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PDBsum entry 1x2r

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Transcription PDB id
1x2r
Jmol
Contents
Protein chain
290 a.a. *
Ligands
LEU-ASP-GLU-GLU-
THR-GLY-GLU-PHE-
LEU
SO4 ×9
Waters ×424
* Residue conservation analysis
PDB id:
1x2r
Name: Transcription
Title: Structural basis for the defects of human lung cancer somatic mutations in the repression activity of keap1 on nrf2
Structure: Kelch-like ech-associated protein 1. Chain: a. Fragment: keap1-dc, residues 309-624. Synonym: cytosolic inhibitor of nrf2. Engineered: yes. Nuclear factor erythroid 2 related factor 2. Chain: b. Fragment: nrf2/neh2 peptide, residues 76-84. Synonym: nf-e2 related factor 2, nfe2-related factor 2,
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: nrf2 peptide, synthetic peptide
Biol. unit: Dimer (from PQS)
Resolution:
1.70Å     R-factor:   0.191     R-free:   0.214
Authors: B.Padmanabhan,K.I.Tong,Y.Nakamura,T.Ohta,M.Scharlock, A.Kobayashi,M.Ohtsuji,M.-I.Kang,M.Yamamoto,S.Yokoyama,Riken Structural Genomics/proteomics Initiative (Rsgi)
Key ref:
B.Padmanabhan et al. (2006). Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell, 21, 689-700. PubMed id: 16507366 DOI: 10.1016/j.molcel.2006.01.013
Date:
26-Apr-05     Release date:   07-Mar-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Z2X8  (KEAP1_MOUSE) -  Kelch-like ECH-associated protein 1
Seq:
Struc:
 
Seq:
Struc:
624 a.a.
290 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1016/j.molcel.2006.01.013 Mol Cell 21:689-700 (2006)
PubMed id: 16507366  
 
 
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer.
B.Padmanabhan, K.I.Tong, T.Ohta, Y.Nakamura, M.Scharlock, M.Ohtsuji, M.I.Kang, A.Kobayashi, S.Yokoyama, M.Yamamoto.
 
  ABSTRACT  
 
Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. Somatic Mutation (G430C) and Gene Variation (G364C) in Keap1 Hamper Repression Activity of Keap1 on Nrf2
Figure 7.
Figure 7. G364C and G430C Mutations Lead to Disruptions of the Intermolecular Interactions
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 21, 689-700) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21057541 A.Martín-Montalvo, J.M.Villalba, P.Navas, and R.de Cabo (2011).
NRF2, cancer and calorie restriction.
  Oncogene, 30, 505-520.  
21205897 D.Ren, N.F.Villeneuve, T.Jiang, T.Wu, A.Lau, H.A.Toppin, and D.D.Zhang (2011).
Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.
  Proc Natl Acad Sci U S A, 108, 1433-1438.  
21365312 L.Baird, and A.T.Dinkova-Kostova (2011).
The cytoprotective role of the Keap1-Nrf2 pathway.
  Arch Toxicol, 85, 241-272.  
20974733 L.Jódar, E.M.Mercken, J.Ariza, C.Younts, J.A.González-Reyes, F.J.Alcaín, I.Burón, R.de Cabo, and J.M.Villalba (2011).
Genetic deletion of nrf2 promotes immortalization and decreases life span of murine embryonic fibroblasts.
  J Gerontol A Biol Sci Med Sci, 66, 247-256.  
21126175 N.S.Rajasekaran, S.Varadharaj, G.D.Khanderao, C.J.Davidson, S.Kannan, M.A.Firpo, J.L.Zweier, and I.J.Benjamin (2011).
Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice.
  Antioxid Redox Signal, 14, 957-971.  
21248763 Q.K.Li, A.Singh, S.Biswal, F.Askin, and E.Gabrielson (2011).
KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma.
  J Hum Genet, 56, 230-234.  
20865015 S.K.Niture, and A.K.Jaiswal (2011).
INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis.
  Cell Death Differ, 18, 439-451.  
21402146 X.Tang, H.Wang, L.Fan, X.Wu, A.Xin, H.Ren, and X.J.Wang (2011).
Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs.
  Free Radic Biol Med, 50, 1599-1609.  
21392184 Y.Hirotsu, F.Katsuoka, K.Itoh, and M.Yamamoto (2011).
Nrf2 degron-fused reporter system: a new tool for specific evaluation of Nrf2 inducers.
  Genes Cells, 16, 406-415.  
21482715 Y.Inami, S.Waguri, A.Sakamoto, T.Kouno, K.Nakada, O.Hino, S.Watanabe, J.Ando, M.Iwadate, M.Yamamoto, M.S.Lee, K.Tanaka, and M.Komatsu (2011).
Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.
  J Cell Biol, 193, 275-284.  
20421418 A.Lau, X.J.Wang, F.Zhao, N.F.Villeneuve, T.Wu, T.Jiang, Z.Sun, E.White, and D.D.Zhang (2010).
A Noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62.
  Mol Cell Biol, 30, 3275-3285.  
20446773 A.Singh, M.Bodas, N.Wakabayashi, F.Bunz, and S.Biswal (2010).
Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance.
  Antioxid Redox Signal, 13, 1627-1637.  
19889935 D.Burdette, M.Olivarez, and G.Waris (2010).
Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway.
  J Gen Virol, 91, 681-690.  
20486759 D.D.Zhang (2010).
The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer.
  Antioxid Redox Signal, 13, 1623-1626.  
20215646 G.P.Sykiotis, and D.Bohmann (2010).
Stress-activated cap'n'collar transcription factors in aging and human disease.
  Sci Signal, 3, re3.  
20440267 G.Rachakonda, K.R.Sekhar, D.Jowhar, P.C.Samson, J.P.Wikswo, R.D.Beauchamp, P.K.Datta, and M.L.Freeman (2010).
Increased cell migration and plasticity in Nrf2-deficient cancer cell lines.
  Oncogene, 29, 3703-3714.  
20446774 H.G.Lee, M.H.Li, E.J.Joung, H.K.Na, Y.N.Cha, and Y.J.Surh (2010).
Nrf2-Mediated heme oxygenase-1 upregulation as adaptive survival response to glucose deprivation-induced apoptosis in HepG2 cells.
  Antioxid Redox Signal, 13, 1639-1648.  
19901266 H.Motohashi, M.Kimura, R.Fujita, A.Inoue, X.Pan, M.Takayama, F.Katsuoka, H.Aburatani, E.H.Bresnick, and M.Yamamoto (2010).
NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation.
  Blood, 115, 677-686.  
20513672 H.Satoh, T.Moriguchi, K.Taguchi, J.Takai, J.M.Maher, T.Suzuki, P.T.Winnard, V.Raman, M.Ebina, T.Nukiwa, and M.Yamamoto (2010).
Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung.
  Carcinogenesis, 31, 1833-1843.  
20446772 J.D.Hayes, M.McMahon, S.Chowdhry, and A.T.Dinkova-Kostova (2010).
Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway.
  Antioxid Redox Signal, 13, 1713-1748.  
20446770 J.Shlomai (2010).
Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication.
  Antioxid Redox Signal, 13, 1429-1476.  
19864258 K.H.Kim, J.Y.Jeong, Y.J.Surh, and K.W.Kim (2010).
Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes.
  Nucleic Acids Res, 38, 48-59.  
20446768 K.Itoh, J.Mimura, and M.Yamamoto (2010).
Discovery of the negative regulator of Nrf2, Keap1: a historical overview.
  Antioxid Redox Signal, 13, 1665-1678.  
20404090 K.Taguchi, J.M.Maher, T.Suzuki, Y.Kawatani, H.Motohashi, and M.Yamamoto (2010).
Genetic analysis of cytoprotective functions supported by graded expression of Keap1.
  Mol Cell Biol, 30, 3016-3026.  
20173742 M.Komatsu, H.Kurokawa, S.Waguri, K.Taguchi, A.Kobayashi, Y.Ichimura, Y.S.Sou, I.Ueno, A.Sakamoto, K.I.Tong, M.Kim, Y.Nishito, S.Iemura, T.Natsume, T.Ueno, E.Kominami, H.Motohashi, K.Tanaka, and M.Yamamoto (2010).
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.
  Nat Cell Biol, 12, 213-223.
PDB code: 3ade
  21228930 N.Chen, X.Yi, N.Abushahin, S.Pang, D.Zhang, B.Kong, and W.Zheng (2010).
Nrf2 expression in endometrial serous carcinomas and its precancers.
  Int J Clin Exp Pathol, 4, 85-96.  
20486766 N.F.Villeneuve, A.Lau, and D.D.Zhang (2010).
Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases.
  Antioxid Redox Signal, 13, 1699-1712.  
20124447 P.Zhang, A.Singh, S.Yegnasubramanian, D.Esopi, P.Kombairaju, M.Bodas, H.Wu, S.G.Bova, and S.Biswal (2010).
Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth.
  Mol Cancer Ther, 9, 336-346.  
20061377 S.Fourquet, R.Guerois, D.Biard, and M.B.Toledano (2010).
Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation.
  J Biol Chem, 285, 8463-8471.  
19538984 S.K.Niture, J.W.Kaspar, J.Shen, and A.K.Jaiswal (2010).
Nrf2 signaling and cell survival.
  Toxicol Appl Pharmacol, 244, 37-42.  
20512470 S.Manandhar, S.Lee, and M.K.Kwak (2010).
Effect of stable inhibition of NRF2 on doxorubicin sensitivity in human ovarian carcinoma OV90 cells.
  Arch Pharm Res, 33, 717-726.  
20840865 S.Reuter, S.C.Gupta, M.M.Chaturvedi, and B.B.Aggarwal (2010).
Oxidative stress, inflammation, and cancer: how are they linked?
  Free Radic Biol Med, 49, 1603-1616.  
20060165 T.Nakamura, and S.A.Lipton (2010).
Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: possible pharmacological strategies.
  Cell Calcium, 47, 190-197.  
20133743 T.Ogura, K.I.Tong, K.Mio, Y.Maruyama, H.Kurokawa, C.Sato, and M.Yamamoto (2010).
Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains.
  Proc Natl Acad Sci U S A, 107, 2842-2847.  
19793802 T.W.Kensler, and N.Wakabayashi (2010).
Nrf2: friend or foe for chemoprevention?
  Carcinogenesis, 31, 90-99.  
20446769 V.Calabrese, C.Cornelius, A.T.Dinkova-Kostova, E.J.Calabrese, and M.P.Mattson (2010).
Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.
  Antioxid Redox Signal, 13, 1763-1811.  
20534351 W.Hur, Z.Sun, T.Jiang, D.E.Mason, E.C.Peters, D.D.Zhang, H.Luesch, P.G.Schultz, and N.S.Gray (2010).
A small-molecule inducer of the antioxidant response element.
  Chem Biol, 17, 537-547.  
20118824 Y.B.Hong, H.J.Kang, S.Y.Kwon, H.J.Kim, K.Y.Kwon, C.H.Cho, J.M.Lee, B.V.Kallakury, and I.Bae (2010).
Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells.
  Pancreas, 39, 463-472.  
19967722 Y.R.Kim, J.E.Oh, M.S.Kim, M.R.Kang, S.W.Park, J.Y.Han, H.S.Eom, N.J.Yoo, and S.H.Lee (2010).
Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin.
  J Pathol, 220, 446-451.  
20389280 Y.R.Lee, W.C.Yuan, H.C.Ho, C.H.Chen, H.M.Shih, and R.H.Chen (2010).
The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses.
  EMBO J, 29, 1748-1761.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
18373731 A.Minelli, C.Conte, S.Grottelli, M.Bellezza, I.Cacciatore, and J.P.Bolaños (2009).
Cyclo(His-Pro) promotes cytoprotection by activating Nrf2-mediated up-regulation of antioxidant defence.
  J Cell Mol Med, 13, 1149-1161.  
19818716 D.F.Lee, H.P.Kuo, M.Liu, C.K.Chou, W.Xia, Y.Du, J.Shen, C.T.Chen, L.Huo, M.C.Hsu, C.W.Li, Q.Ding, T.L.Liao, C.C.Lai, A.C.Lin, Y.H.Chang, S.F.Tsai, L.Y.Li, and M.C.Hung (2009).
KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta.
  Mol Cell, 36, 131-140.  
19751820 G.S.Shim, S.Manandhar, D.H.Shin, T.H.Kim, and M.K.Kwak (2009).
Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway.
  Free Radic Biol Med, 47, 1619-1631.  
19797082 H.Kurokawa, H.Motohashi, S.Sueno, M.Kimura, H.Takagawa, Y.Kanno, M.Yamamoto, and T.Tanaka (2009).
Structural basis of alternative DNA recognition by Maf transcription factors.
  Mol Cell Biol, 29, 6232-6244.
PDB code: 3a5t
18717631 J.Clark, and D.K.Simon (2009).
Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease.
  Antioxid Redox Signal, 11, 509-528.  
19321346 J.D.Hayes, and M.McMahon (2009).
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer.
  Trends Biochem Sci, 34, 176-188.  
19666107 J.W.Kaspar, S.K.Niture, and A.K.Jaiswal (2009).
Nrf2:INrf2 (Keap1) signaling in oxidative stress.
  Free Radic Biol Med, 47, 1304-1309.  
19778285 M.Landriscina, F.Maddalena, G.Laudiero, and F.Esposito (2009).
Adaptation to oxidative stress, chemoresistance, and cell survival.
  Antioxid Redox Signal, 11, 2701-2716.  
19818708 M.Zhuang, M.F.Calabrese, J.Liu, M.B.Waddell, A.Nourse, M.Hammel, D.J.Miller, H.Walden, D.M.Duda, S.N.Seyedin, T.Hoggard, J.W.Harper, K.P.White, and B.A.Schulman (2009).
Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases.
  Mol Cell, 36, 39-50.
PDB codes: 3hqh 3hqi 3hql 3hqm 3hsv 3htm 3hu6 3hve 3ivq 3ivv
19593404 R.H.Hübner, J.D.Schwartz, P.De Bishnu, B.Ferris, L.Omberg, J.G.Mezey, N.R.Hackett, and R.G.Crystal (2009).
Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking.
  Mol Med, 15, 203-219.  
19920073 S.K.Niture, A.K.Jain, and A.K.Jaiswal (2009).
Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance.
  J Cell Sci, 122, 4452-4464.  
19279002 S.K.Niture, and A.K.Jaiswal (2009).
Prothymosin-{alpha} Mediates Nuclear Import of the INrf2/Cul3{middle dot}Rbx1 Complex to Degrade Nuclear Nrf2.
  J Biol Chem, 284, 13856-13868.  
19560419 W.Chen, Z.Sun, X.J.Wang, T.Jiang, Z.Huang, D.Fang, and D.D.Zhang (2009).
Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response.
  Mol Cell, 34, 663-673.  
18618599 W.Li, and A.N.Kong (2009).
Molecular mechanisms of Nrf2-mediated antioxidant response.
  Mol Carcinog, 48, 91.  
19287006 Y.Suzuki, A.Noma, T.Suzuki, R.Ishitani, and O.Nureki (2009).
Structural basis of tRNA modification with CO2 fixation and methylation by wybutosine synthesizing enzyme TYW4.
  Nucleic Acids Res, 37, 2910-2925.
PDB codes: 2zw9 2zwa 2zzk
18435489 A.L.Eggler, K.A.Gay, and A.D.Mesecar (2008).
Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2.
  Mol Nutr Food Res, 52, S84-S94.  
18838122 A.Lau, N.F.Villeneuve, Z.Sun, P.K.Wong, and D.D.Zhang (2008).
Dual roles of Nrf2 in cancer.
  Pharmacol Res, 58, 262-270.  
18829555 A.Singh, S.Boldin-Adamsky, R.K.Thimmulappa, S.K.Rath, H.Ashush, J.Coulter, A.Blackford, S.N.Goodman, F.Bunz, W.H.Watson, E.Gabrielson, E.Feinstein, and S.Biswal (2008).
RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy.
  Cancer Res, 68, 7975-7984.  
18421157 B.Padmanabhan, K.I.Tong, A.Kobayashi, M.Yamamoto, and S.Yokoyama (2008).
Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1.
  J Synchrotron Radiat, 15, 273-276.  
  18391415 B.Padmanabhan, Y.Nakamura, and S.Yokoyama (2008).
Structural analysis of the complex of Keap1 with a prothymosin alpha peptide.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 233-238.
PDB code: 2z32
18194654 G.P.Sykiotis, and D.Bohmann (2008).
Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila.
  Dev Cell, 14, 76-85.  
18785192 I.M.Copple, C.E.Goldring, R.E.Jenkins, A.J.Chia, L.E.Randle, J.D.Hayes, N.R.Kitteringham, and B.K.Park (2008).
The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system.
  Hepatology, 48, 1292-1301.  
18572023 J.Pi, B.A.Diwan, Y.Sun, J.Liu, W.Qu, Y.He, M.Styblo, and M.P.Waalkes (2008).
Arsenic-induced malignant transformation of human keratinocytes: involvement of Nrf2.
  Free Radic Biol Med, 45, 651-658.  
18057000 L.Li, M.Kobayashi, H.Kaneko, Y.Nakajima-Takagi, Y.Nakayama, and M.Yamamoto (2008).
Molecular Evolution of Keap1: TWO Keap1 MOLECULES WITH DISTINCTIVE INTERVENING REGION STRUCTURES ARE CONSERVED AMONG FISH.
  J Biol Chem, 283, 3248-3255.  
18710924 M.Valiyaveettil, A.A.Bentley, P.Gursahaney, R.Hussien, R.Chakravarti, N.Kureishy, S.Prag, and J.C.Adams (2008).
Novel role of the muskelin-RanBP9 complex as a nucleocytoplasmic mediator of cell morphology regulation.
  J Cell Biol, 182, 727-739.  
18542053 N.M.Reddy, S.R.Kleeberger, J.H.Bream, P.G.Fallon, T.W.Kensler, M.Yamamoto, and S.P.Reddy (2008).
Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling.
  Oncogene, 27, 5821-5832.  
18387606 S.C.Lo, and M.Hannink (2008).
PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria.
  Exp Cell Res, 314, 1789-1803.  
17995931 T.Satoh, K.Kosaka, K.Itoh, A.Kobayashi, M.Yamamoto, Y.Shimojo, C.Kitajima, J.Cui, J.Kamins, S.Okamoto, M.Izumi, T.Shirasawa, and S.A.Lipton (2008).
Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1.
  J Neurochem, 104, 1116-1131.  
18692501 T.Shibata, A.Kokubu, M.Gotoh, H.Ojima, T.Ohta, M.Yamamoto, and S.Hirohashi (2008).
Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer.
  Gastroenterology, 135, 1358.  
18757741 T.Shibata, T.Ohta, K.I.Tong, A.Kokubu, R.Odogawa, K.Tsuta, H.Asamura, M.Yamamoto, and S.Hirohashi (2008).
Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.
  Proc Natl Acad Sci U S A, 105, 13568-13573.  
18268004 T.Yamamoto, T.Suzuki, A.Kobayashi, J.Wakabayashi, J.Maher, H.Motohashi, and M.Yamamoto (2008).
Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity.
  Mol Cell Biol, 28, 2758-2770.  
18694732 W.Li, T.O.Khor, C.Xu, G.Shen, W.S.Jeong, S.Yu, and A.N.Kong (2008).
Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.
  Biochem Pharmacol, 76, 1485-1489.  
18413364 X.J.Wang, Z.Sun, N.F.Villeneuve, S.Zhang, F.Zhao, Y.Li, W.Chen, X.Yi, W.Zheng, G.T.Wondrak, P.K.Wong, and D.D.Zhang (2008).
Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.
  Carcinogenesis, 29, 1235-1243.  
18200051 Y.Kawachi, X.Xu, S.Taguchi, H.Sakurai, Y.Nakamura, Y.Ishii, Y.Fujisawa, J.Furuta, T.Takahashi, K.Itoh, M.Yamamoto, F.Yamazaki, and F.Otsuka (2008).
Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice.
  J Invest Dermatol, 128, 1773-1779.  
18423411 Y.M.Janssen-Heininger, B.T.Mossman, N.H.Heintz, H.J.Forman, B.Kalyanaraman, T.Finkel, J.S.Stamler, S.G.Rhee, and A.van der Vliet (2008).
Redox-based regulation of signal transduction: principles, pitfalls, and promises.
  Free Radic Biol Med, 45, 1.  
17848967 B.D'Autréaux, and M.B.Toledano (2007).
ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.
  Nat Rev Mol Cell Biol, 8, 813-824.  
17567462 C.Garcia-Ruiz, and J.C.Fernández-Checa (2007).
Redox regulation of hepatocyte apoptosis.
  J Gastroenterol Hepatol, 22, S38-S42.  
17603223 H.Fukushima-Uesaka, Y.Saito, K.Maekawa, N.Kamatani, H.Kajio, N.Kuzuya, M.Noda, K.Yasuda, and J.Sawada (2007).
Genetic variations and haplotype structures of transcriptional factor Nrf2 and its cytosolic reservoir protein Keap1 in Japanese.
  Drug Metab Pharmacokinet, 22, 212-219.  
17129360 H.Motohashi, and M.Yamamoto (2007).
Carcinogenesis and transcriptional regulation through Maf recognition elements.
  Cancer Sci, 98, 135-139.  
17391074 J.Kaput, A.Perlina, B.Hatipoglu, A.Bartholomew, and Y.Nikolsky (2007).
Nutrigenomics: concepts and applications to pharmacogenomics and clinical medicine.
  Pharmacogenomics, 8, 369-390.  
17785452 K.I.Tong, B.Padmanabhan, A.Kobayashi, C.Shang, Y.Hirotsu, S.Yokoyama, and M.Yamamoto (2007).
Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response.
  Mol Cell Biol, 27, 7511-7521.
PDB code: 2dyh
17925401 O.H.Lee, A.K.Jain, V.Papusha, and A.K.Jaiswal (2007).
An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance.
  J Biol Chem, 282, 36412-36420.  
17049906 S.Prag, A.De Arcangelis, E.Georges-Labouesse, and J.C.Adams (2007).
Regulation of post-translational modifications of muskelin by protein kinase C.
  Int J Biochem Cell Biol, 39, 366-378.  
17137643 T.Satoh, and S.A.Lipton (2007).
Redox regulation of neuronal survival mediated by electrophilic compounds.
  Trends Neurosci, 30, 37-45.  
16968214 T.W.Kensler, N.Wakabayashi, and S.Biswal (2007).
Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.
  Annu Rev Pharmacol Toxicol, 47, 89.  
17609210 W.Wang, A.M.Kwok, and J.Y.Chan (2007).
The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription.
  J Biol Chem, 282, 24670-24678.  
17083568 Y.Kitamura, T.Umemura, K.Kanki, Y.Kodama, S.Kitamoto, K.Saito, K.Itoh, M.Yamamoto, T.Masegi, A.Nishikawa, and M.Hirose (2007).
Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline.
  Cancer Sci, 98, 19-24.  
17903176 Y.Watai, A.Kobayashi, H.Nagase, M.Mizukami, J.McEvoy, J.D.Singer, K.Itoh, and M.Yamamoto (2007).
Subcellular localization and cytoplasmic complex status of endogenous Keap1.
  Genes Cells, 12, 1163-1178.  
17020408 A.Singh, V.Misra, R.K.Thimmulappa, H.Lee, S.Ames, M.O.Hoque, J.G.Herman, S.B.Baylin, D.Sidransky, E.Gabrielson, M.V.Brock, and S.Biswal (2006).
Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer.
  PLoS Med, 3, e420.  
16543142 J.D.Hayes, and M.McMahon (2006).
The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer.
  Mol Cell, 21, 732-734.  
17081101 K.I.Tong, A.Kobayashi, F.Katsuoka, and M.Yamamoto (2006).
Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism.
  Biol Chem, 387, 1311-1320.  
16790436 M.McMahon, N.Thomas, K.Itoh, M.Yamamoto, and J.D.Hayes (2006).
Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex.
  J Biol Chem, 281, 24756-24768.  
17077087 R.Faraonio, P.Vergara, D.Di Marzo, M.G.Pierantoni, M.Napolitano, T.Russo, and F.Cimino (2006).
p53 suppresses the Nrf2-dependent transcription of antioxidant response genes.
  J Biol Chem, 281, 39776-39784.  
17120193 R.Perez-Torrado, D.Yamada, and P.A.Defossez (2006).
Born to bind: the BTB protein-protein interaction domain.
  Bioessays, 28, 1194-1202.  
17046835 S.C.Lo, and M.Hannink (2006).
PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex.
  J Biol Chem, 281, 37893-37903.  
16888629 S.C.Lo, X.Li, M.T.Henzl, L.J.Beamer, and M.Hannink (2006).
Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling.
  EMBO J, 25, 3605-3617.
PDB code: 2flu
16959974 T.Sjöblom, S.Jones, L.D.Wood, D.W.Parsons, J.Lin, T.D.Barber, D.Mandelker, R.J.Leary, J.Ptak, N.Silliman, S.Szabo, P.Buckhaults, C.Farrell, P.Meeh, S.D.Markowitz, J.Willis, D.Dawson, J.K.Willson, A.F.Gazdar, J.Hartigan, L.Wu, C.Liu, G.Parmigiani, B.H.Park, K.E.Bachman, N.Papadopoulos, B.Vogelstein, K.W.Kinzler, and V.E.Velculescu (2006).
The consensus coding sequences of human breast and colorectal cancers.
  Science, 314, 268-274.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.