The role of Keap1 in cellular protective responses

Chemical Research in Toxicology

Volumn 18, Issue 12, 2005, Pages 1779-1791

  Dinkova Kostova, Albena T ^a   Holtzclaw, W David ^a   Kensler, Thomas W ^a,b  

^a SCHOOL OF MEDICINE   (United States)

^b The Johns Hopkins University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL PROTEIN; FAC1 PROTEIN; KEAP1 PROTEIN; METALLOPROTEIN; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; ZINC;

CELL JUNCTION; CELL PROTECTION; ENZYME INDUCTION; GENE DELETION; HUMAN; INTRACELLULAR TRANSPORT; NONHUMAN; PROTEIN FUNCTION; PROTEIN STABILITY; PROTEIN STRUCTURE; PROTEIN TRANSPORT; REVIEW; SENSOR;

ANIMALS; ANTIGENS, NUCLEAR; CELL SURVIVAL; CYSTEINE; CYTOPROTECTION; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; NERVE TISSUE PROTEINS; NF-E2-RELATED FACTOR 2; PROTEINS; TRANSCRIPTION FACTORS;

EID: 29644435115     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx050217c     Document Type: Review

References (92)

1. Talalay, P. (2000) Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12, 5-11.
2. Talalay, P. (1999) The war against cancer: New hope. Proc. Am. Philos. Soc. 143, 52-72.
3. Prestera, T., Talalay, P., Alam, J., Ahn, Y. I., Lee, P. J., and Choi, A. M. (1995) Parallel induction of heme oxygenase-1 and chemoprotective phase 2 enzymes by electrophiles and antioxidants: Regulation by upstream antioxidant-responsive elements (ARE). Mol. Med. 1, 827-837.
4. Primiano, T., Kensler, T. W., Kuppusamy, P., Zweier, J. L., and Sutter, T. R. (1996) Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones. Carcinogenesis 17, 2291-2296.
5. Hayes, J. D., and Pulford, D. J. (1995) The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 30, 445-600.
6. Hayes, J. D., Flanagan, J. U., and Jowsey, I. R. (2005) Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45, 51-88.
7. Talalay, P. (1989) Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Adv. Enzyme Regul. 28, 237-250.
8. Moinova, H. R., and Mulcahy, R. T. (1988) An electrophile responsive element (EpRE) regulates beta-naphthoflavone induction of the human gamma-glutamylcysteine synthetase regulatory subunit gene. Constitutive expression is mediated by an adjacent AP-1 site. J. Biol. Chem. 273, 14683-14689.
9. Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 62, 5196-5203.
10. Hayes, J. D., and McLellan, L. I. (1999) Glutathione and glutathione-dependent enzymes represent a coordinately regulated defence against oxidative stress. Free Radical Res. 31, 273-300.
11. Primiano, T., Li, Y., Kensler, T. W., Trush, M. A., and Sutter, T. R. (1998) Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: Implications for chemoprevention. Carcinogenesis 19, 999-1005.
12. Torti, F. M., and Torti, S. V. (2002) Regulation of ferritin genes and protein. Blood 99, 3505-3516.
13. Wilkinson, J., 4th, Pietsch, E. C., Torti, S. V., and Torti, F. M. (2003) Ferritin regulation by oxidants and chemopreventive xenobiotics. Adv. Enzyme Regul. 43, 135-151.
14. Kwak, M. K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., and 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.
15. Nguyen, T., Sherratt, P. J., and Pickett, C. B. (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu. Rev. Pharmacol. Toxicol. 43, 233-260.
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. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., and 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.
18. Chan, K., Lu, R., Chang, J. C., and Kan, Y. W. (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erthropoiesis, growth, and development. Proc. Natl. Acad. Sci. U.S.A. 93, 13943-13948.
19. 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 induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313-322.
20. 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.
21. Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, 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.
