| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.69266226 |
| These results suggest that association of Nrf 2 with INrf 2 inhibits ubiquitin proteasome degradation of Nrf 2 . 0.69266226^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.59499901 |
| We examined the contribution of Keap 1 to the rapid turnover of Nrf 2 ( half life of less than 20 min ) and found that a direct association between Keap 1 and Nrf 2 is required for Nrf 2 degradation . 0.59499901^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :1.1323483 |
| Under normal constitutive conditions , Nrf 2 associates with the cytoskeletal binding protein Keap 1 , which regulates the subcellular distribution of the bZip factor and also targets it for proteasome dependent degradation . 1.1323483^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.51235159 |
| The cytoplasmic protein Keap 1 interacts with Nrf 2 and represses its function . 0.51235159^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.594864 |
| Keap 1 interacts with Nrf 2 through its C terminal Kelch repeat domain . 0.594864^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.51564428 |
| While both the Cys 273 and Cys 288 residues of Keap 1 are required for suppressing Nrf 2 nuclear accumulation , treatment of cells with electrophiles or mutation of these cysteine residues to alanine did not affect the association of Keap 1 with Nrf 2 either in vivo or in vitro . 0.51564428^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.68780613 |
| The Kelch / DGR ( double glycine repeat ) domain of Keap 1 associates with Nrf 2 as well as with actin filaments . 0.68780613^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.57570976 |
| This two site interaction between Keap 1 and Nrf 2 constrains the mobility of the target lysine residues in the Neh 2 domain , increasing their average concentration in the vicinity of the Rbx bound ubiquitin conjugating enzyme , and thus the rate at which the transcription factor is ubiquitylated . 0.57570976^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Transcription factor NF E 2 related Factor 2 ( Nrf 2 ) and its cytoplasmic anchor protein Kelch like ECH associated protein 1 ( Keap 1 ) are central regulators of the cellular antioxidant response . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Transcription factor Nrf 2 , which is sequestered in the cytoplasm by Keap 1 ( Kelch like ECH associated protein 1 ) under unstimulated conditions , regulates the induction of phase 2 enzymes . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The transcription of ARE driven genes is regulated , at least in part , by nuclear transcription factor erythroid 2p45 ( NF E 2 ) related factor 2 ( Nrf 2 ) , which is sequestered in cytoplasm by Kelch like ECH associated protein 1 ( Keap 1 ) . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| A major mechanism whereby these protective enzymes are induced occurs through activation of the antioxidant response element ( ARE ) by the oxidative stress sensor protein Kelch like ECH associated protein 1 ( Keap 1 ) and the transcription factor NF E 2 related factor 2 ( Nrf 2 ) . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| One important mechanism of GST induction involves an antioxidant responsive response element ( ARE ) and the transcription factor nuclear factor E 2 related factor 2 ( Nrf 2 ) , which is bound to the Kelch like ECH associated protein 1 ( Keap 1 ) in the cytoplasm . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Activation of Nrf 2 results in release from its negative repressor , Kelch like ECH associated protein 1 ( Keap 1 ) , and allows Nrf 2 to translocate into the nucleus to induce gene expression . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Sulforaphane exerts cancer chemopreventive effects by inducing antioxidant / electrophile response element ( ARE ) regulated phase 2 enzyme and antioxidant genes through activation of the transcription factor nuclear factor E 2 related factor 2 ( Nrf 2 ) , which is regulated by the thiol rich sensor protein Kelch like ECH associated protein 1 ( Keap 1 ) . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| After phosphorylation and dissociation from the cytoplasmic inhibitor , Kelch like ECH associated protein 1 ( Keap 1 ) , Nrf 2 translocates to the nucleus and binds to an antioxidant response element ( ARE ) . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Within acidic domain 1 , residues 156 242 share 43 % identity with the Neh 2 ( Nrf 2 ECH homology 2 ) degron of Nrf 2 that serves to destabilize this latter transcription factor through an interaction with Keap 1 ( Kelch like ECH associated protein 1 ) . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| By taking advantage of this antioxidant and electrophilic property of ebselen , we characterized posttranslational modification of Kelch like ECH associated protein 1 ( Keap 1 ) , an electrophile sensor protein , which represses the ability of the transcription factor NF E 2 related factor 2 ( Nrf 2 ) upon induction of the phase 2 detoxification response . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Phosphorylation of Nrf 2 at Ser 40 by protein kinase C in response to antioxidants leads to the release of Nrf 2 from INrf 2 , but is not required for Nrf 2 stabilization / accumulation in the nucleus and transcriptional activation of antioxidant response element mediated NAD ( P ) H : quinone oxidoreductase 1 gene expression . ^^^ Under normal conditions , Nrf 2 is targeted for proteasomal degradation by INrf 2 . ^^^ Oxidative stress causes release of Nrf 2 from INrf 2 . ^^^ We demonstrate that phosphorylation of Ser 40 is necessary for Nrf 2 release from INrf 2 , but is not required for Nrf 2 stabilization / accumulation in the nucleus and transcriptional activation of ARE mediated NQO 1 gene expression . ^^^ A peptide that competes with endogenous Nrf 2 for INrf 2 binding was able to induce ARE activity more effectively than t butylhydroquinone , and Nrf 2 that accumulated in the nucleus as a result was not phosphorylated . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 is retained in the cytoplasm by an inhibitor INrf 2 . ^^^ Nrf 2 binding to INrf 2 leads to proteasomal degradation of Nrf 2 . ^^^ PKC phosphorylation of Nrf 2 at serine 40 results in the escape or release of Nrf 2 from INrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Once this is achieved , Nrf 2 exits the nucleus for binding to INrf 2 and degradation . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nuclear factor Nrf 2 , under normal conditions , is retained in the cytosol by INrf 2 . ^^^ Once this is achieved , Nrf 2 is exported out of the nucleus , binds with INrf 2 , and degrades . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Redox sensitive interaction between KIAA 0132 and Nrf 2 mediates indomethacin induced expression of gamma glutamylcysteine synthetase . ^^^ Immunoprecipitation studies showed that indomethacin treatment also inhibited Nrf 2 tethering to KIAA 0132 ( the human homolog of Keap 1 accession # D 50922 ) , which is believed to be a negative regulator of Nrf 2 . ^^^ Consistent with this idea , over expression of Nrf 2 increased GCLC reporter gene expression and over expression of KIAA 0132 inhibited GCLC reporter gene activity as well as inhibited indomethacin induced increases in the expression of GCLC . ^^^ Finally , simultaneous treatment with NAC inhibited both indomethacin induced release of Nrf 2 from KIAA 0132 and indomethacin induced nuclear translocation of Nrf 2 . ^^^ These results also support the hypothesis that indomethacin induced transcriptional activation of GCLC involves the redox dependent release of KIAA 0132 from Nrf 2 followed by the nuclear translocation of Nrf2 . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 represses nuclear activation of antioxidant responsive elements by Nrf 2 through binding to the amino terminal Neh 2 domain . ^^^ Detailed analysis of differential Nrf 2 activity displayed in transfected cell lines ultimately led to the identification of a new protein , which we named Keap 1 , that suppresses Nrf 2 transcriptional activity by specific binding to its evolutionarily conserved amino terminal regulatory domain . ^^^ The closest homolog of Keap 1 is a Drosophila actin binding protein called Kelch , implying that Keap 1 might be a Nrf 2 cytoplasmic effector . ^^^ We then showed that electrophilic agents antagonize Keap 1 inhibition of Nrf 2 activity in vivo , allowing Nrf 2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response . ^^^ We postulate that Keap 1 and Nrf 2 constitute a crucial cellular sensor for oxidative stress , and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf 2 nuclear shuttling mechanism . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Detailed analysis of the regulatory mechanisms of Nrf 2 activity has ultimately led us to the identification of a new protein , which we have named Keap 1 , that suppresses Nrf 2 activity by specific binding to its evolutionarily conserved N terminal Neh 2 regulatory domain . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Briefly , the Nrf 2 is retained in the cytosplasm by a repressor protein Keap 1 in untreated normal cells . ^^^ The treatment of cells with xenobiotics and antioxidants leads to the activation of unknown cytosolic factor ( s ) that catalyze modification of Nrf 2 and / or Keap 1 . ^^^ The modification follows dissociation of Nrf 2 and Keap 1 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The Keap 1 BTB / POZ dimerization function is required to sequester Nrf 2 in cytoplasm . ^^^ Transactivation of phase 2 detoxification enzymes and antioxidant proteins is mediated by the Cap ' N ' Collar transcription factor , Nrf 2 , which is sequestered in the cytoplasm by the actin binding protein Keap 1 . ^^^ Mutation of a conserved serine ( S104A ) within the Keap 1 BTB / POZ domain disrupts Keap 1 dimerization and eliminates the ability of Keap 1 to sequester Nrf 2 in the cytoplasm and repress Nrf 2 transactivation . ^^^ Disruption of endogenous Keap 1 dimerization using BTB / POZ dominant negative proteins also inhibits the ability of Keap 1 to retain Nrf 2 in the cytoplasm . ^^^ Exposure to an electrophilic agent that induces Nrf 2 release and nuclear translocation disrupts formation of a Keap 1 complex in vivo . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| BACKGROUND : The transcription factor Nrf 2 and its negative regulator Keap 1 play important roles in transcriptional induction of a set of detoxifying and anti oxidant enzymes . ^^^ We consequently identified the presence of Nrf 2 and Keap 1 in zebrafish . ^^^ Both loss and gain of function analyses demonstrated that Nrf 2 is the primary regulator of a subset of cytoprotective enzyme genes , while Keap 1 suppresses Nrf 2 activity in zebrafish . ^^^ CONCLUSION : Taken together , these results indicate that the Nrf 2 Keap1 system is highly conserved among vertebrates and that the interface between Nrf 2 and Keap 1 forms an important molecular basis of this regulatory system . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Inducers disrupt the cytoplasmic complex between the actin bound protein Keap 1 and the transcription factor Nrf 2 , thereby releasing Nrf 2 to migrate to the nucleus where it activates the antioxidant response element ( ARE ) of phase 2 genes and accelerates their transcription . ^^^ We cloned , overexpressed , and purified murine Keap 1 and demonstrated on native gels the formation of complexes of Keap 1 with the Neh 2 domain of Nrf 2 and their concentration dependent disruption by inducers such as sulforaphane and bis ( 2 hydroxybenzylidene ) acetone . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| However , it partially impaired Nrf 2 activation of ARE driven transcription in a reporter gene assay when Keap 1 was overexpressed . ^^^ In vitro transcribed / translated Keap 1 could be coimmunoprecipitated with Nrf 2 . ^^^ Phosphorylation of wild type Nrf 2 by PKC promoted its dissociation from Keap 1 , whereas the Nrf 2 S40A mutant remained associated . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The putative molecular sensor for inducers is Keap 1 , a sulfhydryl rich protein that sequesters the transcription factor Nrf 2 in the cytoplasm . ^^^ Hepatic gene expression profiles were examined by oligonucleotide microarray analysis in vehicle or D3T treated wild type mice as well as in nrf 2 single and keap 1 nrf2 double knockout mice to identify those genes regulated by the Keap 1 Nrf2 pathway . ^^^ Gene expression patterns in keap 1 nrf2 double knockout mice were similar to those in nrf 2 single knockout mice . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 regulates both cytoplasmic nuclear shuttling and degradation of Nrf 2 in response to electrophiles . ^^^ Several lines of evidence suggest that electrophiles and reactive oxygen species liberate Nrf 2 from its cytoplasmic repressor Keap 1 and provoke the accumulation of Nrf 2 in the nucleus . ^^^ We also found constitutive Nrf 2 nuclear accumulation in Keap 1 deficient mouse macrophages . ^^^ CONCLUSIONS : Our results highlight the fact that Nrf 2 protein turnover is regulated by Keap 1 mediated subcellular compartmentalization . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| All mutated Nrf 2 proteins tested interacted with the cytoplasmic repressor Keap 1 in a manner indistinguishable from wild type Nrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 dependent proteasomal degradation of transcription factor Nrf 2 contributes to the negative regulation of antioxidant response element driven gene expression . ^^^ Keap 1 is a negative regulator of Nrf 2 , a bZIP transcription factor that mediates adaptation to oxidative stress . ^^^ Previous studies suggested this negative regulation is a consequence of Keap 1 controlling the subcellular distribution of Nrf 2 . ^^^ We now report that Keap 1 also controls the total cellular level of Nrf 2 protein . ^^^ By heterologously expressing in COS 1 cells epitope tagged Nrf 2 and an Nrf2DeltaETGE mutant lacking the Keap 1 binding site , in both the presence and absence of Keap 1 we demonstrate that Nrf 2 is subject to ubiquitination and proteasomal degradation independently of both Keap 1 and the redox environment of the cell . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 is sequestered in the cytoplasm by Keap 1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element ( ARE ) upon exposure to oxidative insults . ^^^ It has recently been demonstrated that in vitro phosphorylation of Nrf 2 on Ser 40 by protein kinase C ( PKC ) facilitates the dissociation of Nrf 2 from the Keap 1 complex ( Huang HC , Nguyen T , and Pickett CB . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Use of mouse embryo fibroblasts null for Nrf 2 ( nuclear factor erythroid 2p45 related transcription factor ) and HepG 2 cells overexpressing Keap 1 demonstrated that indole analogue mediated GCLC expression was regulated by Nrf 2 Keap1 interactions . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| In unstressed cells , Nrf 2 is maintained in the cytoplasm via association with Keap 1 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Arsenic simultaneously increased the expression of Keap 1 , a regulator of Nrf 2 activity . ^^^ The coordinated induction of Keap 1 expression and nuclear Nrf 2 accumulation induced by arsenic suggests that Keap 1 is important to arsenic induced Nrf 2 activation . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The transcription factor Nrf 2 , which normally exists in an inactive state as a consequence of binding to a cytoskeleton associated protein Keap 1 , can be activated by redox dependent stimuli . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Distinct cysteine residues in Keap 1 are required for Keap 1 dependent ubiquitination of Nrf 2 and for stabilization of Nrf 2 by chemopreventive agents and oxidative stress . ^^^ Nrf 2 is normally sequestered in the cytoplasm by a protein known as Keap 1 . ^^^ Chemopreventive agents allow Nrf 2 to escape from Keap 1 mediated repression , although the molecular mechanism ( s ) responsible for activation of Nrf 2 is not understood . ^^^ In this report , we demonstrate that Keap 1 does not passively sequester Nrf 2 in the cytoplasm but actively targets Nrf 2 for ubiquitination and degradation by the proteosome under basal culture conditions . ^^^ We have identified two critical cysteine residues in Keap 1 , C 273 and C 288 , that are required for Keap 1 dependent ubiquitination of Nrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Transcription factor Nrf 2 ( encoded by Nfe2l2 ) regulates a battery of detoxifying and antioxidant genes , and Keap 1 represses Nrf 2 function . ^^^ Keap 1 null mutation leads to postnatal lethality due to constitutive Nrf 2 activation . ^^^ Biochemical data show that , without Keap 1 , Nrf 2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes . ^^^ Breeding to Nrf 2 deficient mice reversed the phenotypic Keap 1 deficiencies . ^^^ These experiments show that Keap 1 acts upstream of Nrf 2 in the cellular response to oxidative and xenobiotic stress . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The central regulator of the ARE response is the transcription factor Nrf 2 ( NF E 2 related factor 2 ) , which on stimulation dissociates from its cytoplasmic inhibitor Keap 1 , translocates to the nucleus and transactivates ARE dependent genes . ^^^ On exposure to 15 deoxy Delta 12 , 14 prostaglandin J 2 , the dissociation of Nrf 2 from Keap 1 occurred and this was dependent on the modification of thiols in Keap 1 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| We show that in mouse peritoneal macrophages 15d PGJ ( 2 ) can activate Nrf 2 by forming adducts with Keap 1 , resulting in an Nrf 2 dependent induction of heme oxygenase 1 and peroxiredoxin 1 ( PrxI ) gene expression . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under basal conditions , Nrf 2 resides mainly in the cytoplasm bound to its cysteine rich , Kelch domain containing partner Keap 1 , which is itself anchored to the actin cytoskeleton and represses Nrf 2 activity . ^^^ The critical role of C 273 and C 288 was established by ( 1 ) their high reactivity when purified recombinant Keap 1 was treated with dexamethasone mesylate and the dexamethasone modified tryptic peptides were analyzed by mass spectrometry , and ( 2 ) transfection of keap 1 and nrf 2 gene deficient mouse embryonic fibroblasts with constructs expressing cysteine to alanine mutants of Keap 1 , and measurement of the ability of cotransfected Nrf 2 to repress an ARE luciferase reporter . ^^^ Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers , and by the demonstration that whereas C273A and C288A mutants of Keap 1 alone could not repress Nrf 2 activation of the ARE luciferase reporter , an equal mixture of these mutant constructs restored repressor activity . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Scaffolding of Keap 1 to the actin cytoskeleton controls the function of Nrf 2 as key regulator of cytoprotective phase 2 genes . ^^^ Under basal conditions , Nrf 2 is sequestered in the cytoplasm by Keap 1 , a multidomain , cysteinerich protein that is bound to the actin cytoskeleton . ^^^ Keap 1 acts both as a repressor of the Nrf 2 transactivation and as a sensor of phase 2 inducers . ^^^ Electrophiles and oxidants disrupt the Keap 1 Nrf2 complex , resulting in nuclear accumulation of Nrf 2 , where it enhances the transcription of phase 2 genes via a common upstream regulatory element , the antioxidant response element . ^^^ Reporter cotransfection transactivation analyses with a series of Keap 1 deletion mutants revealed that in the absence of the double glycine repeat domain Keap 1 does not bind to Nrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 ( Kelch like ECH associated protein 1 ) , an inhibitory factor of Nrf 2 , decreased the activation of GPE 1 by Nrf 2 and this suppression was restored after treatment with electrophilic compounds . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 activity is usually suppressed by a cytoplasmic repressor , Keap 1 , so disruption of the keap 1 gene causes constitutive activation of Nrf 2 . ^^^ However , simultaneous disruption of nrf 2 rescued keap 1 null mice from the lethality . ^^^ This rescue phenotype of mafG : : mafF : : keap 1 triple compound mutant mice phenocopies that of the nrf 2 : : keap 1 compound mutant mice , indicating that the small Maf proteins MafG and MafF must functionally cooperate with Nrf 2 in vivo . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Activation of Nrf 2 is considered to involve dissociation from a cytoplasmic inhibitor , Kelch like ECH associated protein 1 ( Keap 1 ) , through a redox sensitive mechanism involving either GSH depletion or direct chemical interaction through Michael addition . ^^^ In conclusion , GSH depletion alone is insufficient for Nrf 2 activation : a more direct interaction is required , possibly involving chemical modification of Nrf 2 or Keap 1 , which is facilitated by the prior loss of GSH . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The function of Nrf 2 that bears transcriptional activation depends solely on its nuclear localization , which is regulated by interaction with the cytosolic anchor protein Keap 1 and its own turnover rate . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The Keap 1 BTB protein is an adaptor that bridges Nrf 2 to a Cul 3 based E 3 ligase : oxidative stress sensing by a Cul 3 Keap1 ligase . ^^^ Nrf 2 activity is opposed by the BTB / POZ domain protein Keap 1 . ^^^ Keap 1 is proposed to regulate Nrf 2 activity strictly through its capacity to inhibit Nrf 2 nuclear import . ^^^ To address the contribution of Keap 1 dependent sequestration versus Nrf 2 proteolysis , we identified the E 3 ligase that regulates Nrf 2 ubiquitination . ^^^ We demonstrate that Keap 1 is not solely a cytosolic anchor ; rather , Keap 1 is an adaptor that bridges Nrf 2 to Cul 3 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| However , competition by Nrf 2 for hKeap 1 is reduced by diethylmaleate ( DEM ) , a known disrupter of the Nrf 2 : Keap 1 interaction . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 is a substrate adaptor protein for an ubiquitin ligase complex that targets the Nrf 2 transcription factor for degradation . ^^^ Keap 1 binds Nrf 2 through its C terminal Kelch domain , which contains six copies of the evolutionarily conserved kelch repeat sequence motif . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| A cytoplasmic actin binding protein , Keap 1 , is an inhibitor of Nrf 2 that sequesters it in the cytoplasm . ^^^ This review focuses on ( 1 ) the role of Nrf 2 in the regulation of phase 2 and antioxidative genes , ( 2 ) the molecular actions of dithiolethiones on the Keap 1 Nrf2 pathway , and ( 3 ) the contribution of Nrf 2 regulated gene families to the cytoprotective actions of dithiolethiones and other inducers . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Detailed analysis of the regulatory mechanism governing Nrf 2 activity led to the identification of Keap 1 , which represses Nrf 2 activity by directly binding to the N terminal Neh 2 domain . ^^^ Keap 1 interaction with Neh 2 leads to the sequestration of Nrf 2 in the cytoplasm and to the enhancement of Nrf 2 degradation by proteasomes conferring tight regulation on the response . ^^^ Electrophiles act to counteract sequestration of Nrf 2 by Keap 1 and provoke Nrf 2 activation . ^^^ Constitutive activation of Nrf 2 regulated transcription in Keap 1 knockout mice clearly demonstrated that the disruption of Keap 1 repression is sufficient for the activation of Nrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Evolutionary conserved N terminal domain of Nrf 2 is essential for the Keap 1 mediated degradation of the protein by proteasome . ^^^ This process is dependent on Keap 1 , to which Nrf 2 binds through the Neh 2 domain . ^^^ Deletion of Neh 2 NT or mutation of the DLG motif largely abolished the Keap 1 mediated degradation of Nrf 2 . ^^^ These mutations were found to enfeeble the binding affinity of Nrf 2 to Keap 1 . ^^^ These results thus demonstrate that DLG motif plays essential roles in the Keap 1 mediated proteasomal degradation of Nrf 2 in the cytoplasm . . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| BTB protein Keap 1 targets antioxidant transcription factor Nrf 2 for ubiquitination by the Cullin 3 Roc 1 ligase . ^^^ Here we report that the human BTB Kelch protein Keap 1 , a negative regulator of the antioxidative transcription factor Nrf 2 , binds to CUL 3 and Nrf 2 via its BTB and Kelch domains , respectively . ^^^ The KEAP 1 CUL3 ROC 1 complex promoted NRF 2 ubiquitination in vitro and knocking down Keap 1 or CUL 3 by short interfering RNA resulted in NRF 2 protein accumulation in vivo . ^^^ We suggest that Keap 1 negatively regulates Nrf 2 function in part by targeting Nrf 2 for ubiquitination by the CUL 3 ROC1 ligase and subsequent degradation by the proteasome . ^^^ Blocking NRF 2 degradation in cells expressing both KEAP 1 and NRF 2 by either inhibiting the proteasome activity or knocking down Cul 3 , resulted in NRF 2 accumulation in the cytoplasm . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Exogenously transfected Nrf 2 transactivated the Galpha ( i 2 ) gene promoter ; the cytoskeleton associated protein , Keap 1 , abrogated this effect . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| In unstressed cells , Nrf 2 appears to be sequestered in the cytoplasm via association with an inhibitor protein , Keap 1 . ^^^ Prothymosin alpha was able to liberate Nrf 2 from the Nrf 2 Keap1 inhibitory complex in vitro through competition with Nrf 2 for binding to the same domain of Keap 1 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Since ebselen is a hydrophobic , thio reactive compound capable of interacting with Keap 1 , we tested its ability to activate nrf 2 dependent responses in the human hepatocarcinoma derived cell line , HepG 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 , a BTB Kelch protein , is the major upstream regulator of Nrf 2 and controls both the subcellular localization and steady state levels of Nrf 2 . ^^^ Keap 1 assembles into a functional E 3 ubiquitin ligase complex with Cul 3 and Rbx 1 that targets multiple lysine residues located in the N terminal Neh 2 domain of Nrf 2 for ubiquitin conjugation both in vivo and in vitro . ^^^ Keap 1 dependent ubiquitination of Nrf 2 is inhibited following exposure of cells to quinone induced oxidative stress and sulforaphane , a cancer preventive isothiocyanate . ^^^ Inhibition of Keap 1 dependent ubiquitination of Nrf 2 correlates with decreased association of Keap 1 with Cul 3 . ^^^ Neither quinone induced oxidative stress nor sulforaphane disrupts association between Keap 1 and Nrf 2 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Induction of the phase 2 response , a major cellular reaction to oxidative / electrophile stress depends on a protein triad : actin tethered Keap 1 that binds to Nrf 2 . ^^^ Inducers react with Keap 1 releasing Nrf 2 for nuclear translocation and activation of the antioxidant response element ( ARE ) , which regulates phase 2 genes . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| This siRNA can knockdown Keap 1 mRNA and thereby relieve negative regulation of nuclear factor erythroid 2 p 45 related factor 2 ( Nrf 2 ) mediated gene expression . ^^^ Transfection of human HaCaT cells with Keap 1 siRNA markedly enhanced endogenous levels of nuclear factor erythroid 2 p 45 related factor 2 ( Nrf 2 ) protein and increased transcription of an antioxidant response element driven reporter gene by 2 . 3 fold . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 regulates the oxidation sensitive shuttling of Nrf 2 into and out of the nucleus via a Crm 1 dependent nuclear export mechanism . ^^^ Keap 1 is a negative regulator of Nrf 2 , a transcription factor essential for antioxidant response element ( ARE ) mediated gene expression . ^^^ We find that Keap 1 sequesters Nrf 2 in the cytoplasm , not by docking it to the actin cytoskeleton but instead through an active Crm1 / exportin dependent nuclear export mechanism . ^^^ Mutation of the hydrophobic amino acids resulted in nuclear accumulation of both Keap 1 and Nrf 2 , as did treatment with the drug leptomycin B , which inactivates Crm1 / exportin . ^^^ Based on these data , we propose a new model for regulation of Nrf 2 by Keap 1 . ^^^ |
|
| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under homeostatic conditions Nrf 2 is anchored to cysteine rich Keap 1 and sequestered in the cytoplasm . ^^^ When challenged with oxidative stress , Keap 1 functions as a redox sensitive switch and releases Nrf 2 . ^^^ Because Nrf 2 activation is generally redox sensitive , the redox insensitivity of this Nrf 2 NES indicates the importance of Keap 1 retention as a key rate limiting step in Nrf 2 activation . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under normal conditions , Nrf 2 localizes in the cytoplasm where it interacts with the actin binding protein , Kelch like ECH associating protein 1 ( Keap 1 ) , and is rapidly degraded by the ubiquitin proteasome pathway . ^^^ Signals from reactive oxygen species or electrophilic insults target the Nrf 2 Keap1 complex , dissociating Nrf 2 from Keap 1 . ^^^ Direct participation of Keap 1 in the ubiquitination and degradation of Nrf 2 is plausible . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Thus , induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf 2 ( / ) and keap 1 ( / ) mouse embryonic fibroblasts . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| SUL strongly induced Nrf 2 protein expression and ARE mediated transcription activation , retarded degradation of Nrf 2 through inhibiting Keap 1 , and thereby activating the transcriptional expression of HO 1 . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| A downstream product of COX 2 , 15 deoxy Delta ( 12 , 14 ) prostaglandin J 2 ( 15d PGJ 2 ) , activated the Nrf 2 regulatory pathway in HAECs through binding to the cysteines of Keap 1 . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Specific patterns of electrophile adduction trigger Keap 1 ubiquitination and Nrf 2 activation . ^^^ Nrf 2 concentrations are regulated by the thiol rich sensor protein Keap 1 , which is an adaptor protein for Cul 3 dependent ubiquitination and degradation of Nrf 2 . ^^^ However , the links between site specificity of Keap 1 modification by electrophiles and mechanisms of Nrf 2 activation are poorly understood . ^^^ Treatment of FLAG Keap 1 transfected HEK 293 with the Nrf 2 activating compounds IAB and tBHQ generated high molecular weight Keap 1 forms , which were identified as K 48 linked polyubiquitin conjugates by immunoblotting and liquid chromatography MS MS . ^^^ Keap 1 polyubiquitination coincided with Nrf 2 stabilization and nuclear accumulation . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Transfected Nrf 2 strongly inhibited VCAM 1 promoter activity , which could be reversed by cotransfection with Keap 1 . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 controls constitutive and inducible expression of ARE driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap 1 . ^^^ Previous studies have suggested that activation of Nrf 2 is mediated by mechanisms promoting its dissociation from Keap 1 , a cytosolic repressor that acts to sequester the transcription factor in the cytoplasm . ^^^ As a short lived protein , Nrf 2 is also activated by mechanisms leading to its stabilization in cells under stress , and recent evidence indicates that Keap 1 has an active role in the control of its stability . ^^^ Furthermore , we found evidence indicating that Keap 1 may repress Nrf 2 activity by transiently shuttling into the nucleus to promote its ubiquitylation . ^^^ The data suggested that the steady state level of Nrf 2 is maintained by a dynamic pathway that balances its constitutive expression with a Keap 1 regulated degradation process downstream of its role as a transcriptional activator . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The functional significance of a putative ARE in the GI GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles ( tBHQ , SFN , and curcumin ) or overexpression of Nrf 2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap 1 . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 targets its substrate , the Nrf 2 transcription factor , for ubiquitination and subsequent degradation by the 26 S proteasome . ^^^ Inhibition of Keap 1 dependent ubiquitination of Nrf 2 increases steady state levels of Nrf 2 and enables activation of cytoprotective Nrf 2 dependent genes . ^^^ Ubiquitination of Keap 1 is markedly increased in cells exposed to quinone induced oxidative stress , occurs in parallel with inhibition of Keap 1 dependent ubiquitination of Nrf 2 , and results in decreased steady state levels of Keap 1 , particularly in cells that are unable to synthesize glutathione . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under basal conditions , Nrf 2 is tethered in the cytoplasm to an actin binding protein Keap 1 . ^^^ Pharmacological and food derived agents such as dithiolethiones and isothiocyanates trigger the release of Nrf 2 from Keap 1 , allowing it to translocate into the nucleus and stimulate gene transcription . ^^^ Observations that nrf 2 deficient mice are refractory to the protective actions of some chemopreventive agents highlight the importance of the Keap 1 Nrf2 ARE signaling pathway as a molecular target for prevention . . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| One mechanism by which XH might induce QR could be through interaction with Keap 1 , which sequesters Nrf 2 in the cytoplasm , so that it can not activate the ARE . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Keap 1 is known to block activation of the antioxidant response gene products by direct interaction with the transcriptional activator , Nrf 2 . ^^^ Disruption of the Keap 1 : Nrf 2 interaction enhances FAC 1 induction of apoptosis . ^^^ These findings suggest a role for FAC 1 in apoptosis following release of Nrf 2 from Keap 1 in response to oxidative stress . . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Hepatocyte specific deletion of the keap 1 gene activates Nrf 2 and confers potent resistance against acute drug toxicity . ^^^ Nrf 2 is a key regulator of many detoxifying enzyme genes , and cytoplasmic protein Keap 1 represses the Nrf 2 activity under quiescent conditions . ^^^ Germ line deletion of the keap 1 gene results in constitutive activation of Nrf 2 , but the pups unexpectedly died before weaning . ^^^ To investigate how constitutive activation of Nrf 2 influences the detoxification system in adult mice , we generated mice bearing a hepatocyte specific disruption of the keap 1 gene . ^^^ Microarray analysis revealed that , while many detoxifying enzyme genes are highly expressed , some of the typical Nrf 2 dependent genes are only marginally increased in the Keap 1 deficient liver . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Here , we found that , by using fluorescent tags and immunoprecipitation assays , NEPPs are taken up preferentially into neurons and bind in a thiol dependent manner to Keap 1 , a negative regulator of the transcription factor Nrf 2 . ^^^ By binding to Keap 1 , NEPPs prevent Keap 1 mediated inactivation of Nrf 2 and , thus , enhance Nrf 2 translocation into the nucleus of cultured neuronal cells . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under basal ( reducing ) conditions , Keap 1 anchors the Nrf 2 transcription factor within the cytoplasm , targeting it for ubiquitination and proteasome degradation , thus repressing its ability to induce phase 2 genes . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| CAND 1 mediated substrate adaptor recycling is required for efficient repression of Nrf 2 by Keap 1 . ^^^ Keap 1 , a BTB Kelch protein , is the major upstream regulator of Nrf 2 . ^^^ Keap 1 functions as a substrate adaptor protein for a Cul 3 dependent E 3 ubiquitin ligase complex to repress steady state levels of Nrf 2 and Nrf 2 dependent transcription . ^^^ In this report , we have characterized the importance of substrate adaptor recycling for regulation of Keap 1 mediated repression of Nrf 2 . ^^^ However , both ectopic overexpression and siRNA mediated knockdown of CAND 1 decreased the ability of Keap 1 to target Nrf 2 for ubiquitin dependent degradation , resulting in stabilization of Nrf 2 and activation of Nrf 2 dependent gene expression . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Under normal condition , Nrf 2 is sequestered in the cytoplasm by an actin binding protein , Kelch like ECH associating protein 1 ( Keap 1 ) , and upon exposure of cells to inducers such as oxidative stress and certain chemopreventive agents , Nrf 2 dissociates from Keap 1 , translocates to the nucleus , binds to AREs , and transactivates phase 2 detoxifying and antioxidant genes . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nuclear increase of NF kappaB , Nrf 2 , and thioredoxin contents was observed in all isothiocyanate treated cells , whereas the nuclear Ref 1 and cytoplasmic Keap 1 contents were not changed . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 regulates the cellular oxidative stress response , whereas Keap 1 represses Nrf 2 through its molecular interaction . ^^^ To elucidate the molecular mechanism of the Keap 1 and Nrf 2 interaction , we resolved the six bladed beta propeller crystal structure of the Kelch / DGR and CTR domains of mouse Keap 1 and revealed that extensive inter and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap 1 with Nrf 2 . ^^^ A peptide containing the ETGE motif of Nrf 2 binds the beta propeller of Keap 1 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 Keap 1 ' s affinity for Nrf 2 . ^^^ These results provide a structural basis for the loss of Keap 1 function and gain of Nrf 2 function . . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| The expression of the phase 2 detoxification enzymes and antioxidant proteins is induced at the transcriptional level by Nrf 2 and negatively regulated at the posttranslational level by Keap 1 through protein protein interactions with and subsequent proteolysis of Nrf 2 . ^^^ Based on these observations , we propose that Keap 1 recruits Nrf 2 by the ETGE motif and that the DLG motif of the Neh 2 domain locks its lysine rich central alpha helix in a correct position to benefit ubiquitin signaling . . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Nrf 2 activity is regulated by Keap 1 mediated compartmentalization in the cell . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Arsenic induces NAD ( P ) H quinone oxidoreductase 1 by disrupting the Nrf 2 10 Keap 1 10 Cul 3 complex and recruiting Nrf 2 10 Maf to the antioxidant response element enhancer . ^^^ Arsenic stabilized Nrf 2 protein , extending the t ( 1 / 2 ) of Nrf 2 from 21 to 200 min by inhibiting the Keap 1 10 Cul 3 dependent ubiquitination and proteasomal turnover of Nrf 2 . ^^^ Arsenic markedly inhibited the ubiquitination of Nrf 2 but did not disrupt the Nrf 2 10 Keap 1 10 Cul 3 association in the cytoplasm . ^^^ In the nucleus , arsenic , but not phenolic antioxidant tert butylhydroquinone , dissociated Nrf 2 from Keap 1 and Cul 3 followed by dimerization of Nrf 2 with a Maf protein ( Maf G / Maf K ) . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Structure of the Keap 1 : Nrf 2 interface provides mechanistic insight into Nrf 2 signaling . ^^^ Keap 1 is a BTB Kelch substrate adaptor protein that regulates steady state levels of Nrf 2 , a bZIP transcription factor , in response to oxidative stress . ^^^ We have determined the structure of the Kelch domain of Keap 1 bound to a 16 mer peptide from Nrf 2 containing a highly conserved DxETGE motif . ^^^ Mutagenesis experiments confirmed the role of individual amino acids for binding of Nrf 2 to Keap 1 and for Keap 1 mediated repression of Nrf 2 dependent gene expression . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| Oxidative / electrophilic stress sensor Keap 1 regulates the rapid turnover of transcripition factor Nrf 2 ] . ^^^ |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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| Interacting proteins: Q14145 and Q16236 |
Pubmed |
SVM Score :0.0 |
| NA |
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