [26]. In contrast, p38MAPK may either stimulate or inhibit the nuclear translocation of Nrf2 depending on cell types [27,28]. Several other studies have indicated that the activation of PI-3K signaling cascades results in the activation of Nrf2 [29,30]. Moreover, Nrf2 can be a substrate for PERK that phosphorylates Nrf2 [23], and then enhances its nuclear translocation by disrupting Keap1 binding [23]. Furthermore, the phosphorylation of Nrf2 by CK2 is also a critical controlling factor in Nrf2 activity and degradation [31].
Potential natural chemopreventive agents As mentioned above, the activation of the Nrf2 signaling pathway governs the expression of ARE-driven genes, and dietary chemopreventive compounds function as detoxifying enzyme inducers. For example, phase II detoxification and antioxidant enzymes act against carcinogenic insults. Currently, an increasing number of natural compounds have been found to exert chemopreventive properties against a wide spectrum of cancers by involving the Nrf2–ARE signaling pathway. The chemopreventive activities of cruciferous vegetables have been addressed in several epidemiological studies and in animal models of chemically induced carcinogenesis [32]. Phenolic and sulfur-containing compounds are two major classes of dietary components that also act as promising chemopreventive agents. Phenolic compounds, widely distributed in plants, can be classified into polyphenols such as epigallocatechin-3-gallate (EGCG) from green tea, curcumin from turmeric, resveratrol from grapes, and flavonoids such as quercetin from citrus fruits and genistein from soybean. Sulfur-containing compounds can be generally classified into two major categories, namely, isothiocyanates including sulforaphane (SFN) from broccoli, phenethyl isothiocyanate (PEITC) from turnips and watercress, as well as allyl isothiocyanate from Brussels sprouts, and organosulfur compounds including diallyl sulfides from garlic oil [33].