22. Chan, K., and Kan, Y. W. (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl. Acad. Sci. U.S.A. 96, 12731-12736.
23. Cho, H.-Y., Jedlicka, A. E., Reddy, S. P. M., Kensler, T. W., Yamamoto, M., Zhang, L.-Y., and Kleeberger, S. R. (2002) Role of Nrf2 in protection against hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 26, 175-182.
24. Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., and Johnson, J. A. (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl. Acad. Sci. U.S.A. 102, 244-249.
25. Shih, A. Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., and Murphy, T. H. (2005) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem. 280, 22925-22936.
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. 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.
28. Rangasamy, T., Cho, C. Y., Thimmulappa, R. K., Zhen, L., Srisuma, S. S., Kensler, T. W., Yamamoto, M., Petrache, I., Tuder, R. M., and Biswal, S. (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Invest. 114, 1248-1259.
29. Rangasamy, T., Guo, G., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Ruder, 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.
30. Cullinan, S. B., and Diehl, J. A. (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J. Biol. Chem. 279, 20108-20117.
31. 2. Mol. Cell. Biol. 24, 36-45.
32. Hosoya, T., Maruyama, A., Kang, M.-I., Kawatani, Y., Shibata, T., Uchida, K., Itoh, K., and Yamamoto, M. (2005) Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. J. Biol. Chem. 280, 27244-27250.
33. Talalay, P., De Long, M. J., and Prochaska, H. J. (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 85, 8261-8265.
34. Talalay, P., Fahey, J. W., Holtzclaw, W. D., Prestera, T., and Zhang, Y. (1995) Chemoprotection against cancer by phase 2 enzyme induction. Toxicol. Lett. 82-83, 173-179.
35. Spencer, S. R., Xue, L. A., Klenz, E. M., and Talalay, P. (1991) The potency of inducers of NAD(P)H:(quinone-acceptor) oxidoreductase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations. Biochem. J. 273, 711-717.
36. Dinkova-Kostova, A. T., Massiah, M. A., Bozak, R. E., Hicks, R. J., and Talalay, P. (2001) Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc. Natl. Acad. Sci. U.S.A. 98, 3404-3409.
37. Katoh, Y., Itoh, K., Yoshida, E., Miyagishi, M., Fukamizu, A., and Yamamoto, M. (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6, 857-868.
38. Xue, F., and Cooley, L. (1993) Kelch encodes a component of intracellular bridges in Drosophila egg chambers. Cell 72, 681-693.
39. Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., and Nomura, N. (1995) Prediction of the coding sequences of unidentified human genes, IV. The coding sequences of 40 new genes (KIAA0121KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2, 164-174.
40. Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi, Y., and Yamamoto, M. (2002) Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells 7, 807-820.
41. Bardwell, V. J., and Treisman, R. (1994) The POZ domain: a conserved protein-protein interaction motif. Genes Dev. 8, 1664-1677.
42. Stogios, P. J., and Privé, G. G. (2004) The BACK domain in BTB-kelch proteins. Trends Biochem. Sci. 29, 634-637.
43. Pintard, L., Willems, A., and Peter, M. (2004) Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J. 23, 1681-1687.
44. Ahmad, K. F., Engel, C. K., and Privé, G. G. (1998) Crystal structure of the BTB domain from PLZF. Proc. Natl. Acad. Sci. U.S.A. 95, 12123-12128.
45. Zipper, L. M., and Mulcahy, R. T. (2002) The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J. Biol. Chem. 277, 36544-36552.
46. T'Jampens, D., Devriendt, L., De Corte, V., Vandekerckhove, J., and Gettemans, J. (2002) Selected BTB/POZ-kelch proteins bind ATP. FEBS Lett. 516, 20-26.
47. Adams, J., Kelso, R., and Cooley, L. (2000) The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell. Biol. 10, 17-24.
