KEAP1

Summary

Gene Symbol: KEAP1
Description: kelch like ECH associated protein 1
Alias: INrf2, KLHL19, kelch-like ECH-associated protein 1, KEAP1 delta C, cytosolic inhibitor of Nrf2, kelch-like family member 19, kelch-like protein 19
Species: human
Products:     KEAP1

Top Publications

  1. Zhang D. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769-89 pubmed
    ..Under the basal condition, Nrf2-dependent transcription is repressed by a negative regulator Keap1. When cells are exposed to oxidative stress, electrophiles, or chemopreventive agents, Nrf2 escapes Keap1-mediated ..
  2. Chew E, Hagen T. Substrate-mediated regulation of cullin neddylation. J Biol Chem. 2007;282:17032-40 pubmed
    ..These findings suggest a mechanism through which availability of substrate recognition subunits and substrates can regulate the ubiquitin ligase activity. ..
  3. Luo Y, Eggler A, Liu D, Liu G, Mesecar A, van Breemen R. Sites of alkylation of human Keap1 by natural chemoprevention agents. J Am Soc Mass Spectrom. 2007;18:2226-32 pubmed
    Under basal conditions, the interaction of the cytosolic protein Keap1 (Kelch-like ECH-associated protein 1) with the transcription factor nuclear factor-E(2)-related factor 2 (Nrf2) results in a low level of expression of cytoprotective ..
  4. Baird L, Dinkova Kostova A. Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells. Biochem Biophys Res Commun. 2013;433:58-65 pubmed publisher
    ..Under basal conditions, Kelch-like ECH associated protein 1 (Keap1) targets Nrf2 for ubiquitination and proteasomal degradation via association with Cullin3 (Cul3)-based Rbx1 E3 ..
  5. Chew E, Poobalasingam T, Hawkey C, Hagen T. Characterization of cullin-based E3 ubiquitin ligases in intact mammalian cells--evidence for cullin dimerization. Cell Signal. 2007;19:1071-80 pubmed
    ..We also provide evidence that Cul1 and Cul3, as well as their associated substrate recognition subunits Skp2 and Keap1, respectively, homooligomerize in intact cells, suggesting that cullin-based ligases are dimeric...
  6. Hayes J, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009;34:176-88 pubmed publisher
    ..NRF2 is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1)...
  7. Major M, Camp N, Berndt J, Yi X, Goldenberg S, Hubbert C, et al. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science. 2007;316:1043-6 pubmed
    ..These data provide a possible mechanistic explanation for the tumor suppressor activity of WTX. ..
  8. Taguchi K, Fujikawa N, Komatsu M, Ishii T, Unno M, Akaike T, et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci U S A. 2012;109:13561-6 pubmed publisher
    The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults...
  9. Hong F, Sekhar K, Freeman M, Liebler D. Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J Biol Chem. 2005;280:31768-75 pubmed
    ..Nrf2 concentrations are regulated by the thiol-rich sensor protein Keap1, which is an adaptor protein for Cul3-dependent ubiquitination and degradation of Nrf2...

More Information

Publications74

  1. MacLeod A, McMahon M, Plummer S, Higgins L, Penning T, Igarashi K, et al. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compo. Carcinogenesis. 2009;30:1571-80 pubmed publisher
    ..to cancer chemoprevention, we have knocked down its negative regulators, Kelch-like ECH-associated protein 1 (KEAP1) and broad-complex, tramtrack and bric à brac and cap'n'collar homology 1 (BACH1), in HaCaT keratinocytes...
  2. Kim Y, Oh J, Kim M, Kang M, Park S, Han J, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol. 2010;220:446-51 pubmed publisher
    ..upon oxidative stress and oncogenic NRF2 mutations have been found in lung and head/neck cancers that inactivate KEAP1-mediated degradation of NRF2. The aim of this study was to catalogue NRF2 mutations in other human cancers...
