FASEB J. Pierce now sold as Thermo Scientific
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, J.-M.
Right arrow Articles by Johnson, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.-M.
Right arrow Articles by Johnson, J. A.
(The FASEB Journal. 2005;19:1061-1066.)
© 2005 FASEB

Nrf2, a multi-organ protector?

Jong-Min Lee*,{ddagger}, Jiang Li{dagger}, Delinda A. Johnson{dagger}, Thor D. Stein§, Andrew D. Kraft{dagger}, Marcus J. Calkins{ddagger}, Rebekah J. Jakel§ and Jeffrey A. Johnson{dagger},{ddagger},§,||,{dagger}{dagger},1

* Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and
{dagger} School of Pharmacy,
{ddagger} Molecular and Environmental Toxicology Center,
§ Neuroscience Training Program,
|| Waisman Center, and
{dagger}{dagger} Center for Neuroscience, University of Wisconsin, Madison, Wisconsin, USA

1 Correspondence: School of Pharmacy, University of Wisconsin, 6125 Rennebohm Hall, 777 Highland Ave., Madison, WI 53705, USA. E-mail: jajohnson{at}pharmacy.wisc.edu

ABSTRACT

NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that binds to the promoter sequence "antioxidant responsive element (ARE)" leading to coordinated up-regulation of ARE-driven detoxification and antioxidant genes. Since the expression of a wide array of antioxidant and detoxification genes are positively regulated by the ARE sequence, Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress. In support of this, numerous studies have shown that Nrf2 protects many cell types and organ systems from a broad spectrum of toxic insults and disease pathogenesis. This Nrf2-conferred, multi-organ protection phenomenon raises an interesting question about how a single protein can protect many different organs from various toxic insults. A possible molecular mechanism explaining this phenomenon is that Nrf2 protects many different cell types by coordinately up-regulating classic ARE-driven genes as well as cell type-specific target genes that are required for the defense system of each cell type in its unique environment. This hypothesis is supported by microarray data indicating the protective role of Nrf2 is conveyed through both known ARE-driven genes and novel cell type-specific genes. The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.—Lee, J.-M., Li, J., Johnson, D. A., Stein, T. D., Kraft, A. D., Calkins, M. J., Jakel, R. J., Johnson, J. A. Nrf2, a multi-organ protector?


Key Words: Nrf2 • ARE • multi-organ protection

THE HYPOTHESIS

MANY STUDIES have reported that a basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in protecting a variety of tissues (lung, liver, kidney, stomach, small intestine, central nervous system, splenocytes, macrophages, erythrocytes, and retinal epithelia) from a wide array of toxic insults (carcinogens, electrophiles, reactive oxygen species, diesel exhaust, inflammation, calcium disturbance, UV light, and cigarette smoke). To explain this "single protein-conferred multi-organ protection phenomenon," we suggest a hypothesis that Nrf2 protects various cell types by coordinately up-regulating not only classic ARE-driven genes but also cell type-specific protective genes essential for the basic defense system of each cell type.

ARE AND Nrf2

Reactive oxygen species (ROS) and electrophiles cause cellular damage leading to many diseases including cancer, autoimmune disease, and neurodegenerative disease; such toxic insults are normally detoxified by phase II detoxification enzymes and antioxidant proteins. Therefore, the cis-acting regulatory element "antioxidant responsive element (ARE)" that transcriptionally regulates genes encoding detoxification enzymes and antioxidant proteins plays an important role in cellular defense system. Enhancer sequences originally were described in the rat glutathione S-transferase (GST) -P (1) , rat GST Ya (2) , mouse GST Ya (3) , rat NAD(P)H:quinone oxidoreductase-1 (NQO1) (4) , and human NQO1 genes (5) . Collectively, these studies have identified a common pathway for ARE-driven phase II detoxification gene induction; the underlying ARE activation mechanism was further clarified by investigation of Nrf2. Initially, Venugopal and Jaiswal (6) and Itoh et al (7) implicated Nrf2 function in the ARE-driven gene expression mechanism; subsequent studies have revealed the molecular mechanism by which Nrf2 is activated and participates in ARE-driven gene expression. Briefly, Nrf2 is sequestered in the cytoplasm by Keap1, and ARE activation signals (i.e., protein kinase pathways and electrophiles) disrupt the Nrf2-Keap1 complex leading to nuclear translocation of Nrf2. Upon activation, Nrf2 binds to ARE sites in the promoter regions of many detoxification and antioxidant genes, leading to the coordinate up-regulation of downstream targets that boost cellular detoxification processes and antioxidant potential (Fig. 1 ) (8 9 10 11 12 13 14 15 16) .



