The Nrf2-Antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress

A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed. A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed. The induction of many cytoprotective enzymes in response to reactive chemical stress is regulated primarily at the transcriptional level. This transcriptional response is mediated by a cis-acting element termed ARE, 2The abbreviations used are: ARE, antioxidant response element; ROS, reactive oxygen species; XRE, xenobiotic response element; AhR, aryl hydrocarbon receptor. initially found in the promoters of genes encoding the two major detoxication enzymes, GSTA2 (glutathione S-transferase A2) and NQO1 (NADPH: quinone oxidoreductase 1) (Fig. 1) (1Rushmore T.H. Pickett C.B. J. Biol. Chem. 1990; 265: 14648-14653Abstract Full Text PDF PubMed Google Scholar, 2Friling R.S. Bensimon A. Tichauer Y. Daniel V. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6258-6262Crossref PubMed Scopus (429) Google Scholar, 3Favreau L.V. Pickett C.B. J. Biol. Chem. 1991; 266: 4556-4561Abstract Full Text PDF PubMed Google Scholar, 4Li Y. Jaiswal A.K. J. Biol. Chem. 1992; 267: 15097-15104Abstract Full Text PDF PubMed Google Scholar). The ARE possesses structural and biological features that characterize its unique responsiveness to oxidative stress (5Rushmore T.H. Morton M.R. Pickett C.B. J. Biol. Chem. 1991; 266: 11632-11639Abstract Full Text PDF PubMed Google Scholar). It is activated not only in response to H2O2 but specifically by chemical compounds with the capacity to either undergo redox cycling or be metabolically transformed to a reactive or electrophilic intermediate (6Rushmore T.H. King R.G. Paulson K.E. Pickett C.B. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 3826-3830Crossref PubMed Scopus (393) Google Scholar). Moreover, compounds that have the propensity to react with sulfhydryl groups such as diethyl maleate, the isothiocyanates, and dithiothiones are also potent inducers of ARE activity. Thus, alteration of the cellular redox status due to elevated levels of ROS and electrophilic species and/or a reduced antioxidant capacity (e.g. glutathione) appears to be an important signal for triggering the transcriptional response mediated by this enhancer. Besides its involvement in inducible gene expression, the ARE is also responsible for the low-level constitutive (or basal) expression of several genes under non-stressed conditions. Because reactive oxygen species and other endogenous reactive molecules are constantly generated from normal aerobic metabolism, the involvement of the ARE in controlling constitutive gene expression implies a critical role of the enhancer in the maintenance of cellular redox homeostasis under both stressed and non-stressed conditions. Activation of gene transcription through the ARE is mediated primarily by Nrf2 (nuclear factor E2-related factor 2), first isolated through cloning experiments (7Moi P. Chan K. Asunis I. Cao A. Kan Y.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9926-9930Crossref PubMed Scopus (1252) Google Scholar). Following its isolation, Nrf2 was identified as one of the transcription factors acting on the ARE of human NQO1 to activate gene transcription in cell-based transient transfection experiments (8Venugopal R. Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14960-14965Crossref PubMed Scopus (936) Google Scholar). Similar observations were subsequently made for the AREs of a number of other genes (9Nguyen T. Sherratt P.J. Pickett C.B. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 233-260Crossref PubMed Scopus (1072) Google Scholar). Notably, the involvement of Nrf2 was further corroborated by in vivo studies in which expression of several ARE-dependent genes was found to be severely impaired in nrf2–/– mice (10Itoh K. Chiba T. Takahashi S. Ishii T. Igarashi K. Katoh Y. Oyake T. Hayashi N. Satoh K. Hatayama I. Yamamoto M. Nabeshima Y.I. Biochem. Biophys. Res. Commun. 