48. Prag, S., and Adams, J. C. (2003) Molecular phylogeny of the kelch-repeat superfamily reveals an expansion of BTB/kelch proteins in animals. BMC Bioinformatics 4, 42.
49. Li, X., Zhang, D., Hannink, M., and Beamer, L. J. (2004) Crystal structure of the Kelch domain of human Keap1. J. Biol. Chem. 279, 54750-54758.
50. Woycechowsky, K. J., and Raines, R. T. (2003) The CXC motif: a functional mimic of protein disulfide isomerase. Biochemistry 42, 5387-5394.
51. Dinkova-Kostova, A. T., Holtzclaw, W. D., and Wakabayashi, N. (2005) Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44, 6889-6899.
52. Prestera, T., Holtzclaw, W. D., Zhang, Y., and Talalay, P. (1993) Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc. Natl. Acad. Sci. U.S.A. 90, 2965-2969.
53. Prestera, T., Zhang, Y., Spencer, S. R., Wilczak, C. A., and Talalay, P. (1993) The electrophile counterattack response: Protection against neoplasia and toxicity. Adv. Enzyme Regul. 33, 281-296.
54. Holtzclaw, W. D., Dinkova-Kostova, A. T., and Talalay, P. (2004) Protection against electrophile and oxidative stress by induction of phase 2 genes: The quest for the elusive sensor that responds to inducers. Adv. Enzyme Regul. 44, 335-367.
55. Snyder, G. H., Cennerazzo, M. J., Karalis, A. J., and Field, D. (1981) Electrostatic influence of local cysteine environments on disulfide exchange kinetics. Biochemistry 20, 6509-6519.
56. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and 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. U.S.A. 99, 11908-11913.
57. Dinkova-Kostova, A. T., Liby, K. T., Stephenson, K. K., Holtzclaw, W. D., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, T., Gribble, G. W., Sporn, M. B., and Talalay, P. (2005) Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. Proc. Natl. Acad. Sci. U.S.A. 102, 4584-4589.
58. Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., and 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. U.S.A. 101, 2040-2045.
59. 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.
60. Levonen, A. L., Landar, A., Ramachandran, A., Ceaser, E. K., Dickinson, D. A., Zanoni, G., Morrow, J. D., and Darley-Usmar, V. M. (2004) Cellular mechanisms of redox cell signaling: Role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem. J. 378, 373-382.
61. Zhang, X., Garfinkel, M., and Ruden, D. (2003) Phylogenetic conservation of the Nrf2-Keap1 signaling system. In Signal Transduction by Reactive Oxygen and Nitrogen Species: Pathways and Chemical Principles, pp 256-274, Kluwer Academic Publishers, Dordrecht.
62. 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.
63. Hong, F., Sekhar, K. R., Freeman, M. L., and Liebler, D. C. (2005) Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J. Biol Chem. 280, 31768-31775.
64. Katoh, Y., Iida, K., Kang, M. I., Kobayashi, A., Mizukami, M., Tong, K. I., McMahon, M., Hayes, J. D., Itoh, K., and Yamamoto, M. (2005) Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch. Biochem. Biophys. 433, 342-350.
65. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T., and Yamamoto, M. (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8, 379-391.
66. McMahon, M., Itoh, K., Yamamoto, M., and Hayes, J. D. (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J. Biol. Chem. 278, 21592-21600.
67. Stewart, D., Killeen, E., Naquin, R., Alam, S., and Alam, J. (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J. Biol. Chem. 278, 2396-2402.
68. Kwak, M. K., Itoh, K., Yamamoto, M., Sutter, T. R., and Kensler, T. W. (2001) Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol. Med. 7, 135-145.
69. Kwak, M. K., Itoh, K., Yamamoto, M., and Kensler, T. W. (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol. Cell. Biol. 22, 2883-2892.
70. Sekhar, K. R., Soltaninassab, S. R., Borrelli, M. J., Xu, Z. Q., Meredith, M. J., Domann, F. E., and Freeman, M. L. (2000) Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase. Biochem. Biophys. Res. Commun. 270, 311-317.
71. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., and Hayes, J. D. (2004) Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J. Biol. Chem. 279, 31556-31567.
72. Kobayashi, A., Kang, M. I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., and Yamamoto, M. (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24, 7130-7139.
73. 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.
74. 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.
75. Furukawa, M., and Xiong, Y. (2005) BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol. Cell. Biol. 25, 162-171.
76. van den Heuvel, S. (2004) Protein degradation: CUL-3 and BTB-Partners in proteolysis. Curr. Biol. 14, R59-R61.
77. Zhang, D. D., Lo, S. C., Sun, Z., Habib, G. M., Lieberman, M. W., and Hannink, M. (2005) Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J. Biol. Chem. 280, 30091-30099.
78. Karapetian, R. N., Evstafieva, A. G., Abaeva, I. S., Chichkova, N. V., Filonov, G. S., Rubtsov, Y. P., Sukhacheva, E. A., Melnikov, S. V., Schneider, U., Wanker, E. E., and Vartapetian, A. B. (2005) Nuclear oncoprotein prothymosin α is a partner of Keap1: implications for expression of oxidative stress-protecting genes. Mol. Cell. Biol. 25, 1089-1099.
79. Piñeiro, A., Cordero, O. J., and Nogueira, M. (2000) Fifteen years of prothymosin alpha: Contradictory past and new horizons. Peptides 21, 1433-1446.
80. Fabbro, M., and Henderson, B. R. (2003) Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp. Cell Res. 282, 59-69.
81. Kudo, N., Matsumori, N., Taoka, H., Fujiwara, D., Schreiner, E. P., Wolff, B., Yoshida, M., and Horinouchi, S. (1999) Leptomycin B inactivates CRM1/Exportin1 by covalent modification at a cysteine residue in the central conserved region. Proc. Natl. Acad. Sci. U.S.A. 96, 9112-9117.
82. Velichkova, M., and Hasson, T. (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 in to and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol. Cell. Biol. 25, 4501-4513.
83. Nguyen, T., Sherratt, P. J., Nioi, P., Yang, C. S., and Pickett, C. B. (2005) Nfr2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J. Biol. Chem. 280, 32485-32492.
84. Strachan, G. D., Morgan, K. L., Otis, L. L., Caltagarone, J., Gittis, A., Bowser, R., and Jordan-Sciutto, K. L. (2004) Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein. Biochemistry 43, 12113-12122.
85. Velichkova, M., Guttman, J., Warren, C., Eng, L., Kline, K., Vogl, A. W., and Hasson, T. (2002) A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions. Cell Motil. Cytoskeleton 51, 147-164.
86. Velichkova, M., and Hasson, T. (2003) Keap1 in adhesion complexes. Cell Motil. Cytoskeleton 56, 109-119.
87. Wakabayashi, 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., and Yamamoto, M. (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet. 35, 238-245.
88. Yamamoto, T., Kobayashi, A., Wakabayashi, J., Motohashi, H., and Yamamoto, M. (2005) In vivo analysis of Keap1 functional domains using transgenic complementation rescue approach. Proc. Mol. Mech. Environ. Response Food Oxygen, p 46, Tsukuba, Japan.
89. Kwak, M. K., Ramos-Gomez, M., Wakabayashi, N., and Kensler, T. W. (2004) Chemoprevention by 1,2-dithiole-3-thiones through induction of NQO1 and other phase 2 enzymes. Methods Enzymol. 382, 414-423.
90. Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, A., Kensler, T. W., and Yamamoto, M. (2005) Hepatocyte-specific disruption of keap1 gene confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339, 79-88.
91. Ansher, S. S., Dolan, P., and Bueding, E. (1983) Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology 3, 932-935.
92. Devling, T. W., Lindsay, C. D., McLellan, L. I., McMahon, M., and Hayes, J. D. (2005) Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Proc. Natl. Acad. Sci. U.S.A. 102, 7280-7285.