Keap1

Summary

Gene Symbol: Keap1
Description: Kelch-like ECH-associated protein 1
Alias: Inrf2, kelch-like ECH-associated protein 1, cytosolic inhibitor of Nrf2
Species: rat
Products:     Keap1

Top Publications

  1. 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...
  2. 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...
  3. Palsamy P, Subramanian S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta. 2011;1812:719-31 pubmed publisher
    ..These findings demonstrated the renoprotective nature of resveratrol by attenuating markers of oxidative stress in renal tissues of diabetic rats. ..
  4. Zhong Q, Mishra M, Kowluru R. Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013;54:3941-8 pubmed publisher
    ..In stress conditions, Nrf2 dissociates from its cytosolic inhibitor, Kelch like-ECH-associated protein 1 (Keap1), and moves to the nucleus to regulate the transcription of antioxidant genes including the catalytic subunit of ..
  5. 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...
  6. McMahon M, Itoh K, Yamamoto M, Hayes J. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003;278:21592-600 pubmed
    b>Keap1 is a negative regulator of Nrf2, a bZIP transcription factor that mediates adaptation to oxidative stress...
  7. Tong K, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol. 2006;26:2887-900 pubmed
    ..is induced at the transcriptional level by Nrf2 and negatively regulated at the posttranslational level by Keap1 through protein-protein interactions with and subsequent proteolysis of Nrf2...
  8. Yang C, Liu X, Yang F, Zhang W, Chen Z, Yan D, et al. Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury. In Vitro Cell Dev Biol Anim. 2017;53:248-257 pubmed publisher
    ..in vivo, positively correlated with Bcl-xL expression, negatively correlated with Kelch-ECH associating protein 1 (Keap1) expression...
  9. Mishra M, Zhong Q, Kowluru R. Epigenetic modifications of Keap1 regulate its interaction with the protective factor Nrf2 in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2014;55:7256-65 pubmed publisher
    Diabetes induces oxidative imbalance in the retina and impairs Nrf2-mediated antioxidant response, and elevates Keap1, the cytoplasmic repressor of Nrf2...