1997; 236: 313-322Crossref PubMed Scopus (3226) Google Scholar, 11McMahon M. Itoh K. Yamamoto M. Chanas S.A. Henderson C.J. McLellan L.I. Wolf C.R. Cavin C. Hayes J.D. Cancer Res. 2001; 61: 3299-3307PubMed Google Scholar) and by chromatin immunoprecipitation assays demonstrating direct interaction between endogenous Nrf2 and the ARE in H4IIE cells (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). These studies have also provided evidence that Nrf2 controls both the inducible and constitutive gene expression mediated by the ARE. The significance of Nrf2 having this dual role will be discussed further below, as we attempt to provide a rationale for our understanding of the Nrf2 regulatory pathway. Nrf2 activity is regulated in part by the actin-associated Keap1 protein, which was initially proposed to act by binding and tethering the transcription factor in the cytoplasm. Activation of Nrf2 in response to stress signals was thought to result from a disruption of this association, releasing Nrf2 for translocation into the nucleus to effect its transcriptional activity (13Itoh K. Wakabayashi N. Katoh Y. Ishii T. Igarashi K. Engel J.D. Yamamoto M. Genes Dev. 1999; 13: 76-86Crossref PubMed Scopus (2830) Google Scholar). Independently, Nrf2 has been found to be a highly unstable protein (t½ ∼ 15 min), subject to proteolytic degradation catalyzed by the 26 S proteasome via the ubiquitin-dependent pathway. In this case, activation of Nrf2 was suggested to be dependent on mechanisms that increase its stability, leading to its accumulation in the cell (14Nguyen T. Sherratt P.J. Huang H.-C. Yang C.S. Pickett C.B. J. Biol. Chem. 2003; 278: 4536-4541Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 15Stewart D. Killeen E. Naquin R. Alam S. Alam J. J. Biol. Chem. 2003; 278: 2396-2402Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). The unstable nature of the Nrf2 protein and its regulation through this dynamic mechanism suggest that Nrf2 is unlikely to be tethered in a passive complex in the cytoplasm. This was corroborated by a number of studies demonstrating a more active role of Keap1 in its repression of Nrf2 activity. Keap1 appears to promote Nrf2 ubiquitylation in a constitutive manner (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 16McMahon M. Itoh K. Yamamoto M. Hayes J.D. J. Biol. Chem. 2003; 278: 21592-21600Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar, 17Itoh K. Wakabayashi N. Katoh Y. Ishii T. O'Connor T. Yamamoto M. Genes Cells. 2003; 8: 379-391Crossref PubMed Scopus (669) Google Scholar, 18Zhang D.D. Hannink M. Mol. Cell. Biol. 2003; 23: 8137-8151Crossref PubMed Scopus (1129) Google Scholar) through the cullin-3-dependent pathway (19Kobayashi A. Kang M.I. Okawa H. Ohtsuji M. Zenke Y. Chiba T. Igarashi K. Yamamoto M. Mol. Cell. Biol. 2004; 24: 7130-7139Crossref PubMed Scopus (1666) Google Scholar, 20Cullinan S.B. Gordan J.D. Jin J. Harper J.W. Diehl J.A. Mol. Cell. Biol. 2004; 24: 8477-8486Crossref PubMed Scopus (777) Google Scholar, 21Zhang D.D. Lo S.-C. Cross J.V. Templeton D.J. Hannink M. Mol. Cell. Biol. 2004; 24: 10941-10953Crossref PubMed Scopus (991) Google Scholar, 22Furukawa M. Xiong Y. Mol. Cell. Biol. 2005; 25: 162-171Crossref PubMed Scopus (593) Google Scholar). That Nrf2 is constantly degraded in non-stressed cells implies that Keap1 is a constitutively active protein and that it promotes Nrf2 ubiquitylation in an unregulated manner. This is supported by the observation that overexpression of Keap1 leads to increased levels of ubiquitin-conjugated forms of Nrf2 in cells (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 18Zhang D.D. Hannink M. Mol. Cell. Biol. 2003; 23: 8137-8151Crossref PubMed Scopus (1129) Google Scholar), indicating that Keap1 is expressed as a functionally active protein. Moreover, the rate of Nrf2 ubiquitylation and its degradation in non-stressed cells appear to be dependent in large part on the abundance of the Keap1 protein in the cell, as suggested by the elevated steady-state levels of Nrf2 observed in keap1–/– animals (23Wakabayashi N. Itoh K. Wakabayashi J. Motohashi H. Noda S. Takahashi S. Imakado S. Kotsuji T. Otsuka F. Roop D.R. Harada T. Engel J.D. Yamamoto M. Nat. Genet. 2003; 35: 238-245Crossref PubMed Scopus (700) Google Scholar) or following an artificial reduction of the cellular Keap1 protein level by small interfering RNA (24Devling T.W. Lindsay C.D. McLellan L.I. McMahon M. Hayes J.D. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 7280-7285Crossref PubMed Scopus (108) Google Scholar). Notably, these data suggest that upon interaction with Keap1, Nrf2 is targeted directly for ubiquitylation and degradation. Thus, interaction between the two proteins is more likely a transient encounter rather than a sustained association. Given that the steady-state level of Nrf2 in the cell is maintained in part through its constitutive expression, requiring de novo gene transcription and protein synthesis (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 14Nguyen T. Sherratt P.J. Huang H.-C. Yang C.S. Pickett C.B. J. Biol. Chem. 2003; 278: 4536-4541Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar), the pathway through which Nrf2 activity is regulated, from synthesis to degradation, requires examination in further detail. The involvement of Keap1 in promoting Nrf2 degradation led to the recognition that interaction between the two proteins is a dynamic process that must be regulated through a pathway that enables Nrf2 to control both the basal and inducible expression of its genes (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). The fact that Nrf2 controls basal expression of its genes (10Itoh K. Chiba T. Takahashi S. Ishii T. Igarashi K. Katoh Y. Oyake T. Hayashi N. Satoh K. Hatayama I. Yamamoto M. Nabeshima Y.I. Biochem. Biophys. Res. Commun. 1997; 236: 313-322Crossref PubMed Scopus (3226) Google Scholar, 11McMahon M. Itoh K. Yamamoto M. Chanas S.A. Henderson C.J. McLellan L.I. Wolf C.R. Cavin C. Hayes J.D. Cancer Res. 2001; 61: 3299-3307PubMed Google Scholar) clearly indicates that it is a constitutively and functionally active transcription factor and, notably, implies its presence in the nucleus under homeostatic conditions. That endogenous Nrf2 with the ARE in non-stressed cells not only further to the nature of Nrf2 but is with its involvement in the basal expression of its genes (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). Thus, the evidence that Nrf2 is in the nucleus under constitutive is and not the that Nrf2 with Keap1 in the (13Itoh K. Wakabayashi N. Katoh Y. Ishii T. Igarashi K. Engel J.D. Yamamoto M. Genes Dev. 1999; 13: 76-86Crossref PubMed Scopus (2830) Google Scholar, 18Zhang D.D. Hannink M. Mol. Cell. Biol. 2003; 23: 8137-8151Crossref PubMed Scopus (1129) Google Scholar, Itoh K. Wakabayashi N. Katoh Y. Yamamoto M. P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, N. Kang M.I. A. Yamamoto M. T.W. P. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar, H.-C. T. Pickett C.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Jaiswal A.K. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, S.B. D. Hannink M. E. Diehl J.A. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar). The of these is to be due to the of the used in not this is the fact that the of the Nrf2 protein on not to its molecular (7Moi P. Chan K. Asunis I. Cao A. Kan Y.W. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9926-9930Crossref PubMed Scopus (1252) Google Scholar), its and more These into of studies this provide and in non-stressed the Nrf2 protein level is have an that with and to Nrf2 and with in cells (14Nguyen T. Sherratt P.J. Huang H.-C. Yang C.S. Pickett C.B. J. Biol. Chem. 2003; 278: 4536-4541Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar). this endogenous Nrf2 was observed to in the nucleus of and cells in the of stress inducers (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). This is not unique to these two cell as observations were also made for other cell P. and C. of the of Nrf2 in human cells is in These with from studies nrf2–/– mice and from chromatin immunoprecipitation experiments discussed suggest that Nrf2 is a protein and is active under both constitutive and stress conditions. of Nrf2 into the following its on not appear to be a regulated activation and accumulation of Nrf2 in the nucleus in response to stress signals are likely a result of its mediated by mechanisms that the rate of its degradation. important is Keap1 Nrf2 for in cellular It appears that Keap1 is of in as by several studies (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, U. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, M. T. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar) and observed in a more S. Chan D.D. Mol. Cell. Biol. PubMed Scopus Google Scholar). This activity by Keap1 was not however, in Y. A. H. M. J. J.D. Itoh K. Yamamoto M. Genes Cells. PubMed Scopus Google Scholar), and the for this is not understood. from our that Keap1 the nucleus and Nrf2 for ubiquitylation in this This was on the observation that of proteasome activity by accumulation of both and forms of Nrf2 in the indicating that both the ubiquitylation and degradation are likely and in this (12Nguyen T. Sherratt P.J. Nioi P. Yang C.S. Pickett C.B. J. Biol. Chem. 2005; 280: 32485-32492Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). In it has been suggested in to its role in promoting Nrf2 degradation under non-stressed Keap1 also the nucleus and Nrf2 to the for degradation under stressed conditions. This was on the observation that Nrf2 was primarily in the in cells with Keap1 but was in the nucleus in cells with a signal of Keap1, which was in the in from the Nrf2 was found to be in the with the from cells with Keap1 or with the signal of The for these is not S. Chan D.D. Mol. Cell. Biol. PubMed Scopus Google Scholar). Besides the evidence discussed are several other observations that are to with the that Keap1 Nrf2 for degradation in the and of its Nrf2 to transcription of its genes at the basal and that of Keap1 activity by stress signals promotes Nrf2 translocation into the nucleus (13Itoh K. Wakabayashi N. Katoh Y. Ishii T. Igarashi K. Engel J.D. Yamamoto M. Genes Dev. 1999; 13: 76-86Crossref PubMed Scopus (2830) Google Scholar, 18Zhang D.D. Hannink M. Mol. Cell. Biol. 2003; 23: 8137-8151Crossref PubMed Scopus (1129) Google Scholar, Itoh K. Wakabayashi N. Katoh Y. Yamamoto M. P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, N. Kang M.I. A. Yamamoto M. T.W. P. 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Nrf2 is constitutively expressed in the cell, such a regulatory pathway that Nrf2 is targeted for degradation by Keap1 directly following its de novo a rather mechanism of gene regulation with to cellular In addition, its rate of the fact that Nrf2 is expressed at a steady-state level in the cell indicates that is a ∼ 15 following its and to its degradation. an a which Nrf2 its its role in constitutive by Keap1 provide an mechanism by the degradation of Nrf2 following transcriptional activation of its The mechanism by which Nrf2 is targeted for degradation by Keap1 is not well understood. it is that the of many transcription factors has been to the of which is found to or with M. Nat. Rev. Mol. Biol. 2003; Scopus Google Scholar). Because Nrf2 is highly unstable and possesses a potent to the Y. Itoh K. E. M. A. Yamamoto M. Genes Cells. 2001; PubMed Scopus (385) Google Scholar, V. S. C. J. J. Biol. 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Thus, a regulatory mechanism promoting Nrf2 in response to appears to be a constitutive mechanism promoting its degradation in cells under to its accumulation in an manner. these two mechanisms or in a is not and to be A well established mechanism that controls Nrf2 is that mediated by Because of the large number of its Keap1 an for regulation by chemical and of its activity was suggested to be an important mechanism for Nrf2 activation (13Itoh K. Wakabayashi N. Katoh Y. Ishii T. Igarashi K. Engel J.D. Yamamoto M. Genes Dev. 1999; 13: 76-86Crossref PubMed Scopus (2830) Google Scholar, 18Zhang D.D. Hannink M. Mol. Cell. Biol. 2003; 23: 8137-8151Crossref PubMed Scopus (1129) Google Scholar, Itoh K. Wakabayashi N. Katoh Y. Yamamoto M. P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, N. Kang M.I. A. Yamamoto M. T.W. P. Proc. Natl. Acad. Sci. U. S. 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