Keap1

Summary

Gene Symbol: Keap1
Description: kelch-like ECH-associated protein 1
Alias: INRF2, mKIAA0132, kelch-like ECH-associated protein 1, NRF2 cytosolic inhibitor, cytosolic inhibitor of Nrf2, ring canal protein
Species: mouse
Products:     Keap1

Top Publications

  1. Cho M, Kim W, Ki S, Hwang J, Choi S, Lee C, et al. Role of Galpha12 and Galpha13 as novel switches for the activity of Nrf2, a key antioxidative transcription factor. Mol Cell Biol. 2007;27:6195-208 pubmed
    ..In summary, Galpha12 and Galpha13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Galpha13 regulates Rho-PKC delta-mediated Nrf2 phosphorylation, which is negatively balanced by Galpha12. ..
  2. Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes J, Yamamoto M. Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J Biol Chem. 2008;283:33554-62 pubmed publisher
    ..This study has, thus, identified the first ARE-dependent gene that relies exclusively on Nrf1, suggesting that it plays a distinct functional role in regulating ARE-driven genes. ..
  3. Lee O, Jain A, Papusha V, Jaiswal A. An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance. J Biol Chem. 2007;282:36412-20 pubmed
    b>INrf2:Nrf2 are sensors of chemical/radiation stress. Nrf2 dissociates from INrf2 in response to a stress and translocates in the nucleus. This leads to induction of a battery of antioxidant genes that protect cells...
  4. Okada K, Shoda J, Taguchi K, Maher J, Ishizaki K, Inoue Y, et al. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems. Biochem Biophys Res Commun. 2009;389:431-6 pubmed publisher
    ..of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver...
  5. More V, Xu J, Shimpi P, Belgrave C, Luyendyk J, Yamamoto M, et al. Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding. Free Radic Biol Med. 2013;61:85-94 pubmed publisher
    The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway upregulates antioxidant and biotransformation enzyme expression to counter cellular oxidative stress...
  6. Zhang Y, Wu K, Liu J, Klaassen C. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. Toxicol Appl Pharmacol. 2012;264:305-14 pubmed publisher
    ..In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks...
  7. Reisman S, Yeager R, Yamamoto M, Klaassen C. Increased Nrf2 activation in livers from Keap1-knockdown mice increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species. Toxicol Sci. 2009;108:35-47 pubmed publisher
    ..In a recently engineered mouse with knockdown of kelch-like ECH associated protein 1 (Keap1-kd mice), the cytosolic repressor of Nrf2, there is a 55% decrease in Keap1 mRNA and a 200% increase in Nrf2 ..
  8. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler T, Yamamoto M. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun. 2006;339:79-88 pubmed
    Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions...
  9. Kobayashi M, Li L, Iwamoto N, Nakajima Takagi Y, Kaneko H, Nakayama Y, et al. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol. 2009;29:493-502 pubmed publisher
    ..First, we showed that six of the compounds tested specifically target Cys-151 in Keap1, the ubiquitin ligase for Nrf2, while two compounds target Cys-273...