View larger version (31K):
[in this window]
[in a new window]
  		Figure 1. Cellular protection mechanism conferred by Nrf2-ARE pathway.

MULTI-ORGAN PROTECTION BY THE Nrf2 PATHWAY

The function of Nrf2 and its downstream target genes suggests that Nrf2 plays a central role in protecting cells from ROS and electrophiles. In agreement with this idea, numerous studies have shown that Nrf2 protects multiple organs from various toxic insults.

Lung and liver
Nrf2 protects lung from butylated hydroxytoluene-induced acute respiratory distress syndrome (17) , hyperoxic injury (18) , and bleomycin-mediated pulmonary fibrosis (19) by increasing detoxification pathways and antioxidant potentials. Recent study further demonstrated that genetic ablation of Nrf2 enhanced sensitivity to cigarette smoke-induced emphysema and identified Nrf2-dependent antioxidant and cytoprotective genes using microarray technology (20) . Nrf2 plays a role in protecting liver, as evidenced by increased sensitivity to acetaminophen-induced centrilobular hepatocellular necrosis and hepatotoxicity (21 , 22) as well as increased levels of lipid peroxidation and DNA damage in Nrf2–/– livers (23) .

GI tract
Some studies have shown that Nrf2 protects GI tract from carcinogenesis, implying a role for Nrf2 in cell cycle regulation and cancer prevention. For example, Nrf2–/– mice showed an increased burden of gastric neoplasia after benzo[a]pyrene treatment compared with Nrf2+/+ mice; oltipraz significantly decreased gastric tumors only in Nrf2+/+ mice, implying that the chemopreventive activity of oltipraz is dependent on the Nrf2-ARE pathway (24) . Further support for this anti-carcinogenic effect is evidenced by an increased DNA adduct formation in forestomach after benzo[a]pyrene administration in Nrf2–/– mice (25) . Finally, an ARE-inducer, sulforaphane, is a potent bacteriostatic agent against Helicobacter pylori and blocks benzo[a]pyrene-evoked forestomach tumors (26) . This chemopreventive effect of sulforaphane is not observed in Nrf2–/– mice, suggesting Nrf2 dependency. Thus, constitutive and inducible expression of phase II enzymes through the Nrf2-ARE pathway can modify the susceptibility of GI tract to carcinogenesis.

Nervous system
The Nrf2-ARE pathway appears to contribute to neuroprotection. First, activation of the Nrf2-ARE pathway by tert-butylhydroquinone (tBHQ) protected neuroblastoma cells from oxidative glutamate toxicity (27) and H2O2-induced apoptosis (28) . Primary astrocytes and neurons derived from Nrf2–/– mice were more sensitive to oxidative damage, calcium disturbance, and mitochondrial toxins than were wild-type cells (29 , 30) . Overexpression of Nrf2 and small molecule-mediated activation of the Nrf2-ARE pathway in astrocytes increased resistance of neurons to non-excitotoxic glutamate toxicity (31) . Similarly, dominant negative-Nrf2 stable cells were more sensitive to NO-induced apoptosis, and siRNA-mediated knockdown of Nrf2-sensitized neuroblastoma cells to NO-induced apoptosis (32) . Nrf2–/– mice are more susceptible to lesions produced by the mitochondrial complex II inhibitors, and transplantation of Nrf2-overexpressing astrocytes into the striatum protects from malonate-induced lesions (33) . These data reinforce the pivotal role of the Nrf2-ARE pathway in protecting nervous system.