More Information

Publications52

  1. Kang M, Kobayashi A, Wakabayashi N, Kim S, Yamamoto M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A. 2004;101:2046-51 pubmed
    ..Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, a multidomain, cysteinerich protein that is bound to the actin cytoskeleton...
  2. Tanaka N, Ikeda Y, Ohta Y, Deguchi K, Tian F, Shang J, et al. Expression of Keap1-Nrf2 system and antioxidative proteins in mouse brain after transient middle cerebral artery occlusion. Brain Res. 2011;1370:246-53 pubmed publisher
    ..The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system is currently recognized as the major cellular defense ..
  3. Yang J, Tao H, Hu W, Liu L, Shi K, Deng Z, et al. MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis. Cell Signal. 2014;26:2381-9 pubmed publisher
    ..Moreover, Nrf2 expression is largely regulated through the association of Nrf2 with Keap1, which results in cytoplasmic Nrf2 degradation...
  4. Um H, Jang J, Kim D, Lee C, Surh Y. Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells. Nitric Oxide. 2011;25:161-8 pubmed publisher
    ..which is sequestered in the cytoplasm by forming an inactive complex with Klech-like ECH-associated protein 1 (Keap1)...
  5. Djordjevic J, Djordjevic A, Adzic M, Mitic M, Lukic I, Radojcic M. Alterations in the Nrf2-Keap1 signaling pathway and its downstream target genes in rat brain under stress. Brain Res. 2015;1602:20-31 pubmed publisher
    ..We hypothesized that Nrf2-Keap1 pathway is compromised in the limbic brain after prolonged stress...
  6. Sarlette A, Krampfl K, Grothe C, Neuhoff N, Dengler R, Petri S. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2008;67:1055-62 pubmed publisher
    ..Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH-associated protein 1 (Keap1)...
  7. Hayes J, Dinkova Kostova A. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39:199-218 pubmed publisher
  8. Shanmugam T, Selvaraj M, Poomalai S. Epigallocatechin gallate potentially abrogates fluoride induced lung oxidative stress, inflammation via Nrf2/Keap1 signaling pathway in rats: An in-vivo and in-silico study. Int Immunopharmacol. 2016;39:128-139 pubmed publisher
    ..The antioxidant and anti-inflammatory potential of Epigallocatechin gallate (EGCG) and Nrf2/Keap1 signaling mechanisms in pulmonary toxicity have not been clarified...
  9. Zhang Z, Cui W, Li G, Yuan S, Xu D, Hoi M, et al. Baicalein protects against 6-OHDA-induced neurotoxicity through activation of Keap1/Nrf2/HO-1 and involving PKC? and PI3K/AKT signaling pathways. J Agric Food Chem. 2012;60:8171-82 pubmed publisher
    ..factor 2 (Nrf2)/hemo oxygenase 1(HO-1) protein expression and decreased Kelch-like ECH-associated protein 1 (Keap1) in a time- and concentration-dependent manner in PC12 cells...
  10. Ikeda H, Nishi S, Sakai M. Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem J. 2004;380:515-21 pubmed
    ..b>Keap1 (Kelch-like ECH-associated protein 1), an inhibitory factor of Nrf2, decreased the activation of GPE1 by Nrf2 and ..
  11. Blake D, Singh A, Kombairaju P, Malhotra D, Mariani T, Tuder R, et al. Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation. Am J Respir Cell Mol Biol. 2010;42:524-36 pubmed publisher
    ..To this end we have developed a novel mouse model in which the cytosolic inhibitor of Nrf2, Keap1, is genetically deleted in Clara cells, which predominate in the upper airways in mice...
  12. Villacorta L, Zhang J, Garcia Barrio M, Chen X, Freeman B, Chen Y, et al. Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway. Am J Physiol Heart Circ Physiol. 2007;293:H770-6 pubmed
    ..antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs...
  13. Ohnuma T, Nakayama S, Anan E, Nishiyama T, Ogura K, Hiratsuka A. Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound. Toxicol Appl Pharmacol. 2010;244:27-36 pubmed publisher
    Under basal conditions, the interaction of the cytosolic protein Kelch-like ECH-associated protein 1 (Keap1) with the transcription factor nuclear factor-E2-related factor 2 (Nrf2) results in a low level of expression of cytoprotective ..
  14. Wu K, Wu C, Chao Y, Hung C, Chan J. Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation. Free Radic Biol Med. 2016;97:58-74 pubmed publisher
    ..copy number, increased protein interaction of Nrf2 to its negative regulator, kelch-like ECH-associated protein 1 (Keap1), and reduced DNA binding activity of p-Nrf2 to Tfam gene...