More Information

Publications80

  1. Yates M, Tran Q, Dolan P, Osburn W, Shin S, McCulloch C, et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis. 2009;30:1024-31 pubmed publisher
    ..In contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice, although inactivating mutations ..
  2. Kobayashi A, Kang M, Watai Y, Tong K, Shibata T, Uchida K, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006;26:221-9 pubmed
    The Keap1-Nrf2 system is the major regulatory pathway of cytoprotective gene expression against oxidative and/or electrophilic stresses. Keap1 acts as a stress sensor protein in this system...
  3. 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...
  4. Wu K, Liu J, Klaassen C. Nrf2 activation prevents cadmium-induced acute liver injury. Toxicol Appl Pharmacol. 2012;263:14-20 pubmed publisher
    ..in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were ..
  5. Xu J, Kulkarni S, Donepudi A, More V, Slitt A. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes. 2012;61:3208-18 pubmed publisher
    ..Lep(ob/ob)-Keap1-knockdown (KD) mice, which have increased Nrf2 activity, were generated...
  6. Okada K, Shoda J, Taguchi K, Maher J, Ishizaki K, Inoue Y, et al. Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Am J Physiol Gastrointest Liver Physiol. 2008;295:G735-47 pubmed publisher
    ..The protein level, subcellular localization, and mRNA level of Mrp family members were assessed in livers of Keap1 gene-knockdown (Keap1-kd) mice and those of UDCA-fed wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice...
  7. 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...
  8. 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...
  9. 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 ..
  10. Reisman S, Csanaky I, Yeager R, Klaassen C. Nrf2 activation enhances biliary excretion of sulfobromophthalein by inducing glutathione-S-transferase activity. Toxicol Sci. 2009;109:24-30 pubmed publisher
    ..basal conditions is targeted for proteasomal degradation in the cytosol by kelch-like ECH-associated protein 1 (Keap1)...
  11. Wu K, Cui J, Klaassen C. Effect of graded Nrf2 activation on phase-I and -II drug metabolizing enzymes and transporters in mouse liver. PLoS ONE. 2012;7:e39006 pubmed publisher
    ..Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol...
  12. Shin S, Wakabayashi N, Misra V, Biswal S, Lee G, Agoston E, et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol. 2007;27:7188-97 pubmed
    ..Nrf2-/- MEFs showed markedly accelerated adipogenesis upon stimulation, while Keap1-/- MEFs (which exhibit higher NRF2 signaling) differentiated slowly compared to their congenic wild-type MEFs...
  13. 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...
  14. Wakabayashi N, Shin S, Slocum S, Agoston E, Wakabayashi J, Kwak M, et al. Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal. 2010;3:ra52 pubmed publisher
    The Keap1-Nrf2-ARE signaling pathway elicits an adaptive response for cell survival after endogenous and exogenous stresses, such as inflammation and carcinogens, respectively...
  15. 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...
  16. 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...
  17. 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...
  18. Tong K, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol. 2007;27:7511-21 pubmed
    Nrf2 is the regulator of the oxidative/electrophilic stress response. Its turnover is maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge ..
  19. Dinkova Kostova A, Holtzclaw W, Cole R, Itoh K, Wakabayashi N, Katoh Y, et al. 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. 2002;99:11908-13 pubmed
    ..Inducers disrupt the cytoplasmic complex between the actin-bound protein Keap1 and the transcription factor Nrf2, thereby releasing Nrf2 to migrate to the nucleus where it activates the ..
  20. Suzuki T, Maher J, Yamamoto M. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo. Cancer Res. 2011;71:1700-9 pubmed publisher
    Under homeostatic conditions, Keap1 constitutively mediates the proteasomal degradation Nrf2...
  21. 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...
  22. 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...
  23. Wu K, Cui J, Klaassen C. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci. 2011;123:590-600 pubmed publisher
    ..dose-response" model in livers of Nrf2-null mice, wild-type mice, Kelch-like ECH associating protein 1 (Keap1)-knockdown (Keap1-KD) mice with enhanced Nrf2 activation, and Keap1-hepatocyte knockout (Keap1-HKO) mice with ..
  24. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008;28:2758-70 pubmed publisher
    b>Keap1 and Cul3 constitute a unique ubiquitin E3 ligase that degrades Nrf2, a key activator of cytoprotective genes...
  25. Reisman S, Csanaky I, Aleksunes L, Klaassen C. Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice. Toxicol Sci. 2009;109:31-40 pubmed publisher
    ..determine whether Nrf2 activation alters the biotransformation and excretion of AA, male wild-type, Nrf2-null, and Keap1 (Kelch-like ECH-associated protein 1)-knockdown (Keap1-kd) mice (which have increased activation of Nrf2) were ..
  26. Ke B, Shen X, Zhang Y, Ji H, Gao F, Yue S, et al. KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J Hepatol. 2013;59:1200-7 pubmed publisher
    The Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance...
  27. Kageyama S, Sou Y, Uemura T, Kametaka S, Saito T, Ishimura R, et al. Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway. J Biol Chem. 2014;289:24944-55 pubmed publisher
    ..positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway...