Others
The protective effects of Nrf2 have proved indispensable in many other cell types as well. Phase II gene induction by sulforaphane protected retinal pigment epithelial cells from photooxidative damage (34) , and Nrf2 was important in protecting macrophages and epithelial cells from diesel exhaust chemicals (35) . In addition, Nrf2 has been identified as a putative Lith 1 gallstone gene contributing to gallstone resistance (36) and plays a role in wound healing/keratinocyte differentiation (37 , 38) . Finally, Nrf2–/– mice develop lupus-like autoimmune nephritis (39) , systemic autoimmune disease (23) , hemolytic anemia (40) , and splenomegaly (23 , 40) .

Taken together, the studies outlined indicate that Nrf2 protects many different types of organs and cells, and begs an interesting question as to how a single protein can protect multiple organs from an array of different toxic insults.

PROTECTION MECHANISMS

Our hypothesis for Nrf2-conferred multi-organ protection phenomenon is that Nrf2 protects multiple tissues by coordinately up-regulating classic ARE-driven detoxification and antioxidant genes as well as cell type-specific targets that are required for basic defense in each unique environment. Although the observed protective effects are primarily mediated by classic ARE-driven genes, Nrf2-mediated, cell type-specific pathways (other than classic detoxification and antioxidant genes) may substantially contribute to protection of each cell type. This hypothesis is supported by a series of gene expression profiling experiments using oligonucleotide microarrays for various tissues/cell types (Table 1 ).


View this table:
[in this window]
[in a new window]
  		Table 1. Identification of classic Nrf2 target genes by microarray analysisa

First, Thimmullappa et al. showed that many xenobiotic metabolizing enzymes, detoxification, and antioxidant proteins were increased by Nrf2 in the small intestine and suggested a pivotal role for Nrf2 in modulating cellular defense against carcinogens and toxins (41) . Small intestine-selective Nrf2 target genes identified by microarray experiments (epoxide hydrolase, aflatoxin aldehyde reductase, UGT, GSTs, and multidrug resistance protein) indicate that Nrf2 protects the small intestine by coordinately regulating drug metabolism enzymes in the GI tract, where xenobiotics are absorbed primarily and processed. Considering the basic function of the small intestine, these small intestine-selective genes play a role in maintaining cellular integrity of GI tract against xenobiotics.

Kwak et al. identified Nrf2-dependent, D3T (3H-1,2-dithiol-3-thione) -inducible genes in liver (42) . D3T induced many chaperones and ubiquitin-proteasome pathway genes in a Keap1-Nrf2-dependent manner. Based on liver-selective Nrf2 target genes, the authors expanded the role of the Nrf2-ARE pathway beyond its primary functions into secondary protective effects such as recognition and repair/removal of damaged proteins (42) . This finding indicates that Nrf2 plays an important role in protecting hepatocytes and maintaining hepatocyte function by up-regulating specific target genes involved in recognition, detoxification, repair, and removal of damaged proteins. Since these processes might constantly occur during the xenobiotic metabolism in liver, the Nrf2-ARE pathway is important in supporting specialized hepatocyte functions.

DNA chip experiments have revealed that Nrf2 basally up-regulates many ARE-driven genes in primary astrocytes and neurons. In addition to classical ARE-driven genes (Table 1) , these studies revealed that Nrf2 regulates genes involved in the reducing potential and immune/inflammation in astrocytes as well as calcium homeostasis, growth factors, signaling molecules, and receptors/channels in neuronal cultures (Table 2 ) (29 , 30) . Nrf2-regulated, astrocyte-specific genes may explain the observed antioxidant/reducing potential and anti-inflammatory effects of Nrf2 (18 , 37) , insinuating important functional roles for Nrf2-activated astrocytes in supporting neurons. Furthermore, neuronal functions (i.e., signaling and receptors) and defense activities of neurons (calcium buffering capacity) are greatly enhanced in the presence of Nrf2, suggesting toxic by-products occurring during normal neuronal activities is mitigated by Nrf2-ARE pathway.


View this table:
[in this window]
[in a new window]
  		Table 2. Examples of nervous system-selective Nrf2-dependent genesa

Using a cell sorting technology, Kraft et al. isolated an astrocyte-specific (detoxification and antioxidant) and neuron-specific gene cluster (cell adhesion, synaptic transmission, calcium mobilization) (31) , supporting the notion that Nrf2 regulates target gene expression depending on a cell’s function and the toxic by-products generated in the cell’s microenvironment during routine activities.

Finally, Li et al. showed that Nrf2–/– mice develop an autoimmune disease with multiple organ pathology that closely resembles human systemic lupus erythmatosus (SLE). These data indicate that the lack of Nrf2 can induce pathologies in multiple organs, and SLE might be evoked by oxidative tissue damage. In support of this, the authors identified Nrf2 target genes in liver and spleen. While Nrf2 regulates many classical ARE-driven genes in liver, it also regulates many cytokines as well as B cell and T cell-specific genes, which are important for immune and phagocytosis function of splenocytes (23) .

Overall, these observations show that Nrf2-dependent, ARE-driven detoxification and antioxidant genes commonly play an important role in cellular protection (Table 1 , Fig. 1 ). Furthermore, there are cell type-dependent Nrf2 target genes that further contribute to cellular protection. Although some of these genes have been shown to be regulated through the Nrf2-ARE pathway, many have not been verified as being under direct control of Nrf2. It is quite possible that some of the changed genes could be secondary to an Nrf2 controlled gene; such information has yet to be investigated.

The basic defense system of each cell type has evolved to deal with those most likely toxic insults that each cell could encounter in its specific environment (Fig. 2 ). It would also appear that cell utilizes the Nrf2-ARE pathway as a common mechanism to regulate/activate its defense system.



View larger version (41K):
[in this window]
[in a new window]
  		Figure 2. A multi-organ protector, Nrf2. Nrf2 protects various cell types (lung, liver, kidney, stomach, small intestine, central nervous system, splenocytes, macrophages, erythrocytes, and retinal epithelia) by coordinately increasing classic ARE-driven detoxification and antioxidant genes. Nrf2 contributes to cellular protection by enhancing cellular resistance to potential harmful insults that occur during cells’ normal activities.

CONCLUSIONS

In summary, we have proposed and presented evidence supporting the hypothesis that Nrf2 has the capability to confer and is central to a multi-organ protection phenomenon. Expansion of these known characteristics of the Nrf2-ARE pathway are important in identifying novel pathways necessary to prevent or cure toxic effects involved in multiple disease states. As numerous studies have demonstrated the great potential for the Nrf2-ARE pathway as a therapeutic target in preventing cancer, autoimmune disease, and neurodegenerative disease, it is important to identify ways to modulate cell-specific Nrf2 activity so as to facilitate the development of novel therapeutic strategies for treatment of these diseases.

Received for publication December 14, 2004. Accepted for publication March 3, 2005.