  15. Bayele H, Debnam E, Srai K. Nrf2 transcriptional derepression from Keap1 by dietary polyphenols. Biochem Biophys Res Commun. 2016;469:521-8 pubmed publisher
    ..dietary polyphenolic antioxidants that not only activated these genes but also relieved Nrf2 repression by Keap1, a Cul3-dependent ubiquitin ligase adaptor protein that mediates its degradation...
  16. 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/..
  17. Okada K, Warabi E, Sugimoto H, Horie M, Tokushige K, Ueda T, et al. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J Gastroenterol. 2012;47:924-35 pubmed publisher
    ..Wild-type mice (WT), Nrf2 gene-null mice (Nrf2-null) and Keap1 gene-knockdown mice (Keap1-kd), which represent the sustained activation of Nrf2, were fed a methionine- and ..
  18. Padiya R, Chowdhury D, Borkar R, Srinivas R, Pal Bhadra M, Banerjee S. Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat. PLoS ONE. 2014;9:e94228 pubmed publisher
    ..Our study demonstrates that raw garlic homogenate is effective in reducing cardiac hypertrophy and fructose-induced myocardial oxidative stress through PI3K/AKT/Nrf2-Keap1 dependent pathway.
  19. Wang X, Zhang D. Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level. PLoS ONE. 2009;4:e5492 pubmed publisher
    ..Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox ..
  20. Motohashi H, Katsuoka F, Engel J, Yamamoto M. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci U S A. 2004;101:6379-84 pubmed
    ..Nrf2 activity is usually suppressed by a cytoplasmic repressor, Keap1, so disruption of the keap1 gene causes constitutive activation of Nrf2...
  21. Kim J, Kwon O, Kim M. Differentially expressed genes and morphological changes during lengthened immobilization in rat soleus muscle. Differentiation. 2007;75:147-57 pubmed
    ..Of 11 known genes, seven (Atp5g3, TOM22, INrf2, Slc25a4, Hdac6, Tpm1, and Sv2b) were up and three (Podxl, Myh1, and Surf1) were down-regulated following ..
  22. Wang F, Liu J, Ye Y, Zhang X, Wan L. [Mechanism of cardiac function changes in rat models of Sjogren's syndrome based on Keap1-Nrf2/ARE signaling pathways]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014;30:497-501 pubmed
    ..in the cardiac function in rat models of Sjogren's syndrome (SS) based on Kelch-like ECH-associated protein 1 (Keap1)-Nrf2/ARE signaling pathways...
  23. 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 ..
  24. Goven D, Boutten A, Lecon Malas V, Marchal Somme J, Amara N, Crestani B, et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax. 2008;63:916-24 pubmed publisher
    ..NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively...
  25. Kurzawski M, Dziedziejko V, Urasinska E, Post M, Wojcicki M, Mietkiewski J, et al. Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease. Environ Toxicol Pharmacol. 2012;34:87-95 pubmed publisher
    ..Nrf2 is negatively regulated by KEAP1 protein. Recent studies have shown that Nrf2 might also constitute an important mediator of inflammatory processes...
  26. Nordgren K, Wallace K. Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts. Toxicol Appl Pharmacol. 2014;274:107-16 pubmed publisher
    ..A major cellular defense mechanism against such oxidative stress is activation of the Keap1/Nrf2-antioxidant response element (ARE) signaling pathway, which transcriptionally regulates expression of ..
  27. Kong X, Thimmulappa R, Craciun F, Harvey C, Singh A, Kombairaju P, et al. Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. Am J Respir Crit Care Med. 2011;184:928-38 pubmed publisher
    ..Mice with deletion of Nrf2 or kelch-like ECH-associated protein (Keap1) in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture-induced ..
  28. Wruck C, Claussen M, Fuhrmann G, Romer L, Schulz A, Pufe T, et al. Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J Neural Transm Suppl. 2007;:57-67 pubmed
    ..In particular, we identified luteolin as a promising lead for the search of orally available, blood brain barrier permeable compounds to support the therapy of neurodegenerative disorders. ..
  29. Velichkova M, Guttman J, Warren C, Eng L, Kline K, Vogl A, et al. A human homologue of Drosophila kelch associates with myosin-VIIa in specialized adhesion junctions. Cell Motil Cytoskeleton. 2002;51:147-64 pubmed
    ..We identified Keap1, a human homologue of the Drosophila ring canal protein, kelch...
  30. Gurusamy N, Goswami S, Malik G, Das D. Oxidative injury induces selective rather than global inhibition of proteasomal activity. J Mol Cell Cardiol. 2008;44:419-28 pubmed
    ..This study gives further insight into interrelationship between oxidative injury and catalytic function of the proteasome in heart, where oxidative injury causes selective rather than global inhibition of proteasome. ..
  31. Ogura T, Tong K, Mio K, Maruyama Y, Kurokawa H, Sato C, et al. 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. 2010;107:2842-7 pubmed publisher
    b>Keap1 is a substrate adaptor of a Cullin 3-based E3 ubiquitin ligase complex that recognizes Nrf2, and also acts as a cellular sensor for xenobiotics and oxidative stresses...
  32. Rinaldi Tosi M, Bocanegra V, Manucha W, Gil Lorenzo A, Valles P. The Nrf2-Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO). Cell Stress Chaperones. 2011;16:57-68 pubmed publisher
    ..GSTA2) and NADPH/quinone oxidoreductase 1 (NQO1), whereas the Nrf2 repressor Kelch-like ECH-associated protein-1 (Keap1) was upregulated...
  33. Kim J, Choi Y, Lee K, Cho D, Baek Y, Lee D, et al. Functional dissection of Nrf2-dependent phase II genes in vascular inflammation and endotoxic injury using Keap1 siRNA. Free Radic Biol Med. 2012;53:629-40 pubmed publisher
    b>Keap1 is a cytoplasmic repressor of the transcription factor Nrf2, and its degradation induces Nrf2 activation, leading to upregulation of antioxidant phase II genes...
  34. Mazur W, Lindholm P, Vuorinen K, Myllärniemi M, Salmenkivi K, Kinnula V. Cell-specific elevation of NRF2 and sulfiredoxin-1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. APMIS. 2010;118:703-12 pubmed publisher
    ..Morphometric evaluation revealed NRF2 and KEAP1 to be significantly elevated in the hyperplastic alveolar epithelium compared with the normal alveolar epithelium, ..
  35. 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...
  36. Kim H, Vaziri N. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol. 2010;298:F662-71 pubmed publisher
    ..nuclear translocation) was mildly reduced at 6 wk and markedly reduced at 12 wk, whereas the Nrf2 repressor Keap1 was upregulated and the products of Nrf2 target genes [catalase, superoxide dismutase, glutathione peroxidase, ..
  37. Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M, et al. Ebselen, a seleno-organic antioxidant, as an electrophile. Chem Res Toxicol. 2006;19:1196-204 pubmed
    ..property of ebselen, we characterized posttranslational modification of Kelch-like ECH-associated protein 1 (Keap1), an electrophile sensor protein, which represses the ability of the transcription factor NF-E2-related factor 2 (..
  38. Huang Y, Li W, Su Z, Kong A. The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem. 2015;26:1401-13 pubmed publisher
  39. Wan Y, Li Y, Xia W, Chen J, Lv Z, Zeng H, et al. Alterations in tumor biomarker GSTP gene methylation patterns induced by prenatal exposure to PFOS. Toxicology. 2010;274:57-64 pubmed publisher
    ..of GSTP was observed and this increase was associated with its main pathway of transcription regulation: Keap1-Nrf2/MafK...
  40. Osburn W, Yates M, Dolan P, Chen S, Liby K, Sporn M, et al. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci. 2008;104:218-27 pubmed publisher
    ..of a battery of antioxidative enzymes and Nrf2 signaling can be activated by small-molecule drugs that disrupt Keap1-mediated repression of Nrf2 signaling...
  41. Videla L, Cornejo P, Romanque P, Santibañez C, Castillo I, Vargas R. Thyroid hormone-induced cytosol-to-nuclear translocation of rat liver Nrf2 is dependent on Kupffer cell functioning. ScientificWorldJournal. 2012;2012:301494 pubmed publisher
    ..respiratory burst activity, with enhancement in nuclear inhibitor of Nrf2 kelch-like ECH-associated protein 1 (Keap1)/Nrf2 content ratios suggesting Nrf2 degradation...
  42. Velichkova M, Hasson T. Keap1 in adhesion complexes. Cell Motil Cytoskeleton. 2003;56:109-19 pubmed
    ..b>Keap1 is a newly identified component of cell adhesion complexes...
  43. Pan P, Qiao L, Wen X. Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson's disease through regulating Keap1/Nrf2 signaling pathway. Cell Mol Biol (Noisy-le-grand). 2016;62:11-17 pubmed
    ..Further investigation showed that safranal inhibited the expression of kelch-like ECH-associated protein 1 (Keap1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in rotenone-induced ..