  3. Singh A, Misra V, Thimmulappa R, Lee H, Ames S, Hoque M, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3:e420 pubmed
    ..Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation...
  4. Eggler A, Small E, Hannink M, Mesecar A. Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J. 2009;422:171-80 pubmed publisher
    ..Nrf2 is repressed by the cysteine-rich Keap1 (kelch-like ECH-associated protein 1) protein, which targets Nrf2 for ubiquitination and subsequent degradation by ..
  5. Cullinan S, Gordan J, Jin J, Harper J, Diehl J. 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. 2004;24:8477-86 pubmed
    ..Nrf2 activity is opposed by the BTB/POZ domain protein Keap1. Keap1 is proposed to regulate Nrf2 activity strictly through its capacity to inhibit Nrf2 nuclear import...
  6. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213-23 pubmed publisher
    ..p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2...
  7. Yoo N, Kim H, Kim Y, An C, Lee S. Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology. 2012;60:943-52 pubmed publisher
    b>KEAP1 inhibits nuclear factor erythroid 2-related factor 2 (NRF2)-induced cytoprotection, and is considered to be a candidate tumour suppressor...
  8. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel J, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76-86 pubmed
    ..activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal ..
  9. Lo S, Li X, Henzl M, Beamer L, Hannink M. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J. 2006;25:3605-17 pubmed
    b>Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress...
  10. Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9:336-46 pubmed publisher
    ..mutations in the nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor Kelch-like ECH-associated protein 1 (Keap1) result in increased Nrf2 activity in non-small cell lung cancer and confer therapeutic resistance...
  11. Sekhar K, Yan X, Freeman M. Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene. 2002;21:6829-34 pubmed
    b>INrf2 tethering of the transcription factor Nrf2 in the cytosol prevents Nrf2 activation of antioxidant response element (ARE) mediated gene expression...
  12. Fourquet S, Guerois R, Biard D, Toledano M. Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem. 2010;285:8463-71 pubmed publisher
    ..NRF2 is itself negatively regulated by KEAP1, the adaptor of a Cul3-ubiquitin ligase complex that marks NRF2 for proteasomal degradation by ubiquitination...
  13. Lee D, Kuo H, Liu M, Chou C, Xia W, Du Y, et al. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell. 2009;36:131-40 pubmed publisher
    ..Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination...
  14. Shibata T, Ohta T, Tong K, Kokubu A, Odogawa R, Tsuta K, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105:13568-73 pubmed publisher
    ..nonstressed circumstances, low cellular concentrations of Nrf2 are maintained by proteasomal degradation through a Keap1-Cul3-Roc1-dependent mechanism...
  15. Dinkova Kostova A, Talalay P, Sharkey J, Zhang Y, Holtzclaw W, Wang X, et al. An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1. J Biol Chem. 2010;285:33747-55 pubmed publisher
    The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation...
  16. Hast B, Goldfarb D, Mulvaney K, Hast M, Siesser P, Yan F, et al. Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res. 2013;73:2199-210 pubmed publisher
    Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes...
  17. Furukawa M, Xiong Y. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol. 2005;25:162-71 pubmed
    ..Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch ..
  18. Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology. 2008;135:1358-1368, 1368.e1-4 pubmed publisher
    ..We screened genetic alteration of Keap1, a negative regulator of Nrf2, in BTC including tumors originated from gallbladder and extra- and intrahepatic ..
  19. Patel R, Maru G. Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs. Free Radic Biol Med. 2008;44:1897-911 pubmed publisher
    ..PBP extract did not alter Nrf2 or Keap1 at the transcriptional level but may have increased their levels by posttranslational modifications such as ..
  20. Muscarella L, Barbano R, D Angelo V, Copetti M, Coco M, Balsamo T, et al. Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome. Epigenetics. 2011;6:317-25 pubmed
    In light with the view that KEAP1 loss of function may impact tumour behavior and modify response to chemotherapeutical agents, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas...