  28. 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 ..
  29. Sun Z, Huang Z, Zhang D. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS ONE. 2009;4:e6588 pubmed publisher
    ..oxidative stress, Nrf2 is induced at protein levels through redox-sensitive modifications on cysteine residues of Keap1, a component of the E3 ubiquitin ligase that targets Nrf2 for ubiquitin-dependent degradation...
  30. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet. 2003;35:238-45 pubmed
    Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function...
  31. 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...
  32. Soares M, Cohen O, Low Y, Sartor R, Ellison T, Anil U, et al. Restoration of Nrf2 Signaling Normalizes the Regenerative Niche. Diabetes. 2016;65:633-46 pubmed publisher
    ..The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been ..
  33. Suzuki T, Shibata T, Takaya K, Shiraishi K, Kohno T, Kunitoh H, et al. Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Mol Cell Biol. 2013;33:2402-12 pubmed publisher
    ..characterized that Nrf2 activity is tightly regulated at the protein level through proteasomal degradation via Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination, not much attention has been paid to the supply side ..
  34. Kobayashi E, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624 pubmed publisher
    ..This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. ..
  35. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes J. 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. 2004;279:31556-67 pubmed
    ..through the use of at least two degrons and its redox-sensitive interaction with the Kelch-repeat protein Keap1. In homeostatic COS1 cells, the Neh2 degron confers on Nrf2 a half-life of less than 10 min...
  36. Motohashi H, Kimura M, Fujita R, Inoue A, Pan X, Takayama M, et al. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. Blood. 2010;115:677-86 pubmed publisher
    ..Increased ROS enhanced platelet gene expression. These results suggest that p45 dominates over Nrf2 to enhance megakaryocytic maturation by promoting ROS accumulation. ..
  37. Yao W, Zhang J, Ishima T, Dong C, Yang C, Ren Q, et al. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Sci Rep. 2016;6:30659 pubmed publisher
    The transcription factor Keap1-Nrf2 system plays a key role in inflammation which is involved in depression...
  38. Iso T, Suzuki T, Baird L, Yamamoto M. Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells. Mol Cell Biol. 2016;36:3100-3112 pubmed
    ..b>Keap1 (Kelch-like-ECH-associated-protein 1), an adaptor for a cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 ..
  39. 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...
  40. Wang Y, Li C, Cheng K, Zhang R, Narsinh K, Li S, et al. Activation of liver X receptor improves viability of adipose-derived mesenchymal stem cells to attenuate myocardial ischemia injury through TLR4/NF-?B and Keap-1/Nrf-2 signaling pathways. Antioxid Redox Signal. 2014;21:2543-57 pubmed publisher
    ..Moreover, combined therapy of LXR agonist and AD-MSCs has a synergetic effect on cardiac repair and functional improvement after infarction. ..
  41. Saito R, Suzuki T, Hiramoto K, Asami S, Naganuma E, Suda H, et al. Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response. Mol Cell Biol. 2016;36:271-84 pubmed publisher
    The Keap1-Nrf2 system plays a central role in cytoprotection against electrophilic/oxidative stresses...
  42. Li B, Abdalrahman A, Lai Y, Janicki J, Ward K, Meyer C, et al. Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2. Biochem Biophys Res Commun. 2014;444:555-61 pubmed publisher
    ..did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages...
  43. Satoh T, Harada N, Hosoya T, Tohyama K, Yamamoto M, Itoh K. Keap1/Nrf2 system regulates neuronal survival as revealed through study of keap1 gene-knockout mice. Biochem Biophys Res Commun. 2009;380:298-302 pubmed publisher
    b>Keap1 is proposed to be a sensor protein of electrophilic compounds and a transducer of the signal from electrophilic compounds for transcriptional activation...
  44. Kim S, Lee H, Park S, Kundu J, Keum Y, Cha Y, et al. Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation. PLoS ONE. 2014;9:e85984 pubmed publisher
    ..Cysteine-151, -273 and -288 of Kelch-like ECH-associated protein-1 (Keap1), a cytosolic repressor of Nrf2, have been considered to act as a redox sensor and play a role in Nrf2 activation...
  45. Singh A, Happel C, Manna S, Acquaah Mensah G, Carrerero J, Kumar S, et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest. 2013;123:2921-34 pubmed publisher
    ..by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood...
  46. Keleku Lukwete N, Suzuki M, Otsuki A, Tsuchida K, Katayama S, Hayashi M, et al. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc Natl Acad Sci U S A. 2015;112:12169-74 pubmed publisher
    ..Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice...
  47. Yueh M, Tukey R. Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem. 2007;282:8749-58 pubmed
    ..We elucidate here that an anti-oxidative response leads to induction of UGT1A1 through the Nrf2-Keap1 pathway...
  48. Cino E, Fan J, Yang D, Choy W. ¹H, ¹?N and ¹³C backbone resonance assignments of the Kelch domain of mouse Keap1. Biomol NMR Assign. 2013;7:149-53 pubmed publisher
    Kelch-like ECH-associated Protein 1 (Keap1) is a multi-domain protein that functions as an inhibitor of the transcription factor nuclear factor E2-related factor 2 (Nrf2) in the cellular response to oxidative stress...
  49. Hu M, Zou Y, Nambiar S, Lee J, Yang Y, Dai G. Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver. Cell Cycle. 2014;13:2349-58 pubmed publisher
    b>Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress...
  50. Park J, Kang D, Lee D, Bae S. Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. Biochem Biophys Res Commun. 2015;465:542-7 pubmed publisher
    ..The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is an essential component of the defense mechanism against oxidative stress...
  51. 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...
  52. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66-79 pubmed publisher
    ..The functional expansion of Nrf2 reinforces the metabolic reprogramming triggered by proliferative signals. ..
  53. Harvey C, Thimmulappa R, Sethi S, Kong X, Yarmus L, Brown R, et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3:78ra32 pubmed publisher
  54. Sussan T, Gajghate S, Chatterjee S, Mandke P, McCormick S, Sudini K, et al. Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function. Am J Physiol Lung Cell Mol Physiol. 2015;309:L27-36 pubmed publisher
    ..New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility. ..
  55. Kotilinek L, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman B, et al. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci. 2002;22:6331-5 pubmed
    ..If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients. ..
  56. Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, et al. Nrf2 protects pancreatic ?-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes. 2014;63:605-18 pubmed publisher
    ..b>Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for Cullin3-based ubiquitin E3 ligase and negatively ..
  57. Dinkova Kostova A, Holtzclaw W, Wakabayashi N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry. 2005;44:6889-99 pubmed
    ..2 response, a major cellular reaction to oxidative/electrophile stress depends on a protein triad: actin-tethered Keap1 that binds to Nrf2...
  58. 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...
  59. Kataoka K, Ekuni D, Tomofuji T, Irie K, Kunitomo M, Uchida Y, et al. Visualization of Oxidative Stress Induced by Experimental Periodontitis in Keap1-Dependent Oxidative Stress Detector-Luciferase Mice. Int J Mol Sci. 2016;17: pubmed
    The aim of this study was to investigate whether a Keap1-dependent oxidative stress detector-luciferase (OKD-LUC) mouse model would be useful for the visualization of oxidative stress induced by experimental periodontitis...
  60. 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...
  61. Huebner A, Dai D, Morasso M, Schmidt E, Schafer M, Werner S, et al. Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero. Dev Cell. 2012;23:1238-46 pubmed publisher
    ..5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the ..
  62. Shinkai Y, Kimura T, Itagaki A, Yamamoto C, Taguchi K, Yamamoto M, et al. Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells. Toxicol Appl Pharmacol. 2016;295:37-46 pubmed publisher
    ..an environmental electrophile that modifies protein reactive thiols such as Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear factor-erythroid 2-related factor 2 (Nrf2)...
  63. Zhang Y, Crouch D, Yamamoto M, Hayes J. Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Biochem J. 2006;399:373-85 pubmed
    ..homology 2) degron of Nrf2 that serves to destabilize this latter transcription factor through an interaction with Keap1 (Kelch-like ECH-associated protein 1)...
  64. Kansanen E, Bonacci G, Schopfer F, Kuosmanen S, Tong K, Leinonen H, et al. Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J Biol Chem. 2011;286:14019-27 pubmed publisher
    ..of nucleophilic amino acids in regulatory proteins and enzymes, thus altering downstream signaling events, such as Keap1-Nrf2-antioxidant response element (ARE)-regulated gene expression...
  65. Murakami S, Suzuki T, Harigae H, Romeo P, Yamamoto M, Motohashi H. NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells. Mol Cell Biol. 2017;37: pubmed publisher
    ..The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance...
  66. 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...
  67. Jeong Y, Hoang N, Lovejoy A, Stehr H, Newman A, Gentles A, et al. Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer Discov. 2017;7:86-101 pubmed publisher
    ..Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs...
  68. Gonzalez Rodriguez A, Reibert B, Amann T, Constien R, Rondinone C, Valverde A. In vivo siRNA delivery of Keap1 modulates death and survival signaling pathways and attenuates concanavalin-A-induced acute liver injury in mice. Dis Model Mech. 2014;7:1093-100 pubmed publisher
    ..death and survival signaling pathways in concanavalin A (ConA)-mediated ALF using in vivo siRNA delivery targeting Keap1 in hepatocytes...
  69. Noel S, Arend L, Bandapalle S, Reddy S, Rabb H. Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice. BMC Nephrol. 2016;17:110 pubmed publisher
    ..We recently demonstrated that deletion of Keap1, the endogenous inhibitor of Nrf2, in T lymphocytes significantly protects from AKI...
  70. Wei Y, Gong J, Xu Z, Thimmulappa R, Mitchell K, Welsbie D, et al. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. Proc Natl Acad Sci U S A. 2015;112:E6927-36 pubmed publisher
    ..Our findings reveal a unique function of Nrf2 in reprogramming ischemic tissue toward neurovascular repair via Sema6A regulation, providing a potential therapeutic strategy for ischemic retinal and CNS diseases. ..
  71. Wakabayashi N, Dinkova Kostova A, Holtzclaw W, Kang M, Kobayashi A, Yamamoto M, et al. 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. 2004;101:2040-5 pubmed
    ..basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity...