The transcription factor NF-E2-related factor 2 (nrf2): A protooncogene?

FASEB Journal

Volumn 27, Issue 2, 2013, Pages 414-423

  Shelton, Phillip ^a   Jaiswal, Anil K ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer; Chemoprevention; Oxidative stress; Signal transduction; Targeted therapy

Indexed keywords

ANTIOXIDANT; B RAF KINASE; BRCA2 PROTEIN; BRUCEA JAVANICA EXTRACT; CURCUMIN; CYCLIN D1; EPIGALLOCATECHIN GALLATE; FREE RADICAL; GLUCOSE 6 PHOSPHATE DEHYDROGENASE; GLYCOGEN SYNTHASE KINASE 3BETA; K RAS PROTEIN; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MYC PROTEIN; OLTIPRAZ; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE; PHOSPHOPROTEIN PHOSPHATASE 1; PROTEIN BCL 2; PROTEIN KINASE B; PROTEIN KINASE C DELTA; PROTEIN P21; PROTEIN P62; SULFORAPHANE; TRANSCRIPTION FACTOR NRF2;

ACUTE STRESS; APOPTOSIS; CANCER PREVENTION; CARCINOGENESIS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; DETOXIFICATION; DNA BINDING; HUMAN; IN VIVO STUDY; INFLAMMATION; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; PROTO ONCOGENE; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH;

ANIMALS; ANTIOXIDANT RESPONSE ELEMENTS; CARCINOGENS; GENE EXPRESSION REGULATION; HUMANS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; NEOPLASMS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; PROTO-ONCOGENES; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEINS;

EID: 84873469216     PISSN: None     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.12-217257     Document Type: Review

References (98)

1. Sies, H. (1997) Oxidative stress: oxidants and antioxidants. Exp. Physiol. 82, 291-295
2. Klaunig, J. E., Kamendulis, L. M., and Hocevar, B. A. (2010) Oxidative stress and oxidative damage in carcinogenesis. Toxicol. Path. 38, 96-109
3. Tudek, B., Winczura, A., Janik, J., Siomek, A., Foksinski, M., and Oli ́ nski, R. (2010) Involvement of oxidatively damaged DNA and repair in cancer development and aging. Am. J. Transl. Res. 2, 254-284
4. Wu, R. P., Hayashi, T., Cottam, H. B., Jin, G., Yao, S., Wu, C. C., Rosenbach, M. D., Corr, M., Schwab, R. B., and Carson, D. A. (2010) Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. U. S. A. 107, 7479-7484
5. Nguyen, T., Huang, H. C., and Pickett, C. B. (2000) Transcriptional regulation of the antioxidant response elementactivation by Nrf2 and repression by MafK. J. Biol. Chem. 275, 15466-15473
6. Jaiswal, A. K. (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic. Biol. Med. 36, 1199-1207
7. Niture, S. K., Jain, A. K., and Jaiswal, A. K. (2009) Antioxidant induced modification of INrf2 cysteine151 and PKCd-mediated phosphorylation of Nrf2 serine40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance. J. Cell Sci. 122, 4452-4464
8. Zhang, D. D., and Hannink, M. (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol. Cell. Biol. 23, 8137-8151
9. Bloom, D. A., and Jaiswal, A. K. (2003) Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H: quinone oxidoreductase1 gene expression. J. Biol. Chem. 278, 44675-44682
10. Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., and Mesecar, A. D. (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc. Natl. Acad. Sci. U. S. A. 102, 10070-10075
11. Lau, A., Villeneuve, N. F., Sun, Z., Wong, P. K., and Zhang, D. D. (2008) Dual roles of Nrf2 in cancer. Pharmacol. Res. 58, 262-270
12. Wang, X. J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, Y. X., Wondrack, G. T., Wong, P. K., and Zhang, D. D. (2008) Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29, 1235-1243
13. Homma, S., Ishii, Y., Morishima, Y., Yamadori, T., Matsuno, Y., Haraguchi, N., Kikuchi, N., Satoh, H., Sakamoto, T., Hizawa, N., Itoh, K., and Yamamoto, M. (2009) Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin. Cancer Res. 15, 3423-3432
14. Kensler, T. W., and Wakabayashi, N. (2010) Nrf2: friend or foe for chemopreventionCarcinogenesis 31, 90-99
15. Chan, J. Y., Cheung, M. C., Moi, P., Chan, K., and Kan, Y. W. (1995) Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Hum. Genet. 95, 265-269
16. Motohashi, H., O'Connor, T., Katsuoka, F., Engel, J. D., and Yamamoto, M. (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294, 1-12
17. Sykiotis, G. P., and Bohmann, D. (2010) Stress-activated cap 'n' collar transcription factors in aging and human disease. Sci. Signal. 3(112), re3
18. Sankaranarayanan, K., and Jaiswal, A. K. (2004) Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H: quinone oxidoreductase1 gene. J. Biol. Chem. 279, 50810-50817
19. Leug, L., Kwong, M., Hou, S., Lee, C., and Chan, J. Y. (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J. Biol. Chem. 278, 48021-48029
20. Ohtsuji, M., Katsuoka, F., Kobayashi, A., Aburatani, H., Hayes, J. D., and Yamamoto, M. (2008) Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J. Biol. Chem. 283, 33554-33562
21. Chan, J. Y., Kwong, M., Lu, R., Chang, J., Wang, B., Yen, T. S., and Kan, Y. W. (1998) Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. EMBO J. 17, 1779-1787
22. Xu, Z. R., Chen, L., Leung, L., Yen. T. S. B., Lee, C., and Chan, J. Y. (2005) Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc. Natl. Acad. Sci. U. S. A. A102, 4120-4125
23. Chan, K., Lu, R., Chang, J. C., and Kan, Y. T. (1996) Nrf2, a member of the NF-E2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc. Natl. Acad. Sci. U. S. A. 93, 13943-13948
24. Chan, J. Y., and Kwong, M. (2000) Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim. Biophys. Acta 1517, 19-26
25. Kwak, M. K., Egner, P. A., Dolan, P. M., Ramos-Gomez, M., Groopman, J. D., Itoh, K., Yamamoto, M., and Kensler, T. W. (2001) Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. Mutat. Res. 480-481, 305-315
26. Ramos-Gomez, M., Kwak, M. K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., and 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. U. S. A. 98, 3410-3415
27. Kaspar, J. W., Niture, S. K., Jaiswal, A. K. (2009) Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radic. Biol. Med. 47, 1304-1309
28. Dhakshinamoorthy, S., Long, D. J., 2nd, and Jaiswal, A. K. (2000) Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr. Top. Cell Regul. 36, 201-206
29. Kobayashi, M., and Yamamoto, M. (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv. Enzyme Regul. 46, 113-140
30. Zhang, D. D. (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab. Rev. 38, 769-789
31. Aleksunes, L. M., and Manautou, J. E. (2007) Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Path. 35, 459-473
32. Hayes, J. D., and McMahon, M. (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem. Sci. 34, 176-188
33. Kwak, M. K., Cho, J. M., Huang, B., Shin, S., and Kensler, T. W. (2007) Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxidemediated cytotoxicity in murine neuroblastoma cells. Free Radic. Biol. Med. 43, 809-817
34. Blank, V. (2008) Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulatorsJ. Mol. Biol. 376, 913-925
35. Venugopal, R., and 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 oxidoreductase1gene. Proc. Natl. Acad. Sci. U. S. A. 93, 14960-14965
36. Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., and Cook, J. L. (1999) Nrf2, a cap 'n' collar transcription factor, regulates induction of the heme oxygenase-1 gene. J. Biol. Chem. 274, 26071-26078
37. Wang, W., and Jaiswal, A. K. (2006) Nuclear factor Nrf2 and antioxidant response element regulate NRH: quinone oxidoreductase 2 (NQO2) gene expression and antioxidant induction. Free Radic. Biol. Med. 40, 1119-1130
38. Maher, J. M., Dieter, M. Z., Aleksunes, L. M., Slitt, A. L., Guo, G., Tanaka, Y., Scheffer, G. L., Chan, J. Y., Manautou, J. E., Chen, Y., Dalton, T. P., Yamamoto, M., and Klaassen, C. D. (2007) Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46, 1597-1610
39. Niture, S. K., and Jaiswal, A. K. (2012) Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J. Biol. Chem. 287, 9873-9886
40. Y. Mitsuishi, Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M., and Motohashi, H. (2012) Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66-79
41. Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W., and Diehl, J. A. (2004) The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol. Cell. Biol. 24, 8477-8486
42. Zhang, D. D., Lo, S. C., Cross, J. V., Templeton, D. J., and Hannink, M. (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24, 10941-10953
43. Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., and Yamamoto, M. (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26, 2887-2900
44. Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., and Yamamoto, M. (2007) Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol. Cell. Biol. 27, 7511-7521
45. Dhakshinamoorthy, S., Jain, A. K., Bloom, D. A., and Jaiswal, A. K. (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H: quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J. Biol. Chem. 280, 16891-16900
46. Jain, A. K., and Jaiswal, A. K. (2007) GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J. Biol. Chem. 282, 16502-16510
47. Niture, S. K., Jain, A. K., Shelton, P. M., and Jaiswal, A. K. (2011) Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to switch off Nrf2-mediated antioxidant activation of cytoprotective gene expression. J. Biol. Chem. 286, 28821-28832
48. Doble, B. W., and Woodgett, J. R. (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175-1186
49. Kaspar, J., and Jaiswal, A. K. (2010) Antioxidant induced phosphorylation of tyrosine486 leads to rapid nuclear export of Bach1 that allows Nrf2 to bind to ARE and activate defensive genes expression. J. Biol. Chem. 285, 153-162
50. Kaspar, J. W., and A. K. Jaiswal (2011) Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression. FASEB J. 25, 1076-1087
51. Kaspar, J. W., Niture, S. K., and Jaiswal, A. K. (2012) Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression. J. Cell Sci. 125, 1027-1038
52. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M., and Nabeshima, Y. (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
53. Marini, M. G., Chan, K., Casula, L., Kan, Y. W., Cao, A., and Moi, P. (1997) hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. J. Biol. Chem. 16490-16497
54. Lee, J. M., Hanson, J. M., Chu, W. A., and Johnson, J. A. (2001) Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant responsive element in IMR-32 human neuroblastoma cells. J. Biol. Chem. 276, 20011-20016
55. Vivanco, I., and Sawyers, C. L. (2002) The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501
56. Nakaso, K., Yano, H., Fukuhara, Y., Takeshima, T., Wada-Isoe, K., and Nakashima, K. (2003) PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546, 181-184
57. Martin, D., Rojo, A. I., Salinas, M., Diaz, R., Gallardo, G., Alam, J., De Galarreta, C. M., and Cuadrado, A. (2004) Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J. Biol. Chem. 279, 8919-8929
58. Papaiahgari, S., Zhang, Q., Kleeberger, S. R., Cho, H. Y., and Reddy, S. P. (2006) Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid. Redox Signal. 8, 43-52
59. Lim, J. H., Kim, K. M., Kim, S. W., Hwang, O., and Choi, H. J. (2008) Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage. Pharmacol. Res. 57, 325-331
60. Liu, P., Cheng, H., Roberts, T. M., and Zhao, J. J. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Disc. 8, 627-644
61. Cohen, P., and Frame, S. (2001) The renaissance of GSK3. Nat. Rev. Mol. Cell Biol. 2, 769-776
62. Jain, A. K., and Jaiswal, A. K. (2006) Phosphorylation of tyrosine 568 controls nuclear export of Nrf2. J. Biol. Chem. 281, 12132-12142
63. Shi, Y. (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139, 468-484
64. Hernández, F., Langa, E., Cuadros, R., Avila, J., and Villaneuva, N. (2010) Regulation of GSK3 isoforms by phosphatases PP1 and PP2A. Mol. Cell. Biochem. 344, 211-215
65. Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674
66. Sporn, M. B., and Liby, K. T. (2012) NRF2 and cancer: the good, the bad and the importance of context. Nat. Rev. Cancer 12, 564-571
67. Cho, H.-Y., Gladwell, W., Wang, X., Chorley, B., Bell, D. S., Reddy, P., and Kleeberger, S. R. (2010) Nrf2-regulated PPAR-expression is critical to protection against acute lung injury in mice. Am. J. Respir. Crit. Care Med. 182, 170-182
68. Zhan, L., Zhang, H., Zhang, Q., Woods, C. G., Chen, Y., Xue, P., Dong, J., Tokar, E. J., Xu, Y., Hou, Y., Fu, J., Yarborough, K., Wang, A., Qu, W., Waalkes, M. P., Andersen, M. E., and Pi, J. (2012) Regulatory role of KEAP1 and NRF2 in PPAR-expression and chemoresistance in human non-small-cell lung carcinoma cells. Free Radic. Biol. Med. 53, 758-768
69. Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, T., O'Connor, T., Harada, T., and 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
70. Chan, K., Han, X. D., and Kan, Y. W. (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. U. S. A. 98, 4611-4616
71. Rangasamy, T., Guo, J., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Tuder, R. M., Georas, S. N., and Biswal, S. (2005) Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med. 202, 47-59
72. Iizuka, T., Ishii, Y., Itoh, K., Kiwamoto, T., Kimura, T., Matsuno, Y., Morishima, Y., Hegab, A. E., Homma, S., Nomura, A., Sakamoto, T., Shimura, M., Yoshida, A., Yamamoto, M., and Sekizawa, K. (2005) Nrf2 deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 10, 1113-1125
73. Hu, X., Roberts, J. R., Apopa, P. L., Kan, Y. W., and Ma, Q. (2006) Accelerated ovarian failure induced by 4-Vinyl Cyclohexane diepoxide in Nrf2-null mice. Mol. Cell. Biol. 26, 940-954
74. Aoki, Y., Sato, H., Nishimura, N., Takahashi, S., Itoh, K., and Yamamoto, M. (2001) Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol. Appl. Pharm. 173, 154-160
75. Iida, K., Itoh, K., Kumagai, Y., Oyasu, R., Hattori, K., Kawai, K., Shimazui, T., Akaza, H., and Yamamoto, M. (2004) Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 64, 6424-6431
76. Satoh, H., Moriguchi, T., Taguchi, K., Takai, J., Maher, J., Suzuki, T., Winnard, P. T., Raman, V., Ebina, M., Nukiwa, T., and Yamamoto, M. (2010) Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis 31, 1833-1843
77. Chen, W., Sun, Z., Wang, X. J., Jiang, T., Huang, Z., Fang, D., and Zhang, D. D. (2009) Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol. Cell. 34, 663-673
78. Ma, J., Cai, H., Wu, T., Sobhian, B., Huo, Y., Alcivar, A., Mehta, M., Cheung, K. L., Ganesan, S., Kong, A. N., Zhang, D. D., and Xia, B. (2012) PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol. Cell. Biol. 32, 1506-1517
79. Rada, P. A. I. Rojo, Chowdhry, S., McMahon, M. J. D. Hayes, and A. Cuadrado. (2011) SCF/TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell. Biol. 31, 1121-1133
80. Salazar, M., Rojo, A. I., Velasco, D., de Sagarra, R. M., and Cuadrado, A. (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J. Biol. Chem. 281, 14841-14851
81. DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., Scrimieri, F., Winter, J. M., Hruban, R. H., Iacobuzio-Donahue, C., Kern, S. E., Blair, I. A., and Tuveson, D. A. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109
82. Perera, R. M., and Bardeesy, N. (2011) Cancer: when antioxidants are bad. Nature 475, 43-44
83. Bauer, A. K., Cho, H.-Y., Miller-DeGraff, L., Walker, C., Helms, K., Fostel, J., Yamamoto, M., and Kleeberger, S. R. (2011) Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice. PLoS ONE 6, e26590
84. Ma, Q., and He, X. (2012) Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol. Rev. 64, 1055-1081
85. Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., Brock, M. V., and Biswal, S. (2006) Dysfunctional Keap1-Nrf2 interaction in non-small-cell lung cancer. PLoS Med. 3, e420
86. Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M. I., Kobayashi, A., Yokoyama, S., and Yamamoto, M. (2006) Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol. Cell 87.
87. Kweon, M. H., Adhami, V. M., Lee, J. S., and Mukhtar, H. (2006) Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J. Biol. Chem. 281, 33761-33772
88. Taguchi, K., Motohashi, H., and Yamamoto, M. (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123-140
89. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y. S., Ueno, I., Sakamoto, A., Tong, K. I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K., and Yamamoto, M. (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213-223
90. Lau, A., Wang, X. J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., and Zhang, D. D. (2010) A Noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30, 3275-3285
91. Inami, Y., Waguri, S., Sakamoto, A., Kouno, T., Nakada, K., Hino, O., Watanabe, S., Ando, J., Iwadate, M., Yamamoto, M., Lee, M. S., Tanaka, K., and Komatsu, M. (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 193, 275-284
92. Vollrath, V., Wielandt, A. M., Iruretagoyena, M., and Chianale, M. (2006) Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem. J. 395, 599-609
93. Kim, Y. J., Ahn, J. Y., Liang, P., Ip, C., Zhang, Y., and Park, Y. M. (2007) Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res. 67, 546-554
94. Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, H., Kensler, T. W., and Yamamoto, M. (2006) Hepatocyte-specific deletion of the Keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339, 79-88
95. Stehelin, D., Varmus, H. E., Bishop, J. M., and Vogt, P. K. (1976) DNA related to the transforming gene(s) of avian sarcomaviruses is present in normal avian DNA. Nature 260, 170-173
96. Bishop, J. M. (1988) Oncogenes and proto-oncogenes. J. Cell. Physiol. 129(S4), 1-5
97. Ren, D., Villeneuve, N. F., Jiang, T., Wu, T., Lau, A., Toppin, H. A., and Zhang, D. D. (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc. Natl. Acad. Sci. U. S. A. 108, 1433-1438
98. Ohnuma, T., Matsumoto, T., Itoi, A., Kawana, A., Nishiyama, T., Ogura, K., and Hiratsuka, A. (2011) Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from cinnamomi cortex extract. Biochem. Biophys. Res. Commun. 413, 623-629