  21. Kobayashi A, Kang M, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004;24:7130-9 pubmed
    ..In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system...
  22. Baird L, Lleres D, Swift S, Dinkova Kostova A. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A. 2013;110:15259-64 pubmed publisher
    ..Nrf2), a master regulator of cytoprotective genes, is controlled by dimeric Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor protein for Cullin3/RING-box protein 1 ubiquitin ligase, which normally targets Nrf2 for ..
  23. Clements C, McNally R, Conti B, Mak T, Ting J. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A. 2006;103:15091-6 pubmed
    ..DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination...
  24. Lo S, Hannink M. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res. 2008;314:1789-803 pubmed publisher
    ..b>Keap1, a redox-regulated substrate adaptor for a cullin-based ubiquitin ligase, targets Nrf2 for proteosome-mediated ..
  25. He X, Chen M, Lin G, Ma Q. Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 x Keap1 x Cul3 complex and recruiting Nrf2 x Maf to the antioxidant response element enhancer. J Biol Chem. 2006;281:23620-31 pubmed
    ..Arsenic stabilized Nrf2 protein, extending the t(1/2) of Nrf2 from 21 to 200 min by inhibiting the Keap1 x Cul3-dependent ubiquitination and proteasomal turnover of Nrf2...
  26. Ichimura Y, Waguri S, Sou Y, Kageyama S, Hasegawa J, Ishimura R, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 2013;51:618-31 pubmed publisher
    The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes...
  27. Sun Z, Zhang S, Chan J, Zhang D. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol. 2007;27:6334-49 pubmed
    The transcription factor Nrf2 regulates cellular redox homeostasis. Under basal conditions, Keap1 recruits Nrf2 into the Cul3-containing E3 ubiquitin ligase complex for ubiquitin conjugation and subsequent proteasomal degradation...
  28. Nioi P, Nguyen T. A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun. 2007;362:816-21 pubmed
    b>Keap1 is the substrate recognition module of a Cullin 3-based E3 ubiquitin ligase. Its primary role is to catalyze the ubiquitylation of the Nrf2 transcription factor...
  29. Barbano R, Muscarella L, Pasculli B, Valori V, Fontana A, Coco M, et al. Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics. 2013;8:105-12 pubmed publisher
    b>Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions...
  30. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes J. 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. 2006;281:24756-68 pubmed
    ..We now report that it is as a homodimer that the substrate adaptor Keap1 interacts with Cul3...
  31. Huang C, Zhang L, Ma S, Zhao Z, Wang W, He K, et al. Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma. PLoS ONE. 2013;8:e83479 pubmed publisher
    ..However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated...
  32. Konstantinopoulos P, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S, Grammatikos A, et al. Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res. 2011;71:5081-9 pubmed publisher
    ..Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related ..
  33. Li Y, Paonessa J, Zhang Y. Mechanism of chemical activation of Nrf2. PLoS ONE. 2012;7:e35122 pubmed publisher
    ..Kelch-like ECH-associated protein 1 (Keap1) binds to Nrf2 and orchestrates Nrf2 ubiquitination, and it has been a widely-held view that inhibition of Nrf2 ..
  34. Zhang D, Hannink M. 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. 2003;23:8137-51 pubmed
    ..Nrf2 is normally sequestered in the cytoplasm by a protein known as Keap1. Chemopreventive agents allow Nrf2 to escape from Keap1-mediated repression, although the molecular mechanism(s) ..
  35. Ronkainen H, Vaarala M, Kauppila S, Soini Y, Paavonen T, Rask J, et al. Increased BTB-Kelch type substrate adaptor protein immunoreactivity associates with advanced stage and poor differentiation in renal cell carcinoma. Oncol Rep. 2009;21:1519-23 pubmed
    ..the oxidative system, thioredoxin (Trx), NF-E2-related factor (Nfr2) and BTB-Kelch type substrate adaptor protein (Keap1). Cytoplasmic Keap1 staining was related to poorer prognosis in renal cancer-specific survival...
  36. Ichikawa T, Li J, Meyer C, Janicki J, Hannink M, Cui T. Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes. PLoS ONE. 2009;4:e8391 pubmed publisher
    ..Dh404 interrupted the Keap1-Cul3-Rbx1 E3 ligase complex-mediated Nrf2 ubiquitination and subsequent degradation saturating the binding ..
  37. Watai Y, Kobayashi A, Nagase H, Mizukami M, McEvoy J, Singer J, et al. Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes Cells. 2007;12:1163-78 pubmed
    b>Keap1 acts as a sensor for oxidative/electrophilic stress, an adaptor for Cullin-3-based ubiquitin ligase, and a regulator of Nrf2 activity through the interaction with Nrf2 Neh2 domain...
  38. Ma J, Cai H, Wu T, Sobhian B, Huo Y, Alcivar A, et al. PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol Cell Biol. 2012;32:1506-17 pubmed publisher
    ..Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2...
  39. Lo S, Hannink M. PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. J Biol Chem. 2006;281:37893-903 pubmed
    b>Keap1 is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress...
  40. Padmanabhan B, Tong K, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21:689-700 pubmed
    Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction...
  41. Zipper L, Mulcahy R. The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem. 2002;277:36544-52 pubmed
    ..by the Cap'N'Collar transcription factor, Nrf2, which is sequestered in the cytoplasm by the actin-binding protein Keap1. Mutation of a conserved serine (S104A) within the Keap1 BTB/POZ domain disrupts Keap1 dimerization and eliminates ..
  42. Rachakonda G, Xiong Y, Sekhar K, Stamer S, Liebler D, Freeman M. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol. 2008;21:705-10 pubmed publisher
    ..The Kelch-like ECH-associated protein 1 (Keap1) serves as an adapter between CUL3 and Nrf2...
  43. Choo Y, Hagen T. Mechanism of cullin3 E3 ubiquitin ligase dimerization. PLoS ONE. 2012;7:e41350 pubmed publisher
    ..Our results provide evidence for BTB substrate receptor dependent Cul3 dimerization which is likely to play an important role in promoting substrate ubiquitination. ..
  44. Solis L, Behrens C, Dong W, Suraokar M, Ozburn N, Moran C, et al. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 2010;16:3743-53 pubmed publisher
    ..understand the role of nuclear factor erythroid-2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non-small cell lung cancer (NSCLC), we studied their expression in a large series of tumors with annotated ..
  45. Lo S, Hannink M. CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Mol Cell Biol. 2006;26:1235-44 pubmed
    ..b>Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2...
  46. Dhakshinamoorthy S, Jaiswal A. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene. 2001;20:3906-17 pubmed
    ..A cytosolic inhibitor of Nrf2, INrf2, that retains Nrf2 in the cytoplasm, was cloned and sequenced...
  47. Zhang D, Lo S, Cross J, Templeton D, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24:10941-53 pubmed
    ..b>Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2 and controls both the subcellular localization and ..
  48. Zhan L, Zhang H, Zhang Q, Woods C, Chen Y, Xue P, et al. Regulatory role of KEAP1 and NRF2 in PPAR? expression and chemoresistance in human non-small-cell lung carcinoma cells. Free Radic Biol Med. 2012;53:758-68 pubmed publisher
    ..mutations in NRF2 and/or downregulation of or mutations in its suppressor, Kelch-like ECH-associated protein 1 (KEAP1), is associated with tumorigenicity and chemoresistance of non-small-cell lung carcinomas (NSCLCs)...
  49. Seng S, Avraham H, Birrane G, Jiang S, Li H, Katz G, et al. NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors. Oncogene. 2009;28:378-89 pubmed publisher
    ..This study provides insights into the mechanism by which the NRP/B modulates Nrf2-dependent NQO1 induction in cellular protection against ROS in brain tumors. ..
  50. Buckley B, Li S, Whorton A. Keap1 modification and nuclear accumulation in response to S-nitrosocysteine. Free Radic Biol Med. 2008;44:692-8 pubmed
    b>Keap1 is a key regulator of the Nrf2 transcription factor, which transactivates the antioxidant response element (ARE) and upregulates numerous proteins involved in antioxidant defense...
  51. Jain A, Lamark T, Sjøttem E, Larsen K, Awuh J, Øvervatn A, et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem. 2010;285:22576-91 pubmed publisher
    ..Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that ..
  52. Karihtala P, Kauppila S, Soini Y, Arja Jukkola Vuorinen -. Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas. BMC Cancer. 2011;11:262 pubmed publisher
    ..NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression...
  53. Cullinan S, Zhang D, Hannink M, Arvisais E, Kaufman R, Diehl J. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23:7198-209 pubmed
    ..In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/..
  54. Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, et al. Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. J Neuropathol Exp Neurol. 2013;72:18-28 pubmed publisher
    ..of numerous cytoprotective products are increased via alteration of the Kelch-like ECH-associated protein 1 (Keap1) and NF-E2-related factor 2 (Nrf2) system...
  55. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193:275-84 pubmed publisher
    ..Because p62 interacts with the Nrf2-binding site on Keap1, which is a Cullin 3-based ubiquitin ligase adapter protein, autophagy deficiency causes competitive inhibition of ..
  56. Zhang D, Lo S, Sun Z, Habib G, Lieberman M, Hannink M. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem. 2005;280:30091-9 pubmed
    b>Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex...
  57. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008;68:1303-9 pubmed publisher
    Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins...
  58. Lau A, Wang X, Zhao F, Villeneuve N, Wu T, Jiang T, et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol. 2010;30:3275-85 pubmed publisher
    ..The Nrf2-Keap1 pathway functions as a critical regulator of the cell's defense mechanism against oxidative stress by controlling ..
  59. Nguyen T, Sherratt P, Nioi P, Yang C, Pickett C. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem. 2005;280:32485-92 pubmed
    ..Previous studies have suggested that activation of Nrf2 is mediated by mechanisms promoting its dissociation from Keap1, a cytosolic repressor that acts to sequester the transcription factor in the cytoplasm...
  60. Eggler A, Liu G, Pezzuto J, van Breemen R, Mesecar A. 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. 2005;102:10070-5 pubmed
    ..the antioxidant response element (ARE) by the oxidative-stress sensor protein Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor NF-E2-related factor 2 (Nrf2)...
  61. Thu K, Pikor L, Chari R, Wilson I, MacAulay C, English J, et al. Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. J Thorac Oncol. 2011;6:1521-9 pubmed publisher
    ..gene enhancer in B-cells, kinase beta (IKBKB) (IKK-?/IKK-2), which activates NF-?B, is a substrate of the KEAP1-CUL3-RBX1 E3-ubiquitin ligase complex, implicating this complex in NF-?B pathway regulation...
  62. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16:123-40 pubmed publisher
    The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage...
  63. Copple I, Lister A, Obeng A, Kitteringham N, Jenkins R, Layfield R, et al. Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J Biol Chem. 2010;285:16782-8 pubmed publisher
    ..The activity of Nrf2 is regulated by the Cul3 adaptor Keap1, yet little is known regarding mechanisms of regulation of Keap1 itself...
  64. Fan W, Tang Z, Chen D, Moughon D, Ding X, Chen S, et al. Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. Autophagy. 2010;6:614-21 pubmed publisher
    ..The exact regulatory mechanism of this process is still largely unknown. Here we report the identification of Keap1 as a binding partner for p62 and LC3...
  65. Bloom D, Jaiswal A. 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 el. J Biol Chem. 2003;278:44675-82 pubmed
    ..Under normal conditions, Nrf2 is targeted for proteasomal degradation by INrf2. Oxidative stress causes release of Nrf2 from INrf2...