REFERENCES

  1. Sakai, M., Okuda, A., Muramatsu, M. (1988) Multiple regulatory elements and phorbol 12-O-tetradecanoate 13-acetate responsiveness of the rat placental glutathione transferase gene. Proc. Natl. Acad. Sci. USA 85,9456-9460[Abstract/Free Full Text]
  2. Rushmore, T. H., Pickett, C. B. (1990) Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J. Biol. Chem. 265,14648-14653[Abstract/Free Full Text]
  3. Friling, R. S., Bensimon, A., Tichauer, Y., Daniel, V. (1990) Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc. Natl. Acad. Sci. USA 87,6258-6262[Abstract/Free Full Text]
  4. Favreau, L. V., Pickett, C. B. (1991) Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J. Biol. Chem. 266,4556-4561[Abstract/Free Full Text]
  5. Li, Y., Jaiswal, A. K. (1992) Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element. J. Biol. Chem. 267,15097-15104[Abstract/Free Full Text]
  6. Venugopal, R., Jaiswal, A. K. (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA 93,14960-14965[Abstract/Free Full Text]
  7. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236,313-322[CrossRef][Medline]
  8. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., Yamamoto, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13,76-86[Abstract/Free Full Text]
  9. Huang, H. C., Nguyen, T., Pickett, C. B. (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2.[erratum appears in. Proc. Natl. Acad. Sci. USA 97,12475-12480[Abstract/Free Full Text]
  10. Yu, R., Chen, C., Mo, Y. Y., Hebbar, V., Owuor, E. D., Tan, T. H., Kong, A. N. (2000) Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J. Biol. Chem. 275,39907-39913[Abstract/Free Full Text]
  11. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P. (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. USA 99,11908-11913[Abstract/Free Full Text]
  12. Dhakshinamoorthy, S., Jaiswal, A. K. (2001) Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 20,3906-3917[CrossRef][Medline]
  13. Kang, K. W., Lee, S. J., Park, J. W., Kim, S. G. (2002) Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol. Pharmacol. 62,1001-1010[Abstract/Free Full Text]
  14. Bloom, D. A., Jaiswal, A. K. (2003) Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression. J. Biol. Chem. 278,44675-44682[Abstract/Free Full Text]
  15. Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., Talalay, P. (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc. Natl. Acad. Sci. USA 101,2040-2045[Abstract/Free Full Text]
  16. Kobayashi, A., Ohta, T., Yamamoto, M. (2004) Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Methods Enzymol. 378,273-286[Medline]
  17. Chan, K., Kan, Y. W. (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl. Acad. Sci. USA 96,12731-12736[Abstract/Free Full Text]
  18. Cho, H. Y., Jedlicka, A. E., Reddy, S. P., Kensler, T. W., Yamamoto, M., Zhang, L. Y., Kleeberger, S. R. (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 26,175-182[Abstract/Free Full Text]
  19. Cho, H. Y., Reddy, S. P., Yamamoto, M., Kleeberger, S. R. (2004) The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 18,1258-1260[Abstract/Free Full Text]
  20. Rangasamy, T., Cho, C. Y., Thimmulappa, R. K., Zhen, L., Srisuma, S. S., Kensler, T. W., Yamamoto, M., Petrache, I., Tuder, R. M., Biswal, S. (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Invest. 114,1248-1259[CrossRef][Medline]
  21. Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, T., O’Connor, T., Harada, T., Yamamoto, M. (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59,169-177[Abstract/Free Full Text]
  22. Chan, K., Han, X. D., Kan, Y. W. (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. USA 98,4611-4616[Abstract/Free Full Text]
  23. Li, J., Stein, T. D., Johnson, J. A. (2004) Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiol. Genomics 18,261-272[Abstract/Free Full Text]
  24. Ramos-Gomez, M., Kwak, M. K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., Kensler, T. W. (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl. Acad. Sci. USA 98,3410-3415[Abstract/Free Full Text]
  25. Ramos-Gomez, M., Dolan, P. M., Itoh, K., Yamamoto, M., Kensler, T. W. (2003) Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24,461-467[Abstract/Free Full Text]
  26. Fahey, J. W., Haristoy, X., Dolan, P. M., Kensler, T. W., Scholtus, I., Stephenson, K. K., Talalay, P., Lozniewski, A. (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc. Natl. Acad. Sci. USA 99,7610-7615[Abstract/Free Full Text]
  27. Murphy, T. H., De Long, M. J., Coyle, J. T. (1991) Enhanced NAD(P)H:quinone reductase activity prevents glutamate toxicity produced by oxidative stress. J. Neurochem. 56,990-995[Medline]
  28. Li, J., Lee, J. M., Johnson, J. A. (2002) Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J. Biol. Chem. 277,388-394[Abstract/Free Full Text]
  29. Lee, J. M., Shih, A. Y., Murphy, T. H., Johnson, J. A. (2003) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J. Biol. Chem. 278,37948-37956[Abstract/Free Full Text]
  30. Lee, J. M., Calkins, M. J., Chan, K., Kan, Y. W., Johnson, J. A. (2003) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J. Biol. Chem. 278,12029-12038[Abstract/Free Full Text]
  31. Kraft, A. D., Johnson, D. A., Johnson, J. A. (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J. Neurosci. 24,1101-1112[Abstract/Free Full Text]
  32. Dhakshinamoorthy, S., Porter, A. G. (2004) Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. J. Biol. Chem. 279,20096-20107[Abstract/Free Full Text]
  33. Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W. (2004) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl. Acad. Sci. USA 102,244-249
  34. Gao, X., Talalay, P. (2004) Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage. Proc. Natl. Acad. Sci. USA 101,10446-10451[Abstract/Free Full Text]
  35. Li, N., Alam, J., Venkatesan, M. I., Eiguren-Fernandez, A., Schmitz, D., Di Stefano, E., Slaughter, N., Killeen, E., Wang, X., Huang, A., et al (2004) Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. J. Immunol. 173,3467-3481[Abstract/Free Full Text]
  36. Dyck, P. A., Hoda, F., Osmer, E. S., Green, R. M. (2003) Microarray analysis of hepatic gene expression in gallstone-susceptible and gallstone-resistant mice. Mamm. Genome 14,601-610[CrossRef][Medline]
  37. Braun, S., Hanselmann, C., Gassmann, M. G., auf dem Keller, U., Born-Berclaz, C., Chan, K., Kan, Y. W., Werner, S. (2002) Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol. Cell. Biol. 22,5492-5505[Abstract/Free Full Text]
  38. Motohashi, H., Katsuoka, F., Engel, J. D., Yamamoto, M. (2004) Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc. Natl. Acad. Sci. USA 101,6379-6384[Abstract/Free Full Text]
  39. Yoh, K., Itoh, K., Enomoto, A., Hirayama, A., Yamaguchi, N., Kobayashi, M., Morito, N., Koyama, A., Yamamoto, M., Takahashi, S. (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int. 60,1343-1353[CrossRef][Medline]
  40. Lee, J. M., Chan, K., Kan, Y. W., Johnson, J. A. (2004) Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia. Proc. Natl. Acad. Sci. USA 101,9751-9756[Abstract/Free Full Text]
  41. Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., Biswal, S. (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62,5196-5203[Abstract/Free Full Text]
  42. Kwak, M. K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., Kensler, T. W. (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J. Biol. Chem. 278,8135-8145[Abstract/Free Full Text]
  43. Shih, A. Y., Johnson, D. A., Wong, G., Kraft, A. D., Jiang, L., Erb, H., Johnson, J. A., Murphy, T. H. (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23,3394-3406[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Prevention ResearchHome page
F. Lu, M. Zahid, C. Wang, M. Saeed, E. L. Cavalieri, and E. G. Rogan
Resveratrol Prevents Estrogen-DNA Adduct Formation and Neoplastic Transformation in MCF-10F Cells
Cancer Prevention Research, July 1, 2008; 1(2): 135 - 145.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
A. M. Kivela, E. Kansanen, H.-K. Jyrkkanen, T. Nurmi, S. Yla-Herttuala, and A.-L. Levonen
Enterolactone Induces Heme Oxygenase-1 Expression through Nuclear Factor-E2-Related Factor 2 Activation in Endothelial Cells
J. Nutr., July 1, 2008; 138(7): 1263 - 1268.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Theodore, Y. Kawai, J. Yang, Y. Kleshchenko, S. P. Reddy, F. Villalta, and I. J. Arinze
Multiple Nuclear Localization Signals Function in the Nuclear Import of the Transcription Factor Nrf2
J. Biol. Chem., April 4, 2008; 283(14): 8984 - 8994.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
K. P. Tan, M. Yang, and S. Ito
Activation of Nuclear Factor (Erythroid-2 Like) Factor 2 by Toxic Bile Acids Provokes Adaptive Defense Responses to Enhance Cell Survival at the Emergence of Oxidative Stress
Mol. Pharmacol., November 1, 2007; 72(5): 1380 - 1390.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. E. Purdom-Dickinson, E. V. Sheveleva, H. Sun, and Q. M. Chen
Translational Control of Nrf2 Protein in Activation of Antioxidant Response by Oxidants
Mol. Pharmacol., October 1, 2007; 72(4): 1074 - 1081.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. C.M. Siow and A. T. Churchman
Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in
Cardiovasc Res, September 1, 2007; 75(4): 659 - 668.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. Wang, A. M. Kwok, and J. Y. Chan
The p65 Isoform of Nrf1 Is a Dominant Negative Inhibitor of ARE-mediated Transcription
J. Biol. Chem., August 24, 2007; 282(34): 24670 - 24678.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
L. M. Aleksunes and J. E. Manautou
Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease
Toxicol Pathol, June 1, 2007; 35(4): 459 - 473.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
N. Onishchenko, C. Tamm, M. Vahter, T. Hokfelt, J. A. Johnson, D. A. Johnson, and S. Ceccatelli
Developmental Exposure to Methylmercury Alters Learning and Induces Depression-like Behavior in Male Mice
Toxicol. Sci., June 1, 2007; 97(2): 428 - 437.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Liu, J. T. Kern, J. R. Walker, J. A. Johnson, P. G. Schultz, and H. Luesch
A genomic screen for activators of the antioxidant response element
PNAS, March 20, 2007; 104(12): 5205 - 5210.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Gao, J. Wang, K. R. Sekhar, H. Yin, N. F. Yared, S. N. Schneider, S. Sasi, T. P. Dalton, M. E. Anderson, J. Y. Chan, et al.
Novel n-3 Fatty Acid Oxidation Products Activate Nrf2 by Destabilizing the Association between Keap1 and Cullin3
J. Biol. Chem., January 26, 2007; 282(4): 2529 - 2537.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
M. O. Leonard, N. E. Kieran, K. Howell, M. J. Burne, R. Varadarajan, S. Dhakshinamoorthy, A. G. Porter, C. O'Farrelly, H. Rabb, and C. T. Taylor
Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury
FASEB J, December 1, 2006; 20(14): 2624 - 2626.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
R. Rodrigo, S. Trujillo, and C. Bosco
Biochemical and Ultrastructural Lung Damage Induced by Rhabdomyolysis in the Rat
Experimental Biology and Medicine, September 1, 2006; 231(8): 1430 - 1438.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
A. Y. Shih, H. B. Fernandes, F. Y. Choi, M. G. Kozoriz, Y. Liu, P. Li, C. M. Cowan, and A. Klegeris
Policing the Police: Astrocytes Modulate Microglial Activation
J. Neurosci., April 12, 2006; 26(15): 3887 - 3888.
[Full Text] [PDF]

Home page
 J. Nutr.Home page
Y.-J. Surh, J. K. Kundu, H.-K. Na, and J.-S. Lee
Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals
J. Nutr., December 1, 2005; 135(12): 2993S - 3001S.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, J.-M.
Right arrow Articles by Johnson, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.-M.
Right arrow Articles by Johnson